Journal
ONCOTARGET
Volume 7, Issue 27, Pages 41445-41459Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.9441
Keywords
Rho GTPase; Rho-associated kinase; HCC; drug-resistance; cell survival
Categories
Funding
- 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
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available