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Ko YS, Won JY, Jin H, Nguyen NB, Won Y, Nsanzimana V, Yun SP, Park SW, Kim HJ. ABCG8‑mediated sterol efflux increases cancer cell progression via the LRP6/Wnt/β‑catenin signaling pathway in radiotherapy‑resistant MDA‑MB‑231 triple‑negative breast cancer cells. Int J Mol Med 2025; 55:80. [PMID: 40116083 PMCID: PMC11964413 DOI: 10.3892/ijmm.2025.5521] [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] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 02/03/2025] [Indexed: 03/23/2025] Open
Abstract
Expression levels of ATP‑binding cassette (ABC) transporters are known to be increased in various tumor cells, including in breast cancer, and they are responsible for mediating drug resistance, leading to treatment failure. In the present study, gene expression array analysis revealed that among ABC transporter subtypes, ABC subfamily G member 8 (ABCG8) was one of the most increased in radiotherapy‑resistant triple‑negative breast cancer (RT‑R‑TNBC) cells compared with in TNBC cells. ABCG8 is involved in sterol efflux; however, its role in cancer is not well known. Therefore, the present study investigated the effect of ABCG8 on tumor progression in RT‑R‑TNBC cells. Gene expression profiling was conducted using the QuantiSeq 3' mRNA‑Seq Service, followed by western blotting to confirm protein levels. Loss‑of‑function assays using small interfering RNA (si) transfection were performed to assess the roles of ABCG8 and its regulatory signaling pathways. RT‑R‑MDA‑MB‑231 cells exhibited increased cholesterol levels in both cells and the surrounding media via induction of sterol regulatory element binding protein 1 (mature form) and fatty acid synthase. siABCG8 transfection increased intracellular cholesterol levels but decreased cholesterol levels in the media, indicating an accumulation of cholesterol inside cells. Additionally, RT‑R‑MDA‑MB‑231 cells exhibited increased levels of β‑catenin compared with MDA‑MB‑231 cells, which was significantly reduced by ABCG8 knockdown. Furthermore, ABCG8 knockdown led to cell cycle arrest in the G2/M phase in RT‑R‑MDA‑MB‑231 cells by reducing Polo‑like kinase 1 (PLK1) and Cyclin B1 expression. RT‑R‑MDA‑MB‑231 cells also exhibited increased phosphorylated‑low‑density lipoprotein (LDL) receptor‑related protein 6 (LRP6) levels compared with MDA‑MB‑231 cells, and these were decreased by siABCG8 transfection. LRP6 siRNA transfection decreased β‑catenin, PLK1 and Cyclin B1 expression. In addition, feedback mechanisms such as liver X receptor and inducible degrader of LDL were decreased in RT‑R‑MDA‑MB‑231 cells under normal conditions compared with in MDA‑MB‑231 cells. To the best of our knowledge, the present study was the first to suggest that the cholesterol exported by ABCG8, not inside the cells, may affect cancer progression via the LRP6/Wnt/β‑catenin signaling pathway in RT‑R‑TNBC. The regulation of this pathway may offer a potential therapeutic strategy for the treatment of RT‑R‑TNBC.
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Affiliation(s)
- Young Shin Ko
- Department of Pharmacology, College of Medicine, Institute of Medical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
| | - Ju Yeong Won
- Department of Pharmacology, College of Medicine, Institute of Medical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
| | - Hana Jin
- Department of Pharmacology, College of Medicine, Institute of Medical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
| | - Nam Binh Nguyen
- Department of Pharmacology, College of Medicine, Institute of Medical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
| | - Yaeram Won
- Department of Pharmacology, College of Medicine, Institute of Medical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
| | - Vedaste Nsanzimana
- Department of Pharmacology, College of Medicine, Institute of Medical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
| | - Seung Pil Yun
- Department of Pharmacology, College of Medicine, Institute of Medical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
| | - Sang Won Park
- Department of Pharmacology, College of Medicine, Institute of Medical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
| | - Hye Jung Kim
- Department of Pharmacology, College of Medicine, Institute of Medical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University, Jinju, Gyeongsangnam-do 52727, Republic of Korea
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Nam KY, Kim MS, An J, Min S, Lee JH, Park JS, Huh C, Yun SH, Lee KJ. Human-Centric, Three Dimensional Micro Light-Emitting Diodes for Cosmetic and Medical Phototherapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2416716. [PMID: 39960366 PMCID: PMC11905057 DOI: 10.1002/advs.202416716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/03/2025] [Indexed: 03/14/2025]
Abstract
Phototherapy based on micro light-emitting diodes (µLEDs) has gained enormous attention in the medical field as a patient-friendly therapeutic method due to its advantages of minimal invasiveness, fewer side effects, and versatile device form factors with high stability in biological environment. Effective cosmetic and medical phototherapy depends on deep light penetration, precise irradiation, and simultaneous multi-site stimulation, facilitated by three-dimensional (3D) optoelectronics specifically designed for complex human matters, defined here as 3D µLEDs. This perspective article aims to present the functionalities and strategies of 3D µLEDs for human-centric phototherapy. This study investigates the effectiveness of phototherapy enabled by three key functionalities such as shape morphing, self-adaptation, and multilayered spatiotemporal mapping of 3D µLEDs. Finally, this article provides future insights of 3D µLEDs for human-centric phototherapy applications.
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Affiliation(s)
- Ki Yun Nam
- Department of Materials Science and EngineeringKorea Advanced Institute of Science and Technology (KAIST)291 Daehak‐ro, Yuseong‐guDaejeon34 141Republic of Korea
- School of Electrical EngineeringGraduate School of Semiconductor TechnologyKorea Advanced Institute of Science and Technology (KAIST)291 Daehak‐ro, Yuseong‐guDaejeon34 141Republic of Korea
| | - Min Seo Kim
- Department of Materials Science and EngineeringKorea Advanced Institute of Science and Technology (KAIST)291 Daehak‐ro, Yuseong‐guDaejeon34 141Republic of Korea
| | - Jaehun An
- Department of Materials Science and EngineeringKorea Advanced Institute of Science and Technology (KAIST)291 Daehak‐ro, Yuseong‐guDaejeon34 141Republic of Korea
| | - Seongwook Min
- Department of Materials Science and EngineeringKorea Advanced Institute of Science and Technology (KAIST)291 Daehak‐ro, Yuseong‐guDaejeon34 141Republic of Korea
| | - Jae Hee Lee
- Querrey‐Simpson Institute for BioelectronicsNorthwestern UniversityEvanstonIL60 208USA
| | - Jae Sung Park
- Yonsei Myview Clinic301, Sadang‐ro, Dongjak‐guSeoul0 7008Republic of Korea
| | - Chang‐Hun Huh
- Department of DermatologySeoul National University Bundang Hospital (SNUBH)173–82, Gumi‐ro, Bundang‐guSeongnam13 620Republic of Korea
| | - Seok Hyun Yun
- Harvard Medical School and Wellman Center for PhotomedicineMassachusetts General HospitalBostonMA0 2114USA
| | - Keon Jae Lee
- Department of Materials Science and EngineeringKorea Advanced Institute of Science and Technology (KAIST)291 Daehak‐ro, Yuseong‐guDaejeon34 141Republic of Korea
- School of Electrical EngineeringGraduate School of Semiconductor TechnologyKorea Advanced Institute of Science and Technology (KAIST)291 Daehak‐ro, Yuseong‐guDaejeon34 141Republic of Korea
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Kim YE, Kim M, Kim S, Lee R, Ujihara Y, Marquez-Wilkins EM, Jiang YH, Yang E, Kim H, Lee C, Park C, Kim IH. Endothelial SHANK3 regulates tight junctions in the neonatal mouse blood-brain barrier through β-Catenin signaling. Nat Commun 2025; 16:1407. [PMID: 39915488 PMCID: PMC11802743 DOI: 10.1038/s41467-025-56720-1] [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: 03/06/2024] [Accepted: 01/29/2025] [Indexed: 02/09/2025] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disability condition arising from a combination of genetic and environmental factors. Despite the blood-brain barrier (BBB) serving as a crucial gatekeeper, conveying environmental influences into the brain parenchyma, the contributions of BBB in ASD pathogenesis remain largely uncharted. Here we report that SHANK3, an ASD-risk gene, expresses in the BBB-forming brain endothelial cells (BECs) and regulates tight junctional (TJ) integrity essential for BBB's barrier function. Endothelium-specific Shank3 (eShank3) knockout (KO) neonatal mice exhibit male-specific BBB-hyperpermeability, reduced neuronal excitability, and impaired ultra-sonic communications. Although BBB permeability is restored during adult age, the male mutant mice display reduced neuronal excitability and impaired sociability. Further analysis reveals that the BBB-hyperpermeability is attributed to the β-Catenin imbalance triggered by eShank3-KO. These findings highlight a pathogenic mechanism stemming from the ASD-risk Shank3, emphasizing the significance of neonatal BECs in the BBB as a potential therapeutic target for ASD.
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Affiliation(s)
- Yong-Eun Kim
- Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
- Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Minseong Kim
- Department of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, LA, USA
| | - Sunwhi Kim
- Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
- Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Raham Lee
- Department of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, LA, USA
| | - Yusuke Ujihara
- Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
| | | | - Yong-Hui Jiang
- Department of Genetics, Pediatrics and Neuroscience, Yale University School of Medicine, New Haven, CT, USA
| | - Esther Yang
- Department of Anatomy, College of Medicine, Korea University, Seoul, South Korea
| | - Hyun Kim
- Department of Anatomy, College of Medicine, Korea University, Seoul, South Korea
| | - Changhoon Lee
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Changwon Park
- Department of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, LA, USA.
| | - Il Hwan Kim
- Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA.
- Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN, USA.
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Wu H, Yang ASP, Stelloo S, Roos FJM, te Morsche RHM, Verkerk AH, Luna-Velez MV, Wingens L, de Wilt JHW, Sauerwein RW, Mulder KW, van Heeringen SJ, Verstegen MMA, van der Laan LJW, Marks H, Bártfai R. Multi-omics analysis reveals distinct gene regulatory mechanisms between primary and organoid-derived human hepatocytes. Dis Model Mech 2025; 18:dmm050883. [PMID: 39878507 PMCID: PMC11810045 DOI: 10.1242/dmm.050883] [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: 05/07/2024] [Accepted: 11/25/2024] [Indexed: 01/31/2025] Open
Abstract
Hepatic organoid cultures are a powerful model to study liver development and diseases in vitro. However, hepatocyte-like cells differentiated from these organoids remain immature compared to primary human hepatocytes (PHHs), which are the benchmark in the field. Here, we applied integrative single-cell transcriptome and chromatin accessibility analysis to reveal gene regulatory mechanisms underlying these differences. We found that, in mature human hepatocytes, activator protein 1 (AP-1) factors co-occupy regulatory regions with hepatocyte-specific transcription factors, including HNF4A, suggesting their potential cooperation in governing hepatic gene expression. Comparative analysis identified distinct transcription factor sets that are specifically active in either PHHs or intrahepatic cholangiocyte organoid (ICO)-derived human hepatocytes. ELF3 was one of the factors uniquely expressed in ICO-derived hepatocytes, and its expression negatively correlated with hepatic marker gene expression. Functional analysis further revealed that ELF3 depletion increased the expression of key hepatic markers in ICO-derived hepatocytes. Our integrative analysis provides insights into the transcriptional regulatory networks of PHHs and hepatic organoids, thereby informing future strategies for developing improved hepatic models.
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Affiliation(s)
- Haoyu Wu
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Annie S. P. Yang
- Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen 6500HB, The Netherlands
| | - Suzan Stelloo
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Radboud University, Nijmegen 6525GA, The Netherlands
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Oncode Institute, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Floris J. M. Roos
- Department of Surgery, Erasmus University Medical Center Transplant Institute, University Medical Center Rotterdam,Rotterdam 3000CA, TheNetherlands
| | - René H. M. te Morsche
- Department of Gastroenterology and Hepatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6500HB, The Netherlands
| | - Anne H. Verkerk
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Maria V. Luna-Velez
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Radboud University, Nijmegen 6525GA, The Netherlands
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Oncode Institute, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Laura Wingens
- Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Johannes H. W. de Wilt
- Department of Surgery, Radboud University Medical Center, Nijmegen 6500HB, The Netherlands
| | - Robert W. Sauerwein
- Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen 6500HB, The Netherlands
| | - Klaas W. Mulder
- Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Simon J. van Heeringen
- Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Monique M. A. Verstegen
- Department of Surgery, Erasmus University Medical Center Transplant Institute, University Medical Center Rotterdam,Rotterdam 3000CA, TheNetherlands
| | - Luc J. W. van der Laan
- Department of Surgery, Erasmus University Medical Center Transplant Institute, University Medical Center Rotterdam,Rotterdam 3000CA, TheNetherlands
| | - Hendrik Marks
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Richárd Bártfai
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Radboud University, Nijmegen 6525GA, The Netherlands
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Huang Y, Wen Z, Tao S, Yu Z, Wang X, Li X, Gao L. CLIP170 enhancing FOSL1 expression via attenuating ubiquitin-mediated degradation of β-catenin drives renal cell carcinoma progression. Cell Mol Life Sci 2024; 81:467. [PMID: 39607512 PMCID: PMC11604886 DOI: 10.1007/s00018-024-05504-9] [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: 07/11/2024] [Revised: 10/27/2024] [Accepted: 11/09/2024] [Indexed: 11/29/2024]
Abstract
Protein interactions are fundamental for all cellular metabolic activities. Cytoplasmic linker protein 170 (CLIP170) plays diverse roles in cellular processes and the development of malignant tumors. Renal cell carcinoma (RCC) poses a significant challenge in oncology owing to its invasive nature, metastatic potential, high recurrence rates, and poor prognosis. However, the specific mechanisms and roles of CLIP170 underlying its involvement in RCC progression remain unclear. The findings of this study revealed a significant upregulation of CLIP170 in RCC tumor tissues. Elevated CLIP170 expression correlated positively with advanced clinical and pathological stages and was associated with poor overall survival in RCC patients. Functional assays in vitro demonstrated that elevated CLIP170 levels enhanced RCC cell proliferation, migration and invasion. Mechanistically, 4D-label free proteomics library identified that CLIP170 increased the level of FOSL1 in the Wnt signaling pathway. Immunoprecipitation and molecular docking were performed to unveil that CLIP170 formed a complex with β-catenin, inhibiting β-catenin degradation via the ubiquitin-proteasome pathway. Elevated β-catenin levels within RCC cells played a central role in promoting the transcriptional expression of FOSL1, thereby facilitating RCC cell proliferation and epithelial-mesenchymal transition (EMT) progression. In vivo investigations corroborated these findings, illustrating that CLIP170 regulated β-catenin and FOSL1 expression, driving tumor growth in RCC. This study highlights the crucial role of CLIP170 in promoting FOSL1 expression by preventing β-catenin ubiquitination and degradation, thus promoting RCC tumor progression. It suggests the CLIP170/β-catenin/FOSL1 axis as a potential therapeutic target for RCC treatment.
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Affiliation(s)
- Yuanbin Huang
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, No. 467, Zhongshan Road, Dalian, 116000, China
- School of Stomatology, Dalian Medical University, No. 9 West Section, Lvshun South Road, Dalian, 116044, People's Republic of China
| | - Zhihao Wen
- School of Stomatology, Dalian Medical University, No. 9 West Section, Lvshun South Road, Dalian, 116044, People's Republic of China
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shuyao Tao
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, No. 467, Zhongshan Road, Dalian, 116000, China
| | - Zhenlong Yu
- College of Pharmacy, College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
- Pharmaceutical Research Center, Second Affiliated Hospital, Dalian Medical University, Dalian, 116000, China
| | - Xiaogang Wang
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, No. 467, Zhongshan Road, Dalian, 116000, China
| | - Xiancheng Li
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, No. 467, Zhongshan Road, Dalian, 116000, China.
| | - Lu Gao
- School of Stomatology, Dalian Medical University, No. 9 West Section, Lvshun South Road, Dalian, 116044, People's Republic of China.
- Technology Innovation Center of Immune and Oral Development & Regeneration, Dalian Medical University, Dalian, 116044, China.
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Kanth P, Hazel MW, Schell JC, Rutter J, Yao R, Mills AP, Delker DA. Evaluation of EGFR and COX pathway inhibition in human colon organoids of serrated polyposis and other hereditary cancer syndromes. Fam Cancer 2024; 23:479-489. [PMID: 38609520 PMCID: PMC11512843 DOI: 10.1007/s10689-024-00370-7] [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: 06/14/2023] [Accepted: 03/05/2024] [Indexed: 04/14/2024]
Abstract
Serrated polyposis syndrome (SPS) presents with multiple sessile serrated lesions (SSL) in the large intestine and confers increased colorectal cancer (CRC) risk. However, the etiology of SPS is not known. SSL-derived organoids have not been previously studied but may help provide insights into SPS pathogenesis and identify novel biomarkers and chemopreventive strategies. This study examined effects of EGFR and COX pathway inhibition in organoid cultures derived from uninvolved colon and polyps of SPS patients. We also compared with organoids representing the hereditary gastrointestinal syndromes, Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). Eighteen total organoid colon cultures were generated from uninvolved colon and polyps in SPS, FAP, LS, and non-syndromic screening colonoscopy patients. BRAF and KRAS mutation status was determined for each culture. Erlotinib (EGFR inhibitor) and sulindac (COX inhibitor) were applied individually and in combination. A 44-target gene custom mRNA panel (including WNT and COX pathway genes) and a 798-gene microRNA gene panel were used to quantitate organoid RNA expression by NanoString analysis. Erlotinib treatment significantly decreased levels of mRNAs associated with WNT and MAPK kinase signaling in organoids from uninvolved colon from all four patient categories and from all SSL and adenomatous polyps. Sulindac did not change the mRNA profile in any culture. Our findings suggest that EGFR inhibitors may contribute to the chemopreventive treatment of SSLs. These findings may also facilitate clinical trial design using these agents in SPS patients. Differentially expressed genes identified in our study (MYC, FOSL1, EGR1, IL33, LGR5 and FOXQ1) may be used to identify other new molecular targets for chemoprevention of SSLs.
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Affiliation(s)
- Priyanka Kanth
- MedStar Georgetown University Hospital, Washington, DC, 20007, USA
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, 84132, USA
| | - Mark W Hazel
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, 84132, USA
| | - John C Schell
- Department of Biochemistry, University of Utah, Salt Lake City, UT, 84132, USA
| | - Jared Rutter
- Department of Biochemistry, University of Utah, Salt Lake City, UT, 84132, USA
| | - Ruoxin Yao
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, 84132, USA
| | - Alyssa P Mills
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, 84132, USA
| | - Don A Delker
- Integrative Bioinformatics, National Institutes of Environmental Health Sciences, 111 TW Alexander Drive, Research Triangle Park, NC, 27709, USA.
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Tocci S, Das S, Sayed IM. An Update on Blastocystis: Possible Mechanisms of Blastocystis-Mediated Colorectal Cancer. Microorganisms 2024; 12:1924. [PMID: 39338600 PMCID: PMC11433781 DOI: 10.3390/microorganisms12091924] [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: 08/28/2024] [Revised: 09/15/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Blastocystis is an anaerobic parasite that colonizes the intestinal tract of humans and animals. When it was first discovered, Blastocystis was considered to be a normal flora with beneficial effects on human health, such as maintaining gut hemostasis and improving intestinal barrier integrity. Later, with increasing research on Blastocystis, reports showed that Blastocystis sp. is associated with gastrointestinal disorders, colorectal cancer (CRC), and neurological disorders. The association between Blastocystis sp. and CRC has been confirmed in several countries. Blastocystis sp. can mediate CRC via similar mechanisms to CRC-associated bacteria, including infection-mediated inflammation, increased oxidative stress, induced gut dysbiosis, and damage to intestinal integrity, leading to a leaky gut. IL-8 is the main inflammatory cytokine released from epithelial cells and can promote CRC development. The causal association of Blastocystis sp. with other diseases needs further investigation. In this review, we have provided an update on Blastocystis sp. and summarized the debate about the beneficial and harmful effects of this parasite. We have also highlighted the possible mechanisms of Blastocystis-mediated CRC.
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Affiliation(s)
- Stefania Tocci
- Department of Biomedical & Nutritional Sciences, Zuckerberg College of Health Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA
| | - Soumita Das
- Department of Biomedical & Nutritional Sciences, Zuckerberg College of Health Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA
| | - Ibrahim M Sayed
- Department of Biomedical & Nutritional Sciences, Zuckerberg College of Health Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA
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8
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Landis D, Sutter A, Khemka S, Songtanin B, Nichols J, Nugent K. Metformin as adjuvant treatment in hepatitis C virus infections and associated complications. Am J Med Sci 2024; 368:90-98. [PMID: 38701970 DOI: 10.1016/j.amjms.2024.04.019] [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: 06/11/2023] [Revised: 03/27/2024] [Accepted: 04/29/2024] [Indexed: 05/06/2024]
Abstract
Hepatitis C virus is an important global cause of hepatitis and subsequently cirrhosis and hepatocellular carcinoma. These infections may also cause extrahepatic manifestations, including insulin resistance and type 2 diabetes mellitus. These two complications can potentially reduce sustained virologic responses (SVR) in some drug regimens for this infection. Metformin has important biochemical effects that can limit viral replication in cellular cultures and can improve the response to antiviral drug therapy based on ribavirin and interferon. Clinical studies comparing treatment regimens with interferon, ribavirin, metformin with these regimens without metformin have demonstrated that metformin increases viral clearance, establishes higher rates of SVRs, and increases insulin sensitivity. Metformin also reduces the frequency of hepatocellular carcinoma in patients who have had SVRs. Larger treatment trials are needed to determine metformin's short-term and long-term treatment effects in patients with diabetes using newer antiviral drugs. In particular, if metformin reduces the frequency of cirrhosis and hepatocellular carcinoma, this would significantly reduce the morbidity and mortality associated with this infection.
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Affiliation(s)
- Dylan Landis
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Alex Sutter
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Sachi Khemka
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Busara Songtanin
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Jacob Nichols
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Kenneth Nugent
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States.
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Miao D, Ren J, Jia Y, Jia Y, Li Y, Huang H, Gao R. PAX1 represses canonical Wnt signaling pathway and plays dual roles during endoderm differentiation. Cell Commun Signal 2024; 22:242. [PMID: 38664733 PMCID: PMC11046865 DOI: 10.1186/s12964-024-01629-3] [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: 01/02/2024] [Accepted: 04/21/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND Paired box 1 (PAX1) is a transcription factor and essential for the development of pharyngeal pouches-derived tissues, including thymus. PAX1 mutations are identified in Severe Combined Immunodeficiency (SCID) patients with Otofaciocervical Syndrome Type 2 (OTFCS2). However, despite the critical roles of PAX1 in embryonic development and diseases, detailed insights into its molecular mode of action are critically missing. METHODS The repressing roles of PAX1 and SCID associated mutants on Wnt signaling pathway were investigated by luciferase reporter assays, qRT-PCR and in situ hybridization in HEK293FT, HCT116 cells and zebrafish embryos, respectively. Co-immunoprecipitation (co-IP) and western blotting assays were carried out to identify the molecular mechanisms underlying PAX1's role on Wnt signaling pathway. hESC based endoderm differentiation, flow cytometry, high-throughput sequencing data analysis, and qRT-PCR assays were utilized to determine the roles of PAX1 during endoderm differentiation. RESULTS Here, we show that PAX1 represses canonical Wnt signaling pathway in vertebrate cells. Mechanically, PAX1 competes with SUMO E3 ligase PIASy to bind to TCF7L2, thus perturbing TCF7L2 SUMOylation level, further reducing its transcriptional activity and protein stability. Moreover, we reveal that PAX1 plays dual roles in hESC-derived definitive and foregut/pharyngeal endoderm cells, which give rise to the thymus epithelium, by inhibiting Wnt signaling. Importantly, our data show PAX1 mutations found in SCID patients significantly compromise the suppressing ability of PAX1 on Wnt signaling. CONCLUSIONS Our study presents a novel molecular mode of action of PAX1 in regulation of canonical Wnt signaling and endoderm differentiation, thus providing insights for the molecular basis of PAX1 associated SCID, offering better understanding of the behavior of PAX1 in embryogenesis.
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Affiliation(s)
- Danxiu Miao
- Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital, School of medicine, Xiamen University, Xiamen, 361000, China
- Department of Toxicology, College of Public Health, Harbin Medical University, Harbin, 150000, China
| | - Jie Ren
- Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital, School of medicine, Xiamen University, Xiamen, 361000, China
| | - Yanhan Jia
- Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610000, China
| | - Yihui Jia
- Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital, School of medicine, Xiamen University, Xiamen, 361000, China
| | - Yanshu Li
- Department of Toxicology, College of Public Health, Harbin Medical University, Harbin, 150000, China
- College of Public Health, Shantou University, Shantou, 515063, China
| | - Huizhe Huang
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Rui Gao
- Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital, School of medicine, Xiamen University, Xiamen, 361000, China.
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10
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Borrell-Pages M, Luquero A, Vilahur G, Padró T, Badimon L. Canonical Wnt pathway and the LDL receptor superfamily in neuronal cholesterol homeostasis and function. Cardiovasc Res 2024; 120:140-151. [PMID: 37882606 DOI: 10.1093/cvr/cvad159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/13/2023] [Accepted: 09/04/2023] [Indexed: 10/27/2023] Open
Abstract
AIMS There is little information on the regulation of cholesterol homeostasis in the brain. Whether cholesterol crosses the blood-brain barrier is under investigation, but the present understanding is that cholesterol metabolism in the brain is independent from that in peripheral tissues. Lipoprotein receptors from the LDL receptor family (LRPs) have key roles in lipid particle accumulation in cells involved in vascular and cardiac pathophysiology; however, their function on neural cells is unknown. METHODS AND RESULTS The expression of LRP5 and the components and targets of its downstream signalling pathway, the canonical Wnt pathway, including β-catenin, LEF1, VEGF, OPN, MMP7, and ADAM10, is analysed in the brains of Wt and Lrp5-/- mice and in a neuroblastoma cell line. LRP5 expression is increased in a time- and dose-dependent manner after lipid loading in neuronal cells; however, it does not participate in cholesterol homeostasis as shown by intracellular lipid accumulation analyses. Neurons challenged with staurosporin and H2O2 display an anti-apoptotic protective role for LRP5. CONCLUSIONS For the first time, it has been shown that neurons can accumulate intracellular lipids and lipid uptake is performed mainly by the LDLR, while CD36, LRP1, and LRP5 do not play a major role. In addition, it has been shown that LRP5 triggers the canonical Wnt pathway in neuronal cells to generate pro-survival signals. Finally, Lrp5-/- mice have maintained expression of LRP5 only in the brain supporting the biological plausible concept of the need of brain LRP5 to elicit pro-survival processes and embryonic viability.
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Affiliation(s)
- Maria Borrell-Pages
- Cardiovascular Program ICCC, Sant Pau Institute for Biomedical Research (IIB-Sant Pau), C/Sant Antoni Maria Claret 167, Barcelona 08025, Spain
- CIBER-CV, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain
| | - Aureli Luquero
- Cardiovascular Program ICCC, Sant Pau Institute for Biomedical Research (IIB-Sant Pau), C/Sant Antoni Maria Claret 167, Barcelona 08025, Spain
- CIBER-CV, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain
| | - Gemma Vilahur
- Cardiovascular Program ICCC, Sant Pau Institute for Biomedical Research (IIB-Sant Pau), C/Sant Antoni Maria Claret 167, Barcelona 08025, Spain
- CIBER-CV, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain
| | - Teresa Padró
- Cardiovascular Program ICCC, Sant Pau Institute for Biomedical Research (IIB-Sant Pau), C/Sant Antoni Maria Claret 167, Barcelona 08025, Spain
- CIBER-CV, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain
| | - Lina Badimon
- Cardiovascular Program ICCC, Sant Pau Institute for Biomedical Research (IIB-Sant Pau), C/Sant Antoni Maria Claret 167, Barcelona 08025, Spain
- CIBER-CV, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain
- Cardiovascular Research Chair, Universitat Autònoma de Barcelona, Plaça Cívica, 08193 Bellaterra, Barcelona, Spain
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11
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Facey COB, Hunsu VO, Zhang C, Osmond B, Opdenaker LM, Boman BM. CYP26A1 Links WNT and Retinoic Acid Signaling: A Target to Differentiate ALDH+ Stem Cells in APC-Mutant CRC. Cancers (Basel) 2024; 16:264. [PMID: 38254755 PMCID: PMC10813786 DOI: 10.3390/cancers16020264] [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: 12/14/2023] [Revised: 01/02/2024] [Accepted: 01/02/2024] [Indexed: 01/24/2024] Open
Abstract
APC mutation is the main driving mechanism of CRC development and leads to constitutively activated WNT signaling, overpopulation of ALDH+ stem cells (SCs), and incomplete differentiation. We previously reported that retinoic acid (RA) receptors are selectively expressed in ALDH+ SCs, which provides a way to target cancer SCs with retinoids to induce differentiation. Hypotheses: A functional link exists between the WNT and RA pathways, and APC mutation generates a WNT:RA imbalance that decreases retinoid-induced differentiation and increases ALDH+ SCs. Accordingly, to restore parity in WNT:RA signaling, we induce wt-APC expression in APC-mutant CRC cells, and we assess the ability of all-trans retinoic acid (ATRA) to induce differentiation. We found that ATRA increased expression of the WNT target gene, CYP26A1, and inducing wt-APC reduced this expression by 50%. Thus, the RA and WNT pathways crosstalk to modulate CYP26A1, which metabolizes retinoids. Moreover, inducing wt-APC augments ATRA-induced cell differentiation by: (i) decreasing cell proliferation; (ii) suppressing ALDH1A1 expression; (iii) decreasing ALDH+ SCs; and (iv) increasing neuroendocrine cell differentiation. A novel CYP26A1-based network that links WNT and RA signaling was also identified by NanoString profiling/bioinformatics analysis. Furthermore, CYP26A1 inhibitors sensitized CRC cells to the anti-proliferative effect of drugs that downregulate WNT signaling. Notably, in wt-APC-CRCs, decreased CYP26A1 improved patient survival. These findings have strong potential for clinical translation.
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Affiliation(s)
- Caroline O. B. Facey
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA; (C.O.B.F.); (V.O.H.); (C.Z.); (B.O.); (L.M.O.)
| | - Victoria O. Hunsu
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA; (C.O.B.F.); (V.O.H.); (C.Z.); (B.O.); (L.M.O.)
- Department Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Chi Zhang
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA; (C.O.B.F.); (V.O.H.); (C.Z.); (B.O.); (L.M.O.)
- Department Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Brian Osmond
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA; (C.O.B.F.); (V.O.H.); (C.Z.); (B.O.); (L.M.O.)
- Department Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Lynn M. Opdenaker
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA; (C.O.B.F.); (V.O.H.); (C.Z.); (B.O.); (L.M.O.)
| | - Bruce M. Boman
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA; (C.O.B.F.); (V.O.H.); (C.Z.); (B.O.); (L.M.O.)
- Department Biological Sciences, University of Delaware, Newark, DE 19716, USA
- Department Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA
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12
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Balaguer J, García-Foncillas J, Tuñón J. Natriuretic peptides: Another tool for the management of cancer? Crit Rev Oncol Hematol 2024; 193:104219. [PMID: 38029944 DOI: 10.1016/j.critrevonc.2023.104219] [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: 07/08/2023] [Revised: 11/20/2023] [Accepted: 11/23/2023] [Indexed: 12/01/2023] Open
Abstract
The connection between heart failure (HF) and cancer through multiple pathways such as inflammation, oxidative stress, and neurohormonal activation, among others, is well established. As a consequence, increases in plasma levels of several biomarkers have been described in both disorders. The most consistent information is related to natriuretic peptides (NPs). Although they are known to be produced in the ventricles as a response to myocardial distension, and thus can be useful for the diagnosis and prognosis of HF, and also for the management of chemotherapy-induced myocardial damage, they are also produced by tumour cells. In this regard, increased plasma levels of NPs have been described in patients with multiple malignancies in the absence of volume overload. Natriuretic peptide levels have been shown to correlate directly with the extension of tumours and with poorer outcomes. Moreover, some data indicate that they may help in the detection of subclinical tumours. Given that these peptides have been described to have anti-proliferative and anti-angiogenic effects, a plausible hypothesis is that they may be produced by tumours as a negative feed-back mechanism to avoid tumour progression. This would lead to increased levels of NPs in plasma that could be potentially useful for early detection of malignancies as well as for a prognostic assessment. Nevertheless, since the sample size of many studies published so far is limited, more data are needed to provide consistent data in order to confirm or rule out this hypothesis.
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Affiliation(s)
- Jorge Balaguer
- Division of Cardiology, IIS-Fundación Jiménez Díaz, Madrid, Spain
| | - Jesús García-Foncillas
- Division of Oncology, IIS-Fundación Jiménez Díaz, Madrid, Spain; School of Medicine, Autónoma University, Madrid, Spain
| | - José Tuñón
- Division of Cardiology, IIS-Fundación Jiménez Díaz, Madrid, Spain; School of Medicine, Autónoma University, Madrid, Spain; Laboratory of Vascular Pathology, IIS-Fundación Jiménez Díaz, Madrid, Spain; CIBERCV, ISCIII, Madrid, Spain.
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13
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Yang ZY, Zhang WL, Jiang CW, Sun G. PCBP1-mediated regulation of WNT signaling is critical for breast tumorigenesis. Cell Biol Toxicol 2023; 39:2331-2343. [PMID: 35639300 DOI: 10.1007/s10565-022-09722-4] [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: 09/06/2021] [Accepted: 05/11/2022] [Indexed: 11/28/2022]
Abstract
Loss of expression or protein kinase B (Akt1)-mediated post-translational modification of the RNA binding protein Poly r(C) binding protein 1 (PCBP1) is closely related to metastatic advancement of breast cancer. However, the role of PCBP1 in tumorigenesis is not completely defined. Using a xenograft orthotopic model of breast tumorigenesis (4T1-Pcbp1-/-), we show here that PCBP1 knockdown-induced tumorigenesis is inhibited by activation of the WNT signaling via treating with the glycogen synthase kinase 3 beta inhibitor TWS119, but not the Akt2/Akt3 inhibitor GSK690693. Mass cytometry-based evaluation of the tumor microenvironment (TME) revealed significantly more regulatory T cells (Tregs) and significantly less cytotoxic T cells in 4T1-Pcbp1-/-mice treated with saline control in comparison to mice treated with TWS119. Infiltrating cytotoxic T cells were phenotypically and functionally exhausted. Treatment with TWS119 resulted in rescue of cytotoxic T cell function and inhibition of suppressor activity of Tregs. Using cytotoxic T cells isolated from healthy donors, we show that TWS119-induced WNT signaling-mediated inhibition of cytotoxic T cell expansion is reliant on expression of PCBP1. In conclusion, decreased PCBP1 expression favors breast tumorigenesis by potentiating skewing of tumor infiltrating T cells towards Tregs, thereby effectively suppressing anti-tumor immunity.
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Affiliation(s)
- Zhao-Ying Yang
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, No.126, Xiantai Street, Changchun, Jilin, 130033, China
| | - Wen-Long Zhang
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China
| | - Cheng-Wei Jiang
- Department of Pathology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China
| | - Guang Sun
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, No.126, Xiantai Street, Changchun, Jilin, 130033, China.
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14
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Akhavanfar R, Shafagh SG, Mohammadpour B, Farahmand Y, Lotfalizadeh MH, Kookli K, Adili A, Siri G, Eshagh Hosseini SM. A comprehensive insight into the correlation between ncRNAs and the Wnt/β-catenin signalling pathway in gastric cancer pathogenesis. Cell Commun Signal 2023; 21:166. [PMID: 37386429 PMCID: PMC10308667 DOI: 10.1186/s12964-023-01092-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 02/26/2023] [Indexed: 07/01/2023] Open
Abstract
During the past decades, gastric cancer (GC) has emerged as one of the most frequent malignancies with a growing rate of prevalence around the world. Despite considerable advances in therapeutic methods, the prognosis and management of patients with gastric cancer (GC) continue to be poor. As one of the candidate molecular targets in the treatment of many types of cancer, the Wnt/β-catenin pathway includes a family of proteins that have important functions in adult tissue homeostasis and embryonic development. The aberrant regulation of Wnt/β-catenin signaling is strongly correlated with the initiation and development of numerous cancers, including GC. Therefore, Wnt/β-catenin signaling has been identified as one of the main targets for extending therapeutic approaches for GC patients. Non-coding RNAs (ncRNAs), including microRNAs and long ncRNAs, are important components of epigenetic mechanisms in gene regulation. They play vital roles in various molecular and cellular processes and regulate many signaling pathways, such as Wnt/β-catenin pathways. Insights into these regulatory molecules involved in GC development may lead to the identification of potential targets for overcoming the limitations of current therapeutic approaches. Consequently, this review aimed to provide a comprehensive overview of ncRNAs interactions involved in Wnt/β-catenin pathway function in GC with diagnostic and therapeutic perspectives. Video Abstract.
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Affiliation(s)
- Roozbeh Akhavanfar
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | | | - Yalda Farahmand
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Keihan Kookli
- International Campus, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Adili
- Senior Adult Oncology Department, Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
- Department of Oncology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Goli Siri
- Department of Internal Medicine, Amir Alam Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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15
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Disha-Ibrahimi S, Furlani B, Drevenšek G, Hudoklin S, Marc J, Žitnik IP, Sajovic J, Drevenšek M. Olanzapine decreased osteocyte maturation and Wnt/β-catenin signaling during loading of the alveolar bone in rats. BIOMOLECULES AND BIOMEDICINE 2023; 23:114-125. [PMID: 35880348 PMCID: PMC9901902 DOI: 10.17305/bjbms.2022.7523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/09/2022] [Indexed: 02/08/2023]
Abstract
Several studies indicate the influence of olanzapine on bone metabolism; however, the results are contradictory. We evaluated the effects of olanzapine on the Wnt/β-catenin signaling pathway, physiological alveolar bone turnover, and alveolar bone modeling due to an applied orthodontic force. Adult male rats (n=48) were treated with either olanzapine or a vehicle for 21 days; then 8 rats from each group were sacrificed and the rest were divided into 4 groups: control, appliance-only, olanzapine-only, and olanzapine-appliance. The rats in the appliance groups were mounted with a superelastic closed coil spring that maintained constant orthodontic force between molars and incisors. We studied the effects of olanzapine on physiological alveolar bone turnover on day 21 of the experiment, and on alveolar bone modeling due to orthodontic force on day 56. We determined tooth movement, alveolar bone volume, activity of bone-specific cells, serum alkaline phosphatase (ALP) activity, and gene expression levels of Wnt/β-catenin signaling target genes. During forced bone modeling, olanzapine increased osteoblast volume (P<0.0001) and ALP activity (P=0.0011) and decreased osteoclast volume (P<0.0001) and gene expression of the Wnt/β-catenin signaling target genes Fosl1, Axin2, and Dkk1(P=0.001, P=0.0076, and P=0.036, respectively), and the osteocyte markers Sost and Dmp1 (P=0.0432 and P=0.0021, respectively). Similar results were obtained during physiological alveolar bone turnover on day 21, when olanzapine downregulated the gene expression of osteocyte markers and Wnt/β-catenin signaling target genes. We concluded that olanzapine attenuated osteocyte maturation during forced bone modeling and physiological alveolar bone turnover, potentially through downregulation of the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Saranda Disha-Ibrahimi
- Department of Orthodontics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia,Department of Periodontology and Oral Medicine, Faculty of Medicine, University of Prishtina, Pristina, Kosovo
| | - Borut Furlani
- Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Gorazd Drevenšek
- Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Samo Hudoklin
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Janja Marc
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Irena Prodan Žitnik
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Jakob Sajovic
- Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia,Department of Orthodontics, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Martina Drevenšek
- Department of Orthodontics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia,Department of Orthodontics, University Medical Centre Ljubljana, Ljubljana, Slovenia,Correspondence to Martina Drevenšek:
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16
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Kim DE, Shin SB, Kim CH, Kim YB, Oh HJ, Yim H. PLK1-mediated phosphorylation of β-catenin enhances its stability and transcriptional activity for extracellular matrix remodeling in metastatic NSCLC. Theranostics 2023; 13:1198-1216. [PMID: 36793862 PMCID: PMC9925311 DOI: 10.7150/thno.79318] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 01/21/2023] [Indexed: 02/17/2023] Open
Abstract
Rationale: β-catenin is a component for cell adhesion and a transcriptional coactivator in epithelial-mesenchymal transition (EMT). Previously we found that catalytically active PLK1 drives EMT in non-small cell lung cancer (NSCLC), upregulating extracellular matrix factors including TSG6, laminin γ2, and CD44. To understand the underlying mechanism and clinical significance of PLK1 and β-catenin in NSCLC, their relationship and function in metastatic regulation were investigated. Methods: The clinical relevance between the survival rate of NSCLC patients and the expression of PLK1 and β-catenin was analyzed by a KM plot. Immunoprecipitation, kinase assay, LC-MS/MS spectrometry, and site-directed mutagenesis were performed to reveal their interaction and phosphorylation. A lentiviral doxycycline-inducible system, Transwell-based 3D culture, tail-vein injection model, confocal microscopy, and chromatin immunoprecipitation assays were used to elucidate the function of phosphorylated β-catenin in the EMT of NSCLC. Results: Clinical analysis revealed that the high expression of CTNNB1/PLK1 was inversely correlated with the survival rates of 1,292 NSCLC patients, especially in metastatic NSCLC. In TGF-β-induced or active PLK1-driven EMT, β-catenin, PLK1, TSG6, laminin γ2, and CD44 were concurrently upregulated. β-catenin is a binding partner of PLK1 in TGF-β-induced EMT and is phosphorylated at S311. Phosphomimetic β-catenin promotes cell motility, invasiveness of NSCLC cells, and metastasis in a tail-vein injection mouse model. Its upregulated stability by phosphorylation enhances transcriptional activity through nuclear translocation for the expression of laminin γ2, CD44, and c-Jun, therefore enhancing PLK1 expression by AP-1. Conclusions: Our findings provide evidence for the critical role of the PLK1/β-catenin/AP-1 axis in metastatic NSCLC, implying that β-catenin and PLK1 may serve as a molecular target and prognostic indicator of the therapeutic response in metastatic NSCLC patients.
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Affiliation(s)
- Da-Eun Kim
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Korea
| | - Sol-Bi Shin
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Korea
| | - Chang-Hyeon Kim
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Korea
| | - Yeo-Bin Kim
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Korea
| | - Hyun-Ji Oh
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Korea
| | - Hyungshin Yim
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Korea.,Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Korea
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17
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Neogi K, Murumkar PR, Sharma P, Yadav P, Tewari M, Karunagaran D, Nayak PK, Yadav MR. Design, synthesis and evaluation of 4,7-disubstituted 8-methoxyquinazoline derivatives as potential cytotoxic agents targeting β-catenin/TCF4 signaling pathway. Transl Oncol 2022; 19:101395. [PMID: 35325837 PMCID: PMC8938628 DOI: 10.1016/j.tranon.2022.101395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 02/15/2022] [Accepted: 03/09/2022] [Indexed: 11/18/2022] Open
Abstract
Overactivation of Wnt/β-catenin signaling by accumulated β-catenin in the nucleus has been shown to play a crucial role in the etiology of cancer. Interaction of β-catenin with Transcription factor 4 (TCF4) is a key step for the activation of Wnt genes in response to upstream signals of the Wnt/β-catenin pathway. Hence, down regulation of Wnt/β-catenin signaling or targeting downstream events by selective β-catenin/TCF4 protein-protein interaction inhibitors could be a potential therapeutic strategy against such cancers. In this study structure-based drug design approach was followed to design novel 4,7-disubstituted 8-methoxyquinazoline-based derivatives which could act as potential cytotoxic agents inhibiting the β-catenin/TCF4 protein-protein interactions. Fifteen compounds possessing 4,7-disubstituted 8-methoxyquinazoline scaffold were synthesized. Cytotoxic potential of the synthesised derivatives were determined against constitutively activated β-catenin/TCF4 signaling pathway cancer cells (HCT116 and HepG2) using the sulforhodamine B assay. The most potent compound (18B) was selected for detailed biological evaluation. Cell morphology, Hoechst 33342 and Annexin V/PI staining were used to detect apoptosis, while inhibition of cell migration was assessed by in vitro wound healing assay against HCT116 and HepG2 cells. Effect on β-catenin/TCF mediated transcriptional activity was assessed by TOPFlash/FOPFlash assay, TCF4 and β-catenin protein expression by immunocytofluorescence, and Wnt target genes (like c-MYC and Cyclin D1) mRNA levels by RT-PCR against HCT116 cells. Cytotoxic potency of the most potential compound (18B) against primary human gallbladder cancer cells was also evaluated. The derivatives showed interactions with active site residues of β-catenin and were capable of hindering the TCF4 binding, thereby disrupting β-catenin/TCF4 interactions. Cytotoxic potencies (IC50) of these derivatives ranged from 5.64 ± 0.68 to 23.18 ± 0.45 μM against HCT116 and HepG2 cells respectively. Compound (18B), the most potent compound among the series, induced apoptosis and inhibited cell migration against HCT116 and HepG2 cells. Mechanistic studies indicated that compound (18B) downregulated β-catenin/TCF4 signaling pathway, β-catenin and TCF4 protein expression, and mRNA levels of c-MYC andCyclin D1 in HCT116 cells and showed cytotoxicity against primary human gallbladder cancer cells with IC50 value of 8.50 ± 1.44 μM. Thus, novel 4,7-disubstituted 8-methoxyquinazoline derivatives were identified as potential cytotoxic agents with potencies comparable to that of imatinib mesylate. Compound (18B) represents a promising lead molecule as anticancer agent against colon, hepatocellular and gallbladder cancers targeting β-catenin/TCF4 signaling pathway.
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Affiliation(s)
- Kaushik Neogi
- Department of Pharmaceutical Engineering and Technorlogy, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, India
| | - Prashant R Murumkar
- Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India
| | - Priyanshu Sharma
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Poonam Yadav
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Mallika Tewari
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Devarajan Karunagaran
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Prasanta Kumar Nayak
- Department of Pharmaceutical Engineering and Technorlogy, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, India.
| | - Mange Ram Yadav
- Centre of Research for Development, Parul University, Vadodara, Gujarat, India.
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18
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Ram AK, Vairappan B. Role of zonula occludens in gastrointestinal and liver cancers. World J Clin Cases 2022; 10:3647-3661. [PMID: 35647143 PMCID: PMC9100728 DOI: 10.12998/wjcc.v10.i12.3647] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 08/08/2021] [Accepted: 03/04/2022] [Indexed: 02/06/2023] Open
Abstract
A growing body of evidence suggests that tight junction (TJ) proteins play a crucial role in the pathogenesis of various diseases, including gastrointestinal (GI) cancer and hepatocellular carcinoma (HCC). TJ proteins primarily maintain the epithelial and endothelial cells intact together through integral proteins however, recent reports suggest that they also regulate gene expression necessary for cell proliferation, angiogenesis, and metastasis through adapter proteins such as zonula occludens (ZO). ZO proteins are membrane-associated cytosolic scaffolding proteins that modulate cell proliferation by interacting with several transcription factors. Reduced ZO proteins in GI cancer and HCC are correlated with tumor development and poor prognosis. Pubmed has searched for using the keyword ZO and gastric cancer, ZO and cancer, and ZO and HCC for the last ten years to date. This review summarized the role of ZO proteins in cell proliferation and their expression in GI cancer and HCC. Furthermore, therapeutic interventions targeting ZO in GI and liver cancers are reviewed.
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Affiliation(s)
- Amit Kumar Ram
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India
| | - Balasubramaniyan Vairappan
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India
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19
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Swoboda J, Mittelsdorf P, Chen Y, Weiskirchen R, Stallhofer J, Schüle S, Gassler N. Intestinal Wnt in the transition from physiology to oncology. World J Clin Oncol 2022; 13:168-185. [PMID: 35433295 PMCID: PMC8966512 DOI: 10.5306/wjco.v13.i3.168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 09/07/2021] [Accepted: 02/19/2022] [Indexed: 02/06/2023] Open
Abstract
Adult stem cells are necessary for self-renewal tissues and regeneration after damage. Especially in the intestine, which self-renews every few days, they play a key role in tissue homeostasis. Therefore, complex regulatory mechanisms are needed to prevent hyperproliferation, which can lead in the worst case to carcinogenesis or under-activation of stem cells, which can result in dysfunctional epithelial. One main regulatory signaling pathway is the Wnt/β-catenin signaling pathway. It is a highly conserved pathway, with β-catenin, a transcription factor, as target protein. Translocation of β-catenin from cytoplasm to nucleus activates the transcription of numerous genes involved in regulating stem cell pluripo-tency, proliferation, cell differentiation and regulation of cell death. This review presents a brief overview of the Wnt/β-catenin signaling pathway, the regulatory mechanism of this pathway and its role in intestinal homeostasis. Additionally, this review highlights the molecular mechanisms and the histomorphological features of Wnt hyperactivation. Furthermore, the central role of the Wnt signaling pathway in intestinal carcinogenesis as well as its clinical relevance in colorectal carcinoma are discussed.
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Affiliation(s)
- Julia Swoboda
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Patrick Mittelsdorf
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Yuan Chen
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen 52074, Germany
| | - Johannes Stallhofer
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena 07747, Germany
| | - Silke Schüle
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
| | - Nikolaus Gassler
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
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20
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Valdez BC, Murray D, Yuan B, Nieto Y, Popat U, Andersson BS. ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells. Oncotarget 2022; 13:319-330. [PMID: 35154579 PMCID: PMC8830224 DOI: 10.18632/oncotarget.28193] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 01/28/2022] [Indexed: 11/25/2022] Open
Abstract
The antineoplastic activity of pre-transplant regimens in hematopoietic stem cell transplantation (HSCT) is a critical factor for acute myeloid leukemia (AML) patients. There is an urgent need to identify novel approaches without jeopardizing patient safety. We hypothesized that combination of drugs with different mechanisms of action would provide better cytotoxicity. We, therefore, determined the synergistic cytotoxicity of various combinations of the alkylating agents busulfan (Bu) and 4-hydroperoxycyclophosphamide (4HC), the nucleoside analog fludarabine (Flu) and the BCL2 inhibitor ABT199/venetoclax in AML cells. [Bu+4HC] and [Bu+Flu] inhibited cell proliferation and activated apoptosis; addition of ABT199 to either combinations significantly increased these effects with combination indexes < 1. Apoptosis is suggested by cleavages of PARP1 and CASPASE 3, DNA fragmentation, increased reactive oxygen species, decreased mitochondrial membrane potential, and increased pro-apoptotic proteins in the cytoplasm. A similar enhancement of apoptosis was observed in patient-derived cell samples. ABT199/venetocalx upregulated anti-apoptotic MCL1 as a compensatory mechanism but addition of [Bu+4HC] or [Bu+Flu] negated this effect by CASPASE 3-mediated cleavage of MEK1/2 and its substrate MCL1. CASPASE 3 caused cleavage of pro-survival β-CATENIN, which likely contributed to the activation of stress signaling pathways involving SAPK/JNK and AMPK. The observed synergistic cytotoxicity was associated with an inhibition of pro-survival pathways involving STAT1, STAT5 and PI3K. These findings will be useful in designing clinical trials using these drug combinations as pre-transplant conditioning regimens for AML patients.
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Affiliation(s)
- Benigno C Valdez
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - David Murray
- Division/Department of Experimental Oncology, University of Alberta/Cross Cancer Institute, Edmonton T6G 1Z2, Alberta, Canada
| | - Bin Yuan
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yago Nieto
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Uday Popat
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Borje S Andersson
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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21
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Wasson CW, Caballero-Ruiz B, Gillespie J, Derrett-Smith E, Mankouri J, Denton CP, Canettieri G, Riobo-Del Galdo NA, Del Galdo F. Induction of Pro-Fibrotic CLIC4 in Dermal Fibroblasts by TGF-β/Wnt3a Is Mediated by GLI2 Upregulation. Cells 2022; 11:cells11030530. [PMID: 35159339 PMCID: PMC8834396 DOI: 10.3390/cells11030530] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 01/21/2022] [Accepted: 02/01/2022] [Indexed: 11/16/2022] Open
Abstract
Chloride intracellular channel 4 (CLIC4) is a recently discovered driver of fibroblast activation in Scleroderma (SSc) and cancer-associated fibroblasts (CAF). CLIC4 expression and activity are regulated by TGF-β signalling through the SMAD3 transcription factor. In view of the aberrant activation of canonical Wnt-3a and Hedgehog (Hh) signalling in fibrosis, we investigated their role in CLIC4 upregulation. Here, we show that TGF-β/SMAD3 co-operates with Wnt3a/β-catenin and Smoothened/GLI signalling to drive CLIC4 expression in normal dermal fibroblasts, and that the inhibition of β-catenin and GLI expression or activity abolishes TGF-β/SMAD3-dependent CLIC4 induction. We further show that the expression of the pro-fibrotic marker α-smooth muscle actin strongly correlates with CLIC4 expression in dermal fibroblasts. Further investigations revealed that the inhibition of CLIC4 reverses morphogen-dependent fibroblast activation. Our data highlights that CLIC4 is a common downstream target of TGF-β, Hh, and Wnt-3a through signalling crosstalk and we propose a potential therapeutic avenue using CLIC4 inhibitors
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Affiliation(s)
- Christopher W. Wasson
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS29JT, UK; (J.G.); (F.D.G.)
- Correspondence:
| | - Begoña Caballero-Ruiz
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS29JT, UK; (B.C.-R.); (J.M.); (N.A.R.-D.G.)
- Department of Molecular Medicine, Sapienza University of Rome, 00196 Rome, Italy;
| | - Justin Gillespie
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS29JT, UK; (J.G.); (F.D.G.)
| | - Emma Derrett-Smith
- Centre for Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, London NW32PF, UK; (E.D.-S.); (C.P.D.)
| | - Jamel Mankouri
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS29JT, UK; (B.C.-R.); (J.M.); (N.A.R.-D.G.)
| | - Christopher P. Denton
- Centre for Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, London NW32PF, UK; (E.D.-S.); (C.P.D.)
| | - Gianluca Canettieri
- Department of Molecular Medicine, Sapienza University of Rome, 00196 Rome, Italy;
| | - Natalia A. Riobo-Del Galdo
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS29JT, UK; (B.C.-R.); (J.M.); (N.A.R.-D.G.)
- Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds LS29JT, UK
| | - Francesco Del Galdo
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS29JT, UK; (J.G.); (F.D.G.)
- Scleroderma Programme, NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds LS29JT, UK
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22
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Nayak P, Neogi K, Tewari M, Singh A, Sharma K, Tej GVC, Verma S, Gupta S. Transcription factor 4 expression and correlation with tumor progression in gallbladder cancer. J Cancer Res Ther 2022; 18:668-676. [DOI: 10.4103/jcrt.jcrt_1381_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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23
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Unveiling the tumour-regulatory roles of miR-1275 in cancer. Pathol Res Pract 2021; 230:153745. [PMID: 34953353 DOI: 10.1016/j.prp.2021.153745] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 12/10/2021] [Accepted: 12/16/2021] [Indexed: 12/13/2022]
Abstract
The rapid development of small RNA and molecular biology research in the past 20 years has enabled scientists to discover many new miRNAs that are proven to play essential roles in regulating the development of different cancer types. Among these miRNAs, miR-1275 is one of the well-studied miRNAs that has been described to act as a tumour-promoting or tumour-suppressing miRNA in various cancer types. Even though miR-1275 has been widely reported in different original research articles on its roles in modulating the progression of different cancer types, however, there is scarce an in-depth review that could constructively summarize the findings from different studies on the regulatory roles of miR-1275 in different cancer types. To fill up this literature gap, therefore, this review was aimed to provide an overview and summary of the roles of miR-1275 in modulating the development of different cancers and to unravel the mechanism of how miR-1275 regulates cancer progression. Based on the findings summarized from various sources, it was found that miR-1275 plays a vital role in regulating various cellular signaling pathways like the PI3K/AKT, ERK/JNK, MAPK, and Wnt signaling pathways, and the dysregulation of this miRNA has been shown to contribute to the development of multiple cancer types such as cancers of the liver, breast, lung, gastrointestinal tract and genitourinary tract. Therefore, miR-1275 has great potential to be employed as a biomarker to diagnose cancer and to predict the prognosis of cancer patients. In addition, by inhibiting the expression of its unique downstream targets that are involved in regulating the mentioned cellular pathways, this miRNA could also be utilized as a novel therapeutic agent to halt cancer development.
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24
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Kasthuriarachchi TDW, Harasgama JC, Lee S, Kwon H, Wan Q, Lee J. Cytosolic β-catenin is involved in macrophage M2 activation and antiviral defense in teleosts: Delineation through molecular characterization of β-catenin homolog from redlip mullet (Planiliza haematocheila). FISH & SHELLFISH IMMUNOLOGY 2021; 118:228-240. [PMID: 34284111 DOI: 10.1016/j.fsi.2021.07.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 07/09/2021] [Accepted: 07/15/2021] [Indexed: 06/13/2023]
Abstract
β-catenin is a structural protein that makes the cell-cell connection in adherence junctions. Besides the structural functions, it also plays a role as a central transducer of the canonical Wnt signaling cascade, regulating nearly four hundred genes related to various cellular processes. Recently the immune functions of β-catenin during pathogenic invasion have gained more attention. In the present study, we elucidated the immune function of fish β-catenin by identifying and characterizing the β-catenin homolog (PhCatβ) from redlip mullet, Planiliza haematocheila. The complete open reading frame of PhCatβ consists of 2352 bp, which encodes a putative β-catenin homolog (molecular weight: 85.7 kDa). Multiple sequence alignment analysis revealed that β-catenin is highly conserved in vertebrates. Phylogenetic reconstruction demonstrated the close evolutionary relationship between PhCatβ and other fish β-catenin counterparts. The tissue distribution analysis showed the highest mRNA expression of PhCatβ in heart tissues of the redlip mullet under normal physiological conditions. While in response to pathogenic stress, the PhCatβ transcription level was dramatically increased in the spleen and gill tissues. The overexpression of PhCatβ stimulated M2 polarization and cell proliferation of murine RAW 264.7 macrophage. In fish cells, the overexpression of PhCatβ resulted in a significant upregulation of antiviral gene transcription and vice versa. Moreover, the overexpression of PhCatβ could inhibit the replication of VHSV in FHM cells. Our results strongly suggest that PhCatβ plays a role in macrophage activation and antiviral immune response in redlip mullet.
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Affiliation(s)
- T D W Kasthuriarachchi
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province, 63243, Republic of Korea; Marine Science Institute, Jeju National University, Jeju Self-Governing Province, 63333, Republic of Korea
| | - J C Harasgama
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province, 63243, Republic of Korea; Marine Science Institute, Jeju National University, Jeju Self-Governing Province, 63333, Republic of Korea
| | - Seongdo Lee
- National Fishery Product Quality Management Service, Busan, 49111, Republic of Korea
| | - Hyukjae Kwon
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province, 63243, Republic of Korea; Marine Science Institute, Jeju National University, Jeju Self-Governing Province, 63333, Republic of Korea
| | - Qiang Wan
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province, 63243, Republic of Korea; Marine Science Institute, Jeju National University, Jeju Self-Governing Province, 63333, Republic of Korea.
| | - Jehee Lee
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province, 63243, Republic of Korea; Marine Science Institute, Jeju National University, Jeju Self-Governing Province, 63333, Republic of Korea.
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25
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Song F, Chen FY, Wu SY, Hu B, Liang XL, Yang HQ, Cheng JW, Wang PX, Guo W, Zhou J, Fan J, Chen Z, Yang XR. Mucin 1 promotes tumor progression through activating WNT/β-catenin signaling pathway in intrahepatic cholangiocarcinoma. J Cancer 2021; 12:6937-6947. [PMID: 34729096 PMCID: PMC8558653 DOI: 10.7150/jca.63235] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 09/18/2021] [Indexed: 11/05/2022] Open
Abstract
Background: Current treatment options for intrahepatic cholangiocarcinoma (ICC) are limited by the lack of understanding of the disease pathogenesis. It has been known that mucin 1 (MUC1) is a cell surface mucin that highly expressed in various cancer tissues. However, its role in ICC has not been well studied. The purpose of this study was to investigate the clinical significance and biological function of MUC1 in ICC. Methods: qRT-PCR and western blot assays were performed to examine MUC1 expression. RNA-Seq (RNA Sequencing) s conducted to explore the RNA expression. A tissue microarray study including 214 ICC cases was also conducted to evaluate the clinical relevance and prognostic significance of MUC1. The role and underlying mechanisms of MUC1 in regulating cell growth and invasion were further explored both in vitro and in vivo models. Results: The mRNA and protein levels of MUC1 were significantly up-regulated in ICC compared to paired non-tumor tissues. Depletion of MUC1 in HCCC9810 cells significantly inhibited cell proliferation, migration and invasion in vitro and overexpression of MUC1 in RBE cells resulted in increased cell proliferation, migration and invasion. Both univariate and multivariate analysis revealed that the protein expression of MUC1 was associated with overall survival and relapse-free survival after tumor resection. Clinically, high MUC1 expression was more commonly observed in aggressive tumors. Further studies indicated that MUC1 exerted its function through activating Wnt/ β-catenin pathway. Conclusions: Our data suggests that MUC1 promoted ICC progression via activating Wnt / β-catenin pathway. This study not only deciphered the role of MUC in ICC pathogenesis, but also shed light upon identifying novel potential therapeutic targets.
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Affiliation(s)
- Fei Song
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong 226001, P. R. China
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Fei-Yu Chen
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Sui-Yi Wu
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Bo Hu
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Xiao-liang Liang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong 226001, P. R. China
| | - Hao-Qin Yang
- Nanjing Foreign Language School, Nanjing 210018, P. R. China
| | - Jian-Wen Cheng
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Peng-Xiang Wang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Wei Guo
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Jian Zhou
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P. R. China
| | - Jia Fan
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P. R. China
| | - Zhong Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong 226001, P. R. China
| | - Xin-Rong Yang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
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26
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Guo F, Seldin M, Péterfy M, Charugundla S, Zhou Z, Lee SD, Mouton A, Rajbhandari P, Zhang W, Pellegrini M, Tontonoz P, Lusis AJ, Shih DM. NOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice. Sci Rep 2021; 11:16409. [PMID: 34385484 PMCID: PMC8361163 DOI: 10.1038/s41598-021-95720-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 07/28/2021] [Indexed: 11/29/2022] Open
Abstract
We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promote browning of white adipose. We now report studies of chronic overexpression of NOTUM in liver indicating that it protects against diet-induced obesity and improves glucose homeostasis in mice. Adeno-associated virus (AAV) vectors were used to overexpress GFP or mouse Notum in the livers of male C57BL/6J mice and the mice were fed an obesifying diet. After 14 weeks of high fat, high sucrose diet feeding, the AAV-Notum mice exhibited decreased obesity and improved glucose tolerance compared to the AAV-GFP mice. Gene expression and immunoblotting analysis of the inguinal fat and brown fat revealed increased expression of beige/brown adipocyte markers in the AAV-Notum group, suggesting enhanced thermogenic capacity by NOTUM. A β3 adrenergic receptor agonist-stimulated lipolysis test suggested increased lipolysis capacity by NOTUM. The levels of collagen and C–C motif chemokine ligand 2 (CCL2) in the epididymal white adipose tissue of the AAV-Notum mice were significantly reduced, suggesting decreased fibrosis and inflammation, respectively. RNA sequencing analysis of inguinal white adipose of 4-week chow diet-fed mice revealed a highly significant enrichment of extracellular matrix (ECM) functional cluster among the down-regulated genes in the AAV-Notum group, suggesting a potential mechanism contributing to improved glucose homeostasis. Our in vitro studies demonstrated that recombinant human NOTUM protein blocked the inhibitory effects of WNT3A on brown adipocyte differentiation. Furthermore, NOTUM attenuated WNT3A’s effects on upregulation of TGF-β signaling and its downstream targets. Overall, our data suggest that NOTUM modulates adipose tissue function by promoting thermogenic capacity and inhibiting fibrosis through inhibition of Wnt signaling.
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Affiliation(s)
- Fangfei Guo
- Department of Microbiology, Immunology, and Molecular Genetics, Division of Cardiology, Department of Medicine, Department of Human Genetics, University of California, 10833 Le Conte Avenue, A2-237 CHS, Los Angeles, CA, 90095-1679, USA
| | - Marcus Seldin
- Department of Biological Chemistry and Center for Epigenetics and Metabolism, University of California, Irvine, CA, 92697, USA
| | - Miklós Péterfy
- Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, CA, 91766, USA
| | - Sarada Charugundla
- Department of Microbiology, Immunology, and Molecular Genetics, Division of Cardiology, Department of Medicine, Department of Human Genetics, University of California, 10833 Le Conte Avenue, A2-237 CHS, Los Angeles, CA, 90095-1679, USA
| | - Zhiqiang Zhou
- Department of Microbiology, Immunology, and Molecular Genetics, Division of Cardiology, Department of Medicine, Department of Human Genetics, University of California, 10833 Le Conte Avenue, A2-237 CHS, Los Angeles, CA, 90095-1679, USA
| | - Stephen D Lee
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, 90095, USA
| | - Alice Mouton
- Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA, 90095, USA
| | - Prashant Rajbhandari
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine Mount Sinai, New York, NY, 10029, USA
| | - Wenchao Zhang
- Department of Microbiology, Immunology, and Molecular Genetics, Division of Cardiology, Department of Medicine, Department of Human Genetics, University of California, 10833 Le Conte Avenue, A2-237 CHS, Los Angeles, CA, 90095-1679, USA.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.,Department of Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Matteo Pellegrini
- Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA, 90095, USA
| | - Peter Tontonoz
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, 90095, USA
| | - Aldons J Lusis
- Department of Microbiology, Immunology, and Molecular Genetics, Division of Cardiology, Department of Medicine, Department of Human Genetics, University of California, 10833 Le Conte Avenue, A2-237 CHS, Los Angeles, CA, 90095-1679, USA
| | - Diana M Shih
- Department of Microbiology, Immunology, and Molecular Genetics, Division of Cardiology, Department of Medicine, Department of Human Genetics, University of California, 10833 Le Conte Avenue, A2-237 CHS, Los Angeles, CA, 90095-1679, USA.
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27
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Hinoi T. Cancer Genomic Profiling in Colorectal Cancer: Current Challenges in Subtyping Colorectal Cancers Based on Somatic and Germline Variants. J Anus Rectum Colon 2021; 5:213-228. [PMID: 34395933 PMCID: PMC8321592 DOI: 10.23922/jarc.2021-009] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 03/17/2021] [Indexed: 11/30/2022] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease caused by the accumulation of multistep genetic alterations under the influence of genomic instability. Different backgrounds of genomic instability, such as chromosomal instability, microsatellite instability, hypermutated-single nucleotide variants, and genome stable-induced transformation in the colonic epithelium, can result in adenomas, adenocarcinomas, and metastatic tumors. Characterization of molecular subtypes and establishment of treatment policies based on each subtype will lead to better treatment outcomes and an improved selection of molecularly targeted agents. In Japan, cancer precision medicine has been introduced in the National Health Insurance program through the addition of the cancer genomic profiling (CGP) examination. It has also become possible to access a large amount of genomic information, including information on pathogenic somatic and germline variants, incomparable to conventional diagnostic tests. This information enables us to apply research data to clinical decision-making, benefiting patients and their healthy family members. In this article, we discuss the important molecules and signaling pathways presumed to be the driver genes of CRC progression and the signal transduction system in which they are involved. Molecular subtypes of CRC based on CGP examinations and gene expression profiles have been established in The Cancer Genome Atlas Network with the advent of next-generation sequencing technology. We will also discuss the recommended management of secondary/germline findings, pathogenic germline variants, and presumed germline pathogenic variants obtained from CGP examination and review the current challenges to better understand these data in a new era of cancer genomic medicine.
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Affiliation(s)
- Takao Hinoi
- Department of Clinical and Molecular Genetics, Hiroshima University Hospital, Hiroshima, Japan
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Pang B, Wang Y, Chang X. A Novel Tumor Suppressor Gene, ZNF24, Inhibits the Development of NSCLC by Inhibiting the WNT Signaling Pathway to Induce Cell Senescence. Front Oncol 2021; 11:664369. [PMID: 34386416 PMCID: PMC8353233 DOI: 10.3389/fonc.2021.664369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 07/01/2021] [Indexed: 11/13/2022] Open
Abstract
Objective Understanding the characteristics of tumor suppressor genes (TSGs) is of great significance for the development of new targeted treatment strategies for non-small cell lung cancer (NSCLC). Therefore, this present article is to explore the underlying molecular mechanism of ZFN24 inhibiting the development of NSCLC. Methods We performed RT-PCR and Western blotting for evaluating associated RNA and protein expression. CCK8, colony forming and sphere-forming assays were used to evaluate the proliferation and stemness of NSCLC cells. NSCLC cell senescence was examined by β-galactosidase staining assay. Luciferase assay was performed to evaluate β-catenin transcriptional activity. The effect of ZNF24 on NSCLC cells in vivo was evaluated by the xenograft tumor experiment. Results Ectopic expression of ZNF24 significantly inhibited cell viability, colony forming ability, and stemness of NSCLC cells. WNT signaling pathway was inhibited by ZNF24 resulting in NSCLC cell senescence. β-catenin transcriptional activity was significantly inhibited by ZNF24 (P < 0.05). Ectopic expression of ZNF24 significantly inhibited xenotransplant tumors growth in vivo (P < 0.05). Conclusion ZNF24 could notably inhibit the development of NSCLC by inhibiting the WNT signaling pathway.
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Affiliation(s)
- Bo Pang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yong Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiaoyan Chang
- Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Predicting Agents That Can Overcome 5-FU Resistance in Colorectal Cancers via Pharmacogenomic Analysis. Biomedicines 2021; 9:biomedicines9080882. [PMID: 34440086 PMCID: PMC8389646 DOI: 10.3390/biomedicines9080882] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 01/05/2023] Open
Abstract
5-Fluorouracil (5-FU) is one of several chemotherapeutic agents in clinical use as a standard of care to treat colorectal cancers (CRCs). As an antimetabolite, 5-FU inhibits thymidylate synthase to disrupt the synthesis and repair of DNA and RNA. However, only a small proportion of patients benefit from 5-FU treatment due to the development of drug resistance. This study applied pharmacogenomic analysis using two public resources, the Genomics of Drug Sensitivity in Cancer (GDSC) and the Connectivity Map, to predict agents overcoming 5-FU resistance in CRC cells based on their genetic background or gene expression profile. Based on the genetic status of adenomatous polyposis coli (APC), the most frequent mutated gene found in CRC, we found that combining a MEK inhibitor with 5-FU exhibited synergism effects on CRC cells with APC truncations. While considering the gene expression in 5-FU resistant cells, we demonstrated that targeting ROCK is a potential avenue to restore 5-FU response to resistant cells with wild-type APC background. Our results reveal MEK signaling plays a pivotal role in loss-of-function, APC-mediated 5-FU resistance, and ROCK activation serves as a signature in APC-independent 5-FU resistance. Through the use of these available database resources, we highlight possible approaches to predict potential drugs for combinatorial therapy for patients developing resistance to 5-FU treatment.
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Diaz A, Martin-Jimenez C, Xu Y, Merino P, Woo Y, Torre E, Yepes M. Urokinase-type plasminogen activator-mediated crosstalk between N-cadherin and β-catenin promotes wound healing. J Cell Sci 2021; 134:jcs255919. [PMID: 34085693 PMCID: PMC8214757 DOI: 10.1242/jcs.255919] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 04/26/2021] [Indexed: 11/20/2022] Open
Abstract
Urokinase-type plasminogen activator (uPA; encoded by Plau) is a serine proteinase that, in the central nervous system, induces astrocytic activation. β-Catenin is a protein that links the cytoplasmic tail of cadherins to the actin cytoskeleton, thus securing the formation of cadherin-mediated cell adhesion complexes. Disruption of cell-cell contacts leads to the detachment of β-catenin from cadherins, and β-catenin is then degraded by the proteasome following its phosphorylation by GSK3β. Here, we show that astrocytes release uPA following a scratch injury, and that this uPA promotes wound healing via a plasminogen-independent mechanism. We found that uPA induces the detachment of β-catenin from the cytoplasmic tail of N-cadherin (NCAD; also known as CDH2) by triggering its phosphorylation at Tyr654. Surprisingly, this is not followed by degradation of β-catenin because uPA also induces the phosphorylation of the low density lipoprotein receptor-related protein 6 (LRP6) at Ser1490, which then blocks the kinase activity of GSK3β. Our work indicates that the ensuing cytoplasmic accumulation of β-catenin is followed by its nuclear translocation and β-catenin-triggered transcription of the receptor for uPA (Plaur), which in turn is required for uPA to induce astrocytic wound healing.
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Affiliation(s)
- Ariel Diaz
- Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA 30329, USA
| | - Cynthia Martin-Jimenez
- Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA 30329, USA
| | - Yang Xu
- Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA 30329, USA
| | - Paola Merino
- Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA 30329, USA
| | - Yena Woo
- Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA 30329, USA
| | - Enrique Torre
- Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA 30329, USA
| | - Manuel Yepes
- Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA 30329, USA
- Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Department of Neurology, Veterans Affairs Medical Center, Atlanta, GA 30033, USA
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Ruiz-Bañobre J, Goel A. Genomic and epigenomic biomarkers in colorectal cancer: From diagnosis to therapy. Adv Cancer Res 2021; 151:231-304. [PMID: 34148615 PMCID: PMC10338180 DOI: 10.1016/bs.acr.2021.02.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Despite ongoing efforts aimed at increasing screening for CRC and early detection, and development of more effective therapeutic regimens, the overall morbidity and mortality from this malignancy remains a clinical challenge. Therefore, identifying and developing genomic and epigenomic biomarkers that can improve CRC diagnosis and help predict response to current therapies are of paramount importance for improving survival outcomes in CRC patients, sparing patients from toxicity associated with current regimens, and reducing the economic burden associated with these treatments. Although efforts to develop biomarkers over the past decades have achieved some success, the recent availability of high-throughput analytical tools, together with the use of machine learning algorithms, will likely hasten the development of more robust diagnostic biomarkers and improved guidance for clinical decision-making in the coming years. In this chapter, we provide a systematic and comprehensive overview on the current status of genomic and epigenomic biomarkers in CRC, and comment on their potential clinical significance in the management of patients with this fatal malignancy, including in the context of precision medicine.
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Affiliation(s)
- Juan Ruiz-Bañobre
- Medical Oncology Department, University Clinical Hospital of Santiago de Compostela, University of Santiago de Compostela (USC), CIBERONC, Santiago de Compostela, Spain; Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago de Compostela, University of Santiago de Compostela (USC), CIBERONC, Santiago de Compostela, Spain
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, United States.
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Equine Genital Squamous Cell Carcinoma Associated with EcPV2 Infection: RANKL Pathway Correlated to Inflammation and Wnt Signaling Activation. BIOLOGY 2021; 10:biology10030244. [PMID: 33801021 PMCID: PMC8003831 DOI: 10.3390/biology10030244] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 02/07/2023]
Abstract
Simple Summary Equine genital squamous cell carcinomas (egSCCs) associated with papilloma virus (PV) infection have been recently proposed as model for human PV-induced SCC. In both species, PV mucosal infections often induce cervical, oropharyngeal, penile, anal, vaginal, and vulvar cancer. The aim of this study was to clarify the molecular mechanisms behind egSCCs associated with equine papillomavirus 2 (EcPV2) infection investigating receptor activator of nuclear factor-kappa B ligand (RANKL), Wnt, and interleukin (IL)17 signaling pathways. RANKL has been recently demonstrated to play a crucial role in several human tumors, associated with a poor prognosis and metastatic spread; novel targeted therapies through RANKL silencing monoclonal antibodies have been undertaken. EcPV2-E6 DNA was checked, and viral presence was confirmed in 91% of cases, whereas oncogene expression was 60.8% for E6 and 34.7% for E2. RANKL, NFKBp50, NFKBp65, IL6, IL17, IL23p19, IL8, IL12p35, IL12p40, BCATN1, FOSL1, and LEF1 gene expression showed a significant upregulation in tumor samples compared to healthy tissues. Our results describe an inflammatory environment characterized by the increased expression of several cytokines and the activation of RANKL/RANK, IL17A, and canonical and non-canonical Wnt signaling pathways. These results may be helpful to identify new targets for immunotherapy strategies confirming egSCCs as a model for the human disease. Abstract Equine genital squamous cell carcinomas (egSCCs) are among the most common equine tumors after sarcoids, severely impairing animal health and welfare. Equus caballus papillomavirus type 2 (EcPV2) infection is often related to these tumors. The aim of this study was to clarify the molecular mechanisms behind egSCCs associated with EcPV2 infection, investigating receptor activator of nuclear factor-kappa B ligand (RANKL) signaling in NF-kB pathway, together with the Wnt and IL17 signaling pathways. We analyzed the innate immune response through gene expression evaluation of key cytokines and transcription factors. Moreover, Ki67 index was assessed with immunohistochemistry. EcPV2-E6 DNA was checked, and viral presence was confirmed in 21 positive out to 23 cases (91%). Oncogene expression was confirmed in 14 cases (60.8%) for E6 and in 8 (34.7%) for E2. RANKL, nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB)-p50, NFKBp65, interleukin (IL)-6, IL17, IL23p19, IL8, IL12p35, IL12p40, β-catenin (BCATN1), FOS like 1 (FOSL1), and lymphoid enhancer binding factor 1 (LEF1) showed a significant upregulation in tumor samples compared to healthy tissues. Our results describe an inflammatory environment characterized by the activation of RANKL/RANK and IL17 with the relative downstream pathways, and a positive modulation of inflammatory cytokines genes such as IL6 and IL8. Moreover, the increase of BCATN1, FOSL1, and LEF1 gene expression suggests an activation of both canonical and non-canonical Wnt signaling pathway that could be critical for carcinogenesis and tumor progression.
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Fatty Acids and a High-Fat Diet Induce Epithelial-Mesenchymal Transition by Activating TGFβ and β-Catenin in Liver Cells. Int J Mol Sci 2021; 22:ijms22031272. [PMID: 33525359 PMCID: PMC7865431 DOI: 10.3390/ijms22031272] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/26/2021] [Accepted: 01/27/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease is defined as the accumulation of excessive fat in the liver in the absence of excessive alcohol consumption or any secondary cause. Although the disease generally remains asymptomatic, chronic liver inflammation leads to fibrosis, liver cirrhosis, and even to the development of hepatocellular carcinoma (HCC). Fibrosis results from epithelial–mesenchymal transition (EMT), which leads to dedifferentiation of epithelial cells into cells with a mesenchymal-like phenotype. During EMT, epithelial cells with high expression of E-cadherin, influenced by growth factors, cytokines, and inflammatory processes, undergo morphological changes via enhanced expression of, e.g., vimentin, fibronectin, and N-cadherin. An inducer of EMT and, consequently, of fibrosis development is transforming growth factor beta (TGFβ), a pleiotropic cytokine associated with the progression of hepatocarcinogenesis. However, the understanding of the molecular events that direct the development of steatosis into steatohepatitis and liver fibrosis remains incomplete. Our study revealed that both prolonged exposure of hepatocarcinoma cells to fatty acids in vitro and high-fat diet in mice (20 weeks) result in inflammation. Prolonged treatment with fatty acids increased the levels of TGFβ, MMP9, and β-catenin, important EMT inducers. Moreover, the livers of mice fed a high-fat diet exhibited features of liver fibrosis with increased TGFβ and IL-1 levels. Increased expression of IL-1 correlated with a decrease in monocyte chemoattractant protein-induced protein 1 (MCPIP1), a negative regulator of the inflammatory response that regulates the stability of proinflammatory transcripts encoding IL-1. Our study showed that a high-fat diet induced EMT by increasing the levels of EMT-activating transcription factors, including Zeb1, Zeb2, and Snail and changed the protein profile to a profile characteristic of the mesenchymal phenotype.
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TCF7L2 silencing results in altered gene expression patterns accompanied by local genomic reorganization. Neoplasia 2021; 23:257-269. [PMID: 33422939 PMCID: PMC7809436 DOI: 10.1016/j.neo.2020.12.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 12/15/2020] [Accepted: 12/29/2020] [Indexed: 11/27/2022] Open
Abstract
Canonical Wnt signaling is crucial for intestinal homeostasis as TCF4, the major Wnt signaling effector in the intestines, is required for stem cell maintenance. The capability of TCF4 to maintain the stem cell phenotype is contingent upon β-catenin, a potent transcriptional activator, which interacts with histone acetyltransferases and chromatin remodeling complexes. We used RNAi to explore the influence of TCF4 on chromatin structure (Hi-C) and gene expression (RNA sequencing) across a 72-hour time series in colon cancer. We found that TCF4 reduction results in a disproportionate up-regulation of gene expression, including a powerful induction of SOX2. Integration of RNA sequencing and Hi-C data revealed a TAD boundary loss, which occurred concomitantly with the over-expression of a cluster of CEACAM genes on chromosome 19. We identified EMT and E2F as the 2 most deregulated pathways upon TCF4 depletion and LUM, TMPO, and AURKA as highly influential genes in these networks using measures of centrality. Results from gene expression, chromatin structure, and centrality analyses were integrated to generate a list of candidate transcription factors crucial for colon cancer cell homeostasis. The top ranked factor was c-JUN, an oncoprotein known to interact with TCF4 and β-catenin, confirming the usefulness of this approach.
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Expression patterns of seven key genes, including β-catenin, Notch1, GATA6, CDX2, miR-34a, miR-181a and miR-93 in gastric cancer. Sci Rep 2020; 10:12342. [PMID: 32704077 PMCID: PMC7378835 DOI: 10.1038/s41598-020-69308-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 06/01/2020] [Indexed: 02/08/2023] Open
Abstract
Gastric cancer (GC) is one of the most prevalent cancers and a major cause of cancer related mortality worldwide. Incidence of GC is affected by various factors, including genetic and environmental factors. Despite extensive research has been done for molecular characterization of GC, it remains largely unknown. Therefore, further studies specially conducted among various ethnicities in different geographic locations, are required to know the precise molecular mechanisms leading to tumorigenesis and progression of GC. The expression patterns of seven candidate genes, including β-catenin, Notch1, GATA6, CDX2, miR-34a, miR-181a, and miR-93 were determined in 24 paired GC tissues and corresponding non-cancerous tissues by quantitative Real-Time PCR. The association between the expression of these genes and clinicopathologic factors were also investigated. Our results demonstrated that overall mRNA levels of GATA6 were significantly decreased in the tumor samples in comparison with the non-cancerous tissues (median fold change (FC) = 0.3143; P = 0.0003). Overall miR-93 levels were significantly increased in the tumor samples relative to the non-cancerous gastric tissues (FC = 2.441; P = 0.0002). β-catenin mRNA expression showed a strong positive correlation with miR-34a (r = 0.5784; P = 0.0031), and miR-181a (r = 0.5652; P = 0.004) expression. miR-34a and miR-181a expression showed a significant positive correlation (r = 0.4862; P = 0.016). Moreover, lower expression of Notch1 was related to distant metastasis in GC patients with a borderline statistical significance (p = 0.0549). These data may advance our understanding of the molecular biology that drives GC as well as provide potential targets for defining novel therapeutic strategies for GC treatment.
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A Driver Never Works Alone-Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer. Cancers (Basel) 2020; 12:cancers12061532. [PMID: 32545208 PMCID: PMC7353041 DOI: 10.3390/cancers12061532] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/03/2020] [Accepted: 06/05/2020] [Indexed: 12/12/2022] Open
Abstract
The knowledge accumulating on the occurrence and mechanisms of the activation of oncogenes in human neoplasia necessitates an increasingly detailed understanding of their systemic interactions. None of the known oncogenic drivers work in isolation from the other oncogenic pathways. The cooperation between these pathways is an indispensable element of a multistep carcinogenesis, which apart from inactivation of tumor suppressors, always includes the activation of two or more proto-oncogenes. In this review we focus on representative examples of the interaction of major oncogenic drivers with one another. The drivers are selected according to the following criteria: (1) the highest frequency of known activation in human neoplasia (by mutations or otherwise), (2) activation in a wide range of neoplasia types (universality) and (3) as a part of a distinguishable pathway, (4) being a known cause of phenotypic addiction of neoplastic cells and thus a promising therapeutic target. Each of these universal oncogenic factors—mutant p53, KRAS and CMYC proteins, telomerase ribonucleoprotein, proteasome machinery, HSP molecular chaperones, NF-κB and WNT pathways, AP-1 and YAP/TAZ transcription factors and non-coding RNAs—has a vast network of molecular interrelations and common partners. Understanding this network allows for the hunt for novel therapeutic targets and protocols to counteract drug resistance in a clinical neoplasia treatment.
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Yang R, Liu S, Liang X, Yin N, Ruan T, Jiang L, Faiola F. F-53B and PFOS treatments skew human embryonic stem cell in vitro cardiac differentiation towards epicardial cells by partly disrupting the WNT signaling pathway. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2020; 261:114153. [PMID: 32088431 DOI: 10.1016/j.envpol.2020.114153] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 02/07/2020] [Accepted: 02/08/2020] [Indexed: 06/10/2023]
Abstract
F-53B and PFOS are two per- and polyfluoroalkyl substances (PFASs) widely utilized in the metal plating industry as mist suppressants. Recent epidemiological studies have linked PFASs to cardiovascular diseases and alterations in heart geometry. However, we still have limited understanding of the effects of F-53B and PFOS on the developing heart. In this study, we employed a human embryonic stem cell (hESC)-based cardiac differentiation system and whole transcriptomics analyses to evaluate the potential developmental cardiac toxicity of F-53B and PFOS. We utilized F-53B and PFOS concentrations of 0.1-60 μM, covering the levels detected in human blood samples. We demonstrated that both F-53B and PFOS inhibited cardiac differentiation and promoted epicardial specification via upregulation of the WNT signaling pathway. Most importantly, the effects of F-53B were more robust than those of PFOS. This was because F-53B treatment disrupted the expression of more genes and led to lower cardiac differentiation efficiency. These findings imply that F-53B may not be a safe replacement for PFOS.
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Affiliation(s)
- Renjun Yang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shuyu Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, 100049, China; Wellcome Trust/CRUK Gurdon Institute, Department of Pathology, University of Cambridge, Cambridge, CB2 1QN, UK
| | - Xiaoxing Liang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Nuoya Yin
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ting Ruan
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Linshu Jiang
- Beijing Key Laboratory for Dairy Cow Nutrition, Beijing University of Agriculture, Beijing, 102206, China
| | - Francesco Faiola
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, 100049, China.
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Collins TK, Houghten S. A centrality based multi-objective approach to disease gene association. Biosystems 2020; 193-194:104133. [PMID: 32243908 DOI: 10.1016/j.biosystems.2020.104133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 02/27/2020] [Accepted: 03/23/2020] [Indexed: 01/11/2023]
Abstract
Disease Gene Association finds genes that are involved in the presentation of a given genetic disease. We present a hybrid approach which implements a multi-objective genetic algorithm, where input consists of centrality measures based on various relational biological evidence types merged into a complex network. Multiple objective settings and parameters are studied including the development of a new exchange methodology, safe dealer-based crossover. Successful results with respect to breast cancer and Parkinson's disease compared to previous techniques and popular known databases are shown. In addition, the newly developed methodology is also successfully applied to Alzheimer's disease, further demonstrating its flexibility. Across all three case studies the strongest results were produced by the shortest path-based measures stress and betweenness, either in a single objective parameter setting or when used in conjunction in a multi-objective environment. The new crossover technique achieved the best results when applied to Alzheimer's disease.
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Affiliation(s)
- Tyler K Collins
- Computer Science Department, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, Ontario L2S 3A1, Canada
| | - Sheridan Houghten
- Computer Science Department, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, Ontario L2S 3A1, Canada.
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Lai KKY, Nguyen C, Lee KS, Lee A, Lin DP, Teo JL, Kahn M. Convergence of Canonical and Non-Canonical Wnt Signal: Differential Kat3 Coactivator Usage. Curr Mol Pharmacol 2020; 12:167-183. [PMID: 30836930 PMCID: PMC6687580 DOI: 10.2174/1874467212666190304121131] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 01/30/2019] [Accepted: 02/06/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND The ancient and highly evolutionarily conserved Wnt signaling pathway is critical in nearly all tissues and organs for an organism to develop normally from embryo through adult. Wnt signaling is generally parsed into "canonical" or Wnt-β-catenin-dependent or "non-canonical" β-catenin-independent signaling. Even though designating Wnt signaling as either canonical or noncanonical allows for easier conceptual discourse about this signaling pathway, in fact canonical and non-canonical Wnt crosstalk regulates complex nonlinear networks. OBJECTIVE In this perspective, we discuss the integration of canonical and non-canonical Wnt signaling via differential Kat3 (CBP and p300) coactivator usage, thereby regulating and coordinating gene expression programs associated with both proliferation and cellular differentiation and morphogenesis. METHODS Pharmacologic inhibitors, cell culture, real-time PCR, chromatin immunoprecipitation, protein immunoprecipitation, Western blotting, reporter-luciferase, protein purification, site-directed mutagenesis, in vitro phosphorylation and binding assays, and immunofluorescence were utilized. CONCLUSION Coordinated integration between both canonical and non-canonical Wnt pathways appears to be crucial not only in the control of fundamental morphologic processes but also in the regulation of normal as well as pathologic events. Such integration between both canonical and non-canonical Wnt signaling is presumably effected via reversible phosphorylation mechanism (e.g., protein kinase C) to regulate differential β -catenin/Kat3 coactivator usage in order to coordinate proliferation with differentiation and adhesion.
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Affiliation(s)
- Keane K Y Lai
- Department of Pathology, City of Hope National Medical Center, Duarte, California, United States.,Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California, United States.,City of Hope Comprehensive Cancer Center, Duarte, California, United States
| | - Cu Nguyen
- Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California, United States
| | - Kyung-Soon Lee
- Department of Pharmacology, University of Washington, Seattle, Washington, United States
| | - Albert Lee
- Children's Hospital Los Angeles, Los Angeles, California, United States
| | - David P Lin
- Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California, United States
| | - Jia-Ling Teo
- Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California, United States
| | - Michael Kahn
- Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California, United States.,City of Hope Comprehensive Cancer Center, Duarte, California, United States
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Jung YS, Park JI. Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex. Exp Mol Med 2020; 52:183-191. [PMID: 32037398 PMCID: PMC7062731 DOI: 10.1038/s12276-020-0380-6] [Citation(s) in RCA: 313] [Impact Index Per Article: 62.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/20/2019] [Accepted: 12/26/2019] [Indexed: 02/07/2023] Open
Abstract
Wnt/β-catenin signaling is implicated in many physiological processes, including development, tissue homeostasis, and tissue regeneration. In human cancers, Wnt/β-catenin signaling is highly activated, which has led to the development of various Wnt signaling inhibitors for cancer therapies. Nonetheless, the blockade of Wnt signaling causes side effects such as impairment of tissue homeostasis and regeneration. Recently, several studies have identified cancer-specific Wnt signaling regulators. In this review, we discuss the Wnt inhibitors currently being used in clinical trials and suggest how additional cancer-specific regulators could be utilized to treat Wnt signaling-associated cancer.
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Affiliation(s)
- Youn-Sang Jung
- 0000 0001 2291 4776grid.240145.6Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Jae-Il Park
- 0000 0001 2291 4776grid.240145.6Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA ,0000 0001 2291 4776grid.240145.6Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA ,0000 0001 2291 4776grid.240145.6Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
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41
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Virzì A, Roca Suarez AA, Baumert TF, Lupberger J. Rewiring Host Signaling: Hepatitis C Virus in Liver Pathogenesis. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a037366. [PMID: 31501266 DOI: 10.1101/cshperspect.a037366] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease including metabolic disease, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCV induces and promotes liver disease progression by perturbing a range of survival, proliferative, and metabolic pathways within the proinflammatory cellular microenvironment. The recent breakthrough in antiviral therapy using direct-acting antivirals (DAAs) can cure >90% of HCV patients. However, viral cure cannot fully eliminate the HCC risk, especially in patients with advanced liver disease or comorbidities. HCV induces an epigenetic viral footprint that promotes a pro-oncogenic hepatic signature, which persists after DAA cure. In this review, we summarize the main signaling pathways deregulated by HCV infection, with potential impact on liver pathogenesis. HCV-induced persistent signaling patterns may serve as biomarkers for the stratification of HCV-cured patients at high risk of developing HCC. Moreover, these signaling pathways are potential targets for novel chemopreventive strategies.
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Affiliation(s)
- Alessia Virzì
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
| | - Armando Andres Roca Suarez
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France.,Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France.,Institut Universitaire de France (IUF), 75231 Paris, France
| | - Joachim Lupberger
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
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42
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Nguyen LH, Goel A, Chung DC. Pathways of Colorectal Carcinogenesis. Gastroenterology 2020; 158:291-302. [PMID: 31622622 PMCID: PMC6981255 DOI: 10.1053/j.gastro.2019.08.059] [Citation(s) in RCA: 292] [Impact Index Per Article: 58.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 08/13/2019] [Accepted: 08/15/2019] [Indexed: 12/15/2022]
Abstract
Colorectal cancer is a heterogeneous disease that develops via stepwise accumulation of well-characterized genetic and epigenetic alterations. We review the genetic changes associated with the development of precancerous colorectal adenomas and their progression to tumors, as well as the effects of defective DNA repair, chromosome instability, microsatellite instability, and alterations in the serrated pathway and DNA methylation. We provide insights into the different molecular subgroups of colorectal tumors that develop via each of these different mechanisms and their associations with patient outcomes.
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Affiliation(s)
- Long H Nguyen
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Ajay Goel
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Dallas, Texas; Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas; Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
| | - Daniel C Chung
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Center for Cancer Risk Assessment, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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43
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Lu F, Zhou Q, Liu L, Zeng G, Ci W, Liu W, Zhang G, Zhang Z, Wang P, Zhang A, Gao Y, Yu L, He Q, Chen L. A tumor suppressor enhancing module orchestrated by GATA4 denotes a therapeutic opportunity for GATA4 deficient HCC patients. Theranostics 2020; 10:484-497. [PMID: 31903133 PMCID: PMC6929984 DOI: 10.7150/thno.38060] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 09/30/2019] [Indexed: 01/17/2023] Open
Abstract
Rationale: Effective targeting therapies are limited in Hepatocellular carcinoma (HCC) clinic. Characterization of tumor suppressor genes (TSGs) and elucidation their signaling cascades could shed light on new strategies for developing targeting therapies for HCC. Methods: We checked genome-wide DNA copy number variation (CNV) of HCC samples, focusing on deleted genes for TSG candidates. Clinical data, in vitro and in vivo data were collected to validate the tumor suppressor functions. Results: Focal deletion of GATA4 gene locus was the most prominent feature across all liver cancer samples. Ectopic expression of GATA4 resulted in senescence of HCC cell lines. Mechanistically, GATA4 exerted tumor suppressive role by orchestrating the assembly of a tumor suppressor enhancing module: GATA4 directly bound and potently inhibited the mRNA transcription activity of β-catenin; meanwhile, β-catenin was recruited by GATA4 to promoter regions and facilitated transcription of GATA4 target genes, which were TSGs per se. Expression of GATA4 was effective to shrink GATA4-deficient HCC tumors in vivo. We also showed that β-catenin inhibitor was capable of shrinking GATA4-deficient tumors. Conclusions: Our study unveiled a previously unnoticed tumor suppressor enhancing module assembled by ectopically expressed GATA4 in HCC cells and denoted a therapeutic opportunity for GATA4 deficient HCC patients. Our study also presented an interesting case that an oncogenic transcription factor conditionally functioned as a tumor suppressor when recruited by a TSG transcription factor.
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44
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Martinez M, Torres VI, Vio CP, Inestrosa NC. Canonical Wnt Signaling Modulates the Expression of Pre- and Postsynaptic Components in Different Temporal Patterns. Mol Neurobiol 2019; 57:1389-1404. [DOI: 10.1007/s12035-019-01785-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 09/12/2019] [Indexed: 01/09/2023]
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45
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Pfefferle AD, Darr DB, Calhoun BC, Mott KR, Rosen JM, Perou CM. The MMTV-Wnt1 murine model produces two phenotypically distinct subtypes of mammary tumors with unique therapeutic responses to an EGFR inhibitor. Dis Model Mech 2019; 12:dmm.037192. [PMID: 31213486 PMCID: PMC6679375 DOI: 10.1242/dmm.037192] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 06/06/2019] [Indexed: 12/23/2022] Open
Abstract
The Wnt gene family encodes an evolutionarily conserved group of proteins that regulate cell growth, differentiation and stem cell self-renewal. Aberrant Wnt signaling in human breast tumors has been proposed as a driver of tumorigenesis, especially in the basal-like tumor subtype where canonical Wnt signaling is both enriched and predictive of poor clinical outcomes. The development of effective Wnt-based therapeutics, however, has been slowed in part by a limited understanding of the context-dependent nature with which these aberrations influence breast tumorigenesis. We previously reported that MMTV-Wnt1 mice, an established model for studying Wnt signaling in breast tumors, develop two subtypes of tumors by gene expression classification: Wnt1-EarlyEx and Wnt1-LateEx Here, we extend this initial observation and show that Wnt1-EarlyEx tumors exhibit high expression of canonical Wnt, non-canonical Wnt, and EGFR signaling pathway signatures. Therapeutically, Wnt1-EarlyEx tumors showed a dynamic reduction in tumor volume when treated with an EGFR inhibitor. Wnt1-EarlyEx tumors had primarily Cd49fpos/Epcamneg FACS profiles, but it was not possible to serially transplant these tumors into wild-type FVB female mice. Conversely, Wnt1-LateEx tumors had a bloody gross pathology, which was highlighted by the presence of 'blood lakes' identified by H&E staining. These tumors had primarily Cd49fpos/Epcampos FACS profiles, but also contained a secondary Cd49fpos/Epcamneg subpopulation. Wnt1-LateEx tumors were enriched for activating Hras1 mutations and were capable of reproducing tumors when serially transplanted into wild-type FVB female mice. This study definitively shows that the MMTV-Wnt1 mouse model produces two phenotypically distinct subtypes of mammary tumors that differ in multiple biological aspects including sensitivity to an EGFR inhibitor.
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Affiliation(s)
- Adam D Pfefferle
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - David B Darr
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Benjamin C Calhoun
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Kevin R Mott
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.,Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Jeffrey M Rosen
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Charles M Perou
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA .,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.,Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
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46
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Wnt signaling in intestinal inflammation. Differentiation 2019; 108:24-32. [DOI: 10.1016/j.diff.2019.01.002] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 12/17/2018] [Accepted: 01/18/2019] [Indexed: 12/12/2022]
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47
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Badimon L, Casaní L, Camino-Lopez S, Juan-Babot O, Borrell-Pages M. GSK3β inhibition and canonical Wnt signaling in mice hearts after myocardial ischemic damage. PLoS One 2019; 14:e0218098. [PMID: 31220102 PMCID: PMC6586285 DOI: 10.1371/journal.pone.0218098] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 05/25/2019] [Indexed: 12/22/2022] Open
Abstract
Aims Myocardial infarction induces myocardial injury and tissue damage. During myocardial infarction strong cellular response is initiated to salvage the damaged tissues. This response is associated with the induction of different signaling pathways. Of these, the canonical Wnt signaling is increasingly important for its prosurvival cellular role, making it a good candidate for the search of new molecular targets to develop therapies to prevent heart failure in infarcted patients. Methods Herein we report that GSK3β regulates the canonical Wnt signaling in C57Bl6 mice hearts. GSK3β is a canonical Wnt pathway inhibitor. Using GSK3β inhibitors and inducing myocardial injury (MI) in Lrp5-/- mice model we show that GSK3β phosphorylation levels regulate downstream canonical Wnt pathway genes in the ischemic heart. In the setting of MI, myocardial damage assessment usually correlates with functional and clinical outcomes. Therefore, we measured myocardial injury size in Wt and Lrp5-/- mice in the presence and absence of two different GSK3 inhibitors prior to MI. Myocardial injury was independent of GSK3 inhibitor treatments and GSK3β expression levels. Results These studies support a central role for GSK3β in the activation of the canonical Wnt pathway in the Wt heart. Although LRP5 is protective against myocardial injury, GSK3β expression levels do not regulate heart damage.
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Affiliation(s)
- Lina Badimon
- Cardiovascular Program ICCC, Institut de Recerca de l’-Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- CIBER-CV, Instituto de Salud Carlos III, Madrid, Spain
- Cardiovascular Research Chair, UAB, Barcelona, Spain
| | - Laura Casaní
- Cardiovascular Program ICCC, Institut de Recerca de l’-Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Sandra Camino-Lopez
- Cardiovascular Program ICCC, Institut de Recerca de l’-Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Oriol Juan-Babot
- Cardiovascular Program ICCC, Institut de Recerca de l’-Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Maria Borrell-Pages
- Cardiovascular Program ICCC, Institut de Recerca de l’-Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- CIBER-CV, Instituto de Salud Carlos III, Madrid, Spain
- * E-mail:
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48
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Anvarnia A, Mohaddes‐Gharamaleki F, Asadi M, Akbari M, Yousefi B, Shanehbandi D. Dysregulated microRNAs in colorectal carcinogenesis: New insight to cell survival and apoptosis regulation. J Cell Physiol 2019; 234:21683-21693. [DOI: 10.1002/jcp.28872] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 04/16/2019] [Accepted: 04/17/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Alireza Anvarnia
- Department of Biochemistry and Clinical Laboratories Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
- Student Research Committee, Tabriz University of Medical Sciences Tabriz Iran
| | - Farzad Mohaddes‐Gharamaleki
- Department of Biochemistry and Clinical Laboratories Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
- Student Research Committee, Tabriz University of Medical Sciences Tabriz Iran
| | - Milad Asadi
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
| | - Bahman Yousefi
- Department of Biochemistry and Clinical Laboratories Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
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49
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Ahn SM, Kang S, Min DH. Direct Monitoring of Cancer-Associated mRNAs in Living Cells to Evaluate the Therapeutic RNAi Efficiency Using Fluorescent Nanosensor. ACS Sens 2019; 4:1174-1179. [PMID: 31002230 DOI: 10.1021/acssensors.8b01498] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Cancer-associated mRNA (mRNA) is an important biomarker for early diagnosis, prognosis, and prediction of treatment responses. Despite recent developments in fluorescence live cell imaging, reliable detection and quantification of mRNA in living cells still remain challenging due to a complicated intracellular environment. Herein, we present a fluorescent nanosensor for live-cell monitoring of cancer-related mRNAs involved in the canonical Wnt/β-catenin signaling pathway. The nanosensor enables rapid and accurate assessment of gene downregulation efficiency in a dose- and time-dependent manner by measuring quantitative fluorescence signal corresponding to β-catenin or its target mRNA levels in living cells. It is expected that the fluorescent nanosensor will be applicable to high-throughput screening for the efficient drug discovery and insightful understanding of the molecular mechanisms of potential drug candidate for cancer treatment.
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Affiliation(s)
- Seong Min Ahn
- Department of Chemistry, Seoul National University, Seoul, 08826, Republic of Korea
- Center for RNA Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
| | - Seounghun Kang
- Department of Chemistry, Seoul National University, Seoul, 08826, Republic of Korea
- Center for RNA Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
| | - Dal-Hee Min
- Department of Chemistry, Seoul National University, Seoul, 08826, Republic of Korea
- Center for RNA Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
- Institute of Biotherapeutics Convergence Technology, Lemonex Inc., Seoul, 08826, Republic of Korea
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50
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Okadaic acid activates Wnt/β-catenin-signaling in human HepaRG cells. Arch Toxicol 2019; 93:1927-1939. [PMID: 31115591 DOI: 10.1007/s00204-019-02489-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 05/16/2019] [Indexed: 12/13/2022]
Abstract
The lipophilic phycotoxin okadaic acid (OA) occurs in the fatty tissue and hepatopancreas of filter-feeding shellfish. The compound provokes the diarrhetic shellfish poisoning (DSP) syndrome after intake of seafood contaminated with high levels of the DSP toxin. In animal experiments, long-term exposure to OA is associated with an elevated risk for tumor formation in different organs including the liver. Although OA is a known inhibitor of the serine/threonine protein phosphatase 2A, the mechanisms behind OA-induced carcinogenesis are not fully understood. Here, we investigated the influence of OA on the β-catenin-dependent Wnt-signaling pathway, addressing a major oncogenic pathway relevant for tumor development. We analyzed OA-mediated effects on β-catenin and its biological function, cellular localization, post-translational modifications, and target gene expression in human HepaRG hepatocarcinoma cells treated with non-cytotoxic concentrations up to 50 nM. We detected concentration- and time-dependent effects of OA on the phosphorylation state, cellular redistribution as well as on the amount of transcriptionally active β-catenin. These findings were confirmed by quantitative live-cell imaging of U2OS cells stably expressing a green fluorescent chromobody which specifically recognize hypophosphorylated β-catenin. Finally, we demonstrated that nuclear translocation of β-catenin mediated by non-cytotoxic OA concentrations results in an upregulation of Wnt-target genes. In conclusion, our results show a significant induction of the canonical Wnt/β-catenin-signaling pathway by OA in human liver cells. Our data contribute to a better understanding of the molecular mechanisms underlying OA-induced carcinogenesis.
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