Mismatch repair and multi-drug resistance genes expression in relation to hcv- Associated hepatocellar carcinoma

Abstract EN

DNA mismatch repair (MMR) is an important mechanism involved in maintaining fidelity of genomic DNA.

Defective MMR is implicated in a variety of tumors ; however, its role in hepatocellular carcinoma (HCC) has not been determined yet.

Using a newly developed multiple reverse transcription-PCR assay, expression of four of the human MMR genes (hMLH1, hPMS1, hPMS2, GTBP6) and MDR-1 gene in 23 human HCC cases as well as 7 normal adjacent liver tissue (NALT) were evaluated.

Twenty-one cases were associated with HCV infection.

This was done in an attempt to determine the role of MMR genes in the development of HCC and their possible association with the acquisition of drug resistance.

The ß-actin gene was used as an internal control for RNA degradation and DNA contamination and as a reference for quantifying the levels of their transcription.

Out of the 23 HCC samples, 21 (91.3%) showed reduced expression of at least one of the MMR genes.

Low expression of hMLH1, GTBP, hMPS2 and hMPS1 were found in 61.9 %, 56.5 %, 47.8 % and 9.0 % of the cases, respectively.

MDR-1 expression was detected in 14 out of 23 cases (60.9 %).

Univariate analysis showed a significant correlation between reduced expression of hMPS2 and GTBP6 (p = 0.003), hMPS2 and chronic active hepatitis (p = 0.05) as well as hMPS2 and cirrhosis (p = 0.05); whereas, multi-variate analysis showed that hMPS2 explains 31% and GTBP6 explains 19% of HCC associated with cirrhosis.

On the other hand, 83.3% and 28.5% of the NALT showed low expression of hMLH1 and GTBP6, respectively; while 14.2% showed low expression of hMPS2 and hMPS1 (each) and 42.8 % showed MDR-1 expression.

In conclusion, this study represents the first report illustrating the implication of MMR genes in HCV-associated HCC and their association with MDR-1 overexpression.

It also shows that MMR defects occur at an early stage of hepato-carcinogenesis as reduced expression of some MMR genes was detected in cases of chronic active hepatitis (CAH) and cirrhosis.

This has a clinical impact, since these genes could be used to monitor CAH and cirrhotic patients who are prone to develop HCC.

However, these findings need to be confirmed in a larger cohort including more samples of HCC, CAH and cirrhotic patients.