Hottip, An Oncogenic Long Non-Coding Rna, Is Frequently Up-Regulated In Hepatocellular Carcinoma And Is Negatively Regulated By Tumor Suppressive Microrna Mir-125b

Hepatocellular carcinoma (HCC) is one of the most common human cancers. Due to the lack of early diagnostic and effective treatment modalities, the mortality of HCC is high. The development and progression of HCC is a multistep process driven by the accumulation of genetic and epigenetic alterations. Recently, emerging evidence has suggested the role of long non-coding RNAs (lncRNAs) in human carcinogenesis. Herein, by profiling the expression of 88 well-annotated lncRNAs, we identified that HOTTIP was the most significantly up-regulated lncRNA (81%, 57/70) in human HCCs, even in early stage of HCC formation. Functionally, knockdown of HOTTIP attenuated HCC cell proliferation in vitro and markedly abrogated tumorigenicity in vivo. In addition, knockdown of HOTTIP also inhibited migratory ability of HCC cells and significantly abrogated lung metastasis in orthotopic implantation model in nude mice. HOTTIP is an antisense lncRNA mapped to the distal end of the HOXA gene cluster. Knockdown of HOTTIP significantly suppressed the expression of a number of HOXA genes. Furthermore, we identified miR-125b as a post-transcriptional regulator of HOTTIP. Ectopic expression of miR-125b abolished HOTTIP-coupled luciferase activity and suppressed the endogenous level of HOTTIP. Moreover, in human HCCs, HOTTIP expression negatively correlated with that of miR-125b. In Summary, our findings suggest that HOTTIP is a novel oncogenic lncRNA, with miR-125b being its negative regulator. It contributes to hepatocarcinogenesis by regulating the expression of its neighboring protein-coding genes. Citation Format: Felice H. Tsang, Sandy L. Au, Lai Wei, Dorothy N. Fan, Joyce M. Lee, Carmen C. Wong, Irene O. Ng, Chun-Ming Wong. HOTTIP, an oncogenic long non-coding RNA, is frequently up-regulated in hepatocellular carcinoma and is negatively regulated by tumor suppressive microRNA miR-125b. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 145. doi:10.1158/1538-7445.AM2015-145