Hypomethylated P4 Promoter Induces Expression of the Insulin-Like Growth Factor-II Gene in Hepatocellular Carcinoma in a Chinese Population

Abstract

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.

Serum Insulin-like Growth Factor-I Level Is an Independent Predictor of Recurrence and Survival in Early Hepatocellular Carcinoma: A Prospective Cohort Study

“…The finding that low-serum IGF-I levels were a predictor of poor prognosis seems to be paradoxical because aberrant overexpression of IGF-II and subsequent signaling through its receptor have been known as relevant signaling alterations in hepatocellular carcinoma (22,23). Nonetheless, our results are consistent with recent studies of the levels of circulating IGF-I and prognosis in patients with hepatocellular carcinoma.…”

Hypermethylation of the IGF2 differentially methylated region 2 is a specific event in insulinomas leading to loss-of-imprinting and overexpression

“…However, most of the total RNA could be attributed to transcripts from the P4 promoter, which were significantly increased in insulinomas compared with normal pancreatic tissue or other PETs. Upregulation of IGF2 expression through activation of fetal promoters has previously been reported in various cancers including hepatocellular carcinoma (Tang et al 2006). This increased expression has so far not been correlated with DNA methylation changes in the DMR2, but only at the respective promoter sites.…”

Whole-exome sequencing identifies mutated PCK2 and HUWE1 associated with carcinoma cell proliferation in a hepatocellular carcinoma patient

“…This mitogen, highly expressed during embryonic development, is markedly downregulated after birth by tight epigenetic regulation of the P2-P4 fetal promoters. Reactivation of IGF2 expression involves loss of specific imprinting and hypomethylation (19). Allelic losses of IGF2R has been detected in 60-70% of HCC cases, with inactivating variants in the remaining allele also reported (20).…”