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Xu T, Chakraborty S, Wei D, Tran M, Rhea R, Wei B, Nguyen P, Gagea M, Xie X, Wu L, Cohen L, Liao Z, Yang P. Evaluation of the protective effect of Compound Kushen Injection against radiation‑induced lung injury in mice. Mol Med Rep 2025; 31:88. [PMID: 39917996 PMCID: PMC11831882 DOI: 10.3892/mmr.2025.13453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 11/07/2024] [Indexed: 02/19/2025] Open
Abstract
Radiation‑induced lung injury (RILI) is a prevalent complication following thoracic radiation, and currently there is a lack of effective intervention options. The present study investigated the potential of Compound Kushen Injection (CKI), a botanical drug, to mitigate inflammatory responses in mice with RILI, along with its underlying mechanisms of action. C3H mice underwent total lung irradiation (TLI) and intraperitoneal injection of CKI (2, 4 or 8 ml/kg) once daily for 8 weeks. Pre‑radiation treatment with 4 or 8 ml/kg CKI starting 2 weeks before TLI or concurrent treatment of 8 ml/kg CKI with TLI led to a significantly longer overall survival compared with the TLI vehicle‑treated group. Micro‑computed tomography evaluations showed that concurrent treatment with 8 ml/kg CKI was associated with a significantly lower incidence of RILI. Histological evaluations revealed that concurrent CKI (4 and 8 ml/kg) treatment significantly reduced grades of lung inflammation. Following radiation at 72 h, TLI plus vehicle‑treated mice had significantly elevated serum IL6, IL17A, and transforming growth factor β (TGF‑β) levels compared with non‑irradiated normal mice. Conversely, mice that received TLI plus CKI displayed lower cytokine levels than those in the TLI plus vehicle‑treated mice. Immunohistochemistry staining showed a reduction of TGF‑β positive cells in the lung tissues of TLI mice after CKI treatment. The concurrent TLI CKI‑treated mice had a significantly reduced cyclooxygenase 2 (COX‑2) activity and COX‑2 metabolites compared with TLI vehicle‑treated mice. These data highlight that CKI substantially reduced radiation‑induced lung inflammation, mitigated RILI incidence, and prolonged overall survival.
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Affiliation(s)
- Ting Xu
- Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Sharmistha Chakraborty
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Daoyan Wei
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Megan Tran
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Robyn Rhea
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Bo Wei
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Phuong Nguyen
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mihai Gagea
- Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xiaoxue Xie
- Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lirong Wu
- Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lorenzo Cohen
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhongxing Liao
- Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Peiying Yang
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Tulimilli SV, Karnik M, Bettadapura ADS, Sukocheva OA, Tse E, Kuppusamy G, Natraj SM, Madhunapantula SV. The tumor suppressor role and epigenetic regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in cancer and tumor microenvironment (TME). Pharmacol Ther 2025; 268:108826. [PMID: 39971253 DOI: 10.1016/j.pharmthera.2025.108826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 02/03/2025] [Accepted: 02/14/2025] [Indexed: 02/21/2025]
Abstract
Oxidative stress and inflammation may initiate carcinogenesis and facilitate metastasis via activation of pro-inflammatory signaling network. The side product of arachidonic acid processing by cyclooxygenase-2 (COX-2), the prostaglandin E2 (PGE2), plays a key role in various metabolic disorders and during inflammation-mediated tumorigenesis. It has been demonstrated that PGE2 increases the proliferation, migration, invasion, metastasis, and resistance of cancer cells to apoptosis and other forms of programmed cell death. The expression level of PGE2 metabolizing enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is often decreased in various malignancies. However, the role of 15-PGDH and PGE2 in the regulation of carcinogenesis remains controversial. Numerous cancer cell lines and mouse models have demonstrated the role of 15-PGDH as a tumor suppressor. Downregulation of 15-PGDH increased cancer cell proliferation, migration, anchorage independent growth, colony formation while overexpression reversed these effects, by inducing apoptosis and cell cycle arrest in vitro and in vivo. The expression of 15-PGDH is regulated by various mechanisms, including (a) epigenetic alterations (methylation of promoter region, histone deacetylases, microRNAs (miR-21, miR-26a/b, miR-106b-5p, miR-146b-3p, miR-155, miR-218-5p, and miR-620)); and (b) dysregulated oxidative stress and associated mediators (elevated levels of growth factors and proinflammatory cytokines (such as IL1β and TNFα)). Several transcription factors, such as HNF3β, β-catenin, Snail, Slug, can bind to 15-PGDH promoter region and downregulate the enzyme expression. In contrast, the expression of 15-PGDH can be upregulated by several anti-inflammatory cytokines and anti-cancer agents, such as IL10 and vitamin D. The functional activity of 15-PGDH protein can be modulated by signaling effectors and oxidative stress, including increased production of reactive oxygen species (ROS). However, the role of oxidative stress regulator protein, i.e., nuclear factor erythroid 2-related factor 2 (Nrf2), in the control of 15-PGDH expression remains unclear. This article provides insights and comprehensive overview of the tumor suppressor role of 15-PGDH in various cancers. Epigenetic and post-translational mechanisms regulating 15-PGDH expression and the role of novel ROS-Nrf2-15-PGDH axis were discussed and accented as potential drug targets.
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Affiliation(s)
- SubbaRao V Tulimilli
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST supported center and ICMR Collaborating Center of Excellence - ICMR-CCoE), Department of Biochemistry (DST-FIST supported department), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India.
| | - Medha Karnik
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST supported center and ICMR Collaborating Center of Excellence - ICMR-CCoE), Department of Biochemistry (DST-FIST supported department), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India.
| | - Anjali Devi S Bettadapura
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST supported center and ICMR Collaborating Center of Excellence - ICMR-CCoE), Department of Biochemistry (DST-FIST supported department), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India.
| | - Olga A Sukocheva
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, CALHN, Port Rd, Adelaide, SA 5000, Australia.
| | - Edmund Tse
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, CALHN, Port Rd, Adelaide, SA 5000, Australia.
| | - Gowthamarajan Kuppusamy
- Department of Pharmaceutics (DST-FIST supported department), JSS College of Pharmacy, JSS Academy of Higher Education & Research (JSS AHER), Ooty, Nilgiris, Tamil Nadu, India.
| | - Suma M Natraj
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST supported center and ICMR Collaborating Center of Excellence - ICMR-CCoE), Department of Biochemistry (DST-FIST supported department), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India.
| | - SubbaRao V Madhunapantula
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST supported center and ICMR Collaborating Center of Excellence - ICMR-CCoE), Department of Biochemistry (DST-FIST supported department), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India; Special Interest Group in Cancer Biology and Cancer Stem Cells (SIG-CBCSC), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India.
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Li J, Jia S, Guo J, Xie W, Ma Y, Gao X, Gao M. Two cases of primary hypertrophic osteoarthropathy caused by HPGD variants: a case report and literature review. BMC Pediatr 2025; 25:238. [PMID: 40140750 PMCID: PMC11948709 DOI: 10.1186/s12887-025-05590-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND Primary hypertrophic osteoarthropathy (PHO) is a rare genetic disorder primarily characterized by digital clubbing, pachydermia, and periostitis. The rarity of this disease often leads to misdiagnosis or delayed diagnosis. METHODS We describe the clinical and genetic findings of two pediatric PHO cases caused by HPGD variants and perform a systematic literature review of HPGD-related PHO cases. RESULTS Both patients exhibited congenital digital clubbing and patent ductus arteriosus from birth. Radiographs revealed cortical bone thickening and a periosteal reaction. Patient 1 displayed gait abnormalities and delayed cranial suture closure, while Patient 2 had bilateral leg swelling. Whole exome sequencing identified a compound heterozygous variant (NM_000860.6: c.189C > A, p.C63* and NM_000860.6: c.310_311delCT, p. L104Afs*3) in Patient 1 and a homozygous splice-site variant (NG_011689.1(NM_000860.6): c.324 + 5G > A) in Patient 2. All variants were classified as pathogenic based on the American College of Medical Genetics and Genomics criteria. Among 89 reviewed cases, the c.310_311delCT variant accounted for 37.1% (33/89), predominantly in homozygous form (60.6%, 20/33). The median urinary prostaglandin E2 (PGE2)-to-creatinine ratio in PHO patients was 627.1 ng/mmol (normal: 61.49 ng/mmol). Notably, the median age of symptom onset was 5.1 years, while diagnosis occurred at 22.1 years, with a male predominance (male-to-female ratio: 2.2:1). CONCLUSION We report the first HPGD c.189C > A variant, expanding the genetic spectrum of PHO. The c.310_311delCT variant represents a recurrent hotspot, predominantly in homozygosity. Our findings highlight the importance of early genetic testing and multidisciplinary management to reduce diagnostic delays and improve outcomes.
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Affiliation(s)
- Jun Li
- Department of Nephrology, Shenzhen Children'S Hospital, Shenzhen, Guangdong, China
| | - Shilei Jia
- Department of Nephrology, Shenzhen Children'S Hospital, Shenzhen, Guangdong, China
| | - Jianqun Guo
- Department of Nephrology, Shenzhen Children'S Hospital, Shenzhen, Guangdong, China
| | - Wenhui Xie
- Department of Nephrology, Shenzhen Children'S Hospital, Shenzhen, Guangdong, China
| | - Yijiao Ma
- Department of Nephrology, Shenzhen Children'S Hospital, Shenzhen, Guangdong, China
| | - Xiaojie Gao
- Department of Nephrology, Shenzhen Children'S Hospital, Shenzhen, Guangdong, China
| | - Meihao Gao
- Department of Pediatrics, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China.
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Wu L, Yang J, Chen Y, Lin J, Huang W, Li M. Association of circulating metabolic biomarkers with risk of lung cancer: a population-based prospective cohort study. BMC Med 2025; 23:176. [PMID: 40140895 PMCID: PMC11948749 DOI: 10.1186/s12916-025-03993-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 03/11/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND There is emerging evidence that metabolites might be associated with risk of lung cancer, but their relationships have not been fully characterized. We aimed to investigate the association between circulating metabolic biomarkers and lung cancer risk and the potential underlying pathways. METHODS Nuclear magnetic resonance metabolomic profiling was conducted on baseline plasma samples from 91,472 UK Biobank participants without cancer and pregnancy. Multivariate Cox regression models were employed to assess the hazard ratios (HRs) of 164 metabolic biomarkers (including metabolites and lipoprotein subfractions) and 9 metabolic biomarker principal components (PCs) for lung cancer, after adjusting for covariates and false discovery rate (FDR). Pathway analysis was conducted to investigate the potential metabolic pathways. RESULTS During a median follow-up of 11.0 years, 702 participants developed lung cancer. A total of 109 metabolic biomarkers (30 metabolites and 79 lipoprotein subfractions) were associated with the risk of lung cancer. Glycoprotein acetyls demonstrated a positive association with lung cancer risk [HR = 1.13 (95%CI: 1.04, 1.22)]. Negative associations with lung cancer were found for albumin [0.78 (95%CI: 0.72, 0.83)], acetate [0.91 (95%CI: 0.85, 0.97)], valine [0.90 (95%CI: 0.83, 0.98)], alanine [0.88 (95%CI: 0.82, 0.95)], glucose [0.91 (95%CI: 0.85, 0.99)], citrate [0.91 (95%CI: 0.85, 0.99)], omega-3 fatty acids [0.83 (95%CI: 0.77, 0.90)], linoleic acid [0.83 (95%CI: 0.77, 0.89)], etc. Nine PCs represented over 90% of the total variances, and among those with statistically significant estimates, PC1 [0.85 (95%CI: 0.80, 0.92)], PC2 [0.88 (95%CI: 0.82, 0.95)], and PC9 [0.87 (95%CI: 0.80, 0.93)] were negatively associated with lung cancer risk, whereas PC7 [1.08 (95%CI: 1.00, 1.16)] and PC8 [1.16 (95%CI: 1.08, 1.26)] showed positive associations with lung cancer risk. The pathway analysis showed that the "linoleic acid metabolism" was statistically significant after the FDR adjustment (p value 0.0496). CONCLUSIONS Glycoprotein acetyls had a positive association with lung cancer risk while other metabolites and lipoprotein subfractions showed negative associations. Certain metabolites and lipoprotein subfractions might be independent risk factors for lung cancer. Our findings shed new light on the etiology of lung cancer and might aid the selection of high-risk individuals for lung cancer screening.
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Affiliation(s)
- Lan Wu
- Department of Cancer Prevention, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jun Yang
- School of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Yu Chen
- Department of Cancer Prevention, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jiahao Lin
- Department of Cancer Prevention, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Wenkai Huang
- National Central Cancer Registry Office, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mengmeng Li
- Department of Cancer Prevention, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China.
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Gauderman WJ, Fu Y, Queme B, Kawaguchi E, Wang Y, Morrison J, Brenner H, Chan A, Gruber SB, Keku T, Li L, Moreno V, Pellatt AJ, Peters U, Samadder NJ, Schmit SL, Ulrich CM, Um C, Wu A, Lewinger JP, Drew DA, Mi H. Pathway Polygenic Risk Scores (pPRS) for the Analysis of Gene-environment Interaction. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.16.628610. [PMID: 39763728 PMCID: PMC11702571 DOI: 10.1101/2024.12.16.628610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/01/2025]
Abstract
A polygenic risk score (PRS) is used to quantify the combined disease risk of many genetic variants. For complex human traits there is interest in determining whether the PRS modifies, i.e. interacts with, important environmental (E) risk factors. Detection of a PRS by environment (PRS × E) interaction may provide clues to underlying biology and can be useful in developing targeted prevention strategies for modifiable risk factors. The standard PRS may include a subset of variants that interact with E but a much larger subset of variants that affect disease without regard to E. This latter subset will 'water down' the underlying signal in former subset, leading to reduced power to detect PRS × E interaction. We explore the use of pathway-defined PRS (pPRS) scores, using state of the art tools to annotate subsets of variants to genomic pathways. We demonstrate via simulation that testing targeted pPRS × E interaction can yield substantially greater power than testing overall PRS × E interaction. We also analyze a large study (N=78,253) of colorectal cancer (CRC) where E = non-steroidal anti-inflammatory drugs (NSAIDs), a well-established protective exposure. While no evidence of overall PRS × NSAIDs interaction (p=0.41) is observed, a significant pPRS × NSAIDs interaction (p=0.0003) is identified based on SNPs within the TGF-β / gonadotropin releasing hormone receptor (GRHR) pathway. NSAIDS is protective (OR=0.84) for those at the 5th percentile of the TGF-β/GRHR pPRS (low genetic risk, OR), but significantly more protective (OR=0.70) for those at the 95th percentile (high genetic risk). From a biological perspective, this suggests that NSAIDs may act to reduce CRC risk specifically through genes in these pathways. From a population health perspective, our result suggests that focusing on genes within these pathways may be effective at identifying those for whom NSAIDs-based CRC-prevention efforts may be most effective.
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Affiliation(s)
- W James Gauderman
- Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA
| | - Yubo Fu
- Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA
| | - Bryan Queme
- Division of Bioinformatics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA
| | - Eric Kawaguchi
- Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA
| | - Yinqiao Wang
- Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA
| | - John Morrison
- Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andrew Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Stephen B Gruber
- Center for Precision Medicine and Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Temitope Keku
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Li Li
- Department of Family Medicine, UVA Comprehensive Cancer Center, UVA School of Medicine, Charlottesville, VA, USA
| | - Victor Moreno
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, 08908 Barcelona, Spain
- Colorectal Cancer Group, ONCOBELL Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain
- Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L'Hospitalet de Llobregat, 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
| | | | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | | | - Stephanie L Schmit
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
- Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, OH, USA
| | - Cornelia M Ulrich
- Huntsman Cancer Institute, Salt Lake City, UT, USA
- Department of Population Sciences, University of Utah, USA
| | - Caroline Um
- Department of Population Science, American Cancer Society, Atlanta, GA, USA
| | - Anna Wu
- Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA
| | - Juan Pablo Lewinger
- Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA
| | - David A Drew
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Huaiyu Mi
- Division of Bioinformatics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA
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Chun KS, Kim EH, Kim DH, Song NY, Kim W, Na HK, Surh YJ. Targeting cyclooxygenase-2 for chemoprevention of inflammation-associated intestinal carcinogenesis: An update. Biochem Pharmacol 2024; 228:116259. [PMID: 38705538 DOI: 10.1016/j.bcp.2024.116259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/18/2024] [Accepted: 05/02/2024] [Indexed: 05/07/2024]
Abstract
Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. Cyclooxygenase-2 (COX-2) is a key enzyme involved in inflammatory signaling. While being transiently upregulated upon inflammatory stimuli, COX-2 has been found to be consistently overexpressed in human colorectal cancer and several other malignancies. The association between chronic inflammation and cancer has been revisited: cancer can arise when inflammation fails to resolve. Besides its proinflammatory functions, COX-2 also catalyzes the production of pro-resolving as well as anti-inflammatory metabolites from polyunsaturated fatty acids. This may account for the side effects caused by long term use of some COX-2 inhibitory drugs during the cancer chemopreventive trials. This review summarizes the latest findings highlighting the dual functions of COX-2 in the context of its implications in the development, maintenance, and progression of cancer.
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Affiliation(s)
- Kyung-Soo Chun
- College of Pharmacy, Keimyung University, Daegu 42601, Korea
| | - Eun-Hee Kim
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam 13488, South Korea
| | - Do-Hee Kim
- Department of Chemistry, College of Convergence and Integrated Science, Kyonggi University, Suwon, Gyeonggi-do 16227, South Korea
| | - Na-Young Song
- Department of Oral Biology, BK21 Four Project, Yonsei University College of Dentistry, Seoul 03722, South Korea
| | - Wonki Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, South Korea
| | - Hye-Kyung Na
- Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering, Sungshin Women's University, Seoul 01133, South Korea
| | - Young-Joon Surh
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
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Drew DA, Kim AE, Lin Y, Qu C, Morrison J, Lewinger JP, Kawaguchi E, Wang J, Fu Y, Zemlianskaia N, Díez-Obrero V, Bien SA, Dimou N, Albanes D, Baurley JW, Wu AH, Buchanan DD, Potter JD, Prentice RL, Harlid S, Arndt V, Barry EL, Berndt SI, Bouras E, Brenner H, Budiarto A, Burnett-Hartman A, Campbell PT, Carreras-Torres R, Casey G, Chang-Claude J, Conti DV, Devall MA, Figueiredo JC, Gruber SB, Gsur A, Gunter MJ, Harrison TA, Hidaka A, Hoffmeister M, Huyghe JR, Jenkins MA, Jordahl KM, Kundaje A, Le Marchand L, Li L, Lynch BM, Murphy N, Nassir R, Newcomb PA, Newton CC, Obón-Santacana M, Ogino S, Ose J, Pai RK, Palmer JR, Papadimitriou N, Pardamean B, Pellatt AJ, Peoples AR, Platz EA, Rennert G, Ruiz-Narvaez E, Sakoda LC, Scacheri PC, Schmit SL, Schoen RE, Stern MC, Su YR, Thomas DC, Tian Y, Tsilidis KK, Ulrich CM, Um CY, van Duijnhoven FJ, Van Guelpen B, White E, Hsu L, Moreno V, Peters U, Chan AT, Gauderman WJ. Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer. SCIENCE ADVANCES 2024; 10:eadk3121. [PMID: 38809988 PMCID: PMC11135391 DOI: 10.1126/sciadv.adk3121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 04/26/2024] [Indexed: 05/31/2024]
Abstract
Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.
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Affiliation(s)
- David A. Drew
- Clinical & Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Andre E. Kim
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yi Lin
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - John Morrison
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Juan Pablo Lewinger
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Eric Kawaguchi
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jun Wang
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Yubo Fu
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Natalia Zemlianskaia
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Virginia Díez-Obrero
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Stephanie A. Bien
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Niki Dimou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - James W. Baurley
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
- BioRealm LLC, Walnut, CA, USA
| | - Anna H. Wu
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Daniel D. Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia
- Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - John D. Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Research Centre for Hauora and Health, Massey University, Wellington, New Zealand
| | - Ross L. Prentice
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Volker Arndt
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Elizabeth L. Barry
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Emmanouil Bouras
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Arif Budiarto
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
| | | | - Peter T. Campbell
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Robert Carreras-Torres
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute (IDIBGI), Salt, 17190 Girona, Spain
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany
| | - David V. Conti
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Matthew A.M. Devall
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
| | - Jane C. Figueiredo
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Stephen B. Gruber
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA
- Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA
| | - Andrea Gsur
- Center for Cancer Research, Medical University Vienna, Vienna, Austria
| | - Marc J. Gunter
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK
| | - Tabitha A. Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Akihisa Hidaka
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jeroen R. Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Mark A. Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Kristina M. Jordahl
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Anshul Kundaje
- Department of Genetics, Stanford University, Stanford, CA, USA
- Department of Computer Science, Stanford University, Stanford, CA, USA
| | | | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
- UVA Comprehensive Cancer Center, Charlottesville, VA, USA
| | - Brigid M. Lynch
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Rami Nassir
- Department of Pathology, School of Medicine, Umm Al-Qura’a University, Mecca, Saudi Arabia
| | - Polly A. Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- School of Public Health, University of Washington, Seattle, WA, USA
| | | | - Mireia Obón-Santacana
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
| | - Shuji Ogino
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Jennifer Ose
- Huntsman Cancer Institute, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Rish K. Pai
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Julie R. Palmer
- Slone Epidemiology Center at Boston University, Boston, MA, USA
| | - Nikos Papadimitriou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Bens Pardamean
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
| | - Andrew J. Pellatt
- Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anita R. Peoples
- Huntsman Cancer Institute, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Elizabeth A. Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Gad Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
| | - Edward Ruiz-Narvaez
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Lori C. Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Peter C. Scacheri
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - Stephanie L. Schmit
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
- Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, OH, USA
| | - Robert E. Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Mariana C. Stern
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Yu-Ru Su
- Biostatistics Division, Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
| | - Duncan C. Thomas
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yu Tian
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- School of Public Health, Capital Medical University, Beijing, China
| | - Konstantinos K. Tsilidis
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Cornelia M. Ulrich
- Huntsman Cancer Institute, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Caroline Y. Um
- Department of Population Science, American Cancer Society, Atlanta, GA, USA
| | | | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Victor Moreno
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L’Hospitalet de Llobregat, 08908 Barcelona, Spain
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Andrew T. Chan
- Clinical & Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - W. James Gauderman
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Santiso A, Heinemann A, Kargl J. Prostaglandin E2 in the Tumor Microenvironment, a Convoluted Affair Mediated by EP Receptors 2 and 4. Pharmacol Rev 2024; 76:388-413. [PMID: 38697857 DOI: 10.1124/pharmrev.123.000901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 11/15/2023] [Accepted: 11/20/2023] [Indexed: 05/05/2024] Open
Abstract
The involvement of the prostaglandin E2 (PGE2) system in cancer progression has long been recognized. PGE2 functions as an autocrine and paracrine signaling molecule with pleiotropic effects in the human body. High levels of intratumoral PGE2 and overexpression of the key metabolic enzymes of PGE2 have been observed and suggested to contribute to tumor progression. This has been claimed for different types of solid tumors, including, but not limited to, lung, breast, and colon cancer. PGE2 has direct effects on tumor cells and angiogenesis that are known to promote tumor development. However, one of the main mechanisms behind PGE2 driving cancerogenesis is currently thought to be anchored in suppressed antitumor immunity, thus providing possible therapeutic targets to be used in cancer immunotherapies. EP2 and EP4, two receptors for PGE2, are emerging as being the most relevant for this purpose. This review aims to summarize the known roles of PGE2 in the immune system and its functions within the tumor microenvironment. SIGNIFICANCE STATEMENT: Prostaglandin E2 (PGE2) has long been known to be a signaling molecule in cancer. Its presence in tumors has been repeatedly associated with disease progression. Elucidation of its effects on immunological components of the tumor microenvironment has highlighted the potential of PGE2 receptor antagonists in cancer treatment, particularly in combination with immune checkpoint inhibitor therapeutics. Adjuvant treatment could increase the response rates and the efficacy of immune-based therapies.
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Affiliation(s)
- Ana Santiso
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Akos Heinemann
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Julia Kargl
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
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Chakraborty B, Agarwal S, Kori S, Das R, Kashaw V, Iyer AK, Kashaw SK. Multiple Protein Biomarkers and Different Treatment Strategies for Colorectal Carcinoma: A Comprehensive Prospective. Curr Med Chem 2024; 31:3286-3326. [PMID: 37151060 DOI: 10.2174/0929867330666230505165031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 05/09/2023]
Abstract
In this review, we emphasized important biomarkers, pathogenesis, and newly developed therapeutic approaches in the treatment of colorectal cancer (CRC). This includes a complete description of small-molecule inhibitors, phytopharmaceuticals with antiproliferative potential, monoclonal antibodies for targeted therapy, vaccinations as immunotherapeutic agents, and many innovative strategies to intervene in the interaction of oncogenic proteins. Many factors combine to determine the clinical behavior of colorectal cancer and it is still difficult to comprehend the molecular causes of a person's vulnerability to CRC. It is also challenging to identify the causes of the tumor's onset, progression, and responsiveness or resistance to antitumor treatment. Current recommendations for targeted medications are being updated by guidelines throughout the world in light of the growing number of high-quality clinical studies. So, being concerned about the aforementioned aspects, we have tried to present a summarized pathogenic view, including a brief description of biomarkers and an update of compounds with their underlying mechanisms that are currently under various stages of clinical testing. This will help to identify gaps or shortfalls that can be addressed in upcoming colorectal cancer research.
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Affiliation(s)
- Biswadip Chakraborty
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivangi Agarwal
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivam Kori
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Ratnesh Das
- Department of Chemistry, ISF College of Pharmacy, Moga-Punjab, India
| | - Varsha Kashaw
- Sagar Institute of Pharmaceutical Sciences, Sagar (M.P.), India
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA
- Molecular Imaging Program, Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Sushil Kumar Kashaw
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
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10
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Cui Y, Lv Z, Yang Z, Lei J. Inhibition of Prostaglandin-Degrading Enzyme 15-PGDH Mitigates Acute Murine Lung Allograft Rejection. Lung 2023; 201:591-601. [PMID: 37934242 DOI: 10.1007/s00408-023-00651-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 10/13/2023] [Indexed: 11/08/2023]
Abstract
PURPOSE Acute rejection is a frequent complication among lung transplant recipients and poses substantial therapeutic challenges. 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme responsible for the inactivation of prostaglandin E2 (PGE2), has recently been implicated in inflammatory lung diseases. However, the role of 15-PGDH in lung transplantation rejection remains elusive. The present study was undertaken to examine the expression of 15-PGDH in rejected lung allografts and whether inhibition of 15-PGDH ameliorates acute lung allograft rejection. METHODS Orthotopic mouse lung transplantations were performed between donor and recipient mice of the same strain or allogeneic mismatched pairs. The expression of 15-PGDH in mouse lung grafts was measured. The efficacy of a selective 15-PGDH inhibitor (SW033291) in ameliorating acute rejection was assessed through histopathological examination, micro-CT imaging, and pulmonary function tests. Additionally, the mechanism underlying the effects of SW033291 treatment was explored using CD8+ T cells isolated from mouse lung allografts. RESULTS Increased 15-PGDH expression was observed in rejected allografts and allogeneic CD8+ T cells. Treatment with SW033291 led to an accumulation of PGE2, modulation of CD8+ T-cell responses and mitochondrial activity, and improved allograft function and survival. CONCLUSION Our study provides new insights into the role of 15-PGDH in acute lung rejection and highlights the therapeutic potential of inhibiting 15-PGDH for enhancing graft survival. The accumulation of PGE2 and modulation of CD8+ T-cell responses represent potential mechanisms underlying the benefits of 15-PGDH inhibition in this model. Our findings provide impetus for further exploring 15-PGDH as a target for improving lung transplantation outcomes.
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Affiliation(s)
- Ye Cui
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, #10 Xi Tou Tiao, You An Men Wai, Fengtai, Beijing, 100069, People's Republic of China.
| | - Zhe Lv
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, #10 Xi Tou Tiao, You An Men Wai, Fengtai, Beijing, 100069, People's Republic of China
| | - Zeran Yang
- Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People's Republic of China
| | - Jianfeng Lei
- Research Core Facilities, Capital Medical University, Beijing, 100069, People's Republic of China
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11
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Hu X, Yasuda T, Yasuda-Yosihara N, Yonemura A, Umemoto T, Nakachi Y, Yamashita K, Semba T, Arima K, Uchihara T, Nishimura A, Bu L, Fu L, Wei F, Zhang J, Tong Y, Wang H, Iwamoto K, Fukuda T, Nakagawa H, Taniguchi K, Miyamoto Y, Baba H, Ishimoto T. Downregulation of 15-PGDH enhances MASH-HCC development via fatty acid-induced T-cell exhaustion. JHEP Rep 2023; 5:100892. [PMID: 37942226 PMCID: PMC10628853 DOI: 10.1016/j.jhepr.2023.100892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 08/09/2023] [Accepted: 08/16/2023] [Indexed: 11/10/2023] Open
Abstract
Background & Aims Hepatocellular carcinoma (HCC) mainly develops from chronic hepatitis. Metabolic dysfunction-associated steatohepatitis (MASH) has gradually become the main pathogenic factor for HCC given the rising incidence of obesity and metabolic diseases. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) degrades prostaglandin 2 (PGE2), which is known to exacerbate inflammatory responses. However, the role of PGE2 accumulation caused by 15-PGDH downregulation in the development of MASH-HCC has not been determined. Methods We utilised the steric animal model to establish a MASH-HCC model using wild-type and 15-Pgdh+/- mice to assess the significance of PGE2 accumulation in the development of MASH-HCC. Additionally, we analysed clinical samples obtained from patients with MASH-HCC. Results PGE2 accumulation in the tumour microenvironment induced the production of reactive oxygen species in macrophages and the expression of cell growth-related genes and antiapoptotic genes. Conversely, the downregulation of fatty acid metabolism in the background liver promoted lipid accumulation in the tumour microenvironment, causing a decrease in mitochondrial membrane potential and CD8+ T-cell exhaustion, which led to enhanced development of MASH-HCC. Conclusions 15-PGDH downregulation inactivates immune surveillance by promoting the proliferation of exhausted effector T cells, which enhances hepatocyte survival and proliferation and leads to the development of MASH-HCC. Impact and implications The suppression of PGE2-related inflammation and subsequent lipid accumulation leads to a reduction in the severity of MASH and inhibition of subsequent progression toward MASH-HCC.
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Affiliation(s)
- Xichen Hu
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Tadahito Yasuda
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Noriko Yasuda-Yosihara
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Atsuko Yonemura
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Terumasa Umemoto
- Hematopoietic Stem Cell Engineering, International Research Center of Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | - Yutaka Nakachi
- Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kohei Yamashita
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Takashi Semba
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kota Arima
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Tomoyuki Uchihara
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Akiho Nishimura
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Luke Bu
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Lingfeng Fu
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Feng Wei
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Jun Zhang
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yilin Tong
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Huaitao Wang
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kazuya Iwamoto
- Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Takaichi Fukuda
- Department of Anatomy and Neurobiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology and Hepatology, Mie University, Mie, Japan
| | - Koji Taniguchi
- Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Takatsugu Ishimoto
- Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
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Liang M, Zhan W, Wang L, Bei W, Wang W. Ginsenoside Rb1 Promotes Hepatic Glycogen Synthesis to Ameliorate T2DM Through 15-PGDH/PGE 2/EP4 Signaling Pathway. Diabetes Metab Syndr Obes 2023; 16:3223-3234. [PMID: 37867629 PMCID: PMC10590136 DOI: 10.2147/dmso.s431423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 10/11/2023] [Indexed: 10/24/2023] Open
Abstract
Purpose Ginsenoside Rb1 (Rb1), one of the crucial bioactive constituents in Panax ginseng C. A. Mey., possesses anti-type 2 diabetes mellitus (T2DM) property. Nevertheless, the precise mechanism, particularly the impact of Rb1 on hepatic glycogen production, a crucial process in the advancement of T2DM, remains poorly understood. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is responsible for prostaglandin E2 (PGE2) inactivation. A recent study has reported that inhibition of 15-PGDH promoted hepatic glycogen synthesis and improved T2DM. Therefore, herein, we aimed to investigate whether Rb1 ameliorated T2DM through 15-PGDH/PGE2-regulated hepatic glycogen synthesis. Methods By combining streptozotocin with a high-fat diet, we successfully established a mouse model for T2DM. Afterward, these mice were administered Rb1 or metformin for 8 weeks. An insulin-resistant cell model was established by incubating LO2 cells with palmitic acid. Liver glycogen and PGE2 levels, the expression levels of 15-PGDH, serine/threonine kinase AKT (AKT), and glycogen synthase kinase 3 beta (GSK3β) were measured. Molecular docking was used to predict the binding affinity between 15-PGDH and Rb1. Results Rb1 administration increased the phosphorylation levels of AKT and GSK3β to enhance glycogen synthesis in the liver of T2DM mice. Molecular docking indicated that Rb1 had a high affinity for 15-PGDH. Moreover, Rb1 treatment resulted in the suppression of elevated 15-PGDH levels and the elevation of decreased PGE2 levels in the liver of T2DM mice. Furthermore, in vitro experiments showed that Rb1 administration might enhance glycogen production by modulating the 15-PGDH/PGE2/PGE2 receptor EP4 pathway. Conclusion Our findings indicate that Rb1 may enhance liver glycogen production through a 15-PGDH-dependent pathway to ameliorate T2DM, thereby offering a new explanation for the positive impact of Rb1 on T2DM and supporting its potential as an effective therapeutic approach for T2DM.
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Affiliation(s)
- Mingjie Liang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
| | - Wenjing Zhan
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
| | - Lexun Wang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
| | - Weijian Bei
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
| | - Weixuan Wang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
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13
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Robinson P, Montoya K, Magness E, Rodriguez E, Villalobos V, Engineer N, Yang P, Bharadwaj U, Eckols TK, Tweardy DJ. Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis. Cancers (Basel) 2023; 15:cancers15112977. [PMID: 37296943 DOI: 10.3390/cancers15112977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/13/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND AND AIMS Inflammatory bowel disease (IBD) predisposes to colorectal cancer (CRC). In the current studies, we used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3 α; which has pro-inflammatory and anti-apoptotic functions, and STAT3β; which attenuates the effects of STAT3α). In the current study, we determined the contribution of STAT3 to IBD across all tissues by examining DSS-induced colitis in mice that express only STAT3α and in mice treated with TTI-101, a direct small-molecule inhibitor of both isoforms of STAT3. METHODS We examined mortality, weight loss, rectal bleeding, diarrhea, colon shortening, apoptosis of colonic CD4+ T-cells, and colon infiltration with IL-17-producing cells following 7-day administration of DSS (5%) to transgenic STAT3α knock-in (STAT3β-deficient; ΔβΔβ) mice and wild-type (WT) littermate cage control mice. We also examined the effect of TTI-101 on these endpoints in DSS-induced colitis in WT mice. RESULTS Each of the clinical manifestations of DSS-induced colitis examined was exacerbated in ΔβΔβ transgenic versus cage-control WT mice. Importantly, TTI-101 treatment of DSS-administered WT mice led to complete attenuation of each of the clinical manifestations and also led to increased apoptosis of colonic CD4+ T cells, reduced colon infiltration with IL-17-producing cells, and down-modulation of colon mRNA levels of STAT3-upregulated genes involved in inflammation, apoptosis resistance, and colorectal cancer metastases. CONCLUSIONS Thus, small-molecule targeting of STAT3 may be of benefit in treating IBD and preventing IBD-associated colorectal cancer.
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Affiliation(s)
- Prema Robinson
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Kelsey Montoya
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Emily Magness
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Emma Rodriguez
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Viviana Villalobos
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Nikita Engineer
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Peng Yang
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Uddalak Bharadwaj
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Thomas Kris Eckols
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - David John Tweardy
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
- Department of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
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14
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You M, Xie Z, Zhang N, Zhang Y, Xiao D, Liu S, Zhuang W, Li L, Tao Y. Signaling pathways in cancer metabolism: mechanisms and therapeutic targets. Signal Transduct Target Ther 2023; 8:196. [PMID: 37164974 PMCID: PMC10172373 DOI: 10.1038/s41392-023-01442-3] [Citation(s) in RCA: 95] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 03/20/2023] [Accepted: 04/17/2023] [Indexed: 05/12/2023] Open
Abstract
A wide spectrum of metabolites (mainly, the three major nutrients and their derivatives) can be sensed by specific sensors, then trigger a series of signal transduction pathways and affect the expression levels of genes in epigenetics, which is called metabolite sensing. Life body regulates metabolism, immunity, and inflammation by metabolite sensing, coordinating the pathophysiology of the host to achieve balance with the external environment. Metabolic reprogramming in cancers cause different phenotypic characteristics of cancer cell from normal cell, including cell proliferation, migration, invasion, angiogenesis, etc. Metabolic disorders in cancer cells further create a microenvironment including many kinds of oncometabolites that are conducive to the growth of cancer, thus forming a vicious circle. At the same time, exogenous metabolites can also affect the biological behavior of tumors. Here, we discuss the metabolite sensing mechanisms of the three major nutrients and their derivatives, as well as their abnormalities in the development of various cancers, and discuss the potential therapeutic targets based on metabolite-sensing signaling pathways to prevent the progression of cancer.
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Affiliation(s)
- Mengshu You
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Zhuolin Xie
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Nan Zhang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Yixuan Zhang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Desheng Xiao
- Department of Pathology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Shuang Liu
- Department of Oncology, Institute of Medical Sciences, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Wei Zhuang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, People's Republic of China.
| | - Lili Li
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Ma Liu Shui, Hong Kong.
| | - Yongguang Tao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China.
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China.
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China.
- Department of Thoracic Surgery, Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer, Second Xiangya Hospital, Central South University, 410011, Changsha, China.
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15
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Jin N, Kan CM, Pei XM, Cheung WL, Ng SSM, Wong HT, Cheng HYL, Leung WW, Wong YN, Tsang HF, Chan AKC, Wong YKE, Cho WCS, Chan JKC, Tai WCS, Chan TF, Wong SCC, Yim AKY, Yu ACS. Cell-free circulating tumor RNAs in plasma as the potential prognostic biomarkers in colorectal cancer. Front Oncol 2023; 13:1134445. [PMID: 37091184 PMCID: PMC10115432 DOI: 10.3389/fonc.2023.1134445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 03/24/2023] [Indexed: 04/09/2023] Open
Abstract
BACKGROUND Cell free RNA (cfRNA) contains transcript fragments from multiple cell types, making it useful for cancer detection in clinical settings. However, the pathophysiological origins of cfRNAs in plasma from colorectal cancer (CRC) patients remain unclear. METHODS To identify the tissue-specific contributions of cfRNAs transcriptomic profile, we used a published single-cell transcriptomics profile to deconvolute cell type abundance among paired plasma samples from CRC patients who underwent tumor-ablative surgery. We further validated the differentially expressed cfRNAs in 5 pairs of CRC tumor samples and adjacent tissue samples as well as 3 additional CRC tumor samples using RNA-sequencing. RESULTS The transcriptomic component from intestinal secretory cells was significantly decreased in the in-house post-surgical cfRNA. The HPGD, PACS1, and TDP2 expression was consistent across cfRNA and tissue samples. Using the Cancer Genome Atlas (TCGA) CRC datasets, we were able to classify the patients into two groups with significantly different survival outcomes. CONCLUSIONS The three-gene signature holds promise in applying minimal residual disease (MRD) testing, which involves profiling remnants of cancer cells after or during treatment. Biomarkers identified in the present study need to be validated in a larger cohort of samples in order to ascertain their possible use in early diagnosis of CRC.
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Affiliation(s)
- Nana Jin
- R&D, Codex Genetics Limited, Hong Kong, Hong Kong SAR, China
| | - Chau-Ming Kan
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - Xiao Meng Pei
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - Wing Lam Cheung
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - Simon Siu Man Ng
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Heong Ting Wong
- Department of Pathology, Kiang Wu Hospital, Macau, Macau SAR, China
| | - Hennie Yuk-Lin Cheng
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - Wing Wa Leung
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Yee Ni Wong
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Hin Fung Tsang
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | | | - Yin Kwan Evelyn Wong
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - William Chi Shing Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, Hong Kong SAR, China
| | | | - William Chi Shing Tai
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - Ting-Fung Chan
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Sze Chuen Cesar Wong
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
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16
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Jiang J, Li A, Lai X, Zhang H, Wang C, Wang H, Li L, Liu Y, Xie L, Yang C, Zhang C, Lu S, Li Y. Correlation between Metabolite of Prostaglandin E2 and the incidence of colorectal adenomas. Front Oncol 2023; 13:1068469. [PMID: 36923425 PMCID: PMC10009184 DOI: 10.3389/fonc.2023.1068469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 02/13/2023] [Indexed: 03/02/2023] Open
Abstract
Colorectal cancer is a common malignancy, and the incidence and mortality rates continue to rise. An important factor in the emergence of inflammation-induced colorectal carcinogenesis is elevated cyclooxygenase-2. Prostaglandin E2 (PGE2) over-production is frequently equated with cyclooxygenase-2 gene over-expression. PGE2 can be assessed by measuring the level of prostaglandin's main metabolite, PGE-M, in urine. Colorectal adenoma is a precancerous lesion that can lead to colorectal cancer. We conducted research to evaluate the association between urinary levels of the PGE-M and the risk of colorectal adenomas. In a western Chinese population, we identified 152 cases of adenoma and 152 controls patients without polyps. Adenoma cases were categorized into control, low-risk and high-risk groups. There was no significant change in PGE-M levels, between the control group and the low-risk adenoma group. In the high-risk group, the PGE-M levels were 23% higher than the control group. When compared to people with the lowest urine PGE-M levels (first quartile), people with greater urinary PGE-M levels had a higher chance of developing high-risk colorectal adenomas, with an adjusted odds ratio (95% CI) of 1.65 (0.76-3.57) in the fourth quartile group, (p= 0.013). We conclude urinary PGE-M is associated with the risk of developing high-risk adenomas. Urinary PGE-M level may be used as a non-invasive indicator for estimating cancer risk.
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Affiliation(s)
- Jia Jiang
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Anjie Li
- Department of Medicine-Cardiovascular, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Xiaolian Lai
- Department of Digestive, People's Hospital of Songtao Miao Autonomous County, Tongren, China
| | - Hanqun Zhang
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Chonghong Wang
- Department of Digestive, People's Hospital of Songtao Miao Autonomous County, Tongren, China
| | - Huimin Wang
- Department of Digestive, People's Hospital of Songtao Miao Autonomous County, Tongren, China
| | - Libo Li
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Yuncong Liu
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Lu Xie
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Can Yang
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Cui Zhang
- Zunyi Medical University, Zunyi, China
| | - Shuoyan Lu
- Department of Digestive, People's Hospital of Songtao Miao Autonomous County, Tongren, China
| | - Yong Li
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
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17
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Jin K, Qian C, Lin J, Liu B. Cyclooxygenase-2-Prostaglandin E2 pathway: A key player in tumor-associated immune cells. Front Oncol 2023; 13:1099811. [PMID: 36776289 PMCID: PMC9911818 DOI: 10.3389/fonc.2023.1099811] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 01/12/2023] [Indexed: 01/29/2023] Open
Abstract
Cyclooxygenases-2 (COX-2) and Prostaglandin E2 (PGE2), which are important in chronic inflammatory diseases, can increase tumor incidence and promote tumor growth and metastasis. PGE2 binds to various prostaglandin E receptors to activate specific downstream signaling pathways such as PKA pathway, β-catenin pathway, NF-κB pathway and PI3K/AKT pathway, all of which play important roles in biological and pathological behavior. Nonsteroidal anti-inflammatory drugs (NSAIDs), which play as COX-2 inhibitors, and EP antagonists are important in anti-tumor immune evasion. The COX-2-PGE2 pathway promotes tumor immune evasion by regulating myeloid-derived suppressor cells, lymphocytes (CD8+ T cells, CD4+ T cells and natural killer cells), and antigen presenting cells (macrophages and dendritic cells). Based on conventional treatment, the addition of COX-2 inhibitors or EP antagonists may enhance immunotherapy response in anti-tumor immune escape. However, there are still a lot of challenges in cancer immunotherapy. In this review, we focus on how the COX-2-PGE2 pathway affects tumor-associated immune cells.
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Affiliation(s)
- Kaipeng Jin
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Chao Qian
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jinti Lin
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China,*Correspondence: Bing Liu, ; Jinti Lin,
| | - Bing Liu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China,*Correspondence: Bing Liu, ; Jinti Lin,
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18
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Liu Y, Zhou L, Lv C, Liu L, Miao S, Xu Y, Li K, Zhao Y, Zhao J. PGE2 pathway mediates oxidative stress-induced ferroptosis in renal tubular epithelial cells. FEBS J 2023; 290:533-549. [PMID: 36031392 DOI: 10.1111/febs.16609] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 05/15/2022] [Accepted: 08/26/2022] [Indexed: 02/05/2023]
Abstract
Prostaglandin E2 (PGE2) is one of the most abundant prostaglandins and has been implicated in various diseases. Here, we aimed to explore the role of the PGE2 pathway in mediating ferroptosis during acute kidney injury. When renal tubular epithelial cells stimulated by H2 O2 , the contents of glutathione (GSH) and glutathione peroxidase 4 (GPX4) decreased, whereas the level of lipid peroxide increased. Ferrostatin-1 can effectively attenuate these changes. In this process, the expression levels of cyclooxygenase (COX)-1 and COX-2 were up-regulated. Meanwhile, the expression of microsomal prostaglandin E synthase-2 was elevated, whereas the expression of microsomal prostaglandin E synthase-1 and cytosolic prostaglandin E synthase were down-regulated. Furthermore, the expression of 15-hydroxyprostaglandin dehydrogenase decreased. An excessive accumulation of PGE2 promoted ferroptosis, whereas the PGE2 inhibitor pranoprofen minimized the changes for COX-2, GSH, GPX4 and lipid peroxides. A decrease in the levels of the PGE2 receptor E-series of prostaglandin 1/3 partially restored the decline of GSH and GPX4 levels and inhibited the aggravation of lipid peroxide. Consistent with the in vitro results, increased PGE2 levels led to increased levels of 3,4-methylenedioxyamphetamine, Fe2+ accumulation and decreased GSH and GPX4 levels during renal ischaemia/reperfusion injury injury in mice. Our results indicate that the PGE2 pathway mediated oxidative stress-induced ferroptosis in renal tubular epithelial cells.
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Affiliation(s)
- Ying Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China.,Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, China
| | - Lin Zhou
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China.,Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, China
| | - Caihong Lv
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China.,Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, China
| | - Lingyun Liu
- Hengyang School of Medicine, University of South China, Hengyang, China
| | - Shuying Miao
- Department of Pathology, Nanjing Drum Tower Hospital, Nanjing University Medical School, China
| | - Yunfei Xu
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China.,Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, China
| | - Kexin Li
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China.,Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, China
| | - Yao Zhao
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China.,Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, China
| | - Jie Zhao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
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19
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Grancher A, Michel P, Di Fiore F, Sefrioui D. Colorectal cancer chemoprevention: is aspirin still in the game? Cancer Biol Ther 2022; 23:446-461. [PMID: 35905195 PMCID: PMC9341367 DOI: 10.1080/15384047.2022.2104561] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Screening strategies have demonstrated their potential for decreasing the incidence and mortality of cancers, particularly that of colorectal cancer (CRC). Another strategy that has been developed to reduce CRC occurrence is the use of chemoprevention agents. Among them, aspirin is the most promising. Aspirin acts in colorectal tumourigenesis through several mechanisms, either directly in tumor cells or in their microenvironment, such as through its anti-inflammatory activity or its effect on the modulation of platelet function. Many retrospective studies, as well as follow-up of large cohorts from trials with primary cardiovascular end points, have shown that long-term treatment with daily low-dose aspirin decreases the incidence of adenomas and colorectal cancers. Therefore, aspirin is currently recommended by the United States Preventive Services Task Force (USPSTF) for primary prevention of CRC in all patients aged 50 to 59 with a 10-y risk of cardiovascular events greater than 10%. Furthermore, several studies have also reported that long-term aspirin treatment taking after CRC resection decreases recurrence risk and increases overall survival, especially in patients with PIK3CA-mutated tumors. This review summarizes current knowledge on the pathophysiological mechanisms of aspirin chemoprevention, discusses the primary clinical results on CRC prevention and highlights the potential biomarkers identified to predict aspirin efficacy.
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Affiliation(s)
- Adrien Grancher
- Normandy Centre for Genomic and Personalized Medicine and Department of Hepatogastroenterology, Normandie Univ, Iron Group, Rouen University Hospital, Rouen, France
| | - Pierre Michel
- Normandy Centre for Genomic and Personalized Medicine and Department of Hepatogastroenterology, Normandie Univ, Iron Group, Rouen University Hospital, Rouen, France
| | - Frederic Di Fiore
- Normandy Centre for Genomic and Personalized Medicine, Department of Hepatogastroenterology and Department of Medical Oncology, Henri Becquerel Centre, Normandie Univ, IRON group, Rouen University Hospital, Rouen, France
| | - David Sefrioui
- Normandy Centre for Genomic and Personalized Medicine and Department of Hepatogastroenterology, Normandie Univ, Iron Group, Rouen University Hospital, Rouen, France
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20
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Ho WJ, Smith JNP, Park YS, Hadiono M, Christo K, Jogasuria A, Zhang Y, Broncano AV, Kasturi L, Dawson DM, Gerson SL, Markowitz SD, Desai AB. 15-PGDH regulates hematopoietic and gastrointestinal fitness during aging. PLoS One 2022; 17:e0268787. [PMID: 35587945 PMCID: PMC9119474 DOI: 10.1371/journal.pone.0268787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 05/08/2022] [Indexed: 11/30/2022] Open
Abstract
Emerging evidence implicates the eicosanoid molecule prostaglandin E2 (PGE2) in conferring a regenerative phenotype to multiple organ systems following tissue injury. As aging is in part characterized by loss of tissue stem cells' regenerative capacity, we tested the hypothesis that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) contributes to the diminished organ fitness of aged mice. Here we demonstrate that genetic loss of 15-PGDH (Hpgd) confers a protective effect on aging of murine hematopoietic and gastrointestinal (GI) tissues. Aged mice lacking 15-PGDH display increased hematopoietic output as assessed by peripheral blood cell counts, bone marrow and splenic stem cell compartments, and accelerated post-transplantation recovery compared to their WT counterparts. Loss of Hpgd expression also resulted in enhanced GI fitness and reduced local inflammation in response to colitis. Together these results suggest that 15-PGDH negatively regulates aged tissue regeneration, and that 15-PGDH inhibition may be a viable therapeutic strategy to ameliorate age-associated loss of organ fitness.
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Affiliation(s)
- Won Jin Ho
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Julianne N. P. Smith
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Young Soo Park
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Matthew Hadiono
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Kelsey Christo
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Alvin Jogasuria
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Yongyou Zhang
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Alyssia V. Broncano
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Lakshmi Kasturi
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Dawn M. Dawson
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Stanton L. Gerson
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
- University Hospitals Seidman Cancer Center, Cleveland, Ohio, United States of America
| | - Sanford D. Markowitz
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
- University Hospitals Seidman Cancer Center, Cleveland, Ohio, United States of America
| | - Amar B. Desai
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
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21
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Wilson DJ, DuBois RN. Role of prostaglandin E2 in the progression of gastrointestinal cancer. Cancer Prev Res (Phila) 2022; 15:355-363. [PMID: 35288737 DOI: 10.1158/1940-6207.capr-22-0038] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 03/01/2022] [Accepted: 03/10/2022] [Indexed: 11/16/2022]
Abstract
Chronic inflammation is a well-established risk factor for several diseases, including cancer. It influences tumor cell biology and the type and density of immune cells in the tumor microenvironment (TME), promoting cancer development. While pro-inflammatory cytokines and chemokines modulate cancer development, emerging evidence has shown that prostaglandin E2 (PGE2) is a known mediator connecting chronic inflammation to cancerization. This review highlights recent advances in our understanding of how the elevation of PGE2 production promotes gastrointestinal cancer initiation, progression, invasion, metastasis, and recurrence, including modulation of immune checkpoint signaling and the type and density of immune cells in the tumor/tissue microenvironment.
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Affiliation(s)
- David Jay Wilson
- Medical University of South Carolina, Greenville, South Carolina, United States
| | - Raymond N DuBois
- Medical University of South Carolina, Charleston, SC, United States
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22
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Ballerini P, Contursi A, Bruno A, Mucci M, Tacconelli S, Patrignani P. Inflammation and Cancer: From the Development of Personalized Indicators to Novel Therapeutic Strategies. Front Pharmacol 2022; 13:838079. [PMID: 35308229 PMCID: PMC8927697 DOI: 10.3389/fphar.2022.838079] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/09/2022] [Indexed: 12/15/2022] Open
Abstract
Colorectal (CRC) and hepatocellular carcinoma (HCC) are associated with chronic inflammation, which plays a role in tumor development and malignant progression. An unmet medical need in these settings is the availability of sensitive and specific noninvasive biomarkers. Their use will allow surveillance of high-risk populations, early detection, and monitoring of disease progression. Moreover, the characterization of specific fingerprints of patients with nonalcoholic fatty liver disease (NAFLD) without or with nonalcoholic steatohepatitis (NASH) at the early stages of liver fibrosis is necessary. Some lines of evidence show the contribution of platelets to intestinal and liver inflammation. Thus, low-dose Aspirin, an antiplatelet agent, reduces CRC and liver cancer incidence and mortality. Aspirin also produces antifibrotic effects in NAFLD. Activated platelets can trigger chronic inflammation and tissue fibrosis via the release of soluble mediators, such as thromboxane (TX) A2 and tumor growth factor (TGF)-β, and vesicles containing genetic material (including microRNA). These platelet-derived products contribute to cyclooxygenase (COX)-2 expression and prostaglandin (PG)E2 biosynthesis by tumor microenvironment cells, such as immune and endothelial cells and fibroblasts, alongside cancer cells. Enhanced COX-2-dependent PGE2 plays a crucial role in chronic inflammation and promotes tumor progression, angiogenesis, and metastasis. Antiplatelet agents can indirectly prevent the induction of COX-2 in target cells by inhibiting platelet activation. Differently, selective COX-2 inhibitors (coxibs) block the activity of COX-2 expressed in the tumor microenvironment and cancer cells. However, coxib chemopreventive effects are hampered by the interference with cardiovascular homeostasis via the coincident inhibition of vascular COX-2-dependent prostacyclin biosynthesis, resulting in enhanced risk of atherothrombosis. A strategy to improve anti-inflammatory agents' use in cancer prevention could be to develop tissue-specific drug delivery systems. Platelet ability to interact with tumor cells and transfer their molecular cargo can be employed to design platelet-mediated drug delivery systems to enhance the efficacy and reduce toxicity associated with anti-inflammatory agents in these settings. Another peculiarity of platelets is their capability to uptake proteins and transcripts from the circulation. Thus, cancer patient platelets show specific proteomic and transcriptomic expression profiles that could be used as biomarkers for early cancer detection and disease monitoring.
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Affiliation(s)
- Patrizia Ballerini
- Center for Advanced Studies and Technology (CAST), Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, Chieti, Italy
| | - Annalisa Contursi
- Center for Advanced Studies and Technology (CAST), Chieti, Italy
- Department of Neuroscience, Imaging and Clinical Science, G. d’Annunzio University, Chieti, Italy
| | - Annalisa Bruno
- Center for Advanced Studies and Technology (CAST), Chieti, Italy
- Department of Neuroscience, Imaging and Clinical Science, G. d’Annunzio University, Chieti, Italy
| | - Matteo Mucci
- Center for Advanced Studies and Technology (CAST), Chieti, Italy
- Department of Neuroscience, Imaging and Clinical Science, G. d’Annunzio University, Chieti, Italy
| | - Stefania Tacconelli
- Center for Advanced Studies and Technology (CAST), Chieti, Italy
- Department of Neuroscience, Imaging and Clinical Science, G. d’Annunzio University, Chieti, Italy
| | - Paola Patrignani
- Center for Advanced Studies and Technology (CAST), Chieti, Italy
- Department of Neuroscience, Imaging and Clinical Science, G. d’Annunzio University, Chieti, Italy
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23
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Wang W, Yang C, Deng H. Overexpression of 15-Hydroxyprostaglandin Dehydrogenase Inhibits A549 Lung Adenocarcinoma Cell Growth via Inducing Cell Cycle Arrest and Inhibiting Epithelial-Mesenchymal Transition. Cancer Manag Res 2021; 13:8887-8900. [PMID: 34876851 PMCID: PMC8643138 DOI: 10.2147/cmar.s331222] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 10/20/2021] [Indexed: 01/22/2023] Open
Abstract
Purpose Lung cancer is one of the most commonly diagnosed cancer as well as the leading cause of cancer-related mortality worldwide, among which lung adenocarcinoma (LUAD) is the most frequent form of lung cancer. Previous studies have shown that 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of prostaglandins to reduce their biological activities and behaves as a tumor suppressor in various cancers. Thus, we aimed to systematically examine the effects of 15-PGDH overexpression on cellular processes in lung adenocarcinoma cells. Methods The stable 15-PGDH-overexpressing A549 cell line was constructed using lentivirus particles. CCK-8 assay was used to determine the cell proliferation rate and sensitivity to cisplatin. Tandem mass tag (TMT)-based quantitative proteomic analysis was used to identify differentially expressed proteins between control and 15-PGDH-overexpression cells. The cell cycle was determined by a flow cytometer. The expression levels of mesenchymal and epithelial markers were measured using Western blotting. Wound healing and transwell assays were used to detect the cell migration and cell invasion ability, respectively. Results Analysis of datasets in The Cancer Genome Atlas revealed that the PGDH gene expression level in the lung adenocarcinoma tissues was significantly lower than that in the pericarcinous tissues. 15-PGDH overexpression in A549 cells reduced cell proliferation rate. Quantitative proteomics revealed that 15-PGDH overexpression inhibited PI3K/AKT/mTOR signaling pathway, which is a signaling pathway driving tumor cell growth and epithelial-mesenchymal transition (EMT) process. In addition, both cell cycle and DNA repair-related proteins were down-regulated in 15-PGDH overexpressed cells. 15-PGDH overexpression induced G1/S cell cycle arrest and increased susceptibility to DNA damaging reagent cisplatin. Importantly, overexpression of 15-PGDH inhibited EMT process with the downregulation of β-catenin and Snail-1 as well as upregulation of E-cadherin and ZO-1. Conclusion 15-PGDH is a tumor suppressor in lung cancer and may serve as a potential therapeutic target to prevent lung adenocarcinoma.
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Affiliation(s)
- Weixuan Wang
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China
| | - Changmei Yang
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, People's Republic of China
| | - Haiteng Deng
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, People's Republic of China
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24
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Zhang J, Chen W, Ma W, Song K, Lee S, Han C, Wu T. Epigenetic Silencing of 15-Hydroxyprostaglandin Dehydrogenase by Histone Methyltransferase EHMT2/G9a in Cholangiocarcinoma. Mol Cancer Res 2021; 20:350-360. [PMID: 34880125 DOI: 10.1158/1541-7786.mcr-21-0536] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 11/12/2021] [Accepted: 12/03/2021] [Indexed: 11/16/2022]
Abstract
Cholangiocarcinoma (CCA) is a lethal malignancy with few therapeutic options. NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has been shown to inhibit CCA cell growth in vitro and in xenograft models. However, the role of 15-PGDH in CCA development has not been investigated and the mechanism for 15-PGDH gene regulation remains unclear. Here, we evaluated the role of 15-PGDH in CCA development by using a mouse model with hydrodynamic tail vein injection of transposase-based plasmids expressing Notch1 intracellular domain and myr-Akt, with or without co-injection of 15-PGDH expression plasmids. Our results reveal that 15-PGDH overexpression effectively prevents CCA development. Through patient data mining and experimental approaches, we provide novel evidences that 15-PGDH is epigenetically silenced by histone methyltransferase G9a. We observe that 15-PGDH and G9a expressions are inversely correlated in both human and mouse CCAs. By using CCA cells and mouse models, we show that G9a inhibition restores 15-PGDH expression and inhibited CCA in vitro and in vivo. Mechanistically, our data indicate that G9a is recruited to 15-PGDH gene promoter via protein-protein interaction with the E-box binding Myc/Max heterodimer. The recruited G9a then silences 15-PGDH gene through enhanced methylation of H3K9. Our further experiments have led to the identification of STAT4 as a key transcription factor involved in the regulation of 15-PGDH by G9a. Collectively, our findings disclose a novel G9a-15PGDH signaling axis which is importantly implicated in CCA development and progression. Implications: The current study describes a novel G9a-15PGDH signaling axis which is importantly implicated in cholangiocarcinoma (CCA) development and progression.
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Affiliation(s)
- Jinqiang Zhang
- Pathology and Laboratory Medicine, Tulane University School of Medicine
| | | | - Wenbo Ma
- Tulane University School of Medicine
| | - Kyoungsub Song
- Pathology and Laboratory Medicine, Tulane University School of Medicine
| | - Sean Lee
- Pathology and Laboratory Medicine, Tulane University School of Medicine
| | - Chang Han
- Pathology and Laboratory Medicine, Tulane University School of Medicine
| | - Tong Wu
- Pathology and Laboratory Medicine, Tulane University
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25
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Wang D, Cabalag CS, Clemons NJ, DuBois RN. Cyclooxygenases and Prostaglandins in Tumor Immunology and Microenvironment of Gastrointestinal Cancer. Gastroenterology 2021; 161:1813-1829. [PMID: 34606846 DOI: 10.1053/j.gastro.2021.09.059] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 09/03/2021] [Accepted: 09/19/2021] [Indexed: 12/21/2022]
Abstract
Chronic inflammation is a known risk factor for gastrointestinal cancer. The evidence that nonsteroidal anti-inflammatory drugs suppress the incidence, growth, and metastasis of gastrointestinal cancer supports the concept that a nonsteroidal anti-inflammatory drug target, cyclooxygenase, and its downstream bioactive lipid products may provide one of the links between inflammation and cancer. Preclinical studies have demonstrated that the cyclooxygenase-2-prostaglandin E2 pathway can promote gastrointestinal cancer development. Although the role of this pathway in cancer has been investigated extensively for 2 decades, only recent studies have described its effects on host defenses against transformed epithelial cells. Overcoming tumor-immune evasion remains one of the major challenges in cancer immunotherapy. This review summarizes the impacts of the cyclooxygenase-2-prostaglandin E2 pathway on gastrointestinal cancer development. Our focus was to highlight recent advances in our understanding of how this pathway induces tumor immune evasion.
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Affiliation(s)
- Dingzhi Wang
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina
| | - Carlos S Cabalag
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Nicholas J Clemons
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
| | - Raymond N DuBois
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina.
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26
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Zhang Q, Tombline G, Ablaeva J, Zhang L, Zhou X, Smith Z, Zhao Y, Xiaoli AM, Wang Z, Lin JR, Jabalameli MR, Mitra J, Nguyen N, Vijg J, Seluanov A, Gladyshev VN, Gorbunova V, Zhang ZD. Genomic expansion of Aldh1a1 protects beavers against high metabolic aldehydes from lipid oxidation. Cell Rep 2021; 37:109965. [PMID: 34758328 PMCID: PMC8656434 DOI: 10.1016/j.celrep.2021.109965] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 06/07/2021] [Accepted: 10/19/2021] [Indexed: 12/24/2022] Open
Abstract
The North American beaver is an exceptionally long-lived and cancer-resistant rodent species. Here, we report the evolutionary changes in its gene coding sequences, copy numbers, and expression. We identify changes that likely increase its ability to detoxify aldehydes, enhance tumor suppression and DNA repair, and alter lipid metabolism, potentially contributing to its longevity and cancer resistance. Hpgd, a tumor suppressor gene, is uniquely duplicated in beavers among rodents, and several genes associated with tumor suppression and longevity are under positive selection in beavers. Lipid metabolism genes show positive selection signals, changes in copy numbers, or altered gene expression in beavers. Aldh1a1, encoding an enzyme for aldehydes detoxification, is particularly notable due to its massive expansion in beavers, which enhances their cellular resistance to ethanol and capacity to metabolize diverse aldehyde substrates from lipid oxidation and their woody diet. We hypothesize that the amplification of Aldh1a1 may contribute to the longevity of beavers. Zhang et al. examine the genome of North American beavers and find evolutionary changes that could contribute to beavers’ longevity. In particular, Aldh1a1, encoding an enzyme for aldehyde detoxification, is massively expanded in the beaver genome, protecting them against exposure to aldehydes from lipid oxidation and their woody diet.
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Affiliation(s)
- Quanwei Zhang
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Gregory Tombline
- Department of Biology, University of Rochester, Rochester, NY 14627, USA
| | - Julia Ablaeva
- Department of Biology, University of Rochester, Rochester, NY 14627, USA
| | - Lei Zhang
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Xuming Zhou
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Zachary Smith
- Department of Biology, University of Rochester, Rochester, NY 14627, USA
| | - Yang Zhao
- Department of Biology, University of Rochester, Rochester, NY 14627, USA
| | - Alus M Xiaoli
- Departments of Medicine and Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Zhen Wang
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Jhih-Rong Lin
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - M Reza Jabalameli
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Joydeep Mitra
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Nha Nguyen
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Jan Vijg
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Andrei Seluanov
- Department of Biology, University of Rochester, Rochester, NY 14627, USA
| | - Vadim N Gladyshev
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Vera Gorbunova
- Department of Biology, University of Rochester, Rochester, NY 14627, USA
| | - Zhengdong D Zhang
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
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27
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Karb DB, Cummings LC. The Intestinal Microbiome and Cystic Fibrosis Transmembrane Conductance Regulator Modulators: Emerging Themes in the Management of Gastrointestinal Manifestations of Cystic Fibrosis. Curr Gastroenterol Rep 2021; 23:17. [PMID: 34448955 DOI: 10.1007/s11894-021-00817-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/28/2021] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW While commonly associated with pulmonary manifestations, cystic fibrosis (CF) is a systemic disease with wide-ranging effects on the gastrointestinal (GI) tract. This article reviews major recent updates in gastroenterological CF care and research. RECENT FINDINGS The high burden of GI symptoms in CF has led to recent studies assessing GI-specific symptom questionnaires and scoring systems. Intestinal dysbiosis potentially contributes to gastrointestinal symptoms in patients with CF and an increased risk of gastrointestinal cancers in CF. An increased incidence of colorectal cancer (CRC) has led to CF-specific CRC screening and surveillance recommendations. Pharmacologic therapies targeting specific cystic fibrosis transmembrane conductance regulator (CFTR) mutations have shown promise in treating GI manifestations of CF. New research has highlighted the importance of intestinal dysbiosis in CF. Future studies should assess whether CFTR modulators affect the gut microbiome and whether altering the gut microbiome will impact GI symptoms and GI cancer risk.
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Affiliation(s)
- Daniel B Karb
- Division of Gastroenterology and Liver Disease, Department of Medicine, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue Mailstop 5066, Cleveland, OH, 44106-5066, USA
- Case Western Reserve University, Cleveland, OH, USA
| | - Linda C Cummings
- Division of Gastroenterology and Liver Disease, Department of Medicine, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue Mailstop 5066, Cleveland, OH, 44106-5066, USA.
- Case Western Reserve University, Cleveland, OH, USA.
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28
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Deng Y, Liu B, Fu C, Gao L, Shen Y, Liu K, Li Q, Cao J, Mao W. Lipopolysaccharide stimulates bovine endometrium explants through toll‑like receptor 4 signaling and PGE 2 synthesis. Prostaglandins Leukot Essent Fatty Acids 2021; 168:102272. [PMID: 33895679 DOI: 10.1016/j.plefa.2021.102272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 02/09/2021] [Accepted: 03/22/2021] [Indexed: 02/07/2023]
Abstract
Bovine endometrium infection with gram-negative bacteria commonly causes uterine diseases. Previous studies indicate that prostaglandin E2 (PGE2) is an inflammatory mediator in bacterial endometritis. However, the mechanism underlying lipopolysaccharide (LPS)-induced inflammatory response regulation in bovine endometrial explants remains elusive. In the present study, bovine explants were pre-treated with 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitors before LPS stimulation. PGE2 secretion, prostaglandin synthetase, pro-inflammatory factor, damage-associated molecular pattern (DAMP), and related signaling pathway factor levels were evaluated. Using 15-PGDH inhibitors pre-treatment, LPS-treated bovine endometrial explants exhibited augmentation of PGE2 and DAMP expression, and upregulation of various signaling pathway factors. Protein kinase A (PKA), extracellular-signal-regulated kinase, and c-Jun N-terminal kinase phosphorylation and degradation of nuclear transcription factor-κB (NF-κB) inhibitors were induced in the pre-treated endometrial explants. The mechanism underlying LPS-induced PGE2 accumulation acting as a pro-inflammatory mediator through toll-like receptor 4 signaling in bovine explants could involve the PKA, mitogen-activated protein kinase, and NF-κB pathways.
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Affiliation(s)
- Yang Deng
- School of Public Health, Baotou Medical College, 014040, Baotou, China; Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, 010018, Hohhot, China
| | - Bo Liu
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, 010018, Hohhot, China; Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, 010018, Hohhot, China
| | - Changqi Fu
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, 010018, Hohhot, China; Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, 010018, Hohhot, China
| | - Long Gao
- School of Public Health, Baotou Medical College, 014040, Baotou, China; Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, 010018, Hohhot, China
| | - Yuan Shen
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, 010018, Hohhot, China; Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, 010018, Hohhot, China
| | - Kun Liu
- School of Public Health, Baotou Medical College, 014040, Baotou, China; Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, 010018, Hohhot, China
| | - Qianru Li
- School of Public Health, Baotou Medical College, 014040, Baotou, China; Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, 010018, Hohhot, China
| | - Jinshan Cao
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, 010018, Hohhot, China; Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, 010018, Hohhot, China.
| | - Wei Mao
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, 010018, Hohhot, China; Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, 010018, Hohhot, China.
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29
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Song CH, Kim N, Nam RH, Choi SI, Kang C, Jang JY, Nho H, Shin E, Lee HN. Nuclear Factor Erythroid 2-related Factor 2 Knockout Suppresses the Development of Aggressive Colorectal Cancer Formation Induced by Azoxymethane/Dextran Sulfate Sodium-Treatment in Female Mice. J Cancer Prev 2021; 26:41-53. [PMID: 33842405 PMCID: PMC8020176 DOI: 10.15430/jcp.2021.26.1.41] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Colon tumors develop more frequently in male than in female. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays differential roles in the stage of tumorigenesis. The purpose of this study was to investigate the role of Nrf2 on colitis-associated tumorigenesis using Nrf2 knockout (KO) female mice. Azoxymethane (AOM) and dextran sulfate sodium (DSS)-treated wild-type (WT) and Nrf2 KO female mice were sacrificed at week 2 and 16 after AOM injection. Severity of colitis, tumor incidence, and levels of inflammatory mediators were evaluated in AOM/DSS-treated WT and Nrf2 KO mice. Furthermore, qRT-PCR, Western blot abnalysis, and ELISA were performed in colon tissues. At week 2, AOM/DSS-induced colon tissue damages were significantly greater in Nrf2 KO than in WT mice. At week 16, tumor numbers (> 2 mm size) were significantly lower in both the proximal and distal colon in Nrf2 KO compared to WT. The overall incidences of adenoma/cancer of the proximal colon and submucosal invasive cancer of the distal colon were reduced by Nrf2 KO. The mRNA and protein expression levels of NF-κB-related mediators (i.e., iNOS and COX-2) and Nrf2-related antioxidants (i.e., heme oxygenase-1 and glutamate-cysteine ligase catalytic subunit) were significantly lower in the Nrf2 KO than in WT mice. Interestingly, the protein level of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) was higher in AOM/DSS-treated Nrf2 KO than in WT mice. Our results support the oncogenic effect of Nrf2 in the later stage of carcinogenesis and upregulation of tumor suppressor 15-PGDH might contribute to the repression of colitis-associated tumorigenesis in Nrf2 KO female mice.
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Affiliation(s)
- Chin-Hee Song
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Soo In Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Changhee Kang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Heewon Nho
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Eun Shin
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea
| | - Ha-Na Lee
- Laboratory of Immunology, Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
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30
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Mahesh G, Anil Kumar K, Reddanna P. Overview on the Discovery and Development of Anti-Inflammatory Drugs: Should the Focus Be on Synthesis or Degradation of PGE 2? J Inflamm Res 2021; 14:253-263. [PMID: 33568930 PMCID: PMC7868279 DOI: 10.2147/jir.s278514] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 11/12/2020] [Indexed: 12/13/2022] Open
Abstract
Inflammation is a protective response that develops against tissue injury and infection. Chronic inflammation, on the other hand, is the key player in the pathogenesis of many inflammatory disorders including cancer. The cytokine storm, an inflammatory response flaring out of control, is mostly responsible for the mortality in COVID-19 patients. Anti-inflammatory drugs inhibit cyclooxygenases (COX), which are involved in the biosynthesis of prostaglandins that promote inflammation. The conventional non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastric and renal side-effects, as they inhibit both the constitutive COX-1 and the inducible COX-2. The majority of selective COX-2 inhibitors (COXIBs) are without gastric side-effects but are associated with cardiac side-effects on long-term use. The search for anti-inflammatory drugs without side-effects, therefore, has become a dream and ongoing effort of the Pharma companies. As PGE2 is the key mediator of inflammatory disorders, coming up with a strategy to reduce the levels of PGE2 alone without affecting other metabolites may form a better choice for the development of next generation anti-inflammatory drugs. In this direction the options being explored are on synthesis of PGE2-mPGES-1; PGE2 degradation through a specific PG dehydrogenase, 15-PGDH, and by blocking its activity mediated through a specific PGE receptor, EP4. As leukotrienes formed via the 5-lipoxygenase (5-LOX) pathway also play an important role in the mediation of inflammation, efforts are also being made to target both COX and LOX pathways. This review focuses on addressing the following three points: 1) How NSAIDs and COXIBs are associated with gastric, renal and cardiac side-effects; 2) Should the focus be on the targets upstream or downstream of PGE2; and 3) the status of alternative targets being explored for the discovery and development of anti-inflammatory drugs without side-effects. ![]()
Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/8Uufep6ipBQ
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Affiliation(s)
- Gopa Mahesh
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Kotha Anil Kumar
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Pallu Reddanna
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
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31
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Nakanishi T, Nakamura Y, Umeno J. Recent advances in studies of SLCO2A1 as a key regulator of the delivery of prostaglandins to their sites of action. Pharmacol Ther 2021; 223:107803. [PMID: 33465398 DOI: 10.1016/j.pharmthera.2021.107803] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 12/18/2020] [Indexed: 02/08/2023]
Abstract
Solute carrier organic anion transporter family member 2A1 (SLCO2A1, also known as PGT, OATP2A1, PHOAR2, or SLC21A2) is a plasma membrane transporter consisting of 12 transmembrane domains. It is ubiquitously expressed in tissues, and mediates the membrane transport of prostaglandins (PGs, mainly PGE2, PGF2α, PGD2) and thromboxanes (e.g., TxB2). SLCO2A1-mediated transport is electrogenic and is facilitated by an outwardly directed gradient of lactate. PGs imported by SLCO2A1 are rapidly oxidized by cytoplasmic 15-hydroxyprostaglandin dehydrogenase (15-PGDH, encoded by HPGD). Accumulated evidence suggests that SLCO2A1 plays critical roles in many physiological processes in mammals, and it is considered a potential pharmacological target for diabetic foot ulcer treatment, antipyresis, and non-hormonal contraception. Furthermore, whole-exome analyses suggest that recessive inheritance of SLCO2A1 mutations is associated with two refractory diseases, primary hypertrophic osteoarthropathy (PHO) and chronic enteropathy associated with SLCO2A1 (CEAS). Intriguingly, SLCO2A1 is also a key component of the Maxi-Cl channel, which regulates fluxes of inorganic and organic anions, including ATP. Further study of the bimodal function of SLCO2A1 as a transporter and ion channel is expected to throw new light on the complex pathology of human diseases. Here, we review and summarize recent information on the molecular functions of SLCO2A1, and we discuss its pathophysiological significance.
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Affiliation(s)
- Takeo Nakanishi
- Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Gunma 370-0033, Japan.
| | - Yoshinobu Nakamura
- Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Gunma 370-0033, Japan
| | - Junji Umeno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
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Multifaceted Functions of Platelets in Cancer: From Tumorigenesis to Liquid Biopsy Tool and Drug Delivery System. Int J Mol Sci 2020; 21:ijms21249585. [PMID: 33339204 PMCID: PMC7765591 DOI: 10.3390/ijms21249585] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/11/2020] [Accepted: 12/14/2020] [Indexed: 12/13/2022] Open
Abstract
Platelets contribute to several types of cancer through plenty of mechanisms. Upon activation, platelets release many molecules, including growth and angiogenic factors, lipids, and extracellular vesicles, and activate numerous cell types, including vascular and immune cells, fibroblasts, and cancer cells. Hence, platelets are a crucial component of cell-cell communication. In particular, their interaction with cancer cells can enhance their malignancy and facilitate the invasion and colonization of distant organs. These findings suggest the use of antiplatelet agents to restrain cancer development and progression. Another peculiarity of platelets is their capability to uptake proteins and transcripts from the circulation. Thus, cancer-patient platelets show specific proteomic and transcriptomic expression patterns, a phenomenon called tumor-educated platelets (TEP). The transcriptomic/proteomic profile of platelets can provide information for the early detection of cancer and disease monitoring. Platelet ability to interact with tumor cells and transfer their molecular cargo has been exploited to design platelet-mediated drug delivery systems to enhance the efficacy and reduce toxicity often associated with traditional chemotherapy. Platelets are extraordinary cells with many functions whose exploitation will improve cancer diagnosis and treatment.
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Finetti F, Travelli C, Ercoli J, Colombo G, Buoso E, Trabalzini L. Prostaglandin E2 and Cancer: Insight into Tumor Progression and Immunity. BIOLOGY 2020; 9:E434. [PMID: 33271839 PMCID: PMC7760298 DOI: 10.3390/biology9120434] [Citation(s) in RCA: 159] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/27/2020] [Accepted: 11/29/2020] [Indexed: 12/13/2022]
Abstract
The involvement of inflammation in cancer progression has been the subject of research for many years. Inflammatory milieu and immune response are associated with cancer progression and recurrence. In different types of tumors, growth and metastatic phenotype characterized by the epithelial mesenchymal transition (EMT) process, stemness, and angiogenesis, are increasingly associated with intrinsic or extrinsic inflammation. Among the inflammatory mediators, prostaglandin E2 (PGE2) supports epithelial tumor aggressiveness by several mechanisms, including growth promotion, escape from apoptosis, transactivation of tyrosine kinase growth factor receptors, and induction of angiogenesis. Moreover, PGE2 is an important player in the tumor microenvironment, where it suppresses antitumor immunity and regulates tumor immune evasion, leading to increased tumoral progression. In this review, we describe the current knowledge on the pro-tumoral activity of PGE2 focusing on its role in cancer progression and in the regulation of the tumor microenvironment.
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Affiliation(s)
- Federica Finetti
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy;
| | - Cristina Travelli
- Department of Pharmaceutical Sciences, University of Pavia, 27100 Pavia, Italy; (C.T.); (E.B.)
| | - Jasmine Ercoli
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy;
| | - Giorgia Colombo
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy;
| | - Erica Buoso
- Department of Pharmaceutical Sciences, University of Pavia, 27100 Pavia, Italy; (C.T.); (E.B.)
| | - Lorenza Trabalzini
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy;
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Curcumin induces expression of 15-hydroxyprostaglandin dehydrogenase in gastric mucosal cells and mouse stomach in vivo: AP-1 as a potential target. J Nutr Biochem 2020; 85:108469. [DOI: 10.1016/j.jnutbio.2020.108469] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 07/13/2020] [Accepted: 07/13/2020] [Indexed: 02/06/2023]
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17β-Estradiol strongly inhibits azoxymethane/dextran sulfate sodium-induced colorectal cancer development in Nrf2 knockout male mice. Biochem Pharmacol 2020; 182:114279. [PMID: 33068552 DOI: 10.1016/j.bcp.2020.114279] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/18/2020] [Accepted: 10/07/2020] [Indexed: 12/11/2022]
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) has dual effects on inflammation and cancer progression depending on the microenvironment. Estrogens have a protective effect on colorectal cancer (CRC) development. The aim of this study was to investigate CRC development in Nrf2 knockout (KO) mice. Azoxymethane (AOM) and dextran sulfate sodium (DSS)-treated wild-type (WT) and Nrf2 KO male mice were sacrificed at weeks 2 and 16 after AOM injection with/without 17β-estradiol (E2) treatment during week 1. Disease activity index and colon tissue damage at week 2 showed strong attenuation following E2 administration in WT mice but to a lesser extent in Nrf2 KO male mice. At week 16, E2 significantly diminished AOM/DSS-induced adenoma/cancer incidence at distal colon in the Nrf2 KO group, but not in the WT. Furthermore, mRNA or protein levels of NF-κB-related mediators (i.e., iNOS, TNF-α, and IL-1β) and Nrf2-related antioxidants (i.e., NQO1 and HO-1) were significantly lower in the Nrf2 KO group regardless of E2 treatment compared to the WT. The expression of estrogen receptor beta (ERβ) was higher in the Nrf2 KO group than in the WT. In conclusion, estrogen further inhibits CRC by upregulating ERβ-related alternate pathways in the absence of Nrf2.
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Han YM, A Kang E, Min Park J, Young Oh J, Yoon Lee D, Hye Choi S, Baik Hahm K. Dietary intake of fermented kimchi prevented colitis-associated cancer. J Clin Biochem Nutr 2020; 67:263-273. [PMID: 33293767 PMCID: PMC7705092 DOI: 10.3164/jcbn.20-77] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 05/31/2020] [Indexed: 12/12/2022] Open
Abstract
Kimchi is composed of various chemopreventive phytochemicals and profuse probiotics, defining kimchi as probiotic foods. Concerns had increased on the modulation of intestinal microbiota on various kinds of systemic diseases. Under the hypothesis that dietary intake of kimchi can be ideal intervention for either ameliorating colitis or preventing colitic cancer, we performed the study to validate the efficolitic cancery of fermented kimchi on preventing colitic cancer. Using azoxymethane-initiated and dextran sulfate sodium-promoted colitic cancer models, we have administrated fermented or non-fermented kimchi to modulate colitic cancer preemptively. Detailed molecular mechanisms were explored. Preemptive administration of fermented kimchi significantly afforded colitic cancer prevention through attenuating inflammasomes (IL-18, IL-1β, caspase-1), enhancing antioxidative (NQO1, GST-π), imposing anti-proliferative (Bax, caspase-3, β-catenin), and affording cytoprotective actions (HSP70, 15-PGDH), while non-fermented kimchi did not prevent colitic cancer. Special recipe cancer preventive kimchi (cpkimchi) was more effective compared to standard recipe fermented kimchi (p<0.01), while non-fermented kimchi (kimuchi) worsened colitic cancer development, telling the importance of fermentation in cancer prevention. Repression of NF-kB p65, induction of tumor suppressive 15-PGDH, and inactivation of ERK1/2 by cpkimchi contributed to colitic cancer prevention. Dietary intake of cpkimchi ameliorated colitis and prevented colitic cancer via concerted anti-inflammatory, antioxidative, and anti-mutagenic actions.
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Affiliation(s)
- Young-Min Han
- Western Seoul Center, Korea Basic Science Institute, University-Industry Cooperate Building, 150 Bugahyeon-ro, Seodaemun-gu, Seoul, 03759, Korea
| | - Eun A Kang
- CHA Cancer Preventive Research Center, CHA Bio Complex, 330 Pangyo-dong, Bundang-gu, Seongnam, 13497, Korea
| | - Jong Min Park
- CHA Cancer Preventive Research Center, CHA Bio Complex, 330 Pangyo-dong, Bundang-gu, Seongnam, 13497, Korea
| | - Ji Young Oh
- CJ Food Research Center, CJ Blossome Park, Gwangyo-ro, Yeongtong-gu, Suwon, 16495, Korea
| | - Dong Yoon Lee
- CJ Food Research Center, CJ Blossome Park, Gwangyo-ro, Yeongtong-gu, Suwon, 16495, Korea
| | - Seung Hye Choi
- CJ Food Research Center, CJ Blossome Park, Gwangyo-ro, Yeongtong-gu, Suwon, 16495, Korea
| | - Ki Baik Hahm
- CHA Cancer Preventive Research Center, CHA Bio Complex, 330 Pangyo-dong, Bundang-gu, Seongnam, 13497, Korea.,Medpacto Research Institute, Medpacto Inc., 92, Myeongdal-ro, Seocho-gu, Seoul, Korea
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Saberinia A, Alinezhad A, Jafari F, Soltany S, Akhavan Sigari R. Oncogenic miRNAs and target therapies in colorectal cancer. Clin Chim Acta 2020; 508:77-91. [DOI: 10.1016/j.cca.2020.05.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 12/18/2022]
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Tumour suppressor 15-hydroxyprostaglandin dehydrogenase induces differentiation in colon cancer via GLI1 inhibition. Oncogenesis 2020; 9:74. [PMID: 32814764 PMCID: PMC7438320 DOI: 10.1038/s41389-020-00256-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 07/14/2020] [Accepted: 07/29/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammation is an established risk factor for colorectal cancer. We and others have shown that colorectal cancer patients with elevated cysteinyl leukotriene receptor 2 (CysLT2R) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) levels exhibit good prognoses. However, both CysLT2R and 15-PGDH, which act as tumour suppressors, are often suppressed in colorectal cancer. We previously reported that leukotriene C4 (LTC4)-induced differentiation in colon cancer via CysLT2R signalling. Here, we investigated the involvement of Hedgehog (Hh)-GLI1 signalling, which is often hyperactivated in colorectal cancer. We found that the majority of colorectal cancer patients had high-GLI1 expression, which was negatively correlated with CysLT2R, 15-PGDH, and Mucin-2 and overall survival compared with the low-GLI1 group. LTC4-induced 15-PGDH downregulated both the mRNA and protein expression of GLI1 in a protein kinase A (PKA)-dependent manner. Interestingly, the LTC4-induced increase in differentiation markers and reduction in Wnt targets remained unaltered in GLI1-knockdown cells. The restoration of GLI1 in 15-PGDH-knockdown cells did not ameliorate the LTC4-induced effects, indicating the importance of both 15-PGDH and GLI1. LTC4-mediated reduction in the DCLK1 and LGR5 stemness markers in colonospheres was abolished in cells lacking 15-PGDH or GLI1. Both DCLK1 and LGR5 were highly increased in tumour tissue compared with the matched controls. Reduced Mucin-2 levels were observed both in zebrafish xenografts with GLI1-knockdown cells and in the cysltr2-/- colitis-associated colon cancer (CAC) mouse model. Furthermore, GLI1 expression was positively correlated with stemness and negatively correlated with differentiation in CRC patients when comparing tumour and mucosal tissues. In conclusion, restoring 15-PGDH expression via CysLT2R activation might benefit colorectal cancer patients.
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Dietary n-6 and n-3 PUFA alter the free oxylipin profile differently in male and female rat hearts. Br J Nutr 2020; 122:252-261. [PMID: 31405389 DOI: 10.1017/s0007114519001211] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Oxylipins are bioactive lipid mediators synthesised from PUFA. The most well-known oxylipins are the eicosanoids derived from arachidonic acid (ARA), and many of them influence cardiac physiology in health and disease. Oxylipins are also formed from other n-3 and n-6 PUFA such as α-linolenic acid (ALA), EPA, DHA and linoleic acid (LA), but fundamental data on the heart oxylipin profile, and the effect of diet and sex on this profile, are lacking. Therefore, weanling female and male Sprague-Dawley rats were given American Institute of Nutrition (AIN)-93G-based diets modified in oil composition to provide higher levels of ALA, EPA, DHA, LA and LA + ALA, compared with control diets. After 6 weeks, free oxylipins in rat hearts were increased primarily by their precursor PUFA, except for EPA oxylipins, which were increased not only by dietary EPA but also by dietary ALA or DHA. Dietary DHA had a greater effect than ALA or EPA on reducing ARA oxylipins. An exception to the dietary n-3 PUFA-lowering effects on ARA oxylipins was observed for several ARA-derived PG metabolites that were higher in rats given EPA diets. Higher dietary LA increased LA oxylipins, but it had no effect on ARA oxylipins. Overall, heart oxylipins were higher in female rats, but this depended on dietary treatment: the female oxylipin:male oxylipin ratio was higher in rats provided the ALA compared with the DHA diet, with other diet groups having ratios in between. In conclusion, individual PUFA and sex have unique and interactive effects on the rat heart free oxylipin profile.
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40
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Hidalgo-Estévez AM, Stamatakis K, Jiménez-Martínez M, López-Pérez R, Fresno M. Cyclooxygenase 2-Regulated Genes an Alternative Avenue to the Development of New Therapeutic Drugs for Colorectal Cancer. Front Pharmacol 2020; 11:533. [PMID: 32410997 PMCID: PMC7201075 DOI: 10.3389/fphar.2020.00533] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Accepted: 04/06/2020] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common and recurrent types of cancer, with high mortality rates. Several clinical trials and meta-analyses have determined that the use of pharmacological inhibitors of cyclooxygenase 2 (COX-2), the enzyme that catalyses the rate-limiting step in the synthesis of prostaglandins (PG) from arachidonic acid, can reduce the incidence of CRC as well as the risk of recurrence of this disease, when used together with commonly used chemotherapeutic agents. These observations suggest that inhibition of COX-2 may be useful in the treatment of CRC, although the current drugs targeting COX-2 are not widely used since they increase the risk of health complications. To overcome this difficulty, a possibility is to identify genes regulated by COX-2 activity that could give an advantage to the cells to form tumors and/or metastasize. The modulation of those genes as effectors of COX-2 may cancel the beneficial effects of COX-2 in tumor transformation and metastasis. A review of the available databases and literature and our own data have identified some interesting molecules induced by prostaglandins or COX-2 that have been also described to play a role in colon cancer, being thus potential pharmacological targets in colon cancer. Among those mPGES-1, DUSP4, and 10, Programmed cell death 4, Trop2, and many from the TGFβ and p53 pathways have been identified as genes upregulated in response to COX-2 overexpression or PGs in colon carcinoma lines and overexpressed in colon tumor tissue. Here, we review the available evidence of the potential roles of those molecules in colon cancer in the context of PG/COX signaling pathways that could be critical mediators of some of the tumor growth and metastasis advantage induced by COX-2. At the end, this may allow defining new therapeutic targets/drugs against CRC that could act specifically against tumor cells and would be effective in the prevention and treatment of CRC, lacking the unwanted side effects of COX-2 pharmacological inhibitors, providing alternative approaches in colon cancer.
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Affiliation(s)
| | - Konstantinos Stamatakis
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.,Instituto Sanitario de Investigación Princesa, Madrid, Spain
| | - Marta Jiménez-Martínez
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
| | - Ricardo López-Pérez
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
| | - Manuel Fresno
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.,Instituto Sanitario de Investigación Princesa, Madrid, Spain
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41
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Wang Y, Ma S, Ruzzo WL. Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities. Sci Rep 2020; 10:3490. [PMID: 32103057 PMCID: PMC7044328 DOI: 10.1038/s41598-020-60384-w] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 02/11/2020] [Indexed: 01/24/2023] Open
Abstract
Spatial heterogeneity is a fundamental feature of the tumor microenvironment (TME), and tackling spatial heterogeneity in neoplastic metabolic aberrations is critical for tumor treatment. Genome-scale metabolic network models have been used successfully to simulate cancer metabolic networks. However, most models use bulk gene expression data of entire tumor biopsies, ignoring spatial heterogeneity in the TME. To account for spatial heterogeneity, we performed spatially-resolved metabolic network modeling of the prostate cancer microenvironment. We discovered novel malignant-cell-specific metabolic vulnerabilities targetable by small molecule compounds. We predicted that inhibiting the fatty acid desaturase SCD1 may selectively kill cancer cells based on our discovery of spatial separation of fatty acid synthesis and desaturation. We also uncovered higher prostaglandin metabolic gene expression in the tumor, relative to the surrounding tissue. Therefore, we predicted that inhibiting the prostaglandin transporter SLCO2A1 may selectively kill cancer cells. Importantly, SCD1 and SLCO2A1 have been previously shown to be potently and selectively inhibited by compounds such as CAY10566 and suramin, respectively. We also uncovered cancer-selective metabolic liabilities in central carbon, amino acid, and lipid metabolism. Our novel cancer-specific predictions provide new opportunities to develop selective drug targets for prostate cancer and other cancers where spatial transcriptomics datasets are available.
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Affiliation(s)
- Yuliang Wang
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, 98109, USA.
- Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA, 98195, USA.
| | - Shuyi Ma
- Department of Microbiology, University of Washington, Seattle, WA, 98195, USA
| | - Walter L Ruzzo
- Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA, 98195, USA
- Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA
- Fred Hutchinson Cancer Research Center, Seattle, WA, 98102, USA
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42
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Dayama G, Priya S, Niccum DE, Khoruts A, Blekhman R. Interactions between the gut microbiome and host gene regulation in cystic fibrosis. Genome Med 2020; 12:12. [PMID: 31992345 PMCID: PMC6988342 DOI: 10.1186/s13073-020-0710-2] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 01/05/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cystic fibrosis is the most common autosomal recessive genetic disease in Caucasians. It is caused by mutations in the CFTR gene, leading to poor hydration of mucus and impairment of the respiratory, digestive, and reproductive organ functions. Advancements in medical care have led to markedly increased longevity of patients with cystic fibrosis, but new complications have emerged, such as early onset of colorectal cancer. Although the pathogenesis of colorectal cancer in cystic fibrosis remains unclear, altered host-microbe interactions might play a critical role. To investigate this, we characterized changes in the microbiome and host gene expression in the colonic mucosa of cystic fibrosis patients relative to healthy controls, and identified host gene-microbiome interactions in the colon of cystic fibrosis patients. METHODS We performed RNA-seq on colonic mucosa samples from cystic fibrosis patients and healthy controls to determine differentially expressed host genes. We also performed 16S rRNA sequencing to characterize the colonic mucosal microbiome and identify gut microbes that are differentially abundant between patients and healthy controls. Lastly, we modeled associations between relative abundances of specific bacterial taxa in the gut mucosa and host gene expression. RESULTS We find that 1543 genes, including CFTR, show differential expression in the colon of cystic fibrosis patients compared to healthy controls. These genes are enriched with functions related to gastrointestinal and colorectal cancer, such as metastasis of colorectal cancer, tumor suppression, p53, and mTOR signaling pathways. In addition, patients with cystic fibrosis show decreased gut microbial diversity, decreased abundance of butyrate producing bacteria, such as Ruminococcaceae and Butyricimonas, and increased abundance of other taxa, such as Actinobacteria and Clostridium. An integrative analysis identified colorectal cancer-related genes, including LCN2 and DUOX2, for which gene expression is correlated with the abundance of colorectal cancer-associated bacteria, such as Ruminococcaceae and Veillonella. CONCLUSIONS In addition to characterizing host gene expression and mucosal microbiome in cystic fibrosis patients, our study explored the potential role of host-microbe interactions in the etiology of colorectal cancer in cystic fibrosis. Our results provide biomarkers that may potentially serve as targets for stratifying risk of colorectal cancer in patients with cystic fibrosis.
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Affiliation(s)
- Gargi Dayama
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA
| | - Sambhawa Priya
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA
| | - David E Niccum
- Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Alexander Khoruts
- Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
- Center for Immunology, BioTechnology Institute, University of Minnesota, Minneapolis, MN, USA.
| | - Ran Blekhman
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA.
- Department of Ecology, Evolution, and Behavior, University of Minnesota, Minneapolis, MN, USA.
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RNA Sequencing revealed differentially expressed genes functionally associated with immunity and tumor suppression during latent phase infection of a vv + MDV in chickens. Sci Rep 2019; 9:14182. [PMID: 31578366 PMCID: PMC6775254 DOI: 10.1038/s41598-019-50561-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Accepted: 09/11/2019] [Indexed: 11/08/2022] Open
Abstract
Very virulent plus Marek's disease (MD) virus (vv + MDV) induces tumors in relatively resistant lines of chickens and early mortality in highly susceptible lines of chickens. The vv + MDV also triggers a series of cellular responses in both types of chickens. We challenged birds sampled from a highly inbred chicken line (line 63) that is relatively resistant to MD and from another inbred line (line 72) that is highly susceptible to MD with a vv + MDV. RNA-sequencing analysis was performed with samples extracted from spleen tissues taken at 10-day and 21-day post infection (dpi). A total of 64 and 106 differentially expressed genes was identified in response to the vv + MDV challenge at latent phase in the resistant and susceptible lines of chickens, respectively. Direct comparisons between samples of the two lines identified 90 and 126 differentially expressed genes for control and MDV challenged groups, respectively. The differentially expressed gene profiles illustrated that intensive defense responses were significantly induced by vv + MDV at 10 dpi and 21 dpi but with slight changes in the resistant line. In contrast, vv + MDV induced a measurable suppression of gene expression associated with host defense at 10 dpi but followed by an apparent activation of the defense response at 21 dpi in the susceptible line of chickens. The observed difference in gene expression between the two genetic lines of chickens in response to MDV challenge during the latent phase provided a piece of indirect evidence that time points for MDV reactivation differ between the genetic lines of chickens with different levels of genetic resistance to MD. Early MDV reactivation might be necessary and potent to host defense system readiness for damage control of tumorigenesis and disease progression, which consequently results in measurable differences in phenotypic characteristics including early mortality (8 to 20 dpi) and tumor incidence between the resistant and susceptible lines of chickens. Combining differential gene expression patterns with reported GO function terms and quantitative trait loci, a total of 27 top genes was selected as highly promising candidate genes for genetic resistance to MD. These genes are functionally involved with virus process (F13A1 and HSP90AB1), immunity (ABCB1LB, RGS5, C10ORF58, OSF-2, MMP7, CXCL12, GAL1, GAL2, GAL7, HVCN1, PDE4D, IL4I1, PARP9, EOMES, MPEG1, PDK4, CCLI10, K60 and FST), and tumor suppression (ADAMTS2, LXN, ARRDC3, WNT7A, CLDN1 and HPGD). It is anticipated that these findings will facilitate advancement in the fundamental understanding on mechanisms of genetic resistance to MD. In addition, such advancement may also provide insights on tumor virus-induced tumorigenesis in general and help the research community recognize MD study may serve as a good model for oncology study involving tumor viruses.
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Park JM, Na HK. 15-Deoxy-Δ 12,14-prostaglandin J 2 Upregulates the Expression of 15-Hydroxyprostaglandin Dehydrogenase by Inducing AP-1 Activation and Heme Oxygenase-1 Expression in Human Colon Cancer Cells. J Cancer Prev 2019; 24:183-191. [PMID: 31624724 PMCID: PMC6786809 DOI: 10.15430/jcp.2019.24.3.183] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 09/25/2019] [Accepted: 09/25/2019] [Indexed: 12/19/2022] Open
Abstract
Background Abnormal upregulation of prostaglandin E2 (PGE2) is considered to be a key oncogenic event in the development and progression of inflammation-associated human colon cancer. It has been reported that 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme catabolizing PGE2, is ubiquitously downregulated in human colon cancer. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a peroxisome proliferator-activated receptor γ ligand, has been shown to have anticarcinogenic activities. In this study, we investigate the effect of 15d-PGJ2 on expression of 15-PGDH in human colon cancer HCT116 cells. Methods HCT116 cells were treated with 15d-PGJ2 analysis. The expression of 15-PGDH in the treated cells was measured by Western blot analysis and RT-PCR. In addition, the cells were subjected to a 15-PGDH activity assay. To determine which transcription factor(s) and signaling pathway(s) are involved in 15d-PGJ2-induced 15-PGDH expression, we performed a cDNA microarray analysis of 15d-PGJ2-treated cells. The DNA binding activity of AP-1 was measured by an electrophoretic mobility shift assay. To determine whether the AP-1 plays an important role in the 15d-PGJ2-induced 15-PGDH expression, the cells were transfected with siRNA of c-Jun, a major subunit of AP-1. To elucidate the upstream signaling pathways involved in AP-1 activation by 15d-PGJ2, we examined its effect on phosphorylation of Akt by Western blot analysis in the presence or absence of kinase inhibitor. Results 15d-PGJ2 (10 μM) significantly upregulated 15-PGDH expression at the mRNA and protein levels in HCT-116 cells. 15-PGDH activity was also elevated by 15d-PGJ2. We observed that genes encoding C/EBP delta, FOS-like antigen 1, c-Jun, and heme oxygenase-1 (HO-1) were most highly induced in the HCT116 cells following 15d-PGJ2 treatment. 15d-PGJ2 increased the DNA binding activity of AP-1. Moreover, transfection with specific siRNA against c-Jun significantly reduced 15-PGDH expression induced by 15d-PGJ2. 15d-PGJ2 activates Akt and a pharmacological inhibitor of Akt, LY294002, abrogated 15d-PGJ2-induced 15-PGDH expression. We also observed that an inhibitor of HO-1, zinc protoporphyrin IX, also abrogated upregulation of 15-PGDH and down-regulation of cyclooxygenase-2 expression induced by 15d-PGJ2. Conclusions These finding suggest that 15d-PGJ2 upregulates the expression of 15-PGDH through AP-1 activation in colon cancer HCT116 cells.
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Affiliation(s)
- Jong-Min Park
- Department of Pharmacology, College of Korean Medicine, Daejeon University, Daejeon, Korea
| | - Hye-Kyung Na
- Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering, Sungshin Women's University, Seoul, Korea
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Sun H, Li H. Concordant expression pattern across multiple immune tissues of commercial broilers in response to avian pathogenic Escherichia coli (APEC). 3 Biotech 2019; 9:320. [PMID: 31406642 DOI: 10.1007/s13205-019-1851-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 07/29/2019] [Indexed: 11/29/2022] Open
Abstract
In this study, RNA-seq gene expression data were obtained for three different immune tissues (bone marrow, thymus, and bursa) at two time points from birds with three phenotypes (non-infected, resistant, and susceptible birds). A total of 380 significant differentially expressed genes (DEGs) were commonly expressed in each of the three tissues in the contrast of susceptible vs. non-infected birds at 5 days post-infection (dpi) and 106 significant DEGs were shared in susceptible vs. resistant birds at 5 dpi. For the co-expressed DEGs, a relatively high consistency in expression pattern was identified in the three tissues for the two contrasts. These co-expressed DEGs were involved in the biological process of response to stimulus, regulation of cell proliferation, signal transduction, and immune system. Moreover, three gene networks were identified for the co-expressed DEGs, showing the activation of the humoral immune response, cell survival, growth and death were the concordant response for the three lymphocyte tissues. Several potential biomarker genes, HPGD, PROX1, FOSL2, E2F1, and ANP32A were found, which may have critical functions in resistant birds to resist APEC infection. Taken together, this study provides a novel insight that may elucidate the molecular mechanisms underlying host response to systemic APEC infection, as well as enhances the probability of advancement in biomedical research.
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Affiliation(s)
- Hongyan Sun
- 1College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009 Jiangsu China
| | - Huan Li
- FAMSUN Co., Ltd., National Feed Processing Equipment Engineering Technology Research Center, Yangzhou, China
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Rao MC. Physiology of Electrolyte Transport in the Gut: Implications for Disease. Compr Physiol 2019; 9:947-1023. [PMID: 31187895 DOI: 10.1002/cphy.c180011] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We now have an increased understanding of the genetics, cell biology, and physiology of electrolyte transport processes in the mammalian intestine, due to the availability of sophisticated methodologies ranging from genome wide association studies to CRISPR-CAS technology, stem cell-derived organoids, 3D microscopy, electron cryomicroscopy, single cell RNA sequencing, transgenic methodologies, and tools to manipulate cellular processes at a molecular level. This knowledge has simultaneously underscored the complexity of biological systems and the interdependence of multiple regulatory systems. In addition to the plethora of mammalian neurohumoral factors and their cross talk, advances in pyrosequencing and metagenomic analyses have highlighted the relevance of the microbiome to intestinal regulation. This article provides an overview of our current understanding of electrolyte transport processes in the small and large intestine, their regulation in health and how dysregulation at multiple levels can result in disease. Intestinal electrolyte transport is a balance of ion secretory and ion absorptive processes, all exquisitely dependent on the basolateral Na+ /K+ ATPase; when this balance goes awry, it can result in diarrhea or in constipation. The key transporters involved in secretion are the apical membrane Cl- channels and the basolateral Na+ -K+ -2Cl- cotransporter, NKCC1 and K+ channels. Absorption chiefly involves apical membrane Na+ /H+ exchangers and Cl- /HCO3 - exchangers in the small intestine and proximal colon and Na+ channels in the distal colon. Key examples of our current understanding of infectious, inflammatory, and genetic diarrheal diseases and of constipation are provided. © 2019 American Physiological Society. Compr Physiol 9:947-1023, 2019.
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Affiliation(s)
- Mrinalini C Rao
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA
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Schmidleithner L, Thabet Y, Schönfeld E, Köhne M, Sommer D, Abdullah Z, Sadlon T, Osei-Sarpong C, Subbaramaiah K, Copperi F, Haendler K, Varga T, Schanz O, Bourry S, Bassler K, Krebs W, Peters AE, Baumgart AK, Schneeweiss M, Klee K, Schmidt SV, Nüssing S, Sander J, Ohkura N, Waha A, Sparwasser T, Wunderlich FT, Förster I, Ulas T, Weighardt H, Sakaguchi S, Pfeifer A, Blüher M, Dannenberg AJ, Ferreirós N, Muglia LJ, Wickenhauser C, Barry SC, Schultze JL, Beyer M. Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction. Immunity 2019; 50:1232-1248.e14. [PMID: 31027998 DOI: 10.1016/j.immuni.2019.03.014] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 12/20/2018] [Accepted: 03/15/2019] [Indexed: 01/01/2023]
Abstract
Regulatory T cells (Treg cells) are important for preventing autoimmunity and maintaining tissue homeostasis, but whether Treg cells can adopt tissue- or immune-context-specific suppressive mechanisms is unclear. Here, we found that the enzyme hydroxyprostaglandin dehydrogenase (HPGD), which catabolizes prostaglandin E2 (PGE2) into the metabolite 15-keto PGE2, was highly expressed in Treg cells, particularly those in visceral adipose tissue (VAT). Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ)-induced HPGD expression in VAT Treg cells, and consequential Treg-cell-mediated generation of 15-keto PGE2 suppressed conventional T cell activation and proliferation. Conditional deletion of Hpgd in mouse Treg cells resulted in the accumulation of functionally impaired Treg cells specifically in VAT, causing local inflammation and systemic insulin resistance. Consistent with this mechanism, humans with type 2 diabetes showed decreased HPGD expression in Treg cells. These data indicate that HPGD-mediated suppression is a tissue- and context-dependent suppressive mechanism used by Treg cells to maintain adipose tissue homeostasis.
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Affiliation(s)
- Lisa Schmidleithner
- Molecular Immunology in Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127 Bonn, Germany; LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Yasser Thabet
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Eva Schönfeld
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Maren Köhne
- Molecular Immunology in Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127 Bonn, Germany; LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Daniel Sommer
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Zeinab Abdullah
- Institute of Experimental Immunology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
| | - Timothy Sadlon
- Molecular Immunology, Robinson Research Institute, University of Adelaide, Norwich Centre, 55 King William St, North Adelaide, SA 5006, Australia
| | - Collins Osei-Sarpong
- Molecular Immunology in Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127 Bonn, Germany; LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Kotha Subbaramaiah
- Department of Medicine, Weill Cornell Medical College, 525 E. 68(th) Street, New York, NY 10065, USA
| | - Francesca Copperi
- Institute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, Germany
| | - Kristian Haendler
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany; PRECISE, Platform for Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases and the University of Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany
| | - Tamas Varga
- Molecular Immunology in Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127 Bonn, Germany
| | - Oliver Schanz
- LIMES-Institute, Immunology & Environment, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Svenja Bourry
- Molecular Immunology in Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127 Bonn, Germany
| | - Kevin Bassler
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Wolfgang Krebs
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Annika E Peters
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany; Institute of Experimental Immunology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
| | - Ann-Kathrin Baumgart
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany; Institute of Experimental Immunology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
| | - Maria Schneeweiss
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Kathrin Klee
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Susanne V Schmidt
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Simone Nüssing
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Jil Sander
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Naganari Ohkura
- Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Andreas Waha
- Department of Neuropathology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
| | - Tim Sparwasser
- Institute for Medical Microbiology and Hygiene (IMMH), Johannes Gutenberg-University Mainz, Obere Zahlbacherstr. 67, 55131 Mainz, Germany
| | - F Thomas Wunderlich
- Max Planck Institute for Metabolism Research, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), Gleueler Str. 50, 50931 Cologne, Germany
| | - Irmgard Förster
- LIMES-Institute, Immunology & Environment, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Thomas Ulas
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Heike Weighardt
- LIMES-Institute, Immunology & Environment, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany
| | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Alexander Pfeifer
- Institute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, Germany
| | - Matthias Blüher
- Department of Medicine, University of Leipzig, Liebigstraße 20, 04103 Leipzig, Germany
| | - Andrew J Dannenberg
- Department of Medicine, Weill Cornell Medical College, 525 E. 68(th) Street, New York, NY 10065, USA
| | - Nerea Ferreirós
- Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany
| | - Louis J Muglia
- Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Claudia Wickenhauser
- Institute for Pathology, Martin-Luther University Halle - Wittenberg, Magdeburger Str. 14, 06112 Halle (Saale), Germany
| | - Simon C Barry
- Molecular Immunology, Robinson Research Institute, University of Adelaide, Norwich Centre, 55 King William St, North Adelaide, SA 5006, Australia
| | - Joachim L Schultze
- LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany; PRECISE, Platform for Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases and the University of Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany
| | - Marc Beyer
- Molecular Immunology in Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127 Bonn, Germany; LIMES-Institute, Laboratory for Genomics and Immunoregulation, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany; PRECISE, Platform for Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases and the University of Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany.
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Monteleone NJ, Moore AE, Iacona JR, Lutz CS, Dixon DA. miR-21-mediated regulation of 15-hydroxyprostaglandin dehydrogenase in colon cancer. Sci Rep 2019; 9:5405. [PMID: 30931980 PMCID: PMC6443653 DOI: 10.1038/s41598-019-41862-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 03/19/2019] [Indexed: 02/06/2023] Open
Abstract
Elevated prostaglandin E2 (PGE2) levels are observed in colorectal cancer (CRC) patients, and this increase is associated with poor prognosis. Increased synthesis of PGE2 in CRC has been shown to occur through COX-2-dependent mechanisms; however, loss of the PGE2-catabolizing enzyme, 15-hydroxyprostaglandin dehydrogenase (15-PGDH, HPGD), in colonic tumors contributes to increased prostaglandin levels and poor patient survival. While loss of 15-PGDH can occur through transcriptional mechanisms, we demonstrate that 15-PGDH can be additionally regulated by a miRNA-mediated mechanism. We show that 15-PGDH and miR-21 are inversely correlated in CRC patients, with increased miR-21 levels associating with low 15-PGDH expression. 15-PGDH can be directly regulated by miR-21 through distinct sites in its 3′ untranslated region (3′UTR), and miR-21 expression in CRC cells attenuates 15-PGDH and promotes increased PGE2 levels. Additionally, epithelial growth factor (EGF) signaling suppresses 15-PGDH expression while simultaneously enhancing miR-21 levels. miR-21 inhibition represses CRC cell proliferation, which is enhanced with EGF receptor (EGFR) inhibition. These findings present a novel regulatory mechanism of 15-PGDH by miR-21, and how dysregulated expression of miR-21 may contribute to loss of 15-PGDH expression and promote CRC progression via increased accumulation of PGE2.
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Affiliation(s)
- Nicholas J Monteleone
- Department of Microbiology, Biochemistry, & Molecular Genetics, Rutgers University - School of Graduate Studies, Newark, NJ, 07103, USA
| | | | - Joseph R Iacona
- Department of Microbiology, Biochemistry, & Molecular Genetics, Rutgers University - School of Graduate Studies, Newark, NJ, 07103, USA
| | - Carol S Lutz
- Department of Microbiology, Biochemistry, & Molecular Genetics, Rutgers University - School of Graduate Studies, Newark, NJ, 07103, USA.
| | - Dan A Dixon
- University of Kansas Cancer Center, Kansas City, KS, 66160, USA. .,Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66045, USA.
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Lee EJ, Kim SJ, Hahn YI, Yoon HJ, Han B, Kim K, Lee S, Kim KP, Suh YG, Na HK, Surh YJ. 15-Keto prostaglandin E 2 suppresses STAT3 signaling and inhibits breast cancer cell growth and progression. Redox Biol 2019; 23:101175. [PMID: 31129031 PMCID: PMC6859578 DOI: 10.1016/j.redox.2019.101175] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 03/19/2019] [Accepted: 03/20/2019] [Indexed: 12/20/2022] Open
Abstract
Overproduction of prostaglandin E2 (PGE2) has been linked to enhanced tumor cell proliferation, invasiveness and metastasis as well as resistance to apoptosis. 15-Keto prostaglandin E2 (15-keto PGE2), a product formed from 15-hydroxyprostaglandin dehydrogenase-catalyzed oxidation of PGE2, has recently been shown to have anti-inflammatory and anticarcinogenic activities. In this study, we observed that 15-keto PGE2 suppressed the phosphorylation, dimerization and nuclear translocation of signal transducer and activator of transcription 3 (STAT3) in human mammary epithelial cells transfected with H-ras (MCF10A-ras). 15-Keto PGE2 inhibited the migration and clonogenicity of MCF10A-ras cells. In addition, subcutaneous injection of 15-keto PGE2 attenuated xenograft tumor growth and phosphorylation of STAT3 induced by breast cancer MDA-MB-231 cells. However, a non-electrophilic analogue, 13,14-dihydro-15-keto PGE2 failed to inhibit STAT3 signaling and was unable to suppress the growth and transformation of MCF10A-ras cells. These findings suggest that the α,β-unsaturated carbonyl moiety of 15-keto PGE2 is essential for its suppression of STAT3 signaling. We observed that the thiol reducing agent, dithiothreitol abrogated 15-keto PGE2-induced STAT3 inactivation and disrupted the direct interaction between 15-keto PGE2 and STAT3. Furthermore, a molecular docking analysis suggested that Cys251 and Cys259 residues of STAT3 could be preferential binding sites for this lipid mediator. Mass spectral analysis revealed the covalent modification of recombinant STAT3 by 15-keto PGE2 at Cys259. Taken together, thiol modification of STAT3 by 15-keto PGE2 inactivates STAT3 which may account for its suppression of breast cancer cell proliferation and progression.
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Affiliation(s)
- Eun Ji Lee
- Department of Molecular Medicine and Biopharmaceutical Science, Seoul National University, Seoul 08826, South Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, South Korea
| | - Su-Jung Kim
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, South Korea
| | - Young-Il Hahn
- Department of Molecular Medicine and Biopharmaceutical Science, Seoul National University, Seoul 08826, South Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, South Korea
| | - Hyo-Jin Yoon
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, South Korea
| | - Bitnara Han
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, South Korea
| | - Kyeojin Kim
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Seungbeom Lee
- College of Pharmacy, CHA University, Gyeonggi-do 11160, South Korea
| | - Kwang Pyo Kim
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, South Korea; Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul 02453, South Korea
| | - Young Ger Suh
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; College of Pharmacy, CHA University, Gyeonggi-do 11160, South Korea
| | - Hye-Kyung Na
- Department of Food Science and Biotechnology, Sungshin Women's University, College of Knowledge-Based Services Engineering, Seoul 01133, South Korea.
| | - Young-Joon Surh
- Department of Molecular Medicine and Biopharmaceutical Science, Seoul National University, Seoul 08826, South Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, South Korea; Cancer Research Institute, Seoul National University, Seoul 03080, South Korea.
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50
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Prieto P, Jaén RI, Calle D, Gómez-Serrano M, Núñez E, Fernández-Velasco M, Martín-Sanz P, Alonso S, Vázquez J, Cerdán S, Peinado MÁ, Boscá L. Interplay between post-translational cyclooxygenase-2 modifications and the metabolic and proteomic profile in a colorectal cancer cohort. World J Gastroenterol 2019; 25:433-446. [PMID: 30700940 PMCID: PMC6350170 DOI: 10.3748/wjg.v25.i4.433] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 12/21/2018] [Accepted: 01/09/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the second most common cause of cancer death worldwide. It is broadly described that cyclooxygenase-2 (COX-2) is mainly overexpressed in CRC but less is known regarding post-translational modifications of this enzyme that may regulate its activity, intracellular localization and stability. Since metabolic and proteomic profile analysis is essential for cancer prognosis and diagnosis, our hypothesis is that the analysis of correlations between these specific parameters and COX-2 state in tumors of a high number of CRC patients could be useful for the understanding of the basis of this cancer in humans. AIM To analyze COX-2 regulation in colorectal cancer and to perform a detailed analysis of their metabolic and proteomic profile. METHODS Biopsies from both healthy and pathological colorectal tissues were taken under informed consent from patients during standard colonoscopy procedure in the University Hospital of Bellvitge (Barcelona, Spain) and Germans Trias i Pujol University Hospital (Campus Can Ruti) (Barcelona, Spain). Western blot analysis was used to determine COX-2 levels. Deglycosylation assays were performed in both cells and tumor samples incubating each sample with peptide N-glycosidase F (PNGase F). Prostaglandin E2 (PGE2) levels were determined using a specific ELISA. 1H high resolution magic angle spinning (HRMAS) analysis was performed using a Bruker AVIII 500 MHz spectrometer and proteomic analysis was performed in a nano-liquid chromatography-tandem mass spectrometer (nano LC-MS/MS) using a QExactive HF orbitrap MS. RESULTS Our data show that COX-2 has a differential expression profile in tumor tissue of CRC patients vs the adjacent non-tumor area, which correspond to a glycosylated and less active state of the protein. This fact was associated to a lesser PGE2 production in tumors. These results were corroborated in vitro performing deglycosylation assays in HT29 cell line where COX-2 protein profile was modified after PNGase F incubation, showing higher PGE2 levels. Moreover, HRMAS analysis indicated that tumor tissue has altered metabolic features vs non-tumor counterparts, presenting increased levels of certain metabolites such as taurine and phosphocholine and lower levels of lactate. In proteomic experiments, we detected an enlarged number of proteins in tumors that are mainly implicated in basic biological functions like mitochondrial activity, DNA/RNA processing, vesicular trafficking, metabolism, cytoskeleton and splicing. CONCLUSION In our colorectal cancer cohort, tumor tissue presents a differential COX-2 expression pattern with lower enzymatic activity that can be related to an altered metabolic and proteomic profile.
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Affiliation(s)
- Patricia Prieto
- Department of Metabolism and Physiopathology of Inflammatory Diseases, Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid 28029, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (Ciber-CV), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain
| | - Rafael I Jaén
- Department of Metabolism and Physiopathology of Inflammatory Diseases, Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid 28029, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (Ciber-CV), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain
| | - Daniel Calle
- Laboratorio de Imagen Médica, Hospital Universitario Gregorio Marañón, Madrid 28007, Spain
| | - María Gómez-Serrano
- Laboratorio de Proteómica Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (Ciber-CV), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain
| | - Estefanía Núñez
- Laboratorio de Proteómica Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (Ciber-CV), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain
| | - María Fernández-Velasco
- Instituto de Investigación Sanitaria del Hospital Universitario la Paz (IdiPaz), Madrid 28046, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (Ciber-CV), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain
| | - Paloma Martín-Sanz
- Department of Metabolism and Physiopathology of Inflammatory Diseases, Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid 28029, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (Ciber-CV), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain
| | - Sergio Alonso
- Programa de Medicina Predictiva y Personalizada del Cáncer (PMPPC), Fundación Instituto de investigación en ciencias de la salud Germans Trias i Pujol, Ctra Can Ruti, Badalona 08916, Spain
| | - Jesús Vázquez
- Laboratorio de Proteómica Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (Ciber-CV), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain
| | - Sebastián Cerdán
- Department of Metabolism and Physiopathology of Inflammatory Diseases, Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid 28029, Spain
| | - Miguel Ángel Peinado
- Programa de Medicina Predictiva y Personalizada del Cáncer (PMPPC), Fundación Instituto de investigación en ciencias de la salud Germans Trias i Pujol, Ctra Can Ruti, Badalona 08916, Spain
| | - Lisardo Boscá
- Department of Metabolism and Physiopathology of Inflammatory Diseases, Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid 28029, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (Ciber-CV), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain
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