Liver Cancer
Copyright ©2005 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2005; 11(20): 3020-3026
Published online May 28, 2005. doi: 10.3748/wjg.v11.i20.3020
Mismatch repair genes (hMLH1, hPMS1, hPMS2, GTBP/hMSH6, hMSH2) in the pathogenesis of hepatocellular carcinoma
Abdel-Rahman N. Zekri, Gelane M. Sabry, Abeer A. Bahnassy, Kamal A. Shalaby, Sabrin A. Abdel-Wahabh, Serag Zakaria
Abdel-Rahman N. Zekri, Sabrin A. Abdel-Wahabh, Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Egypt
Abeer A. Bahnassy, Pathology Department, National Cancer Institute, Cairo University, Egypt
Serag Zakaria, Tropical Medicine Department, El-Kaser Al-Aini School of Medicine, Cairo University, Egypt
Gelane M. Sabry, Kamal A. Shalaby, Biochemistry Department, Faculty of Science, Ain Shams University, Egypt
Author contributions: All authors contributed equally to the work.
Correspondence to: Abdel-Rahman N. Zekri, MSc, PhD, Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Kasr El-Aini St., Fom El-Khaig, Cairo 11796, Egypt.
Fax: +202-3644-720
Received: December 10, 2003
Revised: December 11, 2003
Accepted: March 12, 2004
Published online: May 28, 2005

AIM: DNA mismatch repair (MMR) is an important mechanism for maintaining fidelity of genomic DNA. Abnormalities in one or more MMR genes are implicated in the development of many cancers. We investigated the role of expression of MMR genes (hMLH1, hPMS1, hPMS2, GTBP/hMSH6, hMSH2) in hepatocellular carcinogenesis.

METHODS: We evaluated the expression level of MMR genes in 33 hepatocellular carcinoma (HCC) cases using the multiplex reverse transcription (RT) PCR assays, as well as in 16 cases of normal adjacent hepatic tissues. β-actin gene was used as an internal control and calibrator for quantification of gene expression.

RESULTS: Out of the 33 studied cases, 25 were HCV positive and 30 (90.9%) showed reduced expression in one or more of the studied MMR genes. Reduced expression was found in hMSH2 (71.9%), hMLH1 (53.3%), GTBP (51.1%), hPMS2 (33.3%) and hPMS1 (6%). A significant correlation was found between reduced expression of hPMS2 (P = 0.0069) and GTBP (P = 0.0034), hPMS2 and non-cirrhosis (P = 0.0197), hMLH1 and high grade. On the other hand, 57.1%, 50%, 20%, 18.8%, and 6% of the normal tissues distant to tumors showed reduced expression of hMSH2, hMLH1, GTBP, hPMS2, and hPMS1 respectively. Multivariate analysis revealed a significant correlation between the expression level of hMSH2 (P = 0.008), hMLH1 (P = 0.001) and GTBP (P = 0.032) and HCC, between hPMS2, GTBP and HCV-associated HCC (P<0.001, 0.002).

CONCLUSION: Reduced expression of MMR genes seems to play an important role in HCV-associated HCC. hPMS2 is likely involved at an early stage of hepatocarcinogenesis since it was detected in normal adjacent tissues. Reduced expression of hPMS2 provides a growth advantage and stimulates proliferation which encourages malignant transformation in non-cirrhotic HCV-infected patients via acquisition of more genetic damages.

Keywords: Hepatocellular carcinoma, Mismatch repair, Normal distant hepatic tissue