摘要：

Aberrant methylation is implicated in the development of a variety of solid tumors, including hepatocellular carcinoma (HCC). We show here that genome wide hypomethylation and CpG hypermethylation correlate with biological features and clinical outcome of human HCC. Both parameters reached the highest levels in HCCs from patients with shorter survival length, in parallel with increasing genomic instability and upregulation of de novo DNA Methyltransferases (DNMTs) 1, 3A, and 3b. A progressive rise in Interleukin 6 and Fli-1 levels was responsible for upregulation of DNMT1, but not DNMT3s, in surrounding non-neoplastic livers and HCCs. Methylation-specific PCR and combined bisulphite restriction analyses of 100 putative tumor suppressor gene promoters identified the genes both universally and specifically inactivated in distinct subgroups of HCCs based on the length of patient's survival. In particular, we identified activation of the Ras, Jak/Stat, and canonical Wnt/β-catenin pathways via epigenetic silencing on of Ras (ARHI, LOX, NORE1A, RASSF1A, and RIG), Jak/Stat (CIS, PIAS-1, PIAS-γ, SOCS1, 2, 3, and SHP1), and Wnt/β-catenin (APC, E-cadherin, SFRP1, 2, 4, 5, and WIF-1) inhibitors in the majority of HCCs, regardless of clinicopathological features of HCC patients. Furthermore, selective inactivation of genes controlling EGFR signaling and angiogenesis (e.g. SPRY1, 2, SOCS4, 5, EGLN2, BNIP3) was associated with an unfavorable outcome. Taken together, our results assign a therapeutic significance to methylation patterns in human HCC. Treatment approaches aimed at modifying the methylation status and utilizing novel molecular targets identified in this study may inhibit HCC development and progression.

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