Immunohistochemical expression of mismatch repair genes (<i>hMSH2</i> and <i>hMLH1</i>) in hepatocellular carcinoma in Egypt

Helal, Thanaa; Khamis, Nahed Samy; Elsharkawy, Tarek; Nada, Ola; Radwan, Nehal A.

doi:10.1111/j.1600-0463.2010.02658.x

Cited by 9 publications

(15 citation statements)

References 28 publications

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“…Overexpression of two key genes involved in the early steps of the NER process, ERCC1 and XPC, is associated with liver fibrogenesis and cancer and could be related to the well-recognized resistance of HCC to chemotherapeutics [135]. Several studies have revealed multiple genetic alterations of the mismatch repair (MMR) genes in hepatocarcinogenesis [136]. Among the MMR genes, human Mut L homologues 1 and 2 (hMLH1 and hMSH2) play important roles in DNA repair [137–139].…”

Section: The Impact Of Ddr Pathways On Hcc Developmentmentioning

confidence: 99%

“…Reduced expression of hMSH2 and hMLH1 in both HCC and ANCLT suggests that this event occurs at early stages of HCV-related hepatocarcinogenesis. Moreover, the significant association between reduced expression of both MMR genes and poor histologic grades of the tumor claims that these proteins are involved in the process of cancer progression [136]. …”

Section: The Impact Of Ddr Pathways On Hcc Developmentmentioning

confidence: 99%

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Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

Yang

Chang

Wei

et al. 2014

BioMed Research International

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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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Section: The Impact Of Ddr Pathways On Hcc Developmentmentioning

confidence: 99%

Section: The Impact Of Ddr Pathways On Hcc Developmentmentioning

confidence: 99%

Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

Yang

Chang

Wei

et al. 2014

BioMed Research International

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“…However, we detected promoter methylation not only in tumour but also in non-tumour adjacent tissue. In line with this, Helal et al detected reduced MLH1 and MSH2 expression in HCCs but also in adjacent non-cancerous surrounding tissues [22]. Possibly, the used tumour surrounding tissue already contained precancerous cells in some cases which might be detectable by high sensitive MSP analysis.…”

Section: Discussionmentioning

confidence: 80%

“…Others described the influence of HCV on DNA methyltransferase 1 [25], [26] a protein essential for the regulation of MLH1 and MSH2 expression [27]. Since chronic HCV infection is a major risk factor for HCC and HCC samples of HCV infected patients were only [22] or most dominantly analysed [8], [24] in the cited publications we rather hypothesize that promoter methylation of MMR proteins and p16 is frequently occurring during HCC progression in general without close connection to HCV.…”

Section: Discussionmentioning

confidence: 90%

Promoter Methylation of MLH1, PMS2, MSH2 and p16 Is a Phenomenon of Advanced-Stage HCCs

et al. 2014

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Epigenetic silencing of tumour suppressor genes has been observed in various cancers. Looking at hepatocellular carcinoma (HCC) specific protein silencing was previously demonstrated to be associated with the Hepatitis C virus (HCV). However, the proposed HCV dependent promoter methylation of DNA mismatch repair (MMR) genes and thereby enhanced progression of hepatocarcinogenesis has been the subject of controversial discussion. We investigated promoter methylation pattern of the MMR genes MLH1, MSH2 and PMS2 as well as the cyclin-dependent kinase inhibitor 2A gene (p16) in 61 well characterized patients with HCCs associated with HCV, Hepatitis B virus infection or alcoholic liver disease. DNA was isolated from formalin-fixed, paraffin-embedded tumour and non-tumour adjacent tissue and analysed by methylation-specific PCR. Moreover, microsatellite analysis was performed in tissues showing methylation in MMR gene promoters. Our data demonstrated that promoter methylation of MLH1, MSH2, PMS2 and p16 is present among all considered HCCs. Hereby, promoter silencing was detectable more frequently in advanced-stage HCCs than in low-stage ones. However, there was no significant correlation between aberrant DNA methylation of MMR genes or p16 and HCV infection in related HCC specimens. In summary, we show that promoter methylation of essential MMR genes and p16 is detectable in HCCs most dominantly in pT3 stage tumour cases. Since loss of MMR proteins was previously described to be not only responsible for tumour development but also for chemotherapy resistance, the knowledge of mechanisms jointly responsible for HCC progression might enable significant improvement of individual HCC therapy in the future.

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“…Genomic instability is an early and important event in carcinogenesis. Changes such as microsatellite instability and hypermethylation in the promoter regions of the hMLH1 and hMSH2 genes are detected frequently in potentially malignant lesions and cancer . Knowledge of the histological features and pathogenesis of lip lesions such as AC and SCC is important for the early diagnosis and correct treatment of these lesions.…”

Section: Introductionmentioning

confidence: 99%