Abstract C20: The epigenomic fingerprint of hepatocellular carcinoma

Abstract

Abstract Globally, hepatocellular carcinoma (HCC) accounts for 70% to 85% of primary liver cancers. HCC remains in the top 10 among the most common cancers and ranks second in the leading cause of male cancer death worldwide. Patients are typically diagnosed with late-stage disease leading to poor survival rates in the United States and developing countries. Serum alpha-fetoprotein (AFP) is a key HCC biomarker associated with patient prognosis. However, serum AFP levels are heterogeneous among HCC patients, suggesting that the biology of AFP+ and AFP- tumors may be different. Identifying the molecular mechanisms underlying these differences may improve our understanding of HCC development and guide future approaches to increase survival. Recently, microRNAs (miRNAs) have been shown to be deregulated in many cancers and are useful biomarkers for early detection, prognosis, and treatment. In this vein, we performed global miRNA profiling analyses of HCCs that differ in AFP expression. We found that miR-29 family members, including miR-29a, miR-29b, and miR-29c, are top-ranked downregulated miRNAs in AFP+ tumors whose expression is inversely correlated with AFP in 242 HCC specimens, suggesting that miR-29 may act as a tumor suppressor in AFP+ HCC. In fact, we have found an association between decreased miR-29 and poor survival. In addition, there is a significant association between AFP and DNA methyltransferases DNMT3A and DNMT3B, which were recently shown to be direct targets of miR-29. Furthermore, we have found an overall trend toward increased methylation in HCC patients with high levels of AFP. These findings led us to hypothesize that AFP may inhibit miR-29, which in turn increases DNA methyltransferase activity and modulates epigenetic changes that contribute to poor outcome in HCC. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) reveals that AFP and DNMT3B are both inversely correlated with miR-29 expression in HCC cell lines. We are testing currently whether AFP regulates miR-29 expression and alters DNA methylation patterns in HCC cells. We are also examining how miR-29 expression is regulated to determine whether AFP directly targets mir-29 to effect epigenetic changes or whether this occurs through other signaling pathways. Taken together, these studies will elucidate the molecular mechanisms that link AFP and miR-29 expression to epigenetic alterations and may aid in the development of novel therapeutic agents that may improve survival of HCC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C20.