Oncogenic Function And Molecular Mechanism Of H19 Noncoding Rna In Colorectal Cancer

The clinical significance of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) remains largely unknown. We analyzed a large panel of cancer-associated lncRNAs in 483 TCGA CRC cases, and identified that H19 correlates most significantly with overall survival and disease-free survival, independent of stage and other clinical parameters. We validated the TCGA findings with two additional CRC cohorts. As one of the “oldest” lncRNAs, diverse activities of H19 including interaction with epigenetic regulators, regulation of microRNAs as competing endogenous RNA (ceRNA), and production of miR-675 as a primary transcript have been reported. However, an unbiased study to clarify the essential mechanisms of H19 is lacking. To decipher the functional involvement of H19 in CRC, we used an integrative approach combining unbiased microarray analysis, experimental validation, and bioinformatic analysis of clinical data. With such approach, we revealed not only previously reported mechanisms such as let-7 and MYC regulation by H19, but also several novel mechanisms that have not been appreciated before. We discovered a mechanism of H19 on regulating RB-E2F signaling and accordingly controlling cell cycle progression. We also identified for the first time that H19 regulates CDK8, an oncogenic driver in CRC pathogenesis, and consequently affects β-catenin activity (Firestein et al., Nature, 2008). We further identified an interaction of H19 with macroH2A, a histone variant reported to repress CDK8 transcription (Kapoor et al., Nature, 2010). Importantly, expression correlation analysis with clinical samples strongly supported the above-identified mechanisms. Combined analysis of H19 with its targets showed strong independent prediction power for CRC survival. These data indicate the clinical relevance of Rb-E2F and CDK8/β-catenin signaling in mediating H19’s oncogenic activity in CRC. Citation Format: Hui Ling, Masahisa Ohtsuka, Cristina Ivan, Martin Pichler, Meng Chen, Ondrej Slaby, Ajay Goel, Milan Radovich, George Calin. Oncogenic function and molecular mechanism of H19 noncoding RNA in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2548. doi:10.1158/1538-7445.AM2017-2548