Abstract LB-322: The Rac GTPase activating protein 1 as a prognostic biomarker associated with recurrent human hepatocellular carcinoma
Authors: Kam M. Hui, Suk Wang, London Ooi
Journal: Cancer Research (2011)

Abstract Hepatocellular carcinoma (HCC) is a primary cancer of the liver and is the world's third cause of cancer-related death with more than 660,000 deaths per year. Hepatic resection offers the best treatment option for patients with small HCC. However, recurrence complicates the outcome in more than two thirds of these patients and the overall 5-year survival remains dismal. It is a challenge to identify, at diagnosis, patients who are at high risk for recurrence since such high risk patients could potentially benefit from closer surveillance or receive novel interventional measures. We have previously reported a 57-member gene set for selecting HCC patients who are at high risk of having recurrent disease. Here, we have investigated the prognostic significance of individual member of this gene set using multivariate and log rank test and observed that expression of Rac GTPase-activating protein 1 (RACGAP1) gave the best ability to predict recurrent disease and survival outcome. Kaplan-Meier analysis demonstrated that the level of RACGAP1 expression is sufficient to predict recurrence of HCC with high RACGAP1 expression correlated with high risk of post-resection recurrent HCC (p&amp;lt;0.0005). Immuno-staining experiments also validated the observation that RACGAP1 was up-regulated in recurrent HCC biopsies than in non-recurrent HCC samples (p=0.014). Pull-down assays demonstrated that the GAP domain of RACGAP1 strongly stimulated Rac1 and Cdc42 GTPase activity but was almost inactive towards RhoA. Silencing of RACGAP1 in the human HCC cell lines HCCLM3 and MHCC97-H with high endogenous RACGAP1 expression resulted in the inhibition of cell migration and invasiveness. Gene expression studies identified target molecules interacted with RACGAP1 were mainly related to the mitotic roles of the polo-like kinases and BRCA1 in cellular DNA damage response pathways; including PRC1, AURKB, CDC2, ECT2, KIF23, PAK1 and PPP2R5E which were all down-regulated compared to cells treated with control siRNA. Importantly and in corroboration with the silencing experiments, IPA analysis of a HCC gene expression database that we have established previously between HCC patients that gave an early recurrent disease (within 24 months) and patients that did not recur revealed that all these transcripts were differentially up-regulated in HCC patients that exhibited early recurrent disease demonstrating that these genes were clinically relevant. RACGAP1 has not been previously implicated in the carcinogenesis of HCC. Our present study strongly suggests that RACGAP1 could mediate the early recurrence of human HCC and is a prognostic marker for HCC following hepatic resection. (This work was supported by grants from the National Medical Research Council of Singapore, Biomedical Research Council of Singapore and Singapore Millennium Foundation.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-322. doi:10.1158/1538-7445.AM2011-LB-322