The Function And Mechanism Of RRS1in The Development Of Hepatocellual Carcinoma

Hepatocellular carcinoma (HCC) is a malignant tumor prevalent in China. The activationof proto-oncogene and inactivation of tumor suppressor gene are core molecular events of theoccurrence and development of cancer. The discovery of new candidate genes related to HCCmay contribute to dissect its pathogenic mechanism and develop novel prevention, diagnosisand therapy strategies for HCC. Through an integrated analysis of genomics and transcriptomedata, we recently identified a novel candidate HCC related gene RRS1. However, there was noreport about the function and mechanism of RRS1in HCC and other tumors previously. Inthis report we examine the potential role and mechanism of RRS1in HCC pathogenesis. Wefound that the amplification and overexpression of RRS1was frequently detected in clinicalHCC specimens. Functionally, we found that overexpression of RRS1in HCC cells increasedcell cycle progression through G1, cell survival, clonogenicity, cell growth, and tumorformation in nude mice. In contrast, RNA interference (RNAi) silencing of RRS1inhibited itsoncogenic effects. We provide evidence that RRS1promotes HCC growth and survivalthrough RP-MDM2-P53pathway. RRS1binds RPL11, and RPL11is released from nucleoliin the absence of RRS1. In RRS1-deficient cells, increased binding of RPL11to MDM2blocks MDM2-mediated ubiquitination of p53. In human cancer, individuals whose tumorsexpress less RRS1have better prognoses. When RRS1is depleted in tumor cells with intactP53signaling, the cells grow more slowly and accumulate more P53. Thus, RRS1is a potentregulator of the MDM2-P53pathway and promotes tumor progression by retaining RPL11inthe nucleolus. Further characterization of RRS1may provide a prognostic biomarker for HCCoutcome prediction and a novel therapeutic target in HCC treatment.