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1
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Zhao M, Ye M, Zhao Y. Causal link between dietary antioxidant vitamins intake, oxidative stress injury biomarkers and colorectal cancer: A Mendelian randomization study. Medicine (Baltimore) 2025; 104:e41531. [PMID: 39960957 PMCID: PMC11835131 DOI: 10.1097/md.0000000000041531] [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: 06/09/2024] [Accepted: 01/27/2025] [Indexed: 02/20/2025] Open
Abstract
Oxidative stress and reactive oxygen species play a pivotal role in carcinogenesis. Recent studies have indicated a potential reduction in cancer incidence associated with antioxidant intake; however, these results remain controversial. We performed 2-sample Mendelian randomization (MR) analysis to explore the causal relationship between dietary antioxidant vitamins (retinol, carotene, vitamin C, and vitamin E), oxidative stress injury biomarkers (GST, CAT, SOD, and GPX), and the risk of colorectal cancer (CRC). The genetic instrumental variants (IVs) that had previously shown significant association with dietary antioxidant vitamins and oxidative stress injury biomarkers were screened from the UK Biobank and relevant published studies. The genome-wide association study (GWAS) data for total colorectal, colon, and rectal cancer were obtained from the FinnGen cohort. The primary MR analysis employed the inverse-variance-weighted (IVW) method. Furthermore, sensitivity analysis was performed to assess heterogeneity and horizontal pleiotropy. The results revealed no significant causal associations between dietary antioxidant vitamins, oxidative stress injury biomarkers, and the risk of CRC. The odds ratios (ORs) were as follows: 1.22 (95% confidence interval (CI): 0.65-2.28, P = .53) for retinol, 0.77 (95% CI: 0.50-1.18, P = .24) for carotene, 0.82 (95% CI: 0.42-1.63, P = .58) for vitamin C, and 1.20 (95% CI: 0.86-1.68, P = .28) for vitamin E. Regarding oxidative stress injury biomarkers, the ORs were 0.99 (95% CI: 0.93-1.06, P = .88) for GST, 0.99 (95% CI: 0.93-1.05, P = .65) for CAT, 1.02 (95% CI: 0.95-1.09, P = .57) for SOD, and 1.01 (95% CI: 0.95-1.07, P = .76) for GPX. Likewise, stratified analysis by tumor site revealed no beneficial effects in colon and rectal cancers. Our findings indicate that elevated levels of diet-related antioxidant vitamins, as well as biomarkers of oxidative stress injury, do not provide a protective effect against CRC risk.
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Affiliation(s)
- Minghui Zhao
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mujie Ye
- Department of Geriatric Gastroenterology, Institute of Neuroendocrine Tumor, Neuroendocrine Tumor Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yucui Zhao
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Cina C, Majeti B, O'Brien Z, Wang L, Clamme JP, Adami R, Tsang KY, Harborth J, Ying W, Zabludoff S. A Novel Lipid Nanoparticle NBF-006 Encapsulating Glutathione S-Transferase P siRNA for the Treatment of KRAS-Driven Non-small Cell Lung Cancer. Mol Cancer Ther 2025; 24:7-17. [PMID: 39417782 DOI: 10.1158/1535-7163.mct-23-0915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 03/25/2024] [Accepted: 10/15/2024] [Indexed: 10/19/2024]
Abstract
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers, and KRAS mutations occur in 25% to 30% of NSCLC. Our approach to developing a therapeutic with the potential to target KRAS-mutant NSCLC was to identify a new target involved in modulating signaling proteins in the RAS pathway. Glutathione S-transferase P (GSTP), known as a phase II detoxification enzyme, has more recently been identified as a modulator of MAPK-related cell signaling pathways. Therefore, developing a GSTP siRNA may be an effective therapeutic approach to treat KRAS-mutant NSCLC. The lead drug product candidate (NBF-006) is a proprietary siRNA-based lipid nanoparticle comprising GSTP siRNA (NDT-05-1040). Here, studies using a panel of KRAS-mutant NSCLC cell lines demonstrated that NDT-05-1040 is a very potent and selective GSTP siRNA inhibitor. Our Western blot analysis showed that NDT-05-1040 effectively decreased the phosphorylation of MAPK and PI3K pathway components while upregulating apoptotic signaling cascade. Our in vivo studies revealed statistically significant higher distribution of NBF-006 to the lungs and tumor as compared with the liver. In the subcutaneous and orthotopic tumor models, NBF-006 led to a statistically significant and dose-dependent antitumor growth inhibition. Furthermore, quantitative image analysis of proliferating cell nuclear antigen and PARP staining showed that NBF-006 decreased proliferation and induced apoptosis, respectively, in tumors. Additionally, in a surgically implanted orthotopic lung tumor model, the survival rate of the NBF-006 treatment group was significantly prolonged (P < 0.005) as compared with the vehicle control group. Together, these preclinical studies supported advancement of NBF-006 into clinical studies.
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Affiliation(s)
- Cima Cina
- Nitto BioPharma, Inc., San Diego, California
| | | | | | - Li Wang
- Nitto BioPharma, Inc., San Diego, California
| | | | - Roger Adami
- Nitto BioPharma, Inc., San Diego, California
| | | | | | - Wenbin Ying
- Nitto BioPharma, Inc., San Diego, California
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Imbaby S, Elkholy SE, Faisal S, Abdelmaogood AKK, Mehana AE, Mansour BSA, Abd El-Moneam SM, Elaidy SM. The GSTP1/MAPKs/BIM/SMAC modulatory actions of nitazoxanide: Bioinformatics and experimental evidence in subcutaneous solid Ehrlich carcinoma-inoculated mice. Life Sci 2023; 319:121496. [PMID: 36822315 DOI: 10.1016/j.lfs.2023.121496] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/05/2023] [Accepted: 02/08/2023] [Indexed: 02/25/2023]
Abstract
AIMS Ehrlich ascites carcinoma and its subcutaneous inoculated solid tumour form (SEC) are reliable models for chemotherapeutic molecular targets exploration. Novel chemotherapeutic approaches are identified as molecular targets for intrinsic apoptosis, like the modulation of the second mitochondria-derived activator of caspases (SMAC). SMAC is a physiological substrate of mitogen-activated protein kinases (MAPKs). Glutathione-S-transferase P1 (GSTP1) and its close association with MAPKs play an important role in malignant cell proliferation, metastasis, and resistance to chemotherapeutics. Nitazoxanide (NTZ) is an emerging cancer therapy and its targeted GSTP1 evidence remains a knowledge need. MAIN METHODS In the present mice-established SEC, the chemotherapeutic roles of oral NTZ (200 mg/kg/day) and 5-fluorouracil (5-FU; 20 mg/kg/day, intraperitoneally) regimens were evaluated by measuring changes in tumour mass, the tumour MAPKs, cytochrome c, Bcl-2 interacting mediator of cell death (BIM), and SMAC signalling pathway in addition to its molecular downstream; caspases 3 and 9. KEY FINDINGS Computational analysis for these target protein interactions showed direct-ordered interactions. After individual therapy with NTZ and 5-FU regimens, the histological architecture of the extracted tumour discs revealed decreases in viable tumour regions with significant necrosis surrounds. These findings were consistent with gross tumour sizes. Each separate regimen lowered the remarkable GSTP1 and elevated the low MAPKs expressions, cytochrome c, BIM, SMAC, and caspases 3, and 9 in EST tissues. SIGNIFICANCE The chemotherapeutic activity of NTZ in SEC was proven. Additionally, NTZ possesses a SMAC modulatory activity that, following thorough research, should be taken into consideration as a chemotherapeutic approach in solid tumours.
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Affiliation(s)
- Samar Imbaby
- Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, 41522 Ismailia, Egypt.
| | - Shereen E Elkholy
- Department of Clinical Pharmacology, Faculty of Medicine, Port Said University, Port Said, Egypt
| | - Salwa Faisal
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, 41522 Ismailia, Egypt
| | - Asmaa K K Abdelmaogood
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Suez Canal University, 41522 Ismailia, Egypt
| | - Amir E Mehana
- Department of Zoology, Faculty of Science, Suez Canal University, 41522 Ismailia, Egypt
| | - Basma S A Mansour
- Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, 41522 Ismailia, Egypt
| | - Samar M Abd El-Moneam
- Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, 41522 Ismailia, Egypt
| | - Samah M Elaidy
- Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, 41522 Ismailia, Egypt.
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Fujikawa Y, Terakado K, Nezu S, Noritsugu K, Maemoto Y, Ito A, Inoue H. Improving reactivity of naphthalimide-based GST probe by imparting TPP cation: Development and application for live cell imaging. Bioorg Med Chem Lett 2023; 80:129109. [PMID: 36549395 DOI: 10.1016/j.bmcl.2022.129109] [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: 09/30/2022] [Revised: 12/06/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022]
Abstract
Glutathione S-transferases (GSTs) are a superfamily of multifunctional enzymes comprising multiple classes and subtypes. This paper describes the synthesis and characterization of TPPBN-1, a naphthalimide derivative conjugated with a triphenylphosphonium (TPP) cation. When 4-bromonaphthalimide (BrNaph), a previously characterized GST substrate, was conjugated to a TPP cation, the conjugate showed increased reactivity towards most alpha- and mu-class GSTs, particularly the GSTA2 subtype, compared to the parent compound, but hardly towards Pi-class GSTs. Using this probe with enhanced reactivity, the enzymatic activity of endogenous GSTA1/2 in HepG2 cells was visualized by confocal fluorescence microscopy. The results demonstrated that modification with TPP cations, which are often used as tags for targeting mitochondria, can be used to enhance the reactivity of probes for specific GST subtypes.
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Affiliation(s)
- Yuuta Fujikawa
- Laboratory of Molecular and Chemical Biology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
| | - Kenta Terakado
- Laboratory of Molecular and Chemical Biology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
| | - Sayaka Nezu
- Laboratory of Molecular and Chemical Biology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
| | - Kota Noritsugu
- Laboratory of Cell Signaling, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
| | - Yuki Maemoto
- Laboratory of Cell Signaling, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
| | - Akihiro Ito
- Laboratory of Cell Signaling, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
| | - Hideshi Inoue
- Laboratory of Molecular and Chemical Biology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
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Fujikawa Y, Mori M, Tsukada M, Miyahara S, Sato-Fukushima H, Watanabe E, Murakami-Tonami Y, Inoue H. Pi-class Glutathione S-transferase (GSTP1)-selective fluorescent probes for multicolour imaging with various cancer-associated enzymes. Chembiochem 2022; 23:e202200443. [PMID: 36062403 DOI: 10.1002/cbic.202200443] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/03/2022] [Indexed: 11/09/2022]
Abstract
Pi-class glutathione S-transferase (GSTP1) is highly expressed in a wide variety of human cancer tissues compared to the corresponding normal counterpart. Therefore, GSTP1 is a potential target enzyme for overcoming resistance to chemotherapeutic agents or visualizing specific lesions such as cancer. Here, we present orange and red fluorescence-emitting probes selective for GSTP1. Carbofluorescein and TokyoMagenta fluorophores were modified with a previously described GSTP1-selective chromogenic compound to generate orange and red fluorescence probes, respectively. Of these probes, Ps-CF , the orange fluorescence-emitting probe, was confirmed to be highly specific for detecting GSTP1 exogenously or endogenously expressed in various cancer cells. Additionally, it was demonstrated that Ps-CF is applicable for the simultaneous detection of GSTP1 and another cancer-associated enzymes by using a green fluorescence emitting γ-glutamyl transpeptidase (GGT) probe. In conclusion, the fluorescent probes developed in this study enable the simultaneous detection of multiple tumour markers such as GSTP1 with other cancer-associated enzymes by the concurrent use of spectrally distinguished fluorescent probes, potentially broadening the scope of cancer detection.
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Affiliation(s)
- Yuuta Fujikawa
- Tokyo University of Pharmacy and Life Sciences, School of Life Sciences, 1432-1 Horinouchi, 192-0392, Tokyo, JAPAN
| | - Masaya Mori
- Tokyo University of Pharmacy and Life Science: Tokyo Yakka Daigaku, School of Life Sciences, JAPAN
| | - Minami Tsukada
- Tokyo University of Pharmacy and Life Science: Tokyo Yakka Daigaku, School of Life Sciences, JAPAN
| | - Seiya Miyahara
- Tokyo University of Pharmacy and Life Science: Tokyo Yakka Daigaku, School of Life Sciences, JAPAN
| | - Honoka Sato-Fukushima
- Tokyo University of Pharmacy and Life Science: Tokyo Yakka Daigaku, School of Life Sciences, JAPAN
| | - Eita Watanabe
- Tokyo University of Pharmacy and Life Science: Tokyo Yakka Daigaku, School of Life Sciences, JAPAN
| | - Yuko Murakami-Tonami
- Tokyo University of Technology: Tokyo Koka Daigaku, School of Bioscience and Biotechnology, JAPAN
| | - Hideshi Inoue
- Tokyo University of Pharmacy and Life Science: Tokyo Yakka Daigaku, School of Life Sciences, JAPAN
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Watanabe K, Fujikawa Y, Murakami-Tonami Y, Mori M, Sakata M, Inoue H. Design and synthesis of versatile GSTP1-specific fluorogenic substrates for the highly sensitive detection of GSTP1 activity in living cells. Talanta 2022; 251:123796. [DOI: 10.1016/j.talanta.2022.123796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 10/15/2022]
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NIITSU Y, SATO Y, TAKAYAMA T. Implications of glutathione-S transferase P1 in MAPK signaling as a CRAF chaperone: In memory of Dr. Irving Listowsky. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2022; 98:72-86. [PMID: 35153270 PMCID: PMC8890996 DOI: 10.2183/pjab.98.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/14/2021] [Indexed: 06/14/2023]
Abstract
Glutathione-S transferase P1 (GSTP1) is one of the glutathione-S transferase isozymes that belong to a family of phase II metabolic isozymes. The unique feature of GSTP1 compared with other GST isozymes is its relatively high expression in malignant tissues. Thus, clinically, GSTP1 serves as a tumor marker and as a refractory factor against certain types of anticancer drugs through its primary function as a detoxifying enzyme. Additionally, recent studies have identified a chaperone activity of GSTP1 involved in the regulation the function of various intracellular proteins, including factors of the growth signaling pathway. In this review, we will first describe the function of GSTP1 and then extend the details onto its role in the mitogen-activated protein kinase signal pathway, referring to the results of our recent study that proposed a novel autocrine signal loop formed by the CRAF/GSTP1 complex in mutated KRAS and BRAF cancers. Finally, the possibilities of new therapeutic approaches for these cancers by targeting this complex will be discussed.
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Affiliation(s)
- Yoshiro NIITSU
- Oncology Section, Center of Advanced Medicine, Shonan Kamakura Innovation Park, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
- Sapporo Medical University, Sapporo, Hokkaido, Japan
| | - Yasushi SATO
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Tetsuji TAKAYAMA
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
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Liu Y, Zheng C, Huang Y, He M, Xu WW, Li B. Molecular mechanisms of chemo- and radiotherapy resistance and the potential implications for cancer treatment. MedComm (Beijing) 2021; 2:315-340. [PMID: 34766149 PMCID: PMC8554658 DOI: 10.1002/mco2.55] [Citation(s) in RCA: 165] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 12/25/2020] [Accepted: 12/28/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer is a leading cause of death worldwide. Surgery is the primary treatment approach for cancer, but the survival rate is very low due to the rapid progression of the disease and presence of local and distant metastasis at diagnosis. Adjuvant chemotherapy and radiotherapy are important components of the multidisciplinary approaches for cancer treatment. However, resistance to radiotherapy and chemotherapy may result in treatment failure or even cancer recurrence. Radioresistance in cancer is often caused by the repair response to radiation-induced DNA damage, cell cycle dysregulation, cancer stem cells (CSCs) resilience, and epithelial-mesenchymal transition (EMT). Understanding the molecular alterations that lead to radioresistance may provide new diagnostic markers and therapeutic targets to improve radiotherapy efficacy. Patients who develop resistance to chemotherapy drugs cannot benefit from the cytotoxicity induced by the prescribed drug and will likely have a poor outcome with these treatments. Chemotherapy often shows a low response rate due to various drug resistance mechanisms. This review focuses on the molecular mechanisms of radioresistance and chemoresistance in cancer and discusses recent developments in therapeutic strategies targeting chemoradiotherapy resistance to improve treatment outcomes.
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Affiliation(s)
- Ya‐Ping Liu
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education InstitutesInstitute of Life and Health EngineeringJinan UniversityGuangzhouP. R. China
| | - Can‐Can Zheng
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education InstitutesInstitute of Life and Health EngineeringJinan UniversityGuangzhouP. R. China
| | - Yun‐Na Huang
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering MedicineNational Engineering Research Center of Genetic MedicineInstitute of BiomedicineCollege of Life Science and TechnologyJinan UniversityGuangzhouP. R. China
| | - Ming‐Liang He
- Department of Biomedical SciencesCity University of Hong KongHong KongChina
| | - Wen Wen Xu
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering MedicineNational Engineering Research Center of Genetic MedicineInstitute of BiomedicineCollege of Life Science and TechnologyJinan UniversityGuangzhouP. R. China
| | - Bin Li
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education InstitutesInstitute of Life and Health EngineeringJinan UniversityGuangzhouP. R. China
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Hu K, Li K, Lv J, Feng J, Chen J, Wu H, Cheng F, Jiang W, Wang J, Pei H, Chiao PJ, Cai Z, Chen Y, Liu M, Pang X. Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma. J Clin Invest 2020; 130:1752-1766. [PMID: 31874110 DOI: 10.1172/jci124049] [Citation(s) in RCA: 252] [Impact Index Per Article: 50.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 12/19/2019] [Indexed: 12/13/2022] Open
Abstract
Oncogenic KRAS is a major driver in lung adenocarcinoma (LUAD) that has yet to be therapeutically conquered. Here we report that the SLC7A11/glutathione axis displays metabolic synthetic lethality with oncogenic KRAS. Through metabolomics approaches, we found that mutationally activated KRAS strikingly increased intracellular cystine levels and glutathione biosynthesis. SLC7A11, a cystine/glutamate antiporter conferring specificity for cystine uptake, was overexpressed in patients with KRAS-mutant LUAD and showed positive association with tumor progression. Furthermore, SLC7A11 inhibition by either genetic depletion or pharmacological inhibition with sulfasalazine resulted in selective killing across a panel of KRAS-mutant cancer cells in vitro and tumor growth inhibition in vivo, suggesting the functionality and specificity of SLC7A11 as a therapeutic target. Importantly, we further identified a potent SLC7A11 inhibitor, HG106, that markedly decreased cystine uptake and intracellular glutathione biosynthesis. Furthermore, HG106 exhibited selective cytotoxicity toward KRAS-mutant cells by increasing oxidative stress- and ER stress-mediated cell apoptosis. Of note, treatment of KRAS-mutant LUAD with HG106 in several preclinical lung cancer mouse models led to marked tumor suppression and prolonged survival. Overall, our findings reveal that KRAS-mutant LUAD cells are vulnerable to SLC7A11 inhibition, offering potential therapeutic approaches for this currently incurable disease.
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Affiliation(s)
- Kewen Hu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.,Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Kun Li
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Jing Lv
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Jie Feng
- Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Jing Chen
- Key Laboratory of Reproduction and Genetics in Ningxia, Ningxia Medical University, Yinchuan, China
| | - Haigang Wu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Feixiong Cheng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.,Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Wenhao Jiang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Jieqiong Wang
- Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Haixiang Pei
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Paul J Chiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Zhenyu Cai
- National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yihua Chen
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Mingyao Liu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Xiufeng Pang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
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Kashihara T, Muguruma N, Fujimoto S, Miyamoto Y, Sato Y, Takayama T. Recent Advances in Molecular Imaging of Colorectal Tumors. Digestion 2020; 102:57-64. [PMID: 33271567 DOI: 10.1159/000512168] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 10/08/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recent endoscopic studies have revealed that small colorectal tumors are often overlooked during colonoscopy, indicating that more sensitive detection methods are needed. SUMMARY Molecular imaging has received considerable attention as a new endoscopic technique with high sensitivity. It generally employs a fluorescence-labeled compound that specifically binds to a molecule on the tumor. Fluorescent probes for molecular imaging are largely classified as 2 types: a fluorescence-labeled antibody targeting a molecule specifically expressed on the tumor cell surface such as epidermal growth factor receptor or vascular endothelial growth factor (VEGF); and a fluorescence-labeled small molecule compound targeting a molecule specifically expressed in tumor cells including c-Met, glutathione S-transferase, γ-glutamyltranspeptidase, cathepsin, or endothelin A receptor. These probes successfully detected colorectal tumors in several animal studies. Moreover, 3 recent human clinical trials evaluating endoscopic molecular imaging for colorectal tumors have been reported. In one study, a Cy5-labeled synthetic peptide against c-Met was developed, and fluorescent endoscopic observation with this probe detected a greater number of colorectal adenomas than with white light observation. Another trial used IR800-labeled anti-VEGF antibody, which sensitively detected human colorectal adenomas by fluorescent endoscopy. Last, a fluorescent probe with synthetic peptide against BRAF-positive cells was able to visualize sessile serrated lesions. The fluorescent probes accumulated at very high levels in colorectal tumor cells but at lower levels in surrounding nonneoplastic mucosa. Key Messages: We expect that molecular imaging techniques with fluorescent probes will soon lead to the establishment of a highly sensitive endoscopic method for colorectal tumor detection.
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Affiliation(s)
- Takanori Kashihara
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Shota Fujimoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yoshihiko Miyamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yasushi Sato
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan,
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A CRAF/glutathione-S-transferase P1 complex sustains autocrine growth of cancers with KRAS and BRAF mutations. Proc Natl Acad Sci U S A 2020; 117:19435-19445. [PMID: 32719131 PMCID: PMC7430992 DOI: 10.1073/pnas.2000361117] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
A strategy to overcome therapeutic obstacles of mKRAS and mBRAF cancers is devised based on the finding, here, that the RAF/MEK/ERK cascade is by-passed by an autocrine signal loop established by interaction of CRAF with GSTP1. The interaction evokes stabilization of CRAF from proteosomal degradation and facilitation of RAF-dimer formation. Thus, blocking CRAF/GSTP1 interactions should generate additive antiproliferative effects. The Ras/RAF/MEK/ERK pathway is an essential signaling cascade for various refractory cancers, such as those with mutant KRAS (mKRAS) and BRAF (mBRAF). However, there are unsolved ambiguities underlying mechanisms for this growth signaling thereby creating therapeutic complications. This study shows that a vital component of the pathway CRAF is directly impacted by an end product of the cascade, glutathione transferases (GST) P1 (GSTP1), driving a previously unrecognized autocrine cycle that sustains proliferation of mKRAS and mBRAF cancer cells, independent of oncogenic stimuli. The CRAF interaction with GSTP1 occurs at its N-terminal regulatory domain, CR1 motif, resulting in its stabilization, enhanced dimerization, and augmented catalytic activity. Consistent with the autocrine cycle scheme, silencing GSTP1 brought about significant suppression of proliferation of mKRAS and mBRAF cells in vitro and suppressed tumorigenesis of the xenografted mKRAS tumor in vivo. GSTP1 knockout mice showed significantly impaired carcinogenesis of mKRAS colon cancer. Consequently, hindering the autocrine loop by targeting CRAF/GSTP1 interactions should provide innovative therapeutic modalities for these cancers.
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Cui J, Li G, Yin J, Li L, Tan Y, Wei H, Liu B, Deng L, Tang J, Chen Y, Yi L. GSTP1 and cancer: Expression, methylation, polymorphisms and signaling (Review). Int J Oncol 2020; 56:867-878. [PMID: 32319549 DOI: 10.3892/ijo.2020.4979] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 01/17/2020] [Indexed: 01/04/2023] Open
Abstract
Glutathione S‑transferase Pi (GSTP1) is an isozyme encoded by the GST pi gene that plays an important regulatory role in detoxification, anti‑oxidative damage, and the occurrence of various diseases. The aim of the present study was to review the association between the expression of GSTP1 and the development and treatment of various cancers, and discuss GSTP1 methylation in several malignant tumors, such as prostate, breast and lung cancer, as well as hepatocellular carcinoma; to review the association between polymorphism of the GSTP1 gene and various diseases; and to review the effects of GSTP1 on electrophilic oxidative stress, cell signal transduction, and the regulation of carcinogenic factors. Collectively, GSTP1 plays a major role in the development of various diseases.
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Affiliation(s)
- Jian Cui
- Hengyang Medical College, Institute of Cytology and Genetics, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Guoqing Li
- Hengyang Medical College, Institute of Cytology and Genetics, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Jie Yin
- Hengyang Medical College, Institute of Cytology and Genetics, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Linwei Li
- Department of Laboratory, The Second Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yue Tan
- Hengyang Medical College, Institute of Cytology and Genetics, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Haoran Wei
- Hengyang Medical College, Institute of Cytology and Genetics, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Bang Liu
- Hengyang Medical College, Institute of Cytology and Genetics, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Lihong Deng
- Hengyang Medical College, Institute of Cytology and Genetics, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Jialu Tang
- Hengyang Medical College, Institute of Cytology and Genetics, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yonglin Chen
- Hengyang Medical College, Institute of Cytology and Genetics, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Lan Yi
- Hengyang Medical College, Institute of Cytology and Genetics, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, University of South China, Hengyang, Hunan 421001, P.R. China
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13
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Beyerle J, Holowatyj AN, Haffa M, Frei E, Gigic B, Schrotz-King P, Boehm J, Habermann N, Stiborova M, Scherer D, Kölsch T, Skender S, Becker N, Herpel E, Schneider M, Ulrich A, Schirmacher P, Chang-Claude J, Brenner H, Hoffmeister M, Haug U, Owen RW, Ulrich CM. Expression Patterns of Xenobiotic-Metabolizing Enzymes in Tumor and Adjacent Normal Mucosa Tissues among Patients with Colorectal Cancer: The ColoCare Study. Cancer Epidemiol Biomarkers Prev 2019; 29:460-469. [PMID: 31740522 DOI: 10.1158/1055-9965.epi-19-0449] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 07/15/2019] [Accepted: 11/12/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Xenobiotic-metabolizing enzymes (XME) play a critical role in the activation and detoxification of several carcinogens. However, the role of XMEs in colorectal carcinogenesis is unclear. METHODS We investigated the expression of XMEs in human colorectal tissues among patients with stage I-IV colorectal cancer (n = 71) from the ColoCare Study. Transcriptomic profiling using paired colorectal tumor and adjacent normal mucosa tissues of XMEs (GSTM1, GSTA1, UGT1A8, UGT1A10, CYP3A4, CYP2C9, GSTP1, and CYP2W1) by RNA microarray was compared using Wilcoxon rank-sum tests. We assessed associations between clinicopathologic, dietary, and lifestyle factors and XME expression with linear regression models. RESULTS GSTM1, GSTA1, UGT1A8, UGT1A10, and CYP3A4 were all statistically significantly downregulated in colorectal tumor relative to normal mucosa tissues (all P ≤ 0.03). Women had significantly higher expression of GSTM1 in normal tissues compared with men (β = 0.37, P = 0.02). By tumor site, CYP2C9 expression was lower in normal mucosa among patients with rectal cancer versus colon cancer cases (β = -0.21, P = 0.0005). Smokers demonstrated higher CYP2C9 expression levels in normal mucosa (β = 0.17, P = 0.02) when compared with nonsmokers. Individuals who used NSAIDs had higher GSTP1 tumor expression compared with non-NSAID users (β = 0.17, P = 0.03). Higher consumption of cooked vegetables (>1×/week) was associated with higher CYP3A4 expression in colorectal tumor tissues (β = 0.14, P = 0.007). CONCLUSIONS XMEs have lower expression in colorectal tumor relative to normal mucosa tissues and may modify colorectal carcinogenesis via associations with clinicopathologic, lifestyle, and dietary factors. IMPACT Better understanding into the role of drug-metabolizing enzymes in colorectal cancer may reveal biological differences that contribute to cancer development, as well as treatment response, leading to clinical implications in colorectal cancer prevention and management.
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Affiliation(s)
- Jolantha Beyerle
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Andreana N Holowatyj
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.,Huntsman Cancer Institute, Salt Lake City, Utah
| | - Mariam Haffa
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Eva Frei
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Biljana Gigic
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany
| | - Petra Schrotz-King
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Juergen Boehm
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.,Huntsman Cancer Institute, Salt Lake City, Utah
| | - Nina Habermann
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Marie Stiborova
- Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic
| | - Dominique Scherer
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.,Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Torsten Kölsch
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany
| | - Stephanie Skender
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Nikolaus Becker
- NCT Cancer Registry, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Esther Herpel
- Institute of Pathology, University Hospital, Heidelberg, Germany.,Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Germany
| | - Martin Schneider
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany
| | - Alexis Ulrich
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany
| | | | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hermann Brenner
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.,Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ulrike Haug
- Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology, Bremen, Germany.,Faculty of Human and Health Sciences, University of Bremen, Bremen, Germany
| | - Robert W Owen
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Cornelia M Ulrich
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah. .,Huntsman Cancer Institute, Salt Lake City, Utah.,Fred Hutchinson Cancer Research Center, Seattle, Washington
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14
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Mori M, Fujikawa Y, Kikkawa M, Shino M, Sawane M, Sato S, Inoue H. A highly selective fluorogenic substrate for imaging glutathione S-transferase P1: development and cellular applicability in epigenetic studies. Chem Commun (Camb) 2019; 55:8122-8125. [PMID: 31237279 DOI: 10.1039/c9cc03064f] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Pi-class glutathione S-transferase (GSTP1) is a molecular marker enzyme whose expression level is altered in various malignant tumour tissues. Herein, we report the first highly selective fluorogenic GSTP1 substrate, Ps-TG, and its membrane-permeable derivative Ps-TAc, for specific visualization of intracellular GSTP1 activity in cancer cells or epigenetically regulated GSTP1 expression.
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Affiliation(s)
- Masaya Mori
- School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
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15
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Shishido Y, Tomoike F, Kuwata K, Fujikawa H, Sekido Y, Murakami-Tonami Y, Kameda T, Abe N, Kimura Y, Shuto S, Abe H. A Covalent Inhibitor for Glutathione S-Transferase Pi (GSTP 1-1 ) in Human Cells. Chembiochem 2019; 20:900-905. [PMID: 30548113 DOI: 10.1002/cbic.201800671] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Indexed: 11/08/2022]
Abstract
Glutathione S-transferase π (GSTP1-1 ) is overexpressed in many types of cancer and is involved in drug resistance. Therefore, GSTP1-1 is an important target in cancer therapy, and many GST inhibitors have been reported. We had previously developed an irreversible inhibitor, GS-ESF, as an effective GST inhibitor; however, its cellular permeability was too low for it to be used in inhibiting intracellular GST. We have now developed new irreversible inhibitors by introducing sulfonyl fluoride (SF) into chloronitrobenzene (CNB). The mechanism of action was revealed to be that CNBSF first reacts with glutathione (GSH) through an aromatic substitution in the cell, then the sulfonyl group on the GSH conjugate with CNBSF reacts with Tyr108 of GST to form a sulfonyl ester bond. Our new inhibitor irreversible inhibited GSTP1-1 both in vitro and in cellulo with a long duration of action.
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Affiliation(s)
- Yuko Shishido
- Graduate School of Science, Nagoya University, Furo-cho, Chikusa-Ku, Nagoya, Aichi, 464-8602, Japan.,Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-Ku, Sapporo, Hokkaido, 060-0812, Japan
| | - Fumiaki Tomoike
- Research Center for Materials Science, Nagoya University, Furo-cho, Chikusa-Ku, Nagoya, Aichi, 464-8602, Japan
| | - Keiko Kuwata
- Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-Ku, Nagoya, Aichi, 464-8602, Japan
| | - Haruka Fujikawa
- Graduate School of Science, Nagoya University, Furo-cho, Chikusa-Ku, Nagoya, Aichi, 464-8602, Japan
| | - Yoshitaka Sekido
- Division of Cancer Biology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-Ku, Nagoya, Aichi, 464-8681, Japan
| | - Yuko Murakami-Tonami
- Division of Cancer Biology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-Ku, Nagoya, Aichi, 464-8681, Japan.,Juntendo University, Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Tomoshi Kameda
- Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology, 2-4-7, Aomi, Ko-to-ku, Tokyo, 135-0064, Japan
| | - Naoko Abe
- Graduate School of Science, Nagoya University, Furo-cho, Chikusa-Ku, Nagoya, Aichi, 464-8602, Japan
| | - Yasuaki Kimura
- Graduate School of Science, Nagoya University, Furo-cho, Chikusa-Ku, Nagoya, Aichi, 464-8602, Japan
| | - Satoshi Shuto
- Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-Ku, Sapporo, Hokkaido, 060-0812, Japan
| | - Hiroshi Abe
- Graduate School of Science, Nagoya University, Furo-cho, Chikusa-Ku, Nagoya, Aichi, 464-8602, Japan
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16
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Sakurada A, Miyanishi K, Tanaka S, Sato M, Sakamoto H, Kawano Y, Takada K, Nakabeppu Y, Kobune M, Kato J. An intronic single nucleotide polymorphism in the MUTYH gene is associated with increased risk for HCV-induced hepatocellular carcinoma. Free Radic Biol Med 2018; 129:88-96. [PMID: 30218772 DOI: 10.1016/j.freeradbiomed.2018.09.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 08/30/2018] [Accepted: 09/11/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The role of base excision repair genes in human hepatocarcinogenesis has not yet been explored. Here, we investigated relationships between variants of these genes and the risk of developing hepatocellular carcinoma (HCC). METHODS Nineteen tagging SNPs in base excision repair genes (including MUTYH, OGG1 and MTH1) were genotyped using iPLEX assays; one significant SNP was found and confirmed in Japanese patients with chronic hepatitis C (CHC) (n = 38 HCC and 55 controls). The effects of modifying the intronic variants were determined by luciferase assays. MUTYH-null mice were used to examine the involvement of oxidative stress and DNA repair enzymes in hepatocarcinogenesis. RESULTS Significant associations were found for a single intron SNP (rs3219487) in the MUTYH gene. The risk of developing HCC in patients with A/A or G/A genotypes was higher than in those with the G/G genotype (OR = 9.27, 95% CI = 2.39 -32.1, P = 0.0005). MUTYH mRNA levels in both peripheral mononuclear cells were significantly lower in G/A or A/A genotyped subjects (P = 0.0157 and 0.0108, respectively). We found that -2000 in the MUTYH promoter region is involved in enhanced expression of MUTYH by insertion of a major allele sequence of rs3219487. Liver tumors were observed in MUTYH-null mice after 12 months´ high iron diet, but no tumors developed when dietary anti-oxidant (N-Acetyl-L-cysteine) was also provided. CONCLUSIONS CHC patients with the rs3219487 adenine allele had a significantly increased risk of developing HCC. MUTYH-null mice with iron-associated oxidative stress were susceptible to development of liver tumors unless prevented by dietary anti-oxidants.
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MESH Headings
- Aged
- Animals
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Case-Control Studies
- DNA Glycosylases/genetics
- DNA Repair Enzymes/genetics
- Female
- Gene Expression Regulation, Neoplastic
- Genotype
- Hep G2 Cells
- Hepacivirus/pathogenicity
- Hepacivirus/physiology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/pathology
- Hepatitis C, Chronic/virology
- Humans
- Introns
- Iron/administration & dosage
- Liver Neoplasms/etiology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Phosphoric Monoester Hydrolases/genetics
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic
- Reactive Oxygen Species/metabolism
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Affiliation(s)
- Akira Sakurada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan.
| | - Shingo Tanaka
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masanori Sato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroki Sakamoto
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yutaka Kawano
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kohichi Takada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yusaku Nakabeppu
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
| | - Masayoshi Kobune
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan.
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17
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Sato M, Miyanishi K, Tanaka S, Sakurada A, Sakamoto H, Kawano Y, Takada K, Kobune M, Kato J. Increased Duodenal Iron Absorption through Upregulation of Ferroportin 1 due to the Decrement in Serum Hepcidin in Patients with Chronic Hepatitis C. Can J Gastroenterol Hepatol 2018; 2018:2154361. [PMID: 30186818 PMCID: PMC6112088 DOI: 10.1155/2018/2154361] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 07/03/2018] [Accepted: 07/12/2018] [Indexed: 12/15/2022] Open
Abstract
Hepatic iron accumulation is generally increased in the chronic hepatitis C (CHC) liver; however, the precise mechanism of such accumulation remains unclear. We evaluated iron absorption from the gastrointestinal tract of patients with CHC and control participants. We measured the expression of a panel of molecules associated with duodenal iron absorption and serum hepcidin levels to determine the mechanism of iron accumulation in the CHC liver. We enrolled 24 patients with CHC and 9 patients with chronic gastritis without Helicobacter pylori infection or an iron metabolism disorder as control participants. An oral iron absorption test (OIAT) was administered which involved a dosage of 100 mg of sodium ferrous citrate. Serum level of hepcidin-25 was measured by liquid chromatography-tandem mass spectrometry. Ferroportin 1 (FPN) mRNA was measured by RT-PCR and FPN protein was analyzed by western blot. Samples were obtained from duodenum biopsy tissue from each CHC patient and control participant. Caco-2/TC7 cells were incubated in Costar transwells (0.4 μm pores). The OIAT showed significantly greater iron absorption in CHC patients than control participants. Serum hepcidin-25 in the CHC group was significantly lower than in the control group. Compared with control participants, duodenal FPN mRNA expression in CHC patients was significantly upregulated. The FPN mRNA levels and protein levels increased significantly in Caco-2/TC7 cell monolayers cultured in transwells with hepcidin. Lower serum hepcidin-25 levels might upregulate not only FPN protein expression but also mRNA expression in the duodenum and cause iron accumulation in patients with CHC.
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Affiliation(s)
- Masanori Sato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Shingo Tanaka
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Akira Sakurada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Hiroki Sakamoto
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Yutaka Kawano
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Kohichi Takada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Masayoshi Kobune
- Department of Medical Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
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18
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Fujikawa Y, Nampo T, Mori M, Kikkawa M, Inoue H. Fluorescein diacetate (FDA) and its analogue as substrates for Pi-class glutathione S-transferase (GSTP1) and their biological application. Talanta 2017; 179:845-852. [PMID: 29310316 DOI: 10.1016/j.talanta.2017.12.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 12/02/2017] [Accepted: 12/02/2017] [Indexed: 10/18/2022]
Abstract
Pi class glutathione S-transferase (GSTP1) is highly expressed in various cancerous cells and pre-neoplastic legions, where it is involved in apoptotic resistance or metabolism of several anti-tumour chemotherapeutics. Therefore, GSTP1 is a marker of malignant and pre-malignant cells and is a promising target for visualization and drug development. Here we demonstrate that fluorescein diacetate (FDA), a fluorescent probe used for vital staining, is a fluorescently activated by esterolytic activity of human GSTP1 (hGSTP1) selectively among various cytosolic GSTs. Fluorescence activation of FDA susceptible to GST inhibitors was observed in MCF7 cells exogenously overexpressing hGSTP1, but not in cells overexpressing hGSTA1 or hGSTM1. Inhibitor-sensitive fluorescence activation was also observed in several cancer cell lines endogenously expressing GSTP1, suggesting that GSTP1 is involved in FDA esterolysis in these cells. Among the FDA derivatives examined, FOMe-Ac, the acetyl ester of fluorescein O-methyl ether, was found to be a potential reporter for GSH-dependent GSTP1 activity as well as for carboxylesterase activity. Since GSTP1 is highly expressed in various types of cancer cells compared to their normal counterparts, improving the fluorogenic substrates to be more selective to the esterolysis activity of GSTP1 rather than carboxylesterases should lead to development of tools for detecting GSTP1-overexpressing cancer cells and investigating the biological functions of GSTP1.
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Affiliation(s)
- Yuuta Fujikawa
- Laboratory of Molecular and Chemical Biology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
| | - Taiki Nampo
- Laboratory of Molecular and Chemical Biology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
| | - Masaya Mori
- Laboratory of Molecular and Chemical Biology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
| | - Manami Kikkawa
- Laboratory of Molecular and Chemical Biology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
| | - Hideshi Inoue
- Laboratory of Molecular and Chemical Biology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
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19
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Muguruma N, Okamoto K, Nakagawa T, Sannomiya K, Fujimoto S, Mitsui Y, Kimura T, Miyamoto H, Higashijima J, Shimada M, Horino Y, Matsumoto S, Hanaoka K, Nagano T, Shibutani M, Takayama T. Molecular imaging of aberrant crypt foci in the human colon targeting glutathione S-transferase P1-1. Sci Rep 2017; 7:6536. [PMID: 28747791 PMCID: PMC5529364 DOI: 10.1038/s41598-017-06857-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 06/19/2017] [Indexed: 01/06/2023] Open
Abstract
Aberrant crypt foci (ACF), the earliest precursor lesion of colorectal cancers (CRCs), are a good surrogate marker for CRC risk stratification and chemoprevention. However, the conventional ACF detection method with dye-spraying by magnifying colonoscopy is labor- and skill-intensive. We sought to identify rat and human ACF using a fluorescent imaging technique that targets a molecule specific for ACF. We found that glutathione S-transferase (GST) P1-1 was overexpressed in ACF tissues in a screening experiment. We then synthesized the fluorogenic probe, DNAT-Me, which is fluorescently quenched but is activated by GSTP1-1. A CRC cell line incubated with DNAT-Me showed strong fluorescence in the cytosol. Fluorescence intensities correlated significantly with GST activities in cancer cell lines. When we sprayed DNAT-Me onto colorectal mucosa excised from azoxymethane-treated rats and surgically resected from CRC patients, ACF with strong fluorescent signals were clearly observed. The ACF number determined by postoperative DNAT-Me imaging was almost identical to that determined by preoperative methylene blue staining. The signal-to-noise ratio for ACF in DNAT-Me images was significantly higher than that in methylene blue staining. Thus, we sensitively visualized ACF on rat and human colorectal mucosa by using a GST-activated fluorogenic probe without dye-spraying and magnifying colonoscopy.
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Affiliation(s)
- Naoki Muguruma
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8503, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8503, Japan
| | - Tadahiko Nakagawa
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8503, Japan
| | - Katsutaka Sannomiya
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8503, Japan
| | - Shota Fujimoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8503, Japan
| | - Yasuhiro Mitsui
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8503, Japan
| | - Tetsuo Kimura
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8503, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8503, Japan
| | - Jun Higashijima
- Department of Digestive and Pediatric Surgery, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8503, Japan
| | - Mitsuo Shimada
- Department of Digestive and Pediatric Surgery, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8503, Japan
| | - Yoko Horino
- R&D Group, Olympus Corporation, Hachioji, Tokyo, 192-8512, Japan
| | - Shinya Matsumoto
- R&D Group, Olympus Corporation, Hachioji, Tokyo, 192-8512, Japan
| | - Kenjiro Hanaoka
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Tetsuo Nagano
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Makoto Shibutani
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, 183-8509, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8503, Japan.
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20
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Lu J, Zhang ZL, Huang D, Tang N, Li Y, Peng Z, Lu C, Dong Z, Tang F. Cdk3-promoted epithelial-mesenchymal transition through activating AP-1 is involved in colorectal cancer metastasis. Oncotarget 2016; 7:7012-28. [PMID: 26755651 PMCID: PMC4872765 DOI: 10.18632/oncotarget.6875] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Accepted: 01/04/2016] [Indexed: 12/12/2022] Open
Abstract
Cyclin dependent kinase-3 (Cdk3) is a positive regulator of the G1 mammalian cell cycle phase. Cdk3 is involved in cancer progression, but very little is known about its mechanism in cancer development and progression. Herein, we found that Cdk3 increased colorectal cancer metastasis through promoting epithelial-mesenchymal transition (EMT) shift. Cdk3 was found to highly express in metastatic cancer and induce cell motility and invasion. Cdk3 was shown to phosphorylate c-Jun at Ser 63 and Ser 73 in vitro and ex vivo. Cdk3-phosphorylated c-Jun at Ser 63 and Ser 73 resulted in an increased AP-1 activity. Ectopic expression of Cdk3 promoted colorectal cancer from epithelial to mesenchymal transition conjugating AP-1 activation, while AP-1 inhibition dramatically decreased Cdk3-increased EMT shift. These results showed that the Cdk3/c-Jun signaling axis mediating epithelial-mesenchymal transition plays an important role in colorectal cancer metastasis.
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Affiliation(s)
- Jinping Lu
- Clinical Laboratory and Medical Research Center, Zhuhai Hospital of Jinan University, Zhuhai People's Hospital, Zhuhai, P.R. China
| | - Zhen Lin Zhang
- Clinical Laboratory and Medical Research Center, Zhuhai Hospital of Jinan University, Zhuhai People's Hospital, Zhuhai, P.R. China
| | - Damao Huang
- Clinical Laboratory, Xiangya Hospital of Central South University, Changsha, P.R. China
| | - Na Tang
- Institution of Pathogenic Biology, Medical College, University of South China, Hengyang, P.R. China
| | - Yuejin Li
- Clinical Laboratory and Medical Research Center, Zhuhai Hospital of Jinan University, Zhuhai People's Hospital, Zhuhai, P.R. China
| | - Zhengke Peng
- Clinical Laboratory and Medical Research Center, Zhuhai Hospital of Jinan University, Zhuhai People's Hospital, Zhuhai, P.R. China
| | - Chengrong Lu
- Institution of Pathogenic Biology, Medical College, University of South China, Hengyang, P.R. China
| | - Zigang Dong
- Institution of Pathogenic Biology, Medical College, University of South China, Hengyang, P.R. China
| | - Faqing Tang
- Clinical Laboratory and Medical Research Center, Zhuhai Hospital of Jinan University, Zhuhai People's Hospital, Zhuhai, P.R. China.,Clinical Laboratory, Xiangya Hospital of Central South University, Changsha, P.R. China
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21
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Yang Y, Huycke MM, Herman TS, Wang X. Glutathione S-transferase alpha 4 induction by activator protein 1 in colorectal cancer. Oncogene 2016; 35:5795-5806. [PMID: 27065323 DOI: 10.1038/onc.2016.113] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 12/25/2015] [Accepted: 01/04/2016] [Indexed: 01/01/2023]
Abstract
Glutathione S-transferase alpha 4 (GSTA4) is a phase II detoxifying enzyme that metabolizes electrophiles and carcinogens including 4-hydroxy-2-nonenal (4-HNE), an endogenous carcinogen that contributes to colorectal carcinogenesis. In this study, we investigated GSTA4 expression and regulation in murine primary colonic epithelial cells, microbiome-driven murine colitis and human carcinomas. Exposure of YAMC cells to 4-HNE induced Gsta4 expression. Using an inflammation-associated model of colorectal cancer (CRC), Gsta4 expression increased in vivo in colon macrophages and serum after 2 weeks of colonization of IL-10 deficient (Il10-/-) mice with Enterococcus faecalis. Increased expression was noted after 9 months of colonization in colon macrophages and epithelia in areas of inflammation. In human colon biopsies, immunohistochemistry showed no GSTA4 expression in normal epithelial cells, whereas GSTA4 was strongly expressed in the neoplastic epithelia of invasive carcinomas. For tubular adenomas, increased expression was primarily noted in stromal macrophages. Increased GSTA4 was confirmed in established human CRC cell lines and associated with 4-HNE-protein adducts in human colon adenomas and CRC. Next, we showed that 4-HNE induced activation of c-Jun and Nrf2, two components of the oncogenic transcription factor AP-1. AP-1 inhibitors and gene-specific small interfering RNAs partially suppressed GSTA4 expression. Co-immunoprecipitation confirmed interactions between c-Jun and Nrf2 supporting a role for AP-1 in regulating 4-HNE-induced GSTA4 expression. These findings demonstrate GSTA4 activation during 4-HNE-induced neoplastic transformation in colorectal carcinogenesis. GSTA4 is a potential surrogate biomarker for CRC screening and should provide novel approaches for chemoprevention.
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Affiliation(s)
- Y Yang
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.,The Muchmore Laboratories for Infectious Diseases Research, Oklahoma City VA Health Care System, Oklahoma City, OK, USA
| | - M M Huycke
- The Muchmore Laboratories for Infectious Diseases Research, Oklahoma City VA Health Care System, Oklahoma City, OK, USA.,Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - T S Herman
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - X Wang
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.,The Muchmore Laboratories for Infectious Diseases Research, Oklahoma City VA Health Care System, Oklahoma City, OK, USA
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22
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Hoki T, Miyanishi K, Tanaka S, Takada K, Kawano Y, Sakurada A, Sato M, Kubo T, Sato T, Sato Y, Takimoto R, Kobune M, Kato J. Increased duodenal iron absorption through up-regulation of divalent metal transporter 1 from enhancement of iron regulatory protein 1 activity in patients with nonalcoholic steatohepatitis. Hepatology 2015; 62:751-61. [PMID: 25753988 DOI: 10.1002/hep.27774] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 03/04/2015] [Indexed: 12/16/2022]
Abstract
UNLABELLED Increased hepatic iron accumulation is thought to be involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Hepatic iron accumulation, as well as oxidative DNA damage, is significantly increased in NASH livers. However, the precise mechanism of iron accumulation in the NASH liver remains unclear. In this study, 40 cases with a diagnosis of NASH (n = 25) or simple steatosis (SS; n = 15) by liver biopsy were enrolled. An oral iron absorption test (OIAT) was used, in which 100 mg of sodium ferrous citrate was administered to each individual. The OIAT showed that absorption of iron from the gastrointestinal (GI) tract was increased significantly in NASH patients, compared to SS and control subjects. Iron reduction therapy was effective in patients with NASH, who exhibited iron deposition in the liver and no alanine aminotransferase improvement after other therapies (n = 9). Serum hepcidin concentration and messenger RNA (mRNA) levels of divalent metal transporter 1 (DMT1) also were significantly elevated in patients with NASH. OIAT results were correlated with grade of liver iron accumulation and DMT1 mRNA levels. Then, we demonstrated that DMT1 mRNA levels increased significantly in Caco-2/TC7 cell monolayers cultured in transwells with serum from NASH patients. An electrophoresis mobility shift assay showed activation of iron regulatory protein (IRP) in those cells, and IRP1 small interfering RNA clearly inhibited the increase of DMT1 mRNA levels. CONCLUSION In spite of elevation of serum hepcidin, iron absorption from the GI tract increased through up-regulation of DMT1 by IRP1 activation by humoral factor(s) in sera of patients with NASH.
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Affiliation(s)
- Toshifumi Hoki
- Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Koji Miyanishi
- Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Shingo Tanaka
- Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Kohichi Takada
- Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Yutaka Kawano
- Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Akira Sakurada
- Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Masanori Sato
- Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Tomohiro Kubo
- Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Tsutomu Sato
- Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Yasushi Sato
- Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Rishu Takimoto
- Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Masayoshi Kobune
- Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Junji Kato
- Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan
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23
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Fletcher ME, Boshier PR, Wakabayashi K, Keun HC, Smolenski RT, Kirkham PA, Adcock IM, Barton PJ, Takata M, Marczin N. Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism. Am J Physiol Lung Cell Mol Physiol 2015; 308:L1274-85. [DOI: 10.1152/ajplung.00220.2014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 04/01/2015] [Indexed: 11/22/2022] Open
Abstract
Oxidant-mediated tissue injury is key to the pathogenesis of acute lung injury. Glutathione- S-transferases (GSTs) are important detoxifying enzymes that catalyze the conjugation of glutathione with toxic oxidant compounds and are associated with acute and chronic inflammatory lung diseases. We hypothesized that attenuation of cellular GST enzymes would augment intracellular oxidative and metabolic stress and induce lung cell injury. Treatment of murine lung epithelial cells with GST inhibitors, ethacrynic acid (EA), and caffeic acid compromised lung epithelial cell viability in a concentration-dependent manner. These inhibitors also potentiated cell injury induced by hydrogen peroxide (H2O2), tert-butyl-hydroperoxide, and hypoxia and reoxygenation (HR). SiRNA-mediated attenuation of GST-π but not GST-μ expression reduced cell viability and significantly enhanced stress (H2O2/HR)-induced injury. GST inhibitors also induced intracellular oxidative stress (measured by dihydrorhodamine 123 and dichlorofluorescein fluorescence), caused alterations in overall intracellular redox status (as evidenced by NAD+/NADH ratios), and increased protein carbonyl formation. Furthermore, the antioxidant N-acetylcysteine completely prevented EA-induced oxidative stress and cytotoxicity. Whereas EA had no effect on mitochondrial energetics, it significantly altered cellular metabolic profile. To explore the physiological impact of these cellular events, we used an ex vivo mouse-isolated perfused lung model. Supplementation of perfusate with EA markedly affected lung mechanics and significantly increased lung permeability. The results of our combined genetic, pharmacological, and metabolic studies on multiple platforms suggest the importance of GST enzymes, specifically GST-π, in the cellular and whole lung response to acute oxidative and metabolic stress. These may have important clinical implications.
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Affiliation(s)
- Marianne E. Fletcher
- Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, United Kingdom
| | - Piers R. Boshier
- Biosurgery and Surgical Technology, Imperial College London, London, United Kingdom
| | - Kenji Wakabayashi
- Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, United Kingdom
| | - Hector C. Keun
- Biomolecular Medicine, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Ryszard T. Smolenski
- Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
- Department of Surgery and Translational Medicine, University of Milano-Bicocca, Milano, Italy
| | - Paul A. Kirkham
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- Department of Biomedical Sciences, University of Wolverhampton, Wolverhampton, United Kingdom
| | - Ian M. Adcock
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Paul J. Barton
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Masao Takata
- Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, United Kingdom
| | - Nandor Marczin
- Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, United Kingdom
- Department of Anaesthetics, Royal Brompton and Harefield NHS Foundation Trust, Harefield Hospital, Harefield, Middlesex, United Kingdom
- Department of Anaesthesia and Intensive Therapy, Semmelweis University, Budapest, Hungary
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24
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Inoue A, Okamoto K, Fujino Y, Nakagawa T, Muguruma N, Sannomiya K, Mitsui Y, Takaoka T, Kitamura S, Miyamoto H, Okahisa T, Fujimori T, Imoto I, Takayama T. B-RAF mutation and accumulated gene methylation in aberrant crypt foci (ACF), sessile serrated adenoma/polyp (SSA/P) and cancer in SSA/P. Br J Cancer 2015; 112:403-412. [PMID: 25314065 PMCID: PMC4453443 DOI: 10.1038/bjc.2014.545] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 09/17/2014] [Accepted: 09/20/2014] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Sessile serrated adenomas/polyps (SSA/Ps) are a putative precursor of colon cancer with microsatellite instability (MSI). However, the developmental mechanism of SSA/P remains unknown. We performed genetic analysis and genome-wide DNA methylation analysis in aberrant crypt foci (ACF), SSA/P, and cancer in SSA/P specimens to show a close association between ACF and the SSA/P-cancer sequence. We also evaluated the prevalence and number of ACF in SSA/P patients. METHODS ACF in the right-side colon were observed in 36 patients with SSA/Ps alone, 2 with cancers in SSA/P, and 20 normal subjects and biopsied under magnifying endoscopy. B-RAF mutation and MSI were analysed by PCR-restriction fragment length polymorphism (RFLP) and PCR-SSCP, respectively, in 15 ACF, 20 SSA/P, and 2 cancer specimens. DNA methylation array analysis of seven ACF, seven SSA/P, and two cancer in SSA/P specimens was performed using the microarray-based integrated analysis of methylation by isochizomers (MIAMI) method. RESULTS B-RAF mutations were frequently detected in ACF, SSA/P, and cancer in SSA/P tissues. The number of methylated genes increased significantly in the order of ACF CONCLUSIONS Our results suggest that ACF are precursor lesions of the SSA/P-cancer sequence in patients with SSA/P, where ACF arise by B-RAF mutation and methylation of some of the six identified genes and develop into SSA/Ps through accumulated methylation of these genes.
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Affiliation(s)
- A Inoue
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
| | - K Okamoto
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
| | - Y Fujino
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
| | - T Nakagawa
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
| | - N Muguruma
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
| | - K Sannomiya
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
| | - Y Mitsui
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
| | - T Takaoka
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
| | - S Kitamura
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
| | - H Miyamoto
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
| | - T Okahisa
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
| | - T Fujimori
- Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan
| | - I Imoto
- Department of Human Genetics, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima 770-8503, Japan
| | - T Takayama
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
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25
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ZHANG RUI, KANG KYOUNGAH, PIAO MEIJING, KIM KICHEON, ZHENG JIAN, YAO CHENGWEN, CHA JIWON, MAENG YOUNGHEE, CHANG WEONYOUNG, MOON PYONGGON, BAEK MOONCHANG, HYUN JINWON. Epigenetic alterations are involved in the overexpression of glutathione S-transferase π-1 in human colorectal cancers. Int J Oncol 2014; 45:1275-83. [DOI: 10.3892/ijo.2014.2522] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Accepted: 06/06/2014] [Indexed: 11/05/2022] Open
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26
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Qiu Y, Cai G, Zhou B, Li D, Zhao A, Xie G, Li H, Cai S, Xie D, Huang C, Ge W, Zhou Z, Xu LX, Jia W, Zheng S, Yen Y, Jia W. A distinct metabolic signature of human colorectal cancer with prognostic potential. Clin Cancer Res 2014; 20:2136-2146. [PMID: 24526730 PMCID: PMC5902798 DOI: 10.1158/1078-0432.ccr-13-1939] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE Metabolic phenotyping has provided important biomarker findings, which, unfortunately, are rarely replicated across different sample sets due to the variations from different analytical and clinical protocols used in the studies. To date, very few metabolic hallmarks in a given cancer type have been confirmed and validated by use of a metabolomic approach and other clinical modalities. Here, we report a metabolomics study to identify potential metabolite biomarkers of colorectal cancer with potential theranostic value. EXPERIMENTAL DESIGN Gas chromatography-time-of-flight mass spectrometry (GC-TOFMS)-based metabolomics was used to analyze 376 surgical specimens, which were collected from four independent cohorts of patients with colorectal cancer at three hospitals located in China and City of Hope Comprehensive Cancer Center in the United States. Differential metabolites were identified and evaluated as potential prognostic markers. A targeted transcriptomic analysis of 29 colorectal cancer and 27 adjacent nontumor tissues was applied to analyze the gene expression levels for key enzymes associated with these shared metabolites. RESULTS A panel of 15 significantly altered metabolites was identified, which demonstrates the ability to predict the rate of recurrence and survival for patients after surgery and chemotherapy. The targeted transcriptomic analysis suggests that the differential expression of these metabolites is due to robust metabolic adaptations in cancer cells to increased oxidative stress as well as demand for energy, and macromolecular substrates for cell growth and proliferation. CONCLUSIONS These patients with colorectal cancer, despite their varied genetic background, mutations, pathologic stages, and geographic locations, shared a metabolic signature that is of great prognostic and therapeutic potential.
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Affiliation(s)
- Yunping Qiu
- Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital
- Center for translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina
| | - Guoxiang Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University
| | - Bingsen Zhou
- Department of Medical Oncology and Therapeutic Research, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Dan Li
- Cancer Institute, 2nd Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, PR China
| | - Aihua Zhao
- Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital
| | - Guoxiang Xie
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
| | - Houkai Li
- Center for translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina
| | - Sanjun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University
| | - Dong Xie
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
| | - Changzhi Huang
- State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - Weiting Ge
- Cancer Institute, 2nd Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, PR China
| | - Zhanxiang Zhou
- Center for translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina
| | - Lisa X. Xu
- Med-X Institutes, Shanghai Jiao Tong University, Shanghai
| | - Weiping Jia
- Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital
| | - Shu Zheng
- Cancer Institute, 2nd Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, PR China
| | - Yun Yen
- Department of Medical Oncology and Therapeutic Research, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Wei Jia
- Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
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27
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Gañán-Gómez I, Wei Y, Yang H, Boyano-Adánez MC, García-Manero G. Oncogenic functions of the transcription factor Nrf2. Free Radic Biol Med 2013; 65:750-764. [PMID: 23820265 DOI: 10.1016/j.freeradbiomed.2013.06.041] [Citation(s) in RCA: 166] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Revised: 05/30/2013] [Accepted: 06/24/2013] [Indexed: 02/03/2023]
Abstract
Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that controls the expression of a large pool of antioxidant and cytoprotective genes regulating the cellular response to oxidative and electrophilic stress. Nrf2 is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1) and, upon stimulation by an oxidative or electrophilic insult, is rapidly activated by protein stabilization. Owing to its cytoprotective functions, Nrf2 has been traditionally studied in the field of chemoprevention; however, there is accumulated evidence that Keap1/Nrf2 mutations or unbalanced regulation that leads to overexpression or hyperactivation of Nrf2 may participate in tumorigenesis and be involved in chemoresistance of a wide number of solid cancers and leukemias. In addition to protecting cells from reactive oxygen species, Nrf2 seems to play a direct role in cell growth control and is related to apoptosis-regulating pathways. Moreover, Nrf2 activity is connected with oncogenic kinase pathways, structural proteins, hormonal regulation, other transcription factors, and epigenetic enzymes involved in the pathogenesis of various types of tumors. The aim of this review is to compile and summarize existing knowledge of the oncogenic functions of Nrf2 to provide a solid basis for its potential use as a molecular marker and pharmacological target in cancer.
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Affiliation(s)
- Irene Gañán-Gómez
- Department of System Biology, Biochemistry and Molecular Biology Unit, University of Alcalá, 28871 Alcalá de Henares (Madrid), Spain.
| | - Yue Wei
- Department of Leukemia, University of Texas M.D. Anderson Cancer Center, 77030 Houston, TX, USA
| | - Hui Yang
- Department of Leukemia, University of Texas M.D. Anderson Cancer Center, 77030 Houston, TX, USA
| | - María Carmen Boyano-Adánez
- Department of System Biology, Biochemistry and Molecular Biology Unit, University of Alcalá, 28871 Alcalá de Henares (Madrid), Spain
| | - Guillermo García-Manero
- Department of Leukemia, University of Texas M.D. Anderson Cancer Center, 77030 Houston, TX, USA
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28
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Tsuda M, Okamoto K, Muguruma N, Sannomiya K, Nakagawa T, Miyamoto H, Kitamura S, Goji T, Kimura T, Okahisa T, Izumi K, Takayama T. Suppressive effect of RAS inhibitor manumycin A on aberrant crypt foci formation in the azoxymethane-induced rat colorectal carcinogenesis model. J Gastroenterol Hepatol 2013; 28:1616-1623. [PMID: 23730936 DOI: 10.1111/jgh.12287] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/15/2013] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM The chemopreventive effect of RAS inhibitors on colorectal cancer is unknown. Because aberrant crypt foci (ACF), earliest preneoplastic lesions, are highly positive for K-RAS mutation, RAS inhibitors are likely to be effective for chemoprevention. Therefore, in the present study, the suppressive effect of a RAS inhibitor, manumycin A, on ACF formation in an azoxymethane (AOM)-induced rat colorectal carcinogenesis model was investigated. METHODS Rats injected with AOM were administered manumycin A (30 mg/kg) subcutaneously thrice weekly for 8 weeks or for 4 weeks (latter half), sacrificed at 8 weeks, and examined for ACF in the colorectum. Phosphorylated ERK and Ki-67 expression was evaluated by immunohistochemistry. Apoptosis was assessed by TUNEL staining. RESULTS The mean number of ACF in the 8-week manumycin A group (72.9 ± 20.1) was significantly lower than in the vehicle group (155.6 ± 56.7, P < 0.01), and it was significantly lower even in the 4-week manumycin A group than in the vehicle group (92.2 ± 13.0 vs 222.3 ± 83.3, P < 0.01). The positive rate for phosphorylated ERK in the manumycin A group (13.5 ± 19.2%) was significantly lower than in the vehicle group (50.2 ± 19.8%, P < 0.01). The positive rate for Ki-67 in the manumycin A group (2.2 ± 3.4%) was significantly lower than in the vehicle group (14.7 ± 8.2%, P < 0.01). There were significantly more terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive cells in tissue samples from the manumycin A group versus the vehicle group (8.6 ± 9.7% vs 2.9 ± 2.0%, P < 0.05). CONCLUSION Manumycin A suppressed ACF formation in the AOM-induced colorectal carcinogenesis model, demonstrating that RAS inhibitors may be very effective for chemoprevention of colorectal cancers.
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Affiliation(s)
- Miho Tsuda
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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Bedford MR, Anathhanam S, Saleh D, Hickson A, McGregor AK, Boyle K, Burke D. Response of glutathione S-transferase Pi (GSTP1) to neoadjuvant therapy in rectal adenocarcinoma. Colorectal Dis 2012; 14:1483-8. [PMID: 22390478 DOI: 10.1111/j.1463-1318.2012.03022.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM The response of rectal adenocarcinoma to neoadjuvant therapy is variable. Accurate prediction of response would enable selective administration of therapy. The enzyme glutathione S-transferase Pi (GSTP1) has been shown to influence response to therapy in some solid tumours. Few data are available for rectal cancer. METHOD The GSTP1 levels in rectal adenocarcinoma and adjacent normal mucosa were quantified before and after exposure to neoadjuvant therapy. Venous blood samples and biopsies of normal rectal mucosa and tumour were prospectively obtained from patients with primary rectal cancer. Patients were stratified by exposure to neoadjuvant therapy or surgery alone. GSTP1 was quantitatively measured using an enzyme-linked immunosorbent assay. RESULTS Ninety-two patients (54 men; median age 68 years) were recruited. The median GSTP1 level was significantly higher in rectal adenocarcinoma than in matched normal mucosa [6.59 μg/mg vs 4.57 μg/mg; P < 0.001]. The median tumour GSTP1 level was significantly lower in the therapy group compared with unmatched samples from the no-therapy group [4.47 μg/mg vs 7.76 μg/mg; P < 0.001]. CONCLUSION The GSTP1 level is increased in rectal adenocarcinoma compared with adjacent normal mucosa. It decreases following neoadjuvant therapy. Future studies correlating pre-therapy GSTP1 levels with pathological response would be of interest.
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Affiliation(s)
- M R Bedford
- School of Medicine, University of Leeds, Leeds, UK.
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Boušová I, Skálová L. Inhibition and induction of glutathione S-transferases by flavonoids: possible pharmacological and toxicological consequences. Drug Metab Rev 2012; 44:267-86. [PMID: 22998389 DOI: 10.3109/03602532.2012.713969] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Many studies reviewed herein demonstrated the potency of some flavonoids to modulate the activity and/or expression of glutathione S-transferases (GSTs). Because GSTs play a crucial role in the detoxification of xenobiotics, their inhibition or induction may significantly affect metabolism and biological effects of many drugs, industrials, and environmental contaminants. The effect of flavonoids on GSTs strongly depends on flavonoid structure, concentration, period of administration, as well as on GST isoform and origin. Moreover, the results obtained in vitro are often contrary to the vivo results. Based on these facts, the revelation of important flavonoid-drug or flavonoid-pollutant interaction has been complicated. However, it should be borne in mind that ingestion of certain flavonoids in combination with drugs or pollutants (e.g., acetaminophen, simvastatin, cyclophosphamide, cisplatine, polycyclic aromatic hydrocarbons, chlorpyrifos, acrylamide, and isocyanates), which are GST substrates, could have significant pharmacological and toxicological consequences. Although reasonable consumptions of a flavonoids-rich diet (that may lead to GST induction) are mostly beneficial, the uncontrolled intake of high concentrations of certain flavonoids (e.g., quercetin and catechins) in dietary supplements (that may cause GST inhibition) may threaten human health.
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Affiliation(s)
- Iva Boušová
- Department of Biochemical Sciences, Charles University in Prague, Faculty of Pharmacy, Hradec Králové, Czech Republic, European Union
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Sivagami G, Karthikkumar V, Balasubramanian T, Nalini N. The modulatory influence of p-methoxycinnamic acid, an active rice bran phenolic acid, against 1,2-dimethylhydrazine-induced lipid peroxidation, antioxidant status and aberrant crypt foci in rat colon carcinogenesis. Chem Biol Interact 2012; 196:11-22. [PMID: 22326950 DOI: 10.1016/j.cbi.2012.01.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Revised: 01/24/2012] [Accepted: 01/24/2012] [Indexed: 12/21/2022]
Abstract
We investigated the chemopreventive effect of p-methoxycinnamic acid (p-MCA), an active phenolic acid of rice bran, turmeric, and Kaemperfia galanga against 1,2-dimethylhydrazine-induced rat colon carcinogenesis. Male albino Wistar rats were randomly divided into six groups. Group 1 consisted of control rats that received a modified pellet diet and 0.1% carboxymethyl cellulose. The rats in Group 2 received a modified pellet diet supplemented with p-MCA [80 mg/kg body weight (b.wt.) post-orally (p.o.)] everyday. The rats in Groups 3-6 received 1,2-dimethylhydrazine (DMH) (20 mg/kg b.wt.) via subcutaneous injections once a week for the first 4 weeks; additionally, the rats in Groups 4, 5 and 6 received p-MCA at doses of 20, 40 and 80 mg/kg b.wt./day p.o., respectively, everyday for 16 weeks. The rats were sacrificed at the end of the experimental period of 16 weeks. The DMH-treated rats exhibited an increased incidence of aberrant crypt foci (ACF) development; an increased crypt multiplicity; decreased concentrations of tissue lipid peroxidation markers such as thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and lipid hydroperoxides (LOOH); decreased levels of tissue enzymic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR); and decreased levels of non-enzymic antioxidants such as reduced glutathione (GSH) and vitamins C, E and A in the colon. Supplementation with p-MCA significantly reversed these changes and significantly inhibited the formation of ACF and its multiplicity. Thus, our findings demonstrate that p-MCA exerts a strong chemopreventive activity against 1,2-dimethylhydrazine-induced colon carcinogenesis by virtue of its ability to prevent the alterations in DMH-induced circulatory and tissue oxidative stress and preneoplastic changes. p-MCA was more effective when administered at a dose of 40 mg/kg b.wt. than at the other two doses tested.
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Affiliation(s)
- Gunasekaran Sivagami
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608 002 Tamilnadu, India
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Zong J, Guo C, Liu S, Sun MZ, Tang J. Proteomic research progress in lymphatic metastases of cancers. Clin Transl Oncol 2012; 14:21-30. [DOI: 10.1007/s12094-012-0757-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Otsuka K, Satoyoshi R, Nanjo H, Miyazawa H, Abe Y, Tanaka M, Yamamoto Y, Shibata H. Acquired/intratumoral mutation of KRAS during metastatic progression of colorectal carcinogenesis. Oncol Lett 2011; 3:649-653. [PMID: 22740969 DOI: 10.3892/ol.2011.543] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Accepted: 11/22/2011] [Indexed: 12/28/2022] Open
Abstract
Mutations at codons 12 and 13 of the KRAS gene have been identified as level I predictive biomarkers against the treatment of advanced colorectal cancer with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies. It is thought that the genetic analysis of KRAS mutations associated with metastatic colorectal cancer can be routinely conducted using DNA obtained on one occasion from one organ, from the primary or a metastatic site, whichever is preferentially available. However, the issue of tumor heterogeneity resulting from acquired/intratumoral mutations remains. Recently, the possibility of acquired/intratumoral mutations in the KRAS gene has been reported by two research groups and has ranged from 7.4 to 15.4%. Specimens were collected from advanced colorectal cancer patients with resected primary, and at least one metastatic, site. Direct sequence analysis was performed for KRAS, BRAF and PIK3CA, and immunohistochemistry for glutathione S-transferase II (GSTP) and EGFR. In the current study, we identified an acquired mutation rate of approximately 11.1% in the KRAS gene (1/9). This figure is not negligible. Our observation indicates, particularly in the case of metastatic recurrence after a long interval, that there may be considerable tumor heterogeneity resulting from acquired or intratumoral mutations of the KRAS gene.
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Affiliation(s)
- Kazunori Otsuka
- Department of Clinical Oncology, Graduate School of Medicine, Akita University, Akita 010-8543, Japan
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Tan KL, Jankova L, Chan C, Fung CLS, Clarke C, Lin BPC, Robertson G, Molloy M, Chapuis PH, Bokey L, Dent OF, Clarke SJ. Clinicopathological correlates and prognostic significance of glutathione S-transferase Pi expression in 468 patients after potentially curative resection of node-positive colonic cancer. Histopathology 2011; 59:1057-70. [DOI: 10.1111/j.1365-2559.2011.04044.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Tumor suppressive microRNA-133a regulates novel molecular networks in lung squamous cell carcinoma. J Hum Genet 2011; 57:38-45. [PMID: 22089643 DOI: 10.1038/jhg.2011.126] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Analysis of the microRNA (miRNA) expression signature of lung squamous cell carcinoma (lung-SCC) revealed that the expression levels of miR-133a were significantly reduced in cancer tissues compared with normal tissues. In this study, we focused on the functional significance of miR-133a in cancer cell lines derived from lung-SCC and the identification of miR-133a-regulated novel cancer networks in lung-SCC. Restoration of miR-133a expression in PC10 and H157 cell lines resulted in significant inhibition of cell proliferation, suggesting that miR-133a functions as a tumor suppressor. We used genome-wide gene expression analysis to identify the molecular targets of miR-133a regulation. Gene expression data and web-based searching revealed several candidate genes, including transgelin 2 (TAGLN2), actin-related protein2/3 complex, subunit 5, 16kDa (ARPC5), LAG1 homolog, ceramide synthase 2 (LASS2) and glutathione S-transferase pi 1 (GSTP1). ARPC5 and GSTP1 likely represent bona fide targets as their expression is elevated in lung-SCC clinical specimens. Furthermore, transient transfection of miR-133a, repressed ARPC5 and GSTP1 mRNA and protein levels. As cell proliferation was significantly inhibited in lung-SCC cells following RNAi knock down of either gene, ARPC5 and GSTP1 may function as oncogenes in the development of lung-SCC. The identification of a tumor suppressive miRNA and the novel cancer pathways it regulates could provide new insights into potential molecular mechanisms of lung-SCC carcinogenesis.
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MiR-133a induces apoptosis through direct regulation of GSTP1 in bladder cancer cell lines. Urol Oncol 2011; 31:115-23. [PMID: 21396852 DOI: 10.1016/j.urolonc.2010.09.017] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2010] [Revised: 09/28/2010] [Accepted: 09/30/2010] [Indexed: 01/07/2023]
Abstract
OBJECTIVE We previously demonstrated that miR-133a is a tumor-suppressive microRNA (miRNA) and is commonly down-regulated in human bladder cancer (BC). The aim of this study is to determine a novel oncogenic gene targeted by miR-133a in BC. METHODS To identify genes targeted by miR-133a, an oligo-microarray analysis was performed using the miR-133a-transfected BC cell lines. For gain/loss-of-function studies, miR-133a/si-glutathione S-transferase π1 (GSTP1)-transfectants were subjected to XTT assay and flow cytometry to evaluate their cell viability and apoptosis status. The luciferase reporter assay was used to confirm the actual binding sites between miR-133a and GSTP1 mRNA. The mRNA and protein expression of GSTP1 in BC cell lines and clinical samples were evaluated by real-time RT-PCR and Western blot, respectively. RESULTS MiR-133a transfection induced cell viability inhibition and apoptosis in BC cell lines. We focused on the GSTP1 gene that was the top 7 down-regulated one in the gene profile from the miR-133a-transfectants. MiR-133a transfection repressed expression levels of mRNA and protein levels of GSTP1. A luciferase reporter assay suggested that the actual binding may occur between miR-133a and GSTP1 mRNA. Cell viability inhibition and apoptosis were induced in the si-GSTP1 transfectants compared with the controls (P < 0.005). GSTP1 mRNA expression levels in 43 clinical BCs were significantly higher than those in eight normal bladder epitheliums (P = 0.0277). CONCLUSION Our data suggest that tumor suppressive miR-133a directly regulated oncogenic GSTP1 gene in BC, and that an anti-apoptotic effect mediated by GSTP1 is maintained by miR-133a down-regulation in human BC.
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Takayama T, Nagashima H, Maeda M, Nojiri S, Hirayama M, Nakano Y, Takahashi Y, Sato Y, Sekikawa H, Mori M, Sonoda T, Kimura T, Kato J, Niitsu Y. Randomized double-blind trial of sulindac and etodolac to eradicate aberrant crypt foci and to prevent sporadic colorectal polyps. Clin Cancer Res 2011; 17:3803-11. [PMID: 21385928 DOI: 10.1158/1078-0432.ccr-10-2395] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE On the basis of the results of our preliminary trial suggesting that aberrant crypt foci (ACF) could be eradicated by short-term administration of sulindac, in the present study, we explored the feasibility of using ACF as surrogate markers for chemoprevention of colorectal cancer. EXPERIMENTAL DESIGN Randomly assigned to sulindac (300 mg daily), etodolac (400 mg daily), and placebo groups were 189 subjects without polyps or who had undergone polypectomy. Drugs were administered for 2 months. ACF in the rectal region were counted by magnifying endoscopy. Occurrence of polyps was evaluated at 12 months. A planned interim analysis was conducted. RESULTS ACF number at 2 months was significantly suppressed in the sulindac group (P = 0.0075), but not in the etodolac group (P = 0.73). In the sulindac group, the numbers of adenomas plus hyperplastic polyps (total polyps) and adenomas at 12 months were significantly (P = 0.02) and marginally (P = 0.064) lower, respectively, in comparison with the placebo group; no such difference was observed in the etodolac group. In analysis of only polypectomized subjects, the numbers of total polyps and adenomas in the sulindac group were even more markedly lower, with P values of 0.014 and 0.034, respectively. A similar tendency was confirmed by analyses of the incidence of polyps at 12 months. Suppression rates of total polyps and adenomas in ACF responders to sulindac were significantly greater than in nonresponders. In all groups, compliance was more than 90% and no intolerable adverse effects were observed. CONCLUSIONS ACF may be useful as surrogate lesions for chemoprevention of colorectal cancer.
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Affiliation(s)
- Tetsuji Takayama
- Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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Kim JM, Park E. Coenzyme Q10 attenuated DMH-induced precancerous lesions in SD rats. J Nutr Sci Vitaminol (Tokyo) 2010; 56:139-44. [PMID: 20495296 DOI: 10.3177/jnsv.56.139] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Coenzyme Q10 (CoQ10) is known to be a compound with mitochondrial bioenergetic functions and antioxidant activity. In this study, we evaluated the effect of CoQ10 on the formation of aberrant crypt foci (ACF) induced by 1,2-dimethylhydrazine (DMH), DMH-induced leukocytic DNA damage and gene expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) by real-time PCR in colonic mucosa of male SD rats. The animals were divided into three groups and fed a casein-based high-fat and low fiber diet (100 g lard+20 g cellulose/kg diet) with or without CoQ10 (0.4 mg in soybean oil/kg BW/d, i.p.). One week after beginning the diets, the rats were subjected to 6 wk of treatment with DMH (30 mg/kg/wk, s.c.) and CoQ10 treatments continued over the entirety of the experimental period (59 d). Administration of CoQ10 resulted in reduction of ACF numbers, to 20% of the carcinogen control value. CoQ10 supplementation induced an antigenotoxic effect on DMH-induced DNA damage in the blood cells. Colonic mucosa of DMH-injected rats had significantly greater COX-2 and iNOS gene expression than those of control rats, while treatment with CoQ10 induced an inhibitory effect on over-expression of COX-2 and iNOS in colon tumors. Our results provide evidence that CoQ10 has a protective effect on the process of colon carcinogenesis, suppressing the development of preneoplastic lesions, possibly by modulating COX-2 and iNOS gene expression in colonic mucosa and DNA damage in leukocytes, suggesting that CoQ10 has chemotherapeutic activity.
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Affiliation(s)
- Jung-Mi Kim
- Department of Food and Nutrition, Kyungnam University, Gyeongnam, Korea
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Scharlau D, Borowicki A, Habermann N, Hofmann T, Klenow S, Miene C, Munjal U, Stein K, Glei M. Mechanisms of primary cancer prevention by butyrate and other products formed during gut flora-mediated fermentation of dietary fibre. Mutat Res 2009; 682:39-53. [PMID: 19383551 DOI: 10.1016/j.mrrev.2009.04.001] [Citation(s) in RCA: 234] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2008] [Revised: 04/08/2009] [Accepted: 04/14/2009] [Indexed: 05/27/2023]
Abstract
Dietary fibres are indigestible food ingredients that reach the colon and are then fermented by colonic bacteria, resulting mainly in the formation of short-chain fatty acids (SCFA) such as acetate, propionate, and butyrate. Those SCFA, especially butyrate, are recognised for their potential to act on secondary chemoprevention by slowing growth and activating apoptosis in colon cancer cells. Additionally, SCFA can also act on primary prevention by activation of different drug metabolising enzymes. This can reduce the burden of carcinogens and, therefore, decrease the number of mutations, reducing cancer risk. Activation of GSTs by butyrate has been studied on mRNA, protein, and enzyme activity level by real-time RT-PCR, cDNA microarrays, Western blotting, or photometrical approaches, respectively. Butyrate had differential effects in colon cells of different stages of cancer development. In HT29 tumour cells, e.g., mRNA GSTA4, GSTP1, GSTM2, and GSTT2 were induced. In LT97 adenoma cells, GSTM3, GSTT2, and MGST3 were induced, whereas GSTA2, GSTT2, and catalase (CAT) were elevated in primary colon cells. Colon cells of different stages of carcinogenesis differed in post-transcriptional regulatory mechanisms because butyrate increased protein levels of different GST isoforms and total GST enzyme activity in HT29 cells, whereas in LT97 cells, GST protein levels and activity were slightly reduced. Because butyrate increased histone acetylation and phosphorylation of ERK in HT29 cells, inhibition of histone deacetylases and the influence on MAPK signalling are possible mechanisms of GST activation by butyrate. Functional consequences of this activation include a reduction of DNA damage caused by carcinogens like hydrogen peroxide or 4-hydroxynonenal (HNE) in butyrate-treated colon cells. Treatment of colon cells with the supernatant from an in vitro fermentation of inulin increased GST activity and decreased HNE-induced DNA damage in HT29 cells. Additional animal and human studies are needed to define the exact role of dietary fibre and butyrate in inducing GST activity and reducing the risk of colon cancer.
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Affiliation(s)
- Daniel Scharlau
- Institute for Nutrition, Friedrich Schiller University Jena, Dornburger Strasse 24, 07743 Jena, Germany.
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Rhomberg LR, Baetcke K, Blancato J, Bus J, Cohen S, Conolly R, Dixit R, Doe J, Ekelman K, Fenner-Crisp P, Harvey P, Hattis D, Jacobs A, Jacobson-Kram D, Lewandowski T, Liteplo R, Pelkonen O, Rice J, Somers D, Turturro A, West W, Olin S. Issues in the Design and Interpretation of Chronic Toxicity and Carcinogenicity Studies in Rodents: Approaches to Dose Selection. Crit Rev Toxicol 2008; 37:729-837. [DOI: 10.1080/10408440701524949] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Shibata T, Kokubu A, Gotoh M, Ojima H, Ohta T, Yamamoto M, Hirohashi S. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Gastroenterology 2008; 135:1358-1368, 1368.e1-4. [PMID: 18692501 DOI: 10.1053/j.gastro.2008.06.082] [Citation(s) in RCA: 388] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2008] [Revised: 06/16/2008] [Accepted: 06/26/2008] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Biliary tract cancer (BTC) is a highly malignant tumor, and identification of effective therapeutic targets to improve prognosis is urgently required. Oncogenic activation of survival genes is important for cancer cells to overcome oxidative stresses induced by their microenvironments that include chronic inflammation or exposure to anticancer drugs. We attempted to examine whether deregulation of Nrf2, a master transcriptional factor of various cytoprotective genes against oxidative stress, plays a role in the carcinogenesis of BTC. METHODS We screened genetic alteration of Keap1, a negative regulator of Nrf2, in BTC including tumors originated from gallbladder and extra- and intrahepatic bile ducts. Functional analysis of cancer-related mutant Keap1 in Nrf2 repression and the association between Nrf2 activation and resistance to 5-fluorouracil (5-FU) were investigated. RESULTS Recurrent (in 1/11 cell lines and 6/53 primary tumors) Keap1 gene alterations were observed in BTC and were especially frequent (4/13, 30.7%) in gallbladder cancer (GBC). These alterations led to a considerable loss of Nrf2 repression activity, caused constitutive activation of Nrf2, and promoted cell proliferation. Down-regulation of Nrf2 activity by either Keap1 complementation or Nrf2 short interference RNA increased sensitivity to 5-FU in Keap1-altered BTC cells. CONCLUSIONS Keap1 mutation occurs frequently in GBC. Aberrant Nrf2 activation provoked by Keap1 alteration is one of the molecular mechanisms for chemotherapeutic resistance in GBC and will be a novel therapeutic target as an enhancer of sensitivity to 5-FU-based regimens.
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Affiliation(s)
- Tatsuhiro Shibata
- Cancer Genomics Project, National Cancer Center Research Institute, Tokyo, Japan; Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.
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Kukitsu T, Takayama T, Miyanishi K, Nobuoka A, Katsuki S, Sato Y, Takimoto R, Matsunaga T, Kato J, Sonoda T, Sakamaki S, Niitsu Y. Aberrant crypt foci as precursors of the dysplasia-carcinoma sequence in patients with ulcerative colitis. Clin Cancer Res 2008; 14:48-54. [PMID: 18172251 DOI: 10.1158/1078-0432.ccr-07-1835] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Long-standing ulcerative colitis (UC) predisposes patients to the development of colorectal cancer, but surveillance of colitis-associated cancer by detecting the precancerous lesion dysplasia is often difficult because of its rare occurrence and normal-looking appearance. In sporadic colorectal cancer, aberrant crypt foci (ACF) have been reported by many investigators to be precursor lesions of the adenoma-carcinoma sequence. In the present study, we analyzed the genetic background of ACF to determine whether they could be precursors for dysplasia, and we examined the usefulness of endoscopic examination of ACF as a surrogate marker for surveillance of colitis-associated cancer. EXPERIMENTAL DESIGN ACF were examined in 28 UC patients (19 patients with UC alone and 9 patients with UC and dysplasia; 2 of those patients with dysplasia also had cancer) using magnifying endoscopy. K-ras, APC, and p53 mutations were analyzed by two-step PCR RFLP, in vitro--synthesized protein assay, and single-strand conformation polymorphism, respectively. Methylation of p16 was analyzed by methylation-specific PCR. RESULTS ACF that appeared distinct endoscopically and histologically were identified in 27 out of 28 UC patients. They were negative for K-ras, APC, and p53 mutations but were frequently positive for p16 methylation (8 of 11; 73%). In dysplasia, K-ras and APC mutations were negative but p53 mutation (3 of 5; 60%) and p16 methylation (3 of 5; 60%) were positive. There was a significant stepwise increase in the number of ACF from patients with UC alone to patients with dysplasia and to patients with cancer. Univariate and multivariate analyses showed significant correlations between ACF and dysplasia. CONCLUSIONS We have disclosed an ACF-dysplasia-cancer sequence in colitis-associated carcinogenesis similar to the ACF-adenoma-carcinoma sequence in sporadic colon carcinogenesis. This study suggests the use of ACF instead of dysplasia for the surveillance of colitis cancer and warrants further evaluation of ACF as a surveillance marker in large-scale studies.
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Affiliation(s)
- Takehiro Kukitsu
- Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
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Niitsu Y, Takayama T. [Molecular mechanism in the development of cancer of the large intestine and its chemoprevention]. NIHON NAIKA GAKKAI ZASSHI. THE JOURNAL OF THE JAPANESE SOCIETY OF INTERNAL MEDICINE 2007; 96:1819-1826. [PMID: 17929418 DOI: 10.2169/naika.96.1819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
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Glebov OK, Rodriguez LM, Soballe P, DeNobile J, Cliatt J, Nakahara K, Kirsch IR. Gene expression patterns distinguish colonoscopically isolated human aberrant crypt foci from normal colonic mucosa. Cancer Epidemiol Biomarkers Prev 2007; 15:2253-62. [PMID: 17119054 DOI: 10.1158/1055-9965.epi-05-0694] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Aberrant crypt foci (ACF) are considered the earliest identifiable preneoplastic colonic lesions; thus, a greater understanding of the nature of genetic changes underlying the transformation of normal colonic mucosa (NM) into ACF may provide insight into the mechanisms of carcinogenesis. ACF were identified by indigo carmine spraying onto colonic mucosa during colonoscopy and isolated as standard pinch biopsies of the mucosal areas containing the ACF. RNAs isolated from ACF and matched NM biopsies from the ascending and descending colons of 13 patients were analyzed on arrays containing 9128 cDNAs. Thirty-four differentially expressed (P < 0.001) genes were found in a paired comparison of the ACF and NM samples, and 25 of 26 matched pairs of ACF and NM could be correctly classified in leave-one-out cross-validation. Differential expression for seven of eight genes was confirmed by real-time reverse transcription-PCR. Furthermore, ACF and NM samples, including six pairs of ACF and NM samples that had not previously been analyzed by array hybridization, can be correctly classified on the basis of the overexpression in ACF of three selected genes (REG4, SRPN-B5, and TRIM29) evaluated by real-time reverse transcription-PCR. In a separate analysis of 13 biopsy pairs from either ascending or descending colon, ACF and NM samples could also be correctly classified by the gene expression patterns. Analysis of gene expression differences in ACF from the ascending and descending colon versus NM samples indicates that ACF from these distinct colonic locations are converging toward similar gene expression profiles and losing differences in gene expression characteristic of NM from the ascending versus descending colon.
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Affiliation(s)
- Oleg K Glebov
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
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Pei H, Zhu H, Zeng S, Li Y, Yang H, Shen L, Chen J, Zeng L, Fan J, Li X, Gong Y, Shen H. Proteome analysis and tissue microarray for profiling protein markers associated with lymph node metastasis in colorectal cancer. J Proteome Res 2007; 6:2495-501. [PMID: 17542627 DOI: 10.1021/pr060644r] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Understanding the proteins associated with lymph node metastasis (LNM) in colorectal cancer (CRC) will benefit us in the prediction of CRC prognosis and provide us new potential targets in the intervention of CRC. The aim of this study is to investigate the LNM-associated proteins and to evaluate the clinicopathological characteristics of these target proteins' expression in CRC. METHODS Fresh tumor and paired normal mucosa from five cases for each group of non-LNM CRC and LNM CRC were analyzed by two-dimensional electrophoresis coupled with MALDI-TOF-MS, followed by Western blotting confirmation. In 40 paraffin-embedded CRC samples, each for non-LNM CRC and LNM CRC, four differentially expressed proteins identified by proteomics analysis were detected by tissue microarray with immunohistochemistry staining to access the clinicopathological characteristics of these proteins in LNM of CRC. RESULTS Twenty-five proteins were found to be differentially expressed between normal mucosa and CRC tissue. Increased expression levels of heat shock protein-27 (HSP-27), glutathione S-transferase (GST), and Annexin II, but a decreased expression level of liver-fatty acid binding protein (L-FABP), existed in LNM CRC as compared with non-LNM CRC (p<0.01 or p<0.05, respectively). CONCLUSION The techniques of proteomic analysis combined with tissue microarray provide us a dramatic tool for screening of LNM-associated proteins in cancer research. The increased expression of HSP-27, GST, and Annexin II, but decreased expression of L-FABP, suggests a significantly elevated incidence of LNM in CRC.
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Affiliation(s)
- Haiping Pei
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
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Martínez C, Martín F, Fernández JM, García-Martín E, Sastre J, Díaz-Rubio M, Agúndez JA, Ladero JM. Glutathione S-transferases mu 1, theta 1, pi 1, alpha 1 and mu 3 genetic polymorphisms and the risk of colorectal and gastric cancers in humans. Pharmacogenomics 2006; 7:711-8. [PMID: 16886896 DOI: 10.2217/14622416.7.5.711] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Glutathione S-transferases (GSTs) are considered to be cancer susceptibility genes as they play a role in the detoxification of carcinogenic species. This study aimed to elucidate the influence of several GST polymorphisms on colorectal and gastric cancer risk. PATIENTS AND METHODS GST mu1 (GSTM1), theta1 (GSTT1), pi1 (GSTP1), alpha1 (GSTA1) and mu3 (GSTM3) genotypes were determined in 144 colorectal cancer patients, 98 gastric cancer patients and 329 healthy control individuals. RESULTS Colorectal cancer: the risk is greater for carriers of the GSTM1 null genotype (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.25-2.91), for carriers of the GSTT1 null genotype (OR = 3.62, 95% CI = 2.34-5.62), and for simultaneous carriers of both GSTM1 and GSTT1 null genotypes (OR = 4.98, 95% CI = 2.77-9.00). Carriers of the GSTP1 104 Val/Val genotype are at a lower risk (OR = 0.31, 95% CI = 0.09-0.88). Among carriers of the GSTP1 Ile/Ile genotype, smoking increases the risk compared with nonsmoking (OR = 2.35, 95% CI = 1.11-4.99). Gastric cancer: the risk is greater for carriers of the GSTT1 null genotype (OR = 2.58, 95% CI = 1.53-4.36) and for simultaneous carriers of both GSTM1 and GSTT1 null genotypes (OR = 3.32, 95% CI = 1.62-6.77). Carriers of the GSTP1 104 Val/Val genotype are at a lower risk (OR = 0.20, 95% CI = 0.02-0.86). DISCUSSION The GSTT1 null genotype, particularly if it is associated with the GSTM1 null genotype, greatly increases the risk for colorectal and gastric cancers. The GSTP1 104 Val/Val genotype may protect from both malignant tumors. CONCLUSION This study indicates that GST polymorphisms, in particular the GSTM1/GSTT1 double-null haplotype, can be considered low-penetrance genes for gastrointestinal cancer.
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Affiliation(s)
- Carmen Martínez
- Department of Pharmacology and Psychiatry, University of Extremadura, Badajoz, Spain
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Wallace MB, Sullivan D, Rustgi AK. Advanced imaging and technology in gastrointestinal neoplasia: summary of the AGA-NCI Symposium October 4-5, 2004. Gastroenterology 2006; 130:1333-42. [PMID: 16618424 DOI: 10.1053/j.gastro.2006.01.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2005] [Accepted: 12/21/2005] [Indexed: 12/02/2022]
Abstract
Imaging and other advanced technologies for detection of gastrointestinal cancers are undergoing a major revolution on several fronts. This is facilitated by convergence of key technologies including advanced endoscopic-detection systems, more specific contrast agents, rapid and high-resolution cross-sectional imaging, and miniaturization of construction systems for making all imaging equipment smaller and less invasive. This convergence is occurring along traditional translational research pathways (clinical medicine-molecular biology) as well as nontraditional lines (clinical medicine-optical physics/engineering and molecular biology-optical physics/engineering). These new efforts are producing a wide array of technologies aimed at improving detection, classification, and monitoring of gastrointestinal neoplasia, especially for colorectal and esophageal cancer because of easier accessibility. A critical goal is to detect lesions at their premalignant stages, thereby permitting meaningful intervention. Inspired by these advances, the American Gastroenterological Association and the National Cancer Institute sponsored a symposium held in Bethesda, MD, from October 4-5, 2004, bringing together leading investigators with diverse backgrounds in imaging technology. The aims of this symposium were to summarize the state of the art and priorities for research in the coming decade in the field of imaging and advanced technology for gastrointestinal neoplasia. In this overview, we summarize the salient results of that symposium. The initial sections discuss the major technologies in each area of endoluminal imaging and molecular imaging followed by applications to specific diseases such as Barrett's esophagus and colon neoplasia. Each section focuses on the current state of the art then lists major priorities for research in the field.
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Affiliation(s)
- Michael B Wallace
- AGA Section on Imaging and Advanced Technology, Mayo Clinic, Jacksonville, Florida 32224, USA.
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Dang DT, Chen F, Kohli M, Rago C, Cummins JM, Dang LH. Glutathione S-transferase pi1 promotes tumorigenicity in HCT116 human colon cancer cells. Cancer Res 2005; 65:9485-94. [PMID: 16230413 DOI: 10.1158/0008-5472.can-05-1930] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
GSTP1 is a member of the glutathione S-transferase enzyme superfamily, which catalyzes the conjugation of electrophiles with glutathione in the process of detoxification. GSTP1 is widely overexpressed in colorectal cancer, from aberrant crypt foci to advanced carcinomas. Increased expression of GSTP1 is associated with multidrug resistance and a worse clinical prognosis. However, GSTP1-null mice have an increased risk of tumor formation. Thus, the biological function of GSTP1 in colorectal cancer biology remains speculative. In an effort to gain further insights into the role of GSTP1 in tumorigenesis, we disrupted the GSTP1 gene in HCT116 human colorectal cancer cells using targeted homologous recombination. We find that loss of GSTP1 resulted in impaired clonogenic survival and proliferation. Specifically, under growth-limiting conditions, (a) GSTP1 protected HCT116 cells from oxidative stress and associated apoptosis and (b) promoted mitogen-activated protein kinase-extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase-mediated G1-S cell cycle progression. In vivo, GSTP1 was critical for engraftment and growth of HCT116 tumor xenografts. These studies directly show that GSTP1 promotes clonogenic survival and proliferation in HCT116 human colon cancer cells.
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Affiliation(s)
- Duyen T Dang
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical Center, MI 48109-0682, USA
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Loeffler-Ragg J, Skvortsov S, Sarg B, Skvortsova I, Witsch-Baumgartner M, Mueller D, Lindner H, Zwierzina H. Gefitinib-responsive EGFR-positive colorectal cancers have different proteome profiles from non-responsive cell lines. Eur J Cancer 2005; 41:2338-46. [PMID: 16115757 DOI: 10.1016/j.ejca.2005.06.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2005] [Revised: 06/14/2005] [Accepted: 06/21/2005] [Indexed: 10/25/2022]
Abstract
Biomarkers that predict response to therapy with inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase remain largely uncharacterized. In order to define proteins involved in potential resistance mechanisms, we examined the effect of gefitinib (ZD1839, Iressa) in the EGFR-positive colon cancer cell lines Caco-2, DiFi, HRT-18 and HT-29. None of them exhibited an activating mutation in exons 19 or 21 of EGFR. Proteome profiling with two-dimensional polyacrylamide gel electrophoresis followed by mass spectrometry revealed 12 proteins differentially expressed in responsive and non-responsive cells. These proteins are involved in metabolic pathways, partially relevant in malignant growth and four of them are known to interact with the EGFR signalling pathway. Ubiquitin carboxyl-terminated hydrolase isozyme L1 (UCH-L1) and galectin-3 are overexpressed in the responsive cell line Caco-2, whereas fatty acid-binding protein (E-FABP) and heat shock protein (hsp) 27 are expressed more in the resistant cell lines HRT-18 and HT-29 suggesting a role in non-responsiveness of cells to gefitinib.
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Affiliation(s)
- Judith Loeffler-Ragg
- Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria
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Niu ZS, Wang M. Expression of c-erbB-2 and glutathione S-transferase-pi in hepatocellular carcinoma and its adjacent tissue. World J Gastroenterol 2005; 11:4404-4408. [PMID: 16038042 PMCID: PMC4434670 DOI: 10.3748/wjg.v11.i28.4404] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2004] [Revised: 11/13/2004] [Accepted: 11/19/2004] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the possible role of c-erbB-2 and glutathione S-transferase (GST-Pi) in primary hepatocellular carcinogenesis and the relationship between liver hype-rplastic nodule (LHN), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). METHODS The expression of c-erbB-2 and GST-Pi was detected immunohistochemically in 41 tissue specimens of HCC and 77 specimens of its adjacent tissue. RESULTS The positive expression of c-erbB-2 in LHN (28.6%) was significantly higher than that in LC (0%) (P = 0.032<0.05), but no significant difference was seen between HCC and LHN or LC (P>0.05, chi2= 0.002, 3.447). The positive expression of GST-Pi in HCC (89.6%) or LHN (71.1%) was significantly higher than that in LC (22.9%, P<0.001, chi2= 49.91, 16.96). There was a significant difference between HCC and LHN (P<0.05, chi2= 6.353). CONCLUSION The c-erbB-2 expression is an early event in the pathogenesis of HCC. GST-Pi may be a marker enzyme for immunohistochemical detection of human HCC and its preneoplastic lesions. LHN seems to be a preneoplastic lesion related to hepatocarcinogenesis.
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Affiliation(s)
- Zhao-Shan Niu
- Department of Pathology, Medical College of Qingdao University, 38 Dengzhou Road, Qingdao 266021, Shandong Province, China.
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