Abstract 3143: A functional interaction between alpha-fetoprotein and miRNA-29 modulates the HCC epigenome.

Abstract

Abstract Globally, hepatocellular carcinoma (HCC) accounts for 70-85% of primary liver cancers and ranks second in the leading cause of male cancer death. Serum alpha-fetoprotein (AFP), normally expressed during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP+ and AFP- tumors may differ biologically and have different prognosis in HCC patients. Using microarray-based global microRNA and mRNA profiling, we found that members of the miR-29 family are the most significantly (p<1E-5) down-regulated miRs in AFP+ tumors (n=242). Physiologically, during mouse embryonic development, miR-29 family expression is low but gradually increases after birth, contrary to AFP expression which dramatically decreases after birth. In addition, a member of the DNA methyltransferase (DNMT) family, DNMT3A, is one of the most significantly (p=8E-6) up-regulated genes in AFP+ HCC. Interestingly, there is a significant inverse correlation (p<1E-4) between miR-29 and DNMT gene expression, suggesting that they may be functionally antagonistic, which is consistent with the finding showing that DNMT3A and DNMT3B are direct targets of miR-29. Experimentally, we found that increased AFP expression or the addition of AFP+ media to AFP- cells inhibits miR-29a expression in HCC cell lines. We also found that AFP transcriptionally regulates the promoter of miR-29a. Moreover, global DNA methylation array profiling reveals increased methylation in HCC patients with high levels of serum AFP. These results support our hypothesis that AFP inhibits miR-29, which modulates epigenetic changes that contribute to poor outcome. Taken together, this study elucidates the mechanisms that link AFP and miR-29 expression to epigenetic alterations and may aid in the development of novel therapeutic agents to improve survival of HCC patients. Citation Format: Sonya Parpart, Stephanie Roessler, Fei Dong, Vinay Rao, Christopher Loffredo, Xin Wei Wang. A functional interaction between alpha-fetoprotein and miRNA-29 modulates the HCC epigenome. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3143. doi:10.1158/1538-7445.AM2013-3143