title: RhoE/ROCK2 regulates chemoresistance through NF-κB/IL-6/ STAT3 signaling in hepatocellular carcinoma.
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.
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Wei
authors.initials: W
authors.lastname: Ma
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Karen Man-Fong
authors.initials: KM
authors.lastname: Sze
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Lo Kong
authors.initials: LK
authors.lastname: Chan
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Joyce Man-Fong
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Larry Lai
authors.initials: LL
authors.lastname: Wei
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Wong
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Terence Kin-Wah
authors.initials: TK
authors.lastname: Lee
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Carmen Chak-Lui
authors.initials: CC
authors.lastname: Wong
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins; D002945:Cisplatin
keywords: HCC; Rho GTPase; Rho-associated kinase; cell survival; drug-resistance