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, Kin Wah Lee, Carmen Chak Lui Wong, Irene Oi Lin Ng

Research output: Journal article publicationJournal articleAcademic researchpeer-review

23 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)41445-41459
Number of pages15
JournalOncotarget
Volume7
Issue number27
DOIs
Publication statusPublished - 5 Jul 2016
Externally publishedYes

Keywords

  • cell survival
  • drug-resistance
  • HCC
  • Rho GTPase
  • Rho-associated kinase

ASJC Scopus subject areas

  • Oncology

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