期刊
ONCOTARGET
卷 7, 期 27, 页码 41445-41459出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.9441
关键词
Rho GTPase; Rho-associated kinase; HCC; drug-resistance; cell survival
资金
- Hong Kong Research Grants Council General Research Fund [HKU775811M]
- Health and Medical Research Fund [12133191]
- Lee Shiu Family Foundation
- SK Yee Medical Research Fund
- University Development Fund of The University of Hong Kong
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 IKK beta as the direct downstream target of Rho/ROCK, and activation of ROCK2 significantly augmented NF-kB transcription activity and induced IL-6 expression. These data indicate that Rho/ROCK signaling activates a positive feedback loop of IKK beta/NF-.B/IL-6/STAT3 which confers chemoresistance to HCC cells and is a potential molecular target for HCC therapy.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据