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| Alteration of oncogenic IGF-II gene methylation status associates with hepatocyte malignant transformation |
| Bo-Jun Tai a , Min Yao b , Wen-Jie Zheng c , Yu-Cheng Shen d , Li Wang b , Jian-Ying Sun c , Meng-Na Wu c , Zhi-Zhen Dong c , Deng-Fu Yao c , ∗ |
a Department of Infectious Diseases, Affiliated Hospital of Nantong University, Nantong 226001, China
b Department of Immunology, Medical School of Nantong University, Nantong 226001, China
c Department of Oncology, Affiliated Hospital of Nantong University, Nantong 226001, China
d Department of Oncology, Affiliated Haian Hospital of Nantong University, Nantong 226601, China
∗ Corresponding author.
E-mail address: Yaodf@ahnmc.com (D.-F. Yao).
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Abstract Background: Oncogenic insulin-like growth factor-II (IGF-II) is overexpressed in hepatocellular carcinoma (HCC). The present study aimed to analyze the dynamic alteration of IGF-II CpG site methylation status and its molecular mechanism in HCC progression.
Methods: IGF-II alterations were observed in rat hepatocarcinogenesis models induced by 2-acetylaminofluorene. Liver IGF-II expression was compared by immunohistochemistry or tissue IGF-II specific concentration (nmol/mg protein). Status of human IGF-II promoter 3 (P3) or rat IGF-II P2 CpG site methylation was amplified by methylation-specific polymerase chain reaction (MSP). Serum IGF-II levels were quantitatively detected by an enzyme-linked immunosorbent assay.
Results: The levels of hepatic IGF-II expression were significantly elevated in the HCC group ( P < 0.001). The unmethylation rate of IGF-II P3 CpG sites was 100% in the HCC-, 52.5% in the paracancerous-, and none (0%) in the distal noncancerous-tissues. Abnormal IGF-II expression was related to differentiation degree, tumor invasion, and positive HBV-DNA (all P < 0.001), with a negative correlation between P3 methylation degree and IGF-II expression. There was a positive correlation between liver IGF-II specific concentration and circulating IGF-II level ( r = 0.97, P < 0.001). Significantly negative correlation was found between IGF-II P2 CpG site methylation and circulating IGF-II ( r s = −0.89, P < 0.001) or liver IGF-II level ( r s = −0.84, P < 0.001).
Conclusions: The increase of serum IGF-II and the alteration of oncogenic gene IGF-II methylation may be biomarkers for HCC diagnosis and DNA methylation may be the therapeutic target of HCC.
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2019, Vol. 18 
