RhoE/ROCK2 regulates chemoresistance through NF-κB/IL-6/ STAT3 signaling in hepatocellular carcinoma.

// Wei Ma 1 , Karen Man-Fong Sze 1 , Lo Kong Chan 1 , Joyce Man-Fong Lee 1 , Larry Lai Wei 1 , Chun-Ming Wong 1 , Terence Kin-Wah Lee 1 , Carmen Chak-Lui Wong 1 , Irene Oi-Lin Ng 1 1 Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong Correspondence to: Irene Oi-Lin Ng, email: iolng@hku.hk Keywords: Rho GTPase, Rho-associated kinase, HCC, drug-resistance, cell survival Received: August 26, 2015      Accepted: April 18, 2016      Published: May 18, 2016 ABSTRACT Small Rho GTPase (Rho) and its immediate effector Rho kinase (ROCK) are reported to regulate cell survival, but the detailed molecular mechanism remains largely unknown. We had previously shown that Rho/ROCK signaling was highly activated in hepatocellular carcinoma (HCC). In this study, we further demonstrated that downregulation of RhoE, a RhoA antagonist, and upregulation of ROCK enhanced resistance to chemotherapy in HCC in both in vitro cell and in vivo murine xenograft models, whereas a ROCK inhibitor was able to profoundly sensitize HCC tumors to cisplatin treatment. Specifically, the ROCK2 isoform but not ROCK1 maintained the chemoresistance in HCC cells. Mechanistically, we demonstrated that activation of ROCK2 enhanced the phosphorylation of JAK2 and STAT3 through increased expression of IL-6 and the IL-6 receptor complex. We also identified IKKβ as the direct downstream target of Rho/ROCK, and activation of ROCK2 significantly augmented NF-κB transcription activity and induced IL-6 expression. These data indicate that Rho/ROCK signaling activates a positive feedback loop of IKKβ/NF-κB/IL-6/STAT3 which confers chemoresistance to HCC cells and is a potential molecular target for HCC therapy.