Abstract 4468: Oncogenic activation of the RNA binding protein AGO2 in hepatocellular carcinoma

Abstract

Abstract Global transcriptomic alterations of coding and non-coding RNAs are a ubiquitous feature of cancers including Hepatocellular carcinoma (HCC). Dysregulation of RNA-binding proteins (RBPs), key regulators of RNA processing such as RNA maturation and degradation, is one mechanism in which cancer cells select to promote tumorigenesis. RBPs are highly expressed in solid tumors and have been demonstrated to be drivers of carcinogenesis, however, the underlying mechanisms in which RBPs regulate the HCC transcriptome is unknown. We analysed genomic alterations amongst a family of more than 800 mRNA RBPs (mRBPs) in 1,225 clinical specimens from HCC patients and found that RBPs are significantly activated through gene amplification in a subset of tumors with poor prognosis, suggesting their potential oncogenic roles in HCC progression. Amongst the top candidates, Argonaute 2 (AGO2) was further characterized for its oncogenic role and effects on the HCC transcriptome. Elevated AGO2 mRNA expression was highly correlated with elevated somatic copy number alterations across five different cancer types including HCC. Moreover, AGO2 expression was associated with overall survival in two independent data sets (TCGA and the Liver Initiative Cancer), suggesting that AGO2 activation is oncogenic. While the activation of AGO2 induced an oncogenic phenotype, the abrogation of AGO2 in HCC cells significantly decreased cancer associated phenotypes such as cell proliferation, migration/invasion and tumorigenicity in vivo. Further analyses revealed that AGO2-associated genes were tumor-related, including c-Myc. Notably, c-Myc amplification was also found in AGO2 high HCC cells, suggesting an interplay between AGO2 and c-Myc. Our results demonstrate that oncogenic activation of AGO2 is a novel mechanism that may contribute to global transcriptome selective for the activation of c-Myc oncogenic. Our current work suggests that therapies focused on targeting AGO2 may be valuable for clinical treatment of many different tumors with activated c-Myc signalling, including HCC Citation Format: Hien T. Dang, Lucy Knight, Yotsawat Pomyen, Xin Wei Wang. Oncogenic activation of the RNA binding protein AGO2 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 4468. doi:10.1158/1538-7445.AM2017-4468