Epigenetic Alterations of Hepatic IGF-II Gene Promoter and IGF-II Abnormal Expression in HBV-Related Hepatocellular Carcinoma

Zhizhen Dong¹, Min Yao², Li Wang³, Xing Gu⁴, Yun Shi⁴, and Hua Huang⁵

¹Department of Diagnostics, Affiliated Hospital of Nantong University, Jiangsu Province, 226001, China. ²Department of Immunology, Medical School of Nantong University, Jiangsu Province, 226001, China. ³Department of Informatics, Medical School of Nantong University, Jiangsu Province, 226001, China. ⁴Department of Oncology, Affiliated Hospital of Nantong University, Jiangsu Province, 226001, China. ⁵Department of Pathology, Affiliated Hospital of Nantong University, Jiangsu Province, 226001, China.

Abstract: Abnormal expression of liver insulin-like growth factor-II (IGF-II) regulating by the methylation of its gene promoter (P1~4) CpG islands through epigenetic silencing of fetal P2, P3, and P4, or adult P1 is associated with progression of HBV-related hepatocellular carcinoma (HCC). The aims of the present study were to investigate the alteration of methylational status in P3 region CpG islands, and analyze IGF-II expression and clinicopathological features in HBV-related HCC. The methylational status of P3 region CpG islands was observed in the matched parts of HCC tissues by methylation-specific PCR. Hepatic IGF-II expression was analyzed by immunohistochemistry. IGF-II mRNA was amplified by RT-PCR, and confirmed by sequencing. Serum IGF-II levels were quantitatively detected by ELISA assay. The frequencies of IGF-II mRNA positive fragment, IGF-II positive, and the P3 hypomethylated CpG islands were 100%, 87.5%, and 100% in HCC-, 53.3%, 47.5%, and 52.5% in paracancerous-, and none in noncancerous-tissues, respectively. Significant IGF-II expression in HCC tissues was related to differentiation degree (moderate or poor), tumor invasion, and positive-HBV DNA (P<0.05). An inverse correlation was found between P3 methylational degree and IGF-II expression. The levels of hepatic IGF-II and serum IGF-II expression were significantly elevated (P<0.001) in the HCC group more than any of the other groups. Abnormality of hepatic IGF-II expression is associated with hypomethylational status of its fetal promoter CpG sites, and circulating IGF-II abnormality is a useful biomarker for HCC diagnosis.

Keywords: Hepatocellular carcinoma; Insulin-like growth factor-II; Promoter; Methylation-specific PCR; Diagnosis; Biomarker

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