Abstract
Abstract RPS6KA3 encodes the p90 ribosomal S6 kinase 2 (p90RSK2 or RSK2), a protein kinase to relay the upstream transduction signal of the mitogen-activated protein kinase (MAPK) pathway. Currently, no characterization on RSK2 in human HCC has been performed. We determined the RSK2 mRNA expression in paired human HCC samples and their corresponding non-tumorous livers (n = 22) by real time PCR. RSK2 over-expression (≥2 folds) was found in 38% of the human HCCs and this over-expression was associated with tumor microsatellite formation, a feature of HCC metastasis. The oncogenic and pro-metastatic roles of RSK2 were further assessed and demonstrated in vivo by an orthotopic liver injection model in nude mice with stable shRSK2 knockdown HCC cells. Stable shRSK2 knockdown cells showed a significant reduction in tumor incidence in liver and lung metastasis. By exome-sequencing and targeted sequencing in a cohort of HBV-associated HCC patient samples (n = 111), we found that RSK2 was recurrently mutated in 6.3% of the samples being screened (n = 7). All the RSK2 mutants were confirmed by independent Sanger sequencing. Intriguingly, among the identified somatic RSK2 mutants, half of them introduced pre-mature stop gain to the transcript, which leads to the loss-of function of RSK2 through various mechanisms. Taken together, our data suggested that RSK2 may play differential roles in different subsets of HCC patients. Further characterization will definitely derive novel insights on the functional role of mutant RSK2 and its potential use to stratify HCC patients into different molecular subgroups. (This study was supported by a RGC GRF fund (17116414), SK Yee Medical Research Fund 2011 and University Development Fund of The University of Hong Kong. Ng is Loke Yew Professor in Pathology) Citation Format: Lo-Kong Chan, Daniel Wai-Hung Ho, Yung-Tuen Chiu, Alan Ka-Lun Kai, Chun-Ming Wong, Irene Oi-Lin Ng. Functional characterization of RPS6KA3 (RSK2) and identification of its naturally occurring mutants in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 690.
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