SCYL3, as a novel binding partner and regulator of ROCK2, promotes hepatocellular carcinoma progression.

Autor:	Lei MML; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong., Leung CON; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong., Lau EYT; Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong., Leung RWH; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong., Ma VWS; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong., Tong M; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong., Lu YY; Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China., Huang CY; Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China., Zhu QH; Department of Interventional Radiology and Oncology, Shunde Hospital, Southern Medical University, Shunde, China., Ng IOL; Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong.; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong., Ma S; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong., Lee TKW; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong.; Research Institute for Future Food, The Hong Kong Polytechnic University, Hong Kong.; State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong.
Jazyk:	angličtina
Zdroj:	JHEP reports : innovation in hepatology [JHEP Rep] 2022 Oct 13; Vol. 5 (1), pp. 100604. Date of Electronic Publication: 2022 Oct 13 (Print Publication: 2023).
DOI:	10.1016/j.jhepr.2022.100604
Abstrakt:	Background & Aims: SCY1-like pseudokinase 3 (SCYL3) was identified as a binding partner of ezrin, implicating it in metastasis. However, the clinical relevance and functional role of SCYL3 in cancer remain uncharacterized. In this study, we aimed to elucidate the role of SCYL3 in the progression of hepatocellular carcinoma (HCC). Methods: The clinical significance of SCYL3 in HCC was evaluated in publicly available datasets and by qPCR analysis of an in-house HCC cohort. The functional significance and mechanistic consequences of SCYL3 were examined in SCYL3-knockdown/overexpressing HCC cells. In vivo tumor progression was evaluated in Tp53 KO / c-Myc OE mice using the sleeping beauty transposon system. Potential downstream pathways were investigated by co-immunoprecipitation, western blotting analysis and immunofluorescence staining. Results: SCYL3 is often overexpressed in HCC; it is preferentially expressed in metastatic human HCC tumors and is associated with worse patient survival. Suppression of SCYL3 in HCC cells attenuated cell proliferation and migration as well as in vivo metastasis. Intriguingly, endogenous SCYL3 overexpression increased tumor development and metastasis in Tp53 KO / c-Myc OE mice. Mechanistic investigations revealed that SCYL3 physically binds and regulates the stability and transactivating activity of ROCK2 (Rho kinase 2) via its C-terminal domain, leading to the increased formation of actin stress fibers and focal adhesions. Conclusions: These findings reveal that SCYL3 plays a critical role in promoting the progression of HCC and have implications for developing new therapeutic strategies to tackle metastatic HCC. Impact and Implications: SCYL3 was first reported to be a binding partner of a metastasis-related gene, ezrin. To date, the clinical relevance and functional role of SCYL3 in cancer remain uncharacterized. Herein, we uncover its crucial role in liver cancer progression. We show that it physically binds and regulates the stability and transactivating activity of ROCK2 leading to HCC tumor progression. Our data provide mechanistic insight that SCYL3-mediated ROCK2 protein stability plays a pivotal role in growth and metastasis of HCC cells. Targeting SCYL3/ROCK2 signaling cascade may be a novel therapeutic strategy for treatment of HCC patients. Competing Interests: The authors declare no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details. (© 2022 The Author(s).)
Databáze:	MEDLINE
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