Abstract 1489: Function of Rho kinases on HCC tumor growth and metastasis

Abstract

Abstract The Rho/ROCK (Rho-associated protein kinase) pathway has been found to be frequently upregulated in hepatocellular carcinoma (HCC). Clinico-pathological research has shown that increased RhoA and ROCK2 expression are associated with the presence of tumor microsatellite formation. RhoA is over expressed in 69% of HCC, and high RhoA levels are correlated with poor survival. ROCK2 protein level is upregulated in 54% of HCC, and its expression is associated with intrahepatic metastasis. The ROCK2 knockdown by short hairpin (sh)RNA leads to significant reduction of tumor formation. These observations suggest that Rho/ROCK pathway could be a potential therapeutic target for the treatment of liver cancer. Down-regulation of the Rho/ROCK pathway may inhibit tumor metastasis. However, the role of ROCK1 in HCC metastasis is still not clear. In order to dissect out the roles of ROCK1 and ROCK2 in liver tumor formation and metastasis, we used the shRNAmir- lentiviral system to knockdown ROCK1, ROCK2, and ROCK1/ROCK2 in HCC cell lines. The RNA and protein levels of ROCK1 and ROCK2 were significantly reduced in HCC cell lines that expressed shRNAs targeting ROCK1 and ROCK2. Orthotopically implanted HCC cells carrying shRNA targeted at ROCK1 and ROCK2 either alone or in combination were examined for tumor induction in mice. Our data showed that tumor growth was significantly reduced in those mice inoculated with cells expressing shRNAs. In addition, fewer tumor nodules as compared to the control (Non-target shRNA control) group were seen in those mice. Using qRT-PCR, we confirmed that the decreased ROCK activity was associated with the reduction of ROCK1 and ROCK2 RNA levels in mouse liver samples. Conclusion: our results indicate that both ROCK1 and ROCK2 are important for HCC tumor growth. Moreover, we demonstrated that ROCK1 played a more significant role than ROCK2 in HCC intrahepatic metastasis. 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 1489. doi:10.1158/1538-7445.AM2011-1489