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Quiroz Reyes AG, Lozano Sepulveda SA, Martinez-Acuña N, Islas JF, Gonzalez PD, Heredia Torres TG, Perez JR, Garza Treviño EN. Cancer Stem Cell and Hepatic Stellate Cells in Hepatocellular Carcinoma. Technol Cancer Res Treat 2023; 22:15330338231163677. [PMID: 36938618 PMCID: PMC10028642 DOI: 10.1177/15330338231163677] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer. It is highly lethal and has high recurrence. Death among HCC patients occur mainly due to tumor progression, recurrence, metastasis, and chemoresistance. Cancer stem cells (CSCs) are cell subpopulations within the tumor that promote invasion, recurrence, metastasis, and drug resistance. Hepatic stellate cells (HSCs) are important components of the tumor microenvironment (TME) responsible for primary secretory ECM proteins during liver injury and inflammation. These cells promote fibrogenesis, infiltrate the tumor stroma, and contribute to HCC development. Interactions between HSC and CSC and their microenvironment help promote carcinogenesis through different mechanisms. This review summarizes the roles of CSCs and HSCs in establishing the TME in primary liver tumors and describes their involvement in HCC chemoresistance.
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Affiliation(s)
- Adriana G Quiroz Reyes
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Sonia A Lozano Sepulveda
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Natalia Martinez-Acuña
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Jose F Islas
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Paulina Delgado Gonzalez
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Tania Guadalupe Heredia Torres
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Jorge Roacho Perez
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Elsa N Garza Treviño
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
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de Almeida LC, Calil FA, Machado-Neto JA, Costa-Lotufo LV. DNA damaging agents and DNA repair: From carcinogenesis to cancer therapy. Cancer Genet 2021; 252-253:6-24. [DOI: 10.1016/j.cancergen.2020.12.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/30/2020] [Accepted: 12/02/2020] [Indexed: 02/09/2023]
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FGF/FGFR Signaling in Hepatocellular Carcinoma: From Carcinogenesis to Recent Therapeutic Intervention. Cancers (Basel) 2021; 13:cancers13061360. [PMID: 33802841 PMCID: PMC8002748 DOI: 10.3390/cancers13061360] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 03/11/2021] [Accepted: 03/13/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary As the most common primary liver cancer, HCC is a tricky cancer resistant to systemic therapies. The fibroblast growth factor family and its receptors are gaining more and more attention in various cancers. Noticing an explosion in the number of studies about aberrant FGF/FGFR signaling in HCC being studied, we were encouraged to summarize them. This review discusses how FGF/FGFR signaling influences HCC development and its implications in HCC prediction and target treatment, and combination treatment. Abstract Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, ranking third in cancer deaths worldwide. Over the last decade, several studies have emphasized the development of tyrosine kinase inhibitors (TKIs) to target the aberrant pathways in HCC. However, the outcomes are far from satisfactory due to the increasing resistance and adverse effects. The family of fibroblast growth factor (FGF) and its receptors (FGFR) are involved in various biological processes, including embryogenesis, morphogenesis, wound repair, and cell growth. The aberrant FGF/FGFR signaling is also observed in multiple cancers, including HCC. Anti-FGF/FGFR provides delightful benefits for cancer patients, especially those with FGF signaling alteration. More and more multi-kinase inhibitors targeting FGF signaling, pan-FGFR inhibitors, and selective FGFR inhibitors are now under preclinical and clinical investigation. This review summarizes the aberrant FGF/FGFR signaling in HCC initiating, development and treatment status, and provide new insights into the treatment of HCC.
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Ramai D, Tai W, Rivera M, Facciorusso A, Tartaglia N, Pacilli M, Ambrosi A, Cotsoglou C, Sacco R. Natural Progression of Non-Alcoholic Steatohepatitis to Hepatocellular Carcinoma. Biomedicines 2021; 9:184. [PMID: 33673113 PMCID: PMC7918599 DOI: 10.3390/biomedicines9020184] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 02/01/2021] [Accepted: 02/09/2021] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a chronic and progressive form of non-alcoholic fatty liver disease (NAFLD). Its global incidence is increasing which makes NASH an epidemic and a public health threat. Due to repeated insults to the liver, patients are at risk for developing hepatocellular carcinoma (HCC). The progression of NASH to HCC was initially defined according to a two-hit model which involved the development of steatosis, followed by lipid peroxidation and inflammation. However, current research defines a "multi-hit" or "multi-parallel hit" model which synthesizes several contributing pathways involved in progressive fibrosis and oncogenesis. This perspective considers the effects of cellular, genetic, immunologic, metabolic, and endocrine pathways leading up to HCC which underscores the complexity of this condition. This article will provide an updated review of the pathogenic mechanisms leading from NASH to HCC as well as an exploration of the role of biomarkers and screening.
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Affiliation(s)
- Daryl Ramai
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, NY 11201, USA; (D.R.); (W.T.); (M.R.)
| | - Waqqas Tai
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, NY 11201, USA; (D.R.); (W.T.); (M.R.)
| | - Michelle Rivera
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, NY 11201, USA; (D.R.); (W.T.); (M.R.)
| | - Antonio Facciorusso
- Section of Gastroenterology, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
| | - Nicola Tartaglia
- General Surgery Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (N.T.); (M.P.); (A.A.)
| | - Mario Pacilli
- General Surgery Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (N.T.); (M.P.); (A.A.)
| | - Antonio Ambrosi
- General Surgery Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (N.T.); (M.P.); (A.A.)
| | - Christian Cotsoglou
- General Surgey Unit, Department of Surgery, ASST-Vimercate, 20871 Vimercate, Italy;
| | - Rodolfo Sacco
- Section of Gastroenterology, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
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Gillman R, Lopes Floro K, Wankell M, Hebbard L. The role of DNA damage and repair in liver cancer. Biochim Biophys Acta Rev Cancer 2020; 1875:188493. [PMID: 33316376 DOI: 10.1016/j.bbcan.2020.188493] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/25/2020] [Accepted: 12/08/2020] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma is rapidly becoming a major cause of global mortality due to the ever-increasing prevalence of obesity. DNA damage is known to play an important role in cancer initiation, however DNA repair systems are also vital for the survival of cancer cells. Given the function of the liver and its exposure to the gut, it is likely that DNA damage and repair would be of particular importance in hepatocellular carcinoma. However, many contemporary reports have neglected the role of individual pathways of DNA damage and repair in their hypotheses. This review, therefore, aims to provide a concise overview for researchers in the field of liver cancer to understand the pathways of DNA damage and repair and their individual roles in hepatocellular carcinoma.
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Affiliation(s)
- Rhys Gillman
- Department of Molecular and Cell Biology, College of Public Health, Medical, and Veterinary Sciences, James Cook University, Townsville, Queensland, Australia
| | - Kylie Lopes Floro
- Department of Molecular and Cell Biology, College of Public Health, Medical, and Veterinary Sciences, James Cook University, Townsville, Queensland, Australia; Department of Radiation Oncology, Townsville University Hospital, Townsville, Queensland, Australia
| | - Miriam Wankell
- Department of Molecular and Cell Biology, College of Public Health, Medical, and Veterinary Sciences, James Cook University, Townsville, Queensland, Australia; Australian Institute for Tropical Health and Medicine, Townsville, Queensland, Australia
| | - Lionel Hebbard
- Department of Molecular and Cell Biology, College of Public Health, Medical, and Veterinary Sciences, James Cook University, Townsville, Queensland, Australia; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia; Australian Institute for Tropical Health and Medicine, Townsville, Queensland, Australia.
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Marin JJ, Macias RI, Monte MJ, Romero MR, Asensio M, Sanchez-Martin A, Cives-Losada C, Temprano AG, Espinosa-Escudero R, Reviejo M, Bohorquez LH, Briz O. Molecular Bases of Drug Resistance in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12061663. [PMID: 32585893 PMCID: PMC7352164 DOI: 10.3390/cancers12061663] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/19/2020] [Accepted: 06/20/2020] [Indexed: 12/11/2022] Open
Abstract
The poor outcome of patients with non-surgically removable advanced hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer, is mainly due to the high refractoriness of this aggressive tumor to classical chemotherapy. Novel pharmacological approaches based on the use of inhibitors of tyrosine kinases (TKIs), mainly sorafenib and regorafenib, have provided only a modest prolongation of the overall survival in these HCC patients. The present review is an update of the available information regarding our understanding of the molecular bases of mechanisms of chemoresistance (MOC) with a significant impact on the response of HCC to existing pharmacological tools, which include classical chemotherapeutic agents, TKIs and novel immune-sensitizing strategies. Many of the more than one hundred genes involved in seven MOC have been identified as potential biomarkers to predict the failure of treatment, as well as druggable targets to develop novel strategies aimed at increasing the sensitivity of HCC to pharmacological treatments.
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Affiliation(s)
- Jose J.G. Marin
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Correspondence: (J.J.G.M.); (O.B.); Tel.: +34-663182872 (J.J.G.M.); +34-923294674 (O.B.)
| | - Rocio I.R. Macias
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Maria J. Monte
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Marta R. Romero
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Anabel Sanchez-Martin
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Candela Cives-Losada
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Alvaro G. Temprano
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Ricardo Espinosa-Escudero
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Maria Reviejo
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Laura H. Bohorquez
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Correspondence: (J.J.G.M.); (O.B.); Tel.: +34-663182872 (J.J.G.M.); +34-923294674 (O.B.)
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Identification of the possible therapeutic targets in the insulin-like growth factor 1 receptor pathway in a cohort of Egyptian hepatocellular carcinoma complicating chronic hepatitis C type 4. Drug Target Insights 2020; 14:1-11. [PMID: 33132693 PMCID: PMC7597224 DOI: 10.33393/dti.2020.1548] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 01/20/2020] [Indexed: 11/24/2022] Open
Abstract
Background: Molecular targeted drugs are the first line of treatment of advanced hepatocellular carcinoma (HCC) due to its chemo- and radioresistant nature. HCC has several well-documented etiologic factors that drive hepatocarcinogenesis through different molecular pathways. Currently, hepatitis C virus (HCV) is a leading cause of HCC. Therefore, we included a unified cohort of HCV genotype 4-related HCCs to study the expression levels of genes involved in the insulin-like growth factor 1 receptor (IGF1R) pathway, which is known to be involved in all aspects of cancer growth and progression. Aim: Determine the gene expression patterns of IGF1R pathway genes in a cohort of Egyptian HCV-related HCCs. Correlate them with different patient/tumor characteristics. Determine the activity status of involved pathways. Methods: Total ribonucleic acid (RNA) was extracted from 32 formalin-fixed paraffin-embedded tissues of human HCV-related HCCs and 6 healthy liver donors as controls. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT2 Profiler PCR Array for Human Insulin Signaling Pathway was done to determine significantly up- and downregulated genes with identification of most frequently coregulated genes, followed by correlation of gene expression with different patient/tumor characteristics. Finally, canonical pathway analysis was performed using the Ingenuity Pathway Analysis software. Results: Six genes – AEBP1, AKT2, C-FOS, PIK3R1, PRKCI, SHC1 – were significantly overexpressed. Thirteen genes – ADRB3, CEBPA, DUSP14, ERCC1, FRS3, IGF2, INS, IRS1, JUN, MTOR, PIK3R2, PPP1CA, RPS6KA1 – were significantly underexpressed. Several differentially expressed genes were related to different tumor/patient characteristics. Nitric oxide and reactive oxygen species production pathway was significantly activated in the present cohort, while the growth hormone signaling pathway was inactive. Conclusions: The gene expression patterns identified in this study may serve as possible therapeutic targets in HCV-related HCCs. The most frequently coregulated genes may serve to guide combined molecular targeted therapies. The IGF1R pathway showed evidence of inactivity in the present cohort of HCV-related HCCs, so targeting this pathway in therapy may not be effective.
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Zhao J, Sun Y, Lin H, Chou F, Xiao Y, Jin R, Cai X, Chang C. Olaparib and enzalutamide synergistically suppress HCC progression via the AR-mediated miR-146a-5p/BRCA1 signaling. FASEB J 2020; 34:5877-5891. [PMID: 32134529 DOI: 10.1096/fj.201903045rr] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/23/2020] [Accepted: 02/25/2020] [Indexed: 12/26/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of most common cancers worldwide, however, the treatment for advanced HCC remains unsatisfactory. We focused on the function of the androgen receptor (AR) in HCC and tried to find new treatment strategy based on antiandrogen enzalutamide (Enz). Here, we found that olaparib, a FDA-approved PARP inhibitor, could enhance the cytotoxicity in HCC cells with a lower BRCA1 expression, and suppressing the AR with either Enz or AR-shRNA could further increase the olaparib sensitivity to better suppress the HCC cell growth via a synergistic mechanism that may involve suppressing the expression of BRCA1 and other DNA damage response (DDR) genes. Mechanism studies revealed that Enz/AR signaling might transcriptionally regulate the miR-146a-5p expression via binding to the Androgen Response Elements on its 5' promoter region, which could then lead to suppress the homologous recombination-related BRCA1 expression via direct binding to the mRNA 3'UTR. Preclinical studies using an in vivo mouse model also demonstrated that combining Enz plus olaparib led to better suppression of the HCC progression. Together, these in vitro/in vivo data suggest that combining Enz and olaparib may help in the development of a novel therapy to better suppress the HCC progression.
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Affiliation(s)
- Jie Zhao
- Department of General Surgery, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Urology, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,George Whipple Lab for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Yin Sun
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Hui Lin
- Department of General Surgery, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Urology, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Fuju Chou
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Yao Xiao
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Ren'an Jin
- Department of General Surgery, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Urology, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,George Whipple Lab for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Xiujun Cai
- Department of General Surgery, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Urology, Innovation Center for Minimally Invasive Technique and Device, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chawnshang Chang
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.,Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan
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Liao X, Li Y, Li H, Huang W, Wang H, Xie W. Expression and Clinical Significance of ERCC1 and XPF in Human Hepatocellular Carcinoma. Onco Targets Ther 2020; 13:1059-1072. [PMID: 32099408 PMCID: PMC7007798 DOI: 10.2147/ott.s237916] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 01/20/2020] [Indexed: 12/22/2022] Open
Abstract
Objective To investigate the correlation between the ERCC1 and XPF expression and the clinicopathological parameters of hepatocellular carcinoma (HCC) patients through assessment of the expression of the DNA repair genes ERCC1 and XPF. Methods ERCC1 and XPF mRNA expression in HCC (n= 177) and adjacent para-cancer tissues (n=21) were assessed by RT-PCR. The correlation between ERCC1 and XPF expression, clinicopathological features and HCC prognosis were compared. Results ERCC1 expression in liver cancer tissues was significantly lower than that of adjacent tissues (9.5% (2/21) vs 38.1% (8/21); P<0.05). The positive expression rates of XPF in liver cancer tissues was lower than that of adjacent tissues (14.3% (3/21) vs 71.4% (15/21); P<0.05). ERCC1 and XPF expression were associated with hepatic capsular invasion and microvascular invasion. HCC patients with hepatic capsular invasion and microvascular tumor embolus formation had significantly lower levels of ERCC1 and XPF mRNA than those without hepatic capsular invasion and microvascular tumor embolus formation (P<0.05). In addition, ERCC1 expression was associated with TNM staging of HCC. The expression of ERCC1 mRNA in patients with stage II and III HCC were lower than that of patients with stage I HCC (P<0.05). The low levels of ERCC1 and XPF mRNA significantly correlated with relapse-free survival times (RFS) in HCC patients. The median RFS of the low ERCC1 expression group and low XPF expression group were shorter than those of the high expression group (15.0 months vs 32.0 months, P<0.05) and (19.0 months vs 33.0 months, P<0.05). The decrease in XPF mRNA expression was significantly associated with the overall survival (OS) of HCC patients. The median OS in the low XPF expression group was shorter than that of the high expression group (46.0 months vs 78.0 months, P<0.05). However, no significant difference in OS between the low ERCC1 expression group and the high ERCC1 expression groups were observed (63.0 months vs 64.0 months, P>0.05). Multivariate analysis showed that tumor size and the extent of differentiation were independent factors affecting the RFS in HCC patients (P<0.05). The extent of differentiation and XPF were independent factors affecting the OS in HCC (P<0.05). Conclusion The expression in ERCC1 and XPF were low in HCC and associated with early relapse after HCC surgery. Low XPF expression may be a potential indicator of a high risk of death.
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Affiliation(s)
- Xiaoli Liao
- Department of First Chemotherapy, Affiliated Guangxi Medical University Cancer Hospital, Nanning 530021, People's Republic of China
| | - Yongqiang Li
- Department of First Chemotherapy, Affiliated Guangxi Medical University Cancer Hospital, Nanning 530021, People's Republic of China
| | - Hualan Li
- Department of First Chemotherapy, Affiliated Guangxi Medical University Cancer Hospital, Nanning 530021, People's Republic of China
| | - Wenfeng Huang
- Department of Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, People's Republic of China
| | - Hongxue Wang
- Department of Fifth Chemotherapy, Affiliated Guangxi Medical University Cancer Hospital, Nanning 530021, People's Republic of China
| | - Weimin Xie
- Department of Fifth Chemotherapy, Affiliated Guangxi Medical University Cancer Hospital, Nanning 530021, People's Republic of China
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Han Y, Qu YQ, Mok SWF, Chen J, Xia CL, He HQ, Li Z, Zhang W, Qiu CL, Liu L, Law BYK, Wong VKW. A Novel Drug Resistance Mechanism: Genetic Loss of Xeroderma Pigmentosum Complementation Group C ( XPC) Enhances Glycolysis-Mediated Drug Resistance in DLD-1 Colon Cancer Cells. Front Pharmacol 2019; 10:912. [PMID: 31551763 PMCID: PMC6746939 DOI: 10.3389/fphar.2019.00912] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 07/18/2019] [Indexed: 02/04/2023] Open
Abstract
The pro-apoptotic proteins BAX and BAK are critical regulatory factors constituting the apoptosis machinery. Downregulated expression of BAX and BAK in human colorectal cancer lead to chemotherapeutic failure and poor survival rate in patients. In this study, isogenic DLD-1 colon cancer cells and the BAX and BAK double knockout counterpart were used as the cellular model to investigate the role of BAX/BAK-associated signaling network and the corresponding downstream effects in the development of drug resistance. Our data suggested that DLD-1 colon cancer cells with BAX/BAK double-knockout were selectively resistant to a panel of FDA-approved drugs (27 out of 66), including etoposide. PCR array analysis for the transcriptional profiling of genes related to human cancer drug resistance validated the altered level of 12 genes (3 upregulated and 9 downregulated) in DLD-1 colon cancer cells lack of BAX and BAK expression. Amongst these genes, XPC responsible for DNA repairment and cellular respiration demonstrated the highest tolerance towards etoposide treatment accompanying upregulated glycolysis as revealed by metabolic stress assay in DLD-1 colon cancer cells deficient with XPC. Collectively, our findings provide insight into the search of novel therapeutic strategies and pharmacological targets to against cancer drug resistance genetically associated with BAX, BAK, and XPC, for improving the therapy of colorectal cancer via the glycolytic pathway.
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Affiliation(s)
- Yu Han
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Yuan Qing Qu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Simon Wing Fai Mok
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Juan Chen
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Cheng Lai Xia
- Foshan Maternal and Child Health Research Institute, Foshan Women and Children's Hospital Affiliated to Southern Medical University, Foshan, China
| | - Hu Qiang He
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Zheng Li
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Wei Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Cong Ling Qiu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Liang Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Betty Yuen Kwan Law
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Vincent Kam Wai Wong
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
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11
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Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol 2019; 16:411-428. [PMID: 31028350 DOI: 10.1038/s41575-019-0145-7] [Citation(s) in RCA: 947] [Impact Index Per Article: 157.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Caloric excess and sedentary lifestyle have led to a global epidemic of obesity and metabolic syndrome. The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), is estimated to affect up to one-third of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Owing to the high prevalence of NAFLD, especially in industrialized countries but also worldwide, and the consequent burden of progressive liver disease, there is mounting epidemiological evidence that NAFLD has rapidly become a leading aetiology underlying many cases of hepatocellular carcinoma (HCC). In this Review, we discuss NAFLD-associated HCC, including its epidemiology, the key features of the hepatic NAFLD microenvironment (for instance, adaptive and innate immune responses) that promote hepatocarcinogenesis and the management of HCC in patients with obesity and associated metabolic comorbidities. The challenges and future directions of research will also be discussed, including clinically relevant biomarkers for early detection, treatment stratification and monitoring as well as approaches to therapies for both prevention and treatment in those at risk or presenting with NAFLD-associated HCC.
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Affiliation(s)
- Quentin M Anstee
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
- The Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
| | - Helen L Reeves
- The Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
- Northern Institute for Cancer Research, Medical School, Newcastle upon Tyne, UK
- Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Elena Kotsiliti
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Olivier Govaere
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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12
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Tarasov VV, Chubarev VN, Ashraf GM, Dostdar SA, Sokolov AV, Melnikova TI, Sologova SS, Grigorevskich EM, Makhmutovа A, Kinzirsky AS, Klochkov SG, Aliev G. How Cancer Cells Resist Chemotherapy: Design and Development of Drugs Targeting Protein-Protein Interactions. Curr Top Med Chem 2019; 19:394-412. [DOI: 10.2174/1568026619666190305130141] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Revised: 09/20/2018] [Accepted: 11/15/2018] [Indexed: 02/07/2023]
Abstract
Background:Resistance toward chemotherapeutics is one of the main obstacles on the way to effective cancer treatment. Personalization of chemotherapy could improve clinical outcome. However, despite preclinical significance, most of the potential markers have failed to reach clinical practice partially due to the inability of numerous studies to estimate the marker’s impact on resistance properly.Objective:The analysis of drug resistance mechanisms to chemotherapy in cancer cells, and the proposal of study design to identify bona fide markers.Methods:A review of relevant papers in the field. A PubMed search with relevant keywords was used to gather the data. An example of a search request: drug resistance AND cancer AND paclitaxel.Results:We have described a number of drug resistance mechanisms to various chemotherapeutics, as well as markers to underlie the phenomenon. We also proposed a model of a rational-designed study, which could be useful in determining the most promising potential biomarkers.Conclusion:Taking into account the most reasonable biomarkers should dramatically improve clinical outcome by choosing the suitable treatment regimens. However, determining the leading biomarkers, as well as validating of the model, is a work for further investigations.
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Affiliation(s)
- Vadim V. Tarasov
- Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russian Federation
| | - Vladimir N. Chubarev
- Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russian Federation
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Samira A. Dostdar
- Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russian Federation
| | - Alexander V. Sokolov
- Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russian Federation
| | - Tatiana I. Melnikova
- Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russian Federation
| | - Susanna S. Sologova
- Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russian Federation
| | - Ekaterina M. Grigorevskich
- Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russian Federation
| | - Alfiya Makhmutovа
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russian Federation
| | - Alexander S. Kinzirsky
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russian Federation
| | - Sergey G. Klochkov
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russian Federation
| | - Gjumrakch Aliev
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russian Federation
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13
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Hu LB, Chen Y, Meng XD, Yu P, He X, Li J. Nucleotide Excision Repair Factor XPC Ameliorates Prognosis by Increasing the Susceptibility of Human Colorectal Cancer to Chemotherapy and Ionizing Radiation. Front Oncol 2018; 8:290. [PMID: 30109214 PMCID: PMC6079218 DOI: 10.3389/fonc.2018.00290] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Accepted: 07/10/2018] [Indexed: 01/20/2023] Open
Abstract
Nucleotide excision repair (NER) is a DNA damage repair mechanism in mammals, but the relationship between NER and human colorectal cancer (HRC) progression has not been clarified yet. In this study, the expression of the NER genes XPA, XPC, XPF, XPG, ERCC1, and XPD was measured in normal and cancerous human colorectal tissue. Among them, only the XPC gene expression was significantly increased in colorectal cancer tissue. To establish the role of XPC in colorectal cancer, small interference RNA (siRNA) targeting XPC was used to knockdown the expression of XPC in HRC cell lines. In addition, an expression vector plasmid containing the XPC cDNA was constructed and stably transfected into HRC cell lines to overexpress the XPC gene. Interestingly, MTT and apoptosis assay demonstrated that XPC gene overexpression significantly increased the susceptibility of HRC cell lines to cisplatin and X-ray radiation. In order to study the relationship between XPC expression and the progression of HRC, XPC expression was measured in 167 patients with colorectal cancer. The results showed that patients with high XPC expression had longer survival time. Cox regression analysis showed that high XPC expression might be a potential predictive factor for colorectal cancer. In conclusion, XPC plays a key role in the susceptibility of colorectal cancer to chemotherapy and ionizing radiation and is associated with a good patients' prognosis.
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Affiliation(s)
- Liang-Bo Hu
- Department of Radiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China
| | - Yin Chen
- Department of General Surgery, The People's Liberation Army 324 Hospital, Chongqing, China
| | - Xiao-Dong Meng
- Department of Urology, Bethune International Peace Hospital, Shijiazhuang, China
| | - Pan Yu
- Department of Burn and Plastic Surgery, Jinling Hospital, Nanjing, China
| | - Xu He
- Department of General Surgery, The People's Liberation Army 324 Hospital, Chongqing, China
| | - Jie Li
- Department of Nephrology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China
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14
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Marin JJG, Briz O, Herraez E, Lozano E, Asensio M, Di Giacomo S, Romero MR, Osorio-Padilla LM, Santos-Llamas AI, Serrano MA, Armengol C, Efferth T, Macias RIR. Molecular bases of the poor response of liver cancer to chemotherapy. Clin Res Hepatol Gastroenterol 2018; 42:182-192. [PMID: 29544679 DOI: 10.1016/j.clinre.2017.12.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 12/19/2017] [Indexed: 02/08/2023]
Abstract
A characteristic shared by most frequent types of primary liver cancer, i.e., hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) in adults, and in a lesser extent hepatoblastoma (HB) mainly in children, is their high refractoriness to chemotherapy. This is the result of synergic interactions among complex and diverse mechanisms of chemoresistance (MOC) in which more than 100 genes are involved. Pharmacological treatment, although it can be initially effective, frequently stimulates the expression of MOC genes, which results in the relapse of the tumor, usually with a more aggressive and less chemosensitive phenotype. Identification of the MOC genetic signature accounting for the "resistome" present at each moment of tumor life would prevent the administration of chemotherapeutic regimens without chance of success but still with noxious side effects for the patient. Moreover, a better description of cancer cells strength is required to develop novel strategies based on pharmacological, cellular or gene therapy to overcome liver cancer chemoresistance.
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Affiliation(s)
- Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Elisa Herraez
- Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Elisa Lozano
- Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Silvia Di Giacomo
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
| | - Marta R Romero
- Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Luis M Osorio-Padilla
- Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Ana I Santos-Llamas
- Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Maria A Serrano
- Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Carolina Armengol
- Childhood Liver Oncology Group, Program of Predictive and Personalized Medicine of Cancer (PMPCC), Health Sciences Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Thomas Efferth
- Department Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany
| | - Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
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15
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Wen HJ, Walsh MP, Yan IK, Takahashi K, Fields A, Patel T. Functional Modulation of Gene Expression by Ultraconserved Long Non-coding RNA TUC338 during Growth of Human Hepatocellular Carcinoma. iScience 2018; 2:210-220. [PMID: 29888750 PMCID: PMC5993207 DOI: 10.1016/j.isci.2018.03.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
TUC338 is an ultraconserved long non-coding RNA that contributes to transformed cell growth in hepatocellular carcinoma (HCC). Genomic regions of TUC338 occupancy were enriched in unique or known binding motifs homologous to the tumor suppressors Pax6 and p53. Genes involved in cell proliferation were enriched within a 9-kb range of TUC338-binding sites. TUC338 RNA-based purification was used to isolate chromatin for mass spectrometry, and the plasminogen activator inhibitor-1 RNA-binding protein (PAI-RBP1) was identified as a TUC338 RNA-binding partner. The PAI-RBP1 target gene plasminogen activator inhibitor-1 (PAI-1) itself could also be post-transcriptionally regulated by TUC338. Thus modulation of transformed cell growth by TUC338 may involve binding to PAI-RBP1 as well as to sequence-defined cis-binding sites to modulate gene expression. These findings suggest that ultraconserved RNAs such as TUC338 can function in a manner analogous to transcription factors to modulate cell proliferation and transformed cell growth in HCC.
TUC338 can modulate cell proliferation by sequence-specific genomic binding TUC338 binds to motifs homologous to those of the tumor suppressors Pax6 and p53 Plasminogen activator inhibitor-1 mRNA binding protein is a TUC338-binding protein TUC338 can regulate PAI-RBP1 target gene plasminogen activator inhibitor-1
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Affiliation(s)
- Hui-Ju Wen
- Department of Transplantation, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Michael P Walsh
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Irene K Yan
- Department of Transplantation, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Kenji Takahashi
- Department of Transplantation, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Alan Fields
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Tushar Patel
- Department of Transplantation, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
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16
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Zhang Y, Cao J, Meng Y, Qu C, Shen F, Xu L. Overexpression of xeroderma pigmentosum group C decreases the chemotherapeutic sensitivity of colorectal carcinoma cells to cisplatin. Oncol Lett 2018; 15:6336-6344. [PMID: 29616110 PMCID: PMC5876430 DOI: 10.3892/ol.2018.8127] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Accepted: 11/20/2017] [Indexed: 11/09/2022] Open
Abstract
Xeroderma pigmentosum group C (XPC) is a DNA-damage-recognition gene active at the early stage of DNA repair. XPC also participates in regulation of cell-cycle checkpoint and DNA-damage-induced apoptosis. In the present study, the expression levels of genes involved in nucleotide excision repair (NER) were assessed in human colorectal cancer (CRC) tissue. This analysis revealed that expression of XPC mRNA significantly increased in colorectal carcinoma tissues compared with matched normal controls. Expression of XPC gradually increased along with the degree of progression of CRC. In vitro, an XTT assay demonstrated that small interfering RNA (siRNA) targeting XPC significantly increased the sensitivity of CRC SW480 cells to cisplatin, whereas cells transfected with a XPC-overexpression plasmid became more resistant to cisplatin. Furthermore, flow cytometry revealed that the proportion of apoptotic cells significantly increased in XPC-knockdown cells upon cisplatin treatment. However, the overexpression XPC significantly increased the resistance of cells to cisplatin. In vivo, tumor growth was significantly reduced in tumor-bearing mice when the XPC gene was knocked down. Upregulation of the expression of pro-apoptotic Bcl-associated X and downregulation of the anti-apoptotic B-cell lymphoma 2 proteins was observed in the implanted tumor tissue. In conclusion, XPC serves a key role in chemotherapeutic sensitivity of CRC to cisplatin, meaning that it may be a potential target for chemotherapy of CRC.
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Affiliation(s)
- Yi Zhang
- Department of Digestive Endoscopic Diagnosis and Treatment, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, P.R. China
| | - Jia Cao
- Department of Digestive Endoscopic Diagnosis and Treatment, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, P.R. China
| | - Yanni Meng
- Department of Digestive Endoscopic Diagnosis and Treatment, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, P.R. China
| | - Chunying Qu
- Department of Digestive Endoscopic Diagnosis and Treatment, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, P.R. China
| | - Feng Shen
- Department of Digestive Endoscopic Diagnosis and Treatment, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, P.R. China
| | - Leiming Xu
- Department of Digestive Endoscopic Diagnosis and Treatment, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, P.R. China
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17
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RAD4 and RAD23/HMR Contribute to Arabidopsis UV Tolerance. Genes (Basel) 2017; 9:genes9010008. [PMID: 29283431 PMCID: PMC5793161 DOI: 10.3390/genes9010008] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 12/15/2017] [Accepted: 12/19/2017] [Indexed: 11/16/2022] Open
Abstract
In plants, exposure to solar ultraviolet (UV) light is unavoidable, resulting in DNA damage. Damaged DNA causes mutations, replication arrest, and cell death, thus efficient repair of the damaged DNA is essential. A light-independent DNA repair pathway called nucleotide excision repair (NER) is conserved throughout evolution. For example, the damaged DNA-binding protein Radiation sensitive 4 (Rad4) in Saccharomyces cerevisiae is homologous to the mammalian NER protein Xeroderma Pigmentosum complementation group C (XPC). In this study, we examined the role of the Arabidopsis thaliana Rad4/XPC homologue (AtRAD4) in plant UV tolerance by generating overexpression lines. AtRAD4 overexpression, both with and without an N-terminal yellow fluorescent protein (YFP) tag, resulted in increased UV tolerance. YFP-RAD4 localized to the nucleus, and UV treatment did not alter this localization. We also used yeast two-hybrid analysis to examine the interaction of AtRAD4 with Arabidopsis RAD23 and found that RAD4 interacted with RAD23B as well as with the structurally similar protein HEMERA (HMR). In addition, we found that hmr and rad23 mutants exhibited increased UV sensitivity. Thus, our analysis suggests a role for RAD4 and RAD23/HMR in plant UV tolerance.
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18
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The 5'UTR variant of ERCC5 fails to influence outcomes in ovarian and lung cancer patients undergoing treatment with platinum-based drugs. Sci Rep 2016; 6:39217. [PMID: 27966655 PMCID: PMC5155271 DOI: 10.1038/srep39217] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 11/21/2016] [Indexed: 11/08/2022] Open
Abstract
The common polymorphic variant in the 5' untranslated region of the excision repair cross-complementation group 5 (ERCC5) gene was described to generate an upstream open reading frame that regulates both the basal ERCC5 expression and its ability to be synthesized following DNA damage. This variant was reported to affect response to platinum therapy in a cohort of patients with pediatric ependymoma. The role of this variant was investigated in two cohorts of cancer patients, specifically in non-small-cell lung cancer (NSCLC) patients (N = 137) and in epithelial ovarian carcinoma (EOC) patients (N = 240), treated in first-line with platinum-based compounds. Differently from what reported for pediatric ependymoma, the analysis of the polymorphism in NSCLC patients cohort was not able to detect any difference among patients harboring different genotypes both in progression free survival (HR = 0.93; 95%CI 0.64-1.33; p-value = 0.678) and overall survival (HR = 0.90; 95%CI 0.62-1.33; p-value = 0.625). These data were corroborated in a EOC patients cohort, where similar progression free survival (HR = 0.91; 95% CI 0.67-1.24; p-value = 0.561) and overall survival (HR = 0.98; 95% CI 0.71-1.35; p-value = 0.912) were found for the different genotypes. These data, obtained in appropriately sized populations, indicate that the effect of this ERCC5 polymorphism is likely to be relevant only in specific tumors.
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19
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Ferroudj S, Yildiz G, Bouras M, Iscan E, Ekin U, Ozturk M. Role of Fanconi anemia/BRCA pathway genes in hepatocellular carcinoma chemoresistance. Hepatol Res 2016; 46:1264-1274. [PMID: 26885668 DOI: 10.1111/hepr.12675] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 01/26/2016] [Accepted: 02/12/2016] [Indexed: 02/08/2023]
Abstract
AIM To investigate the expression of DNA repair genes and the impact of the breast cancer 1, early onset (BRCA1) protein on chemoresistance of hepatocellular carcinoma (HCC). METHODS Microarray gene expression datasets were analyzed using the gene set enrichment analysis method. BRCA1 protein was tested by Western blotting. Response of HCC cells to interstrand cross-links was investigated by cell viability assay following exposure to mitomycin C, cisplatin, and melphalan. Effects of BRCA1 ectopic expression were studied in HepG2 cells with BRCA1-expression plasmids. Effects of BRCA1 downregulation were studied in SNU449 cells with BRCA1-specific siRNAs. Response of transfected SNU449 cells to mitomycin C was analyzed by cell viability tests and cell cycle analysis using flow cytometry. RESULTS Expression of Fanconi anemia and double-stranded DNA break repair genes was significantly upregulated in HCC tumors. This upregulation displayed a gradual amplification during tumor progression. BRCA1 and BRCA2 genes were among consistently upregulated genes. Epithelial-like HCC cells had low BRCA1 expression and low chemoresistance, whereas mesenchymal-like HCC cells had high BRCA1 expression and increased chemoresistance. Ectopic expression of BRCA1 increased the chemoresistance of epithelial-like HepG2 cells. Conversely, BRCA1 knockdown chemosensitized mesenchymal-like SNU449 cells. Chemosensitization of SNU449 cells was due to cell cycle arrest at 4N stage. CONCLUSION Increased expression of Fanconi anemia and double-stranded DNA repair genes such as BRCA1 is a novel mechanism of HCC chemoresistance. However, functional inactivation of BRCA1 expression is sufficient to reverse such chemoresistance.
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Affiliation(s)
- Sana Ferroudj
- CRI INSERM/UJF U823, Grenoble, France.,Biochemistry Department, Faculty of Natural and Life Sciences, University of Sétif, Algeria.,Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, İzmir, Turkey
| | - Gokhan Yildiz
- CRI INSERM/UJF U823, Grenoble, France.,Department of Medical Biology, Faculty of Medicine, Erzincan University, Erzincan, Turkey
| | - Mourad Bouras
- CRI INSERM/UJF U823, Grenoble, France.,Biochemistry and Molecular Biology Department of Pharmacy, School of Medicine, University of Batna, Algeria
| | - Evin Iscan
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, İzmir, Turkey
| | - Umut Ekin
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, İzmir, Turkey
| | - Mehmet Ozturk
- CRI INSERM/UJF U823, Grenoble, France.,Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, İzmir, Turkey
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20
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Involvement of DNA damage response pathways in hepatocellular carcinoma. BIOMED RESEARCH INTERNATIONAL 2014; 2014:153867. [PMID: 24877058 PMCID: PMC4022277 DOI: 10.1155/2014/153867] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 01/23/2014] [Accepted: 03/25/2014] [Indexed: 12/16/2022]
Abstract
Hepatocellular carcinoma (HCC) has been known as one of the most lethal human malignancies, due to the difficulty of early detection, chemoresistance, and radioresistance, and is characterized by active angiogenesis and metastasis, which account for rapid recurrence and poor survival. Its development has been closely associated with multiple risk factors, including hepatitis B and C virus infection, alcohol consumption, obesity, and diet contamination. Genetic alterations and genomic instability, probably resulted from unrepaired DNA lesions, are increasingly recognized as a common feature of human HCC. Dysregulation of DNA damage repair and signaling to cell cycle checkpoints, known as the DNA damage response (DDR), is associated with a predisposition to cancer and affects responses to DNA-damaging anticancer therapy. It has been demonstrated that various HCC-associated risk factors are able to promote DNA damages, formation of DNA adducts, and chromosomal aberrations. Hence, alterations in the DDR pathways may accumulate these lesions to trigger hepatocarcinogenesis and also to facilitate advanced HCC progression. This review collects some of the most known information about the link between HCC-associated risk factors and DDR pathways in HCC. Hopefully, the review will remind the researchers and clinicians of further characterizing and validating the roles of these DDR pathways in HCC.
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Li YW, Wang JX, Yin X, Qiu SJ, Wu H, Liao R, Yi Y, Xiao YS, Zhou J, Zhang BH, Fan J. Decreased expression of GATA2 promoted proliferation, migration and invasion of HepG2 in vitro and correlated with poor prognosis of hepatocellular carcinoma. PLoS One 2014; 9:e87505. [PMID: 24498120 PMCID: PMC3907524 DOI: 10.1371/journal.pone.0087505] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Accepted: 12/26/2013] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND GATA family of transcription factors are critical for organ development and associated with progression of various cancer types. However, their expression patterns and prognostic values for hepatocellular carcinoma (HCC) are still largely unknown. METHODS Expression of GATA transcription factors in HCC cell lines and tissues (n = 240) were evaluated by RT-qPCR, western blot and immunohistochemistry. Cellular proliferation, migration and invasion of HepG2 was evaluated by CCK-8 kit, scratch wound assay and transwell matrigel invasion assay, respectively. RESULTS GATA2 expression was decreased in HCC cell lines (p = 0.056 for mRNA, p = 0.040 for protein) and tissues (p = 1.27E-25) compared with normal hepatocytes. Decreased expression of intratumoral GATA2 protein significantly correlated with elevated alpha feto-protein (p = 2.7E-05), tumor size >5 cm (p = 0.049), absence of tumor capsule (p = 0.002), poor differentiation (p = 0.005), presence of tumor thrombi (p = 0.005) and advanced TNM stage (p = 0.001) and was associated with increased recurrence rate and decreased overall survival rate by univariate (p = 1.6E-04 for TTR, p = 1.7E-04 for OS) and multivariate analyses (HR = 0.63, 95% CI = 0.43-0.90, p = 0.012 for TTR; HR = 0.67, 95% CI = 0.47-0.95, p = 0.026 for OS). RNAi-mediated knockdown of GATA2 expression significantly enhanced proliferation, migration and invasion of HepG2 cell in vitro. CONCLUSIONS Decreased expression of hematopoietic factor GATA2 was associated with poor prognosis of HCC following resection.
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Affiliation(s)
- Yi-Wei Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Jia-Xing Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Xin Yin
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Shuang-Jian Qiu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Han Wu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Rui Liao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Yong Yi
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Yong-Sheng Xiao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Bo-Heng Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
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Ahmad Aizat AA, Siti Nurfatimah MS, Aminudin MM, Ankathil R. XPC Lys939Gln polymorphism, smoking and risk of sporadic colorectal cancer among Malaysians. World J Gastroenterol 2013; 19:3623-3628. [PMID: 23801864 PMCID: PMC3691041 DOI: 10.3748/wjg.v19.i23.3623] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Revised: 11/29/2012] [Accepted: 03/09/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the risk association of xeroderma pigmentosum group C (XPC) Lys939Gln polymorphism alone and in combination with cigarette smoking on colorectal cancer (CRC) predisposition.
METHODS: Peripheral blood samples of 510 study subjects (255 CRC patients, 255 controls)were collected. DNA was extracted and genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. The association between polymorphic genotype and CRC predisposition was determined using the OR and 95%CI.
RESULTS: The frequency of the homozygous variant (Gln/Gln) genotype was significantly higher in cases compared with controls (16.0% vs 10.2%, P = 0.049). The Gln/Gln genotype of XPC showed a significantly higher association with the risk of CRC (OR = 1.884; 95%CI: 1.082-3.277; P = 0.025). In the case of allele frequencies, variant allele C was associated with a significantly increased risk of CRC (OR = 1.375; 95%CI: 1.050-1.802; P = 0.020). Moreover, the risk was markedly higher for those who were carriers of the Gln/Gln variant genotype and were also cigarette smokers (OR = 3.409; 95%CI: 1.061-10.949; P = 0.032).
CONCLUSION: The XPC Gln/Gln genotype alone and in combination with smoking increases the risk of CRC among Malaysians.
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Chen G, Qiu H, Ke S, Hu S, Yu S, Zou S. The fibroblast growth factor receptor 2-mediated extracellular signal-regulated kinase 1/2 signaling pathway plays is important in regulating excision repair cross-complementary gene 1 expression in hepatocellular carcinoma. Biomed Rep 2013; 1:604-608. [PMID: 24648994 DOI: 10.3892/br.2013.96] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Accepted: 04/15/2013] [Indexed: 12/19/2022] Open
Abstract
Excision repair cross-complementary gene 1 (ERCC1) is a downstream regulatory target of fibroblast growth factor receptor 2 (FGFR2); however, the mechanism of its action has not been elucidated. The cascades downstream of FGFR2 include the PKC, Ras/Raf/MEK/ERK, JAK/STAT and PI3K pathways. ERCC1 is considered to be a closely related downstream target gene of extracellular signal-regulated kinase (ERK)1/2, since ERCC1 mRNA and protein levels may be inhibited by the ERK inhibitor U0126. It was hypothesized that FGFR2, which specifically binds with fibroblast growth factor 7 (FGF7), may regulate ERCC1 gene expression through the ERK signaling pathway. The aim of the present study was to explore the association between the regulatory effect of FGFR2 on ERCC1 gene expression and the p-ERK1/2 signaling pathway in a drug-resistant hepatocellular carcinoma (HCC) cell line. The drug-resistant cell line HepG2/OXA and its parental cell line HepG2 were transfected with Bek shRNA in the logarithmic growth phase. Transfected and untransfected HepG2 and HepG2/OXA cells were then stimulated with FGF7 and changes in the protein expression of FGFR2, p-ERK1/2 and ERCC1 was detected with western blot analysis. Following transfection, HepG2/T and HepG2/OXA/T cells were observed to grow stably in a screening medium containing puromycin. The western blot analysis demonstrated a significant decrease in the protein expressions of FGFR2, p-ERK1/2 and ERCC1 in HepG2/T and HepG2/OXA/T cells as compared to untransfected cells. Expression of FGFR2, p-ERK1/2 and ERCC1 in HepG2/OXA cells was significantly increased compared to the parental HepG2 cells. Following stimulation with FGF7, the expression of FGFR2, p-ERK1/2 and ERCC1 was increased, with significant differences between HepG2 and HepG2/OXA cells in the expression of p-ERK1/2 and ERCC1. No differences were detected in the protein levels following Bek shRNA transfection in HepG2/T and HepG2/OXA/T cells. In conclusion, the FGFR2-mediated ERK1/2 signaling pathway in HCC cells plays an important role in the regulation of ERCC1 expression.
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Affiliation(s)
- Gang Chen
- Departments of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Hong Qiu
- Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Shandong Ke
- Departments of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Shaoming Hu
- Departments of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Shiying Yu
- Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Shengquan Zou
- Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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Bassullu N, Turkmen I, Dayangac M, Yagiz Korkmaz P, Yasar R, Akyildiz M, Yaprak O, Tokat Y, Yuzer Y, Bulbul Dogusoy G. The Predictive and Prognostic Significance of c-erb-B2, EGFR, PTEN, mTOR, PI3K, p27, and ERCC1 Expression in Hepatocellular Carcinoma. HEPATITIS MONTHLY 2012; 12:e7492. [PMID: 23162604 PMCID: PMC3496900 DOI: 10.5812/hepatmon.7492] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2012] [Revised: 07/04/2012] [Accepted: 07/17/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the fifth most common fatal cancer and an important healthcare problem worldwide. There are many studies describing the prognostic and predictive effects of epidermal growth factor receptor 2 (c-erb-B2) and epidermal growth factor receptor 1 (EGFR), transmembrane tyrosine kinases that influence cell growth and proliferation in many tumors. OBJECTIVES The current study aimed to investigate the expression levels of c-erb-B2, EGFR, PTEN, mTOR, PI3K, p27, and ERCC1 in hepatocellular carcinoma (HCC) and their correlation with other clinicopathologic features. PATIENTS AND METHODS Fifty HCC cases were stained immunohistochemically with these markers. Correlations between the markers and clinicopathologic characteristics and survival rates were analyzed. RESULTS No membranous c-erb-B2 staining was seen, whereas cytoplasmic positivity was present in 92% of HCC samples, membranous EGFR was observed in 40%, PI3K was found in all samples, and mTOR was seen in 30%, whereas reduced or absent PTEN expression was observed in 56% of samples and loss of p27 was seen in 92% of the cases. c-erb-B2 and mTOR overexpression, as well as reduced expression of p27, all correlated with multiple tumors (P = 0.041, P < 0.001, and P < 0.001, respectively). P27 loss, and mTOR and EGFR positivity were significantly correlated with AFP (P = 0.047, P = 0.004, and P = 0.008, respectively). Angiolymphatic invasion was more commonly seen in EGFR- and ERCC1-positive cases (P = 0.003 and P = 0.005). EGFR was also correlated with histological grade (P = 0.039). No significant correlations were found among PTEN , PI3K, and the clinicopathological parameters. Disease-free or overall survival rates showed significant differences among therapy modalities, AFP levels, angiolymphatic or lymph node invasions, and ERCC1 and p27 expression levels (P < 0.05). CONCLUSIONS c-erb-B2, EGFR, mTOR, ERCC1 overexpression levels, and loss of p27 may play roles in hepatocarcinogenesis and may be significant predictors of aggressive tumor behavior. These markers were found to be correlated with certain clinicopathologic features, therapy modalities, and survival rates in the current study. These findings may help in planning new, targeted treatment strategies .
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Affiliation(s)
- Nuray Bassullu
- Department of Pathology, Istanbul Bilim University Medical Faculty, Istanbul, Turkey
- Corresponding author: Nuray Bassullu, Department of Pathology, Istanbul Bilim University Medical Faculty, Mehmetcik Street, Cahit Yalcın Sokak No: 1 Mecidiyeköy, Sisli, Istanbul, Turkey. Tel.: +90-2122883400/4819, Fax: +90-2122883456, E-mail:
| | - Ilknur Turkmen
- Department of Pathology, Istanbul Bilim University Medical Faculty, Istanbul, Turkey
| | - Murat Dayangac
- Department of General Surgery, Florence Nigthingale Hospital, Istanbul, Turkey
| | | | - Reyhan Yasar
- Department of Pathology, Florence Nigthingale Hospital, Istanbul, Turkey
| | - Murat Akyildiz
- Department of Gastroenterology, Istanbul Bilim University Medical Faculty, Istanbul, Turkey
| | - Onur Yaprak
- Department of General Surgery, Florence Nigthingale Hospital, Istanbul, Turkey
| | - Yaman Tokat
- Department of General Surgery, Florence Nigthingale Hospital, Istanbul, Turkey
| | - Yildiray Yuzer
- Department of General Surgery, Florence Nigthingale Hospital, Istanbul, Turkey
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Li J, Zhang J, Liu Y, Ye G. Increased expression of DNA repair gene XPF enhances resistance to hydroxycamptothecin in bladder cancer. Med Sci Monit 2012; 18:BR156-62. [PMID: 22460090 PMCID: PMC3560829 DOI: 10.12659/msm.882618] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Background Xeroderma pigmentosum group F (XPF) is an important participant in the nucleotide excision repair process. This study aimed to investigate the expression of DNA repair gene xeroderma pigmentosum group F (XPF) in bladder cancer and its clinical significance. Material/Methods Total RNA and protein were extracted from 45 untreated bladder cancer tissues and 21 hydroxycamptothecin (HCPT)-treated bladder cancer specimens. Real-time PCR and Western blot assay were used to detect the mRNA and protein levels of XPF, respectively. siRNA targeting XPF was used to knock down the XPF expression in T24 cells and 5637 cells, and the sensitivity of XPF-depleted cells to HCPT was measured. Results The XPF expressions in the HCPT-treated cancer tissues was significantly higher than those in the untreated cancer tissues at both mRNA and protein levels. Importantly, the enhanced XPF expression decreased the sensitivity of T24 cells and 5637 cells to HCPT. Furthermore, the HCPT treatment significantly increased the apoptosis of T24 cells and 5637 cells. Alternatively, after the XPF gene silencing, the chemotherapeutic resistance of bladder cancer cells was significantly decreased. Conclusions Our results show the increased expression of XPF is involved in the chemotherapeutic resistance of bladder cancer, and decreasing XPF expression may become a promising therapeutic strategy for bladder cancer.
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Affiliation(s)
- Jie Li
- Department of Urology, 2nd Affiliated Hospital, 3rd Military Medical University, Chongqing, China
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Asghar U, Meyer T. Are there opportunities for chemotherapy in the treatment of hepatocellular cancer? J Hepatol 2012; 56:686-95. [PMID: 21971559 DOI: 10.1016/j.jhep.2011.07.031] [Citation(s) in RCA: 152] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2010] [Revised: 07/25/2011] [Accepted: 07/28/2011] [Indexed: 02/07/2023]
Abstract
Hepatocellular cancer is a significant global health problem yet the prognosis for the majority of patients has not changed significantly over the past few decades. For patients with advanced disease, sorafenib is currently the standard of care providing a survival advantage of 2-3 months in selected patients. Cytotoxic chemotherapy has been used for over 30 years but definite evidence that it prolongs survival has been lacking. Resistance remains a significant barrier for both targeted and cytotoxic agents and an understanding of the underlying mechanisms is critical if outcomes are to be improved. Here, we summarise the past and current data that constitute the evidence base for chemotherapy in HCC, review the causes of chemoresistance and suggest strategies to overcome these barriers.
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Affiliation(s)
- Uzma Asghar
- Department of Oncology, UCL Medical School, Royal Free Campus, London, UK
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Clinicopathological significance and prognostic value of Xeroderma pigmentosum complementary group C (XPC) expression in sporadic breast cancer patients. Med Oncol 2011; 29:1543-53. [PMID: 22038723 DOI: 10.1007/s12032-011-0086-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2011] [Accepted: 10/07/2011] [Indexed: 10/15/2022]
Abstract
Breast cancer is the most common type of cancer among women worldwide, and the incidence of breast cancer is increasing in the developing world. Estrogen exposure is a major risk factor for breast cancer, and estrogen oxidative metabolites have been implicated in chemical carcinogenesis. Xeroderma pigmentosum complementary group C (XPC) plays an important and multifaceted role in cell protection from oxidative DNA damage. Thus, XPC inactivation may be involved in the early stage of breast cancer. The aim of this study was to investigate the expression of XPC protein in sporadic breast cancer tissues and determine whether XPC expression influences breast cancer malignancy and clinical outcome. Fifteen cases of adjacent non-tumor breast tissue, 28 cases of fibroadenomas and 235 cases of breast carcinomas were examined by immunohistochemistry using polyclonal antibody to XPC. Both cytoplasmic and nuclear expression level of XPC were downregulated in breast carcinoma when compared to non-tumor tissues (P < 0.05). The nuclear expression level of XPC was significantly associated with expression of BCL2 (r = 0.231, P = 0.033) and p53 (r = 0.205, P = 0.011), and nuclear expression of XPC was significantly associated with patients' age (P = 0.024). Neither cytoplasmic nor nuclear expression level of XPC had impact on patients' survival in the whole samples. However, XPC expression was correlated with adverse survival in HER2-positive, but not HER2-negative, tumors, as demonstrated by Kaplan-Meier analysis. Our results suggested that the XPC protein is involved in the occurrence and progression of breast cancer.
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Rageul J, Frëmin C, Ezan F, Baffet G, Langouët S. The knock-down of ERCC1 but not of XPF causes multinucleation. DNA Repair (Amst) 2011; 10:978-90. [DOI: 10.1016/j.dnarep.2011.07.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2011] [Revised: 07/18/2011] [Accepted: 07/19/2011] [Indexed: 11/26/2022]
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Ueda S, Shirabe K, Morita K, Umeda K, Kayashima H, Uchiyama H, Soejima Y, Taketomi A, Maehara Y. Evaluation of ERCC1 Expression for Cisplatin Sensitivity in Human Hepatocellular Carcinoma. Ann Surg Oncol 2010; 18:1204-11. [DOI: 10.1245/s10434-010-1414-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Indexed: 12/24/2022]
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Long XD, Ma Y, Zhou YF, Ma AM, Fu GH. Polymorphism in xeroderma pigmentosum complementation group C codon 939 and aflatoxin B1-related hepatocellular carcinoma in the Guangxi population. Hepatology 2010; 52:1301-1309. [PMID: 20658464 DOI: 10.1002/hep.23807] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
UNLABELLED Genetic polymorphisms in DNA repair genes may influence individual variations in DNA repair capacity, and this may be associated with the risk and outcome of hepatocellular carcinoma (HCC) related to aflatoxin B1 (AFB1) exposure. In this study, we focused on the polymorphism of xeroderma pigmentosum complementation group C (XPC) codon 939 (rs#2228001), which is involved in nucleotide excision repair. We conducted a case-control study including 1156 HCC cases and 1402 controls without any evidence of hepatic disease to evaluate the associations between this polymorphism and HCC risk and prognosis in the Guangxi population. AFB1 DNA adduct levels, XPC genotypes, and XPC protein levels were tested with a comparative enzyme-linked immunosorbent assay, TaqMan polymerase chain reaction for XPC genotypes, and immunohistochemistry, respectively. Higher AFB1 exposure was observed among HCC patients versus the control group [odds ratio (OR) = 9.88 for AFB1 exposure years and OR = 6.58 for AFB1 exposure levels]. The XPC codon 939 Gln alleles significantly increased HCC risk [OR = 1.25 (95% confidence interval = 1.03-1.52) for heterozygotes of the XPC codon 939 Lys and Gln alleles (XPC-LG) and OR = 1.81 (95% confidence interval = 1.36-2.40) for homozygotes of the XPC codon 939 Gln alleles (XPC-GG)]. Significant interactive effects between genotypes and AFB1 exposure status were also observed in the joint-effects analysis. This polymorphism, moreover, was correlated with XPC expression levels in cancerous tissues (r = -0.369, P < 0.001) and with the overall survival of HCC patients (the median survival times were 30, 25, and 19 months for patients with homozygotes of the XPC codon 939 Lys alleles, XPC-LG, and XPC-GG, respectively), especially under high AFB1 exposure conditions. Like AFB1 exposure, the XPC codon 939 polymorphism was an independent prognostic factor influencing the survival of HCC. Additionally, this polymorphism multiplicatively interacted with the xeroderma pigmentosum complementation group D codon 751 polymorphism with respect to HCC risk (OR(interaction) = 1.71). CONCLUSION These results suggest that the XPC codon 939 polymorphism may be associated with the risk and outcome of AFB1-related HCC in the Guangxi population and may interact with AFB1 exposure in the process of HCC induction by AFB1.
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Affiliation(s)
- Xi-Dai Long
- Department of Pathology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Sakurada T, Yoshikawa M, Sunaga M, Kobayashi E, Satoh N, Yokosuka O, Ueda S. Expression of Drug-Resistant Factor Genes in Hepatocellular Carcinoma Patients Undergoing Chemotherapy with Platinum Complex by Arterial Infusion. Pharmaceutics 2010; 2:300-312. [PMID: 27721358 PMCID: PMC3967139 DOI: 10.3390/pharmaceutics2030300] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2010] [Accepted: 09/01/2010] [Indexed: 01/13/2023] Open
Abstract
This study investigated gene expression of drug resistance factors in biopsy tissue samples from hepatocellular carcinoma (HCC) patients undergoing chemotherapy by platinum complex. Liver biopsy was performed to collect tissue from the tumor site (T) and the non-tumor site (NT) prior to the start of treatment. For drug-resistant factors, drug excretion transporters cMOAT and MDR-1, intracellular metal binding protein MT2, DNA repair enzyme ERCC-l and inter-nucleic cell transport protein MVP, were investigated. The comparison of the expression between T and NT indicated a significant decrease of MT2 and MDR-1 in T while a significant increase in ERCC-1 was noted in T. Further, expression was compared between the response cases and non-response cases using the ratios of expression in T to those in NT. The response rate was significantly low in the high expression group when the cutoff value of cMOAT and MT2 was set at 1.5 and 1.0, respectively. Furthermore, when the patients were classified into A group (cMOAT ≧ 1.5 or MT2 ≧ 1.0) and B group (cMOAT < 1.5 and MT2 < 1.0), the response rate of A group was significantly lower than B group when we combined the cutoff values of cMOAT and MT2. It is considered possible to estimate the therapeutic effect of platinum complex at a high probability by combining the expression condition of these two genes.
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Affiliation(s)
- Tomoya Sakurada
- Department of Drug Information and Communication, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan.
| | - Masaharu Yoshikawa
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan
| | - Masahiko Sunaga
- Department of Gastroenterology, Chiba Central Medical Center, 1835-1 Kasoricho, Wakaba-ku, Chiba, 264-0017, Japan
| | - Eriko Kobayashi
- Department of Drug Information and Communication, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan
| | - Nobunori Satoh
- Department of Clinical Education and Research, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan
| | - Osamu Yokosuka
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan
| | - Shiro Ueda
- Department of Drug Information and Communication, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan
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Wu CC, Liu MT, Chang YT, Fang CY, Chou SP, Liao HW, Kuo KL, Hsu SL, Chen YR, Wang PW, Chen YL, Chuang HY, Lee CH, Chen M, Wayne Chang WS, Chen JY. Epstein-Barr virus DNase (BGLF5) induces genomic instability in human epithelial cells. Nucleic Acids Res 2009; 38:1932-49. [PMID: 20034954 PMCID: PMC2847232 DOI: 10.1093/nar/gkp1169] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Epstein–Barr Virus (EBV) DNase (BGLF5) is an alkaline nuclease and has been suggested to be important in the viral life cycle. However, its effect on host cells remains unknown. Serological and histopathological studies implied that EBV DNase seems to be correlated with carcinogenesis. Therefore, we investigate the effect of EBV DNase on epithelial cells. Here, we report that expression of EBV DNase induces increased formation of micronucleus, an indicator of genomic instability, in human epithelial cells. We also demonstrate, using γH2AX formation and comet assay, that EBV DNase induces DNA damage. Furthermore, using host cell reactivation assay, we find that EBV DNase expression repressed damaged DNA repair in various epithelial cells. Western blot and quantitative PCR analyses reveal that expression of repair-related genes is reduced significantly in cells expressing EBV DNase. Host shut-off mutants eliminate shut-off expression of repair genes and repress damaged DNA repair, suggesting that shut-off function of BGLF5 contributes to repression of DNA repair. In addition, EBV DNase caused chromosomal aberrations and increased the microsatellite instability (MSI) and frequency of genetic mutation in human epithelial cells. Together, we propose that EBV DNase induces genomic instability in epithelial cells, which may be through induction of DNA damage and also repression of DNA repair, subsequently increases MSI and genetic mutations, and may contribute consequently to the carcinogenesis of human epithelial cells.
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Affiliation(s)
- Chung-Chun Wu
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan
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A national collection of liver tumours: Lessons learnt from 6 years of biobanking in France. Cancer Lett 2009; 286:140-4. [DOI: 10.1016/j.canlet.2009.04.034] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2008] [Revised: 03/29/2009] [Accepted: 04/23/2009] [Indexed: 11/20/2022]
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Andrieux LO, Fautrel A, Bessard A, Guillouzo A, Baffet G, Langouët S. GATA-1 is essential in EGF-mediated induction of nucleotide excision repair activity and ERCC1 expression through ERK2 in human hepatoma cells. Cancer Res 2007; 67:2114-23. [PMID: 17332341 DOI: 10.1158/0008-5472.can-06-3821] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The nucleotide excision repair (NER) pathway and its leading gene excision-repair cross-complementary 1 (ERCC1) have been shown to be up-regulated in hepatocellular carcinomas even in the absence of treatment with chemotherapeutics. The aim of this study was to determine the mechanism involved in NER regulation during the liver cell growth observed in hepatocellular carcinoma. Both NER activity and ERCC1 expression were increased after exposure to the epidermal growth factor (EGF) in cultured normal and tumoral human hepatocytes. These increases correlated with the activation of the kinase signaling pathway mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK that is known to be a key regulator in the G(1) phase of the hepatocyte cell cycle. Moreover, EGF-mediated activation of ERCC1 was specifically inhibited by either the addition of U0126, a MEK/ERK inhibitor or small interfering RNA-mediated knockdown of ERK2. Basal expression of ERCC1 was decreased in the presence of the phosphoinositide-3-kinase (PI3K) inhibitor and small hairpin RNA (shRNA) against the PI3K pathway kinase FKBP12-rapamycin-associated protein or mammalian target of rapamycin. Transient transfection of human hepatocytes with constructs containing different sizes of the 5'-flanking region of the ERCC1 gene upstream of the luciferase reporter gene showed an increase in luciferase activity in EGF-treated cells, which correlated with the presence of the nuclear transcription factor GATA-1 recognition sequence. The recruitment of GATA-1 was confirmed by chromatin immunoprecipitation assay. In conclusion, these results represent the first demonstration of an up-regulation of NER and ERCC1 in EGF-stimulated proliferating hepatocytes. The transcription factor GATA-1 plays an essential role in the induction of ERCC1 through the mitogen-activated protein kinase (MAPK) pathway, whereas the PI3K signaling pathway contributes to ERCC1 basal expression.
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Affiliation(s)
- Lise O Andrieux
- Institut National de la Santé et de la Recherche Médicale U620, Université de Rennes I, Hôpital Pontchaillou, IFR 140, 2 avenue du Pr Léon Bernard, 35043 Rennes Cedex, France
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