Oncotarget

Research Papers:

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

Wei Ma, Karen Man-Fong Sze, Lo Kong Chan, Joyce Man-Fong Lee, Larry Lai Wei, Chun-Ming Wong, Terence Kin-Wah Lee, Carmen Chak-Lui Wong and Irene Oi-Lin Ng _

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Oncotarget. 2016; 7:41445-41459. https://doi.org/10.18632/oncotarget.9441

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Abstract

Wei Ma1, Karen Man-Fong Sze1, Lo Kong Chan1, Joyce Man-Fong Lee1, Larry Lai Wei1, Chun-Ming Wong1, Terence Kin-Wah Lee1, Carmen Chak-Lui Wong1, Irene Oi-Lin Ng1

1Department 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.


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