Abstract 3443: Functional and mechanistic characterization of oncogenic long intervening non-coding RNA Linc-CHD1L-1 in hepatocellular carcinoma

Abstract

Abstract Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. Due to the asymptomatic nature of HCC, many patients were diagnosed at advance stages and available therapeutic options are very limited. Therefore, a better understanding of the molecular mechanism underlying hepatocarcinogenesis is urgently needed and is crucial for the development of effective treatment. Long intervening non-coding RNAs (lincRNAs) are emerging class of regulatory RNA involved in diverse molecular processes. In this study, we aimed to interrogate lincRNAs expression in HCC and identify novel lincRNAs that contribute to hepatocarcinogenesis. To investigate the global expression profile of lincRNAs in human HCCs, next-generation transcriptome sequencing (RNA-Seq) was performed in 16 pairs of HBV-associated primary HCCs and their corresponding non-tumorous liver tissues. Interestingly, the lincRNA expressions in human HCCs can be unambiguously segregated from their non-tumorous counterparts by unsupervised clustering analysis, suggesting that global lincRNA expression profiles between tumors and non-tumors were remarkably different. From this analysis, we identified linc-CHD1L-1 as the most significant up-regulated lincRNA in HCCs. Clinically, linc-CHD1L-1 was overexpressed in over 80% of HCC patients. Linc-CHD1L-1 expression level in tumors was also shown to be a promising marker for HCC diagnosis. Functionally, knockdown of linc-CHD1L-1 by shRNAs had significantly reduced HCC cell proliferation and cell migration in vitro. Besides, knockdown of linc-CHD1L-1 in HCC cells also substantially abrogated tumorigenicity in subcutaneous tumor model. Mechanistically, the expression of linc-CHD1L-1 was significantly and positively correlated to the expression of its neighboring genes located on the chromosome 1q. Knockout of linc-CHD1L-1 by CRISPR/Cas9 also significantly repressed its neighboring genes expression, suggesting that linc-CHD1L-1 may positively regulate gene expression in a cis-manner. Finally, DAVID pathway analysis performed on linc-CHD1L co-expressed protein coding genes further suggested that linc-CHD1L-1 was significantly co-expressed with genes that are involved in transcription and chromatin modifications. In conclusion, overexpression of linc-CHD1L-1 contributes to hepatocarcinogenesis by promoting HCC cell proliferation and migration through transcriptional and epigenetic mechanisms. Citation Format: Felice H. Tsang, Daniel W. Ho, Irene O. Ng, Jack C. Wong. Functional and mechanistic characterization of oncogenic long intervening non-coding RNA Linc-CHD1L-1 in hepatocellular carcinoma [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 3443. doi:10.1158/1538-7445.AM2017-3443