Hypomethylated P4 promoter induces expression of the insulin-like growth factor-II gene in hepatocellular carcinoma in a Chinese population.

PURPOSE The expression of human insulin-like growth factor-II (IGF-II) is regulated by the activation of four promoters (P1-P4) acting in a development-dependent, tissue-specific manner. IGF-II overexpression associated with P3 and P4 activation is observed in animal and human hepatocarcinogenesis. We correlated P4 epigenetic alteration with P4 transcript activation and clinicopathologic features. EXPERIMENTAL DESIGN We analyzed P4 epigenetic alteration using methylation-specific PCR in 34 hepatocellular carcinoma (HCC) specimens, 34 matched adjacent nontumor specimens, and 8 normal adult liver specimens. The data were correlated with activation of P4 transcription by using reverse transcription-PCR. Epigenetic alteration was compared with patients' clinicopathologic features. RESULTS Compared with normal liver tissue, hypomethylation of P4 CpG islands was significantly more frequent in HCC (P = 0.03) and matched tissues (P = 0.047). P4 mRNA levels in HCC with unmethylated alleles were significantly higher than in HCC without unmethylated alleles (P = 0.001); P4 mRNA levels in matched nontumor tissues with unmethylated alleles were significantly higher than in matched nontumor tissues without unmethylated alleles (P = 0.005). P4 hypomethylation in HCC was associated with portal vein tumor embolus (P = 0.017) and poorer tumor differentiation (P = 0.025). CONCLUSIONS These findings suggest that IGF-II P4 hypomethylation may be an early and frequent event and that it may contribute to P4 transcription expression activation during the transformation of a premalignant liver lesion to HCC. Furthermore, aberrant hypomethylation of P4 CpG islands not only may play an important role during hepatocarcinogenesis but might also be a useful biomarker for poor prognosis of patients with HCC.