Mismatch repair genes (hMLH1, hPMS1, hPMS2, GTBP/hMSH6, hMSH2) in the pathogenesis of hepatocellular carcinoma.
OBJECTIVE
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. beta-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).


CONCLUSIONS
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.
Zekri
Abdel-Rahman N
AR
Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Kasr El-Aini St., Fom El-Khaig, Cairo 11796, Egypt. ncizakri@starnet.com.eg
Sabry
Gelane M
GM
Bahnassy
Abeer A
AA
Shalaby
Kamal A
KA
Abdel-Wahabh
Sabrin A
SA
Zakaria
Serag
S
D020137:Base Pair Mismatch / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000821:virology; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D016174:Hepacivirus / Q000502:physiology; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged