Genome-wide hypomethylation in hepatocellular carcinogenesis

Aberrant genome-wide hypomethylation has been thought to be related to tumo rigenesis, However, its mechanism and implications in hepatocellular carcin ogenesis remain to be elucidated. Samples of hepatoma (hepatocellular carci noma, HCC) and paired non-HCC liver tissues were obtained from 17 HCC patie nts. Normal liver tissues obtained from three individuals were used as cont rols. Compared with the paired non-HCC liver tissues, genome-wide 5-methylc ytosine content in HCC was reduced in all of the tested HCC samples (P < 0. 001). Conversely, genome-wide 5-methylcytosine content did not significantl y differ among normal, noncirrhotic, and cirrhotic liver tissues. Moreover, the degree of reduced DNA methylation was related to late histopathologica l HCC grade (P = 0.005) and large tumor size (P = 0.079). Compared with the paired non-HCC liver tissues, expression of DNA methyltransferases DNMT-1, DNMT-3A, and DNMT-3B and the DNA methyltransferase-like gent, DNMT-2, was up-regulated in 53, 41, 59, and 47% of the HCC samples, respectively. Surpr isingly, small amounts of LINE-1 retrotransposon transcripts mere detected in HCC and non-HCC as well as normal liver tissues, and the expression leve ls were not significantly different in HCC compared with the paired non-HCC or normal liver tissues. Of interest, the 3 ' ends of these LINE-1 transcr ipts were truncated. Our findings suggest that genome-wide hypomethylation in HCC is a continuing process that persists throughout the lifetime of the tumor cells rather than a historical event occurring in precancer stages o r in cell origins for HCC. Up-regulation of DNA methyltransferases might si mply be a result of increased cell proliferation in cancer. In addition, ou r results did not support the hypothesis of activation of transposable elem ents in HCC via genome-wide hypomethylation.