Stearoyl-CoA desaturase regulates sorafenib resistance via modulation of ER stress-induced differentiation.

Autor: Ma MKF; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong., Lau EYT; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong; Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong., Leung DHW; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong., Lo J; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong., Ho NPY; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong., Cheng LKW; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong., Ma S; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong., Lin CH; Centre for Genomic Science, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong., Copland JA; Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States., Ding J; Eastern Hepatobiliary Surgery Hospital, The International Cooperation Laboratory on Signal Transduction, China., Lo RCL; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong., Ng IOL; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. Electronic address: iolng@hku.hk., Lee TKW; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong; State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hong Kong. Electronic address: terence.kw.lee@polyu.edu.hk.
Jazyk: angličtina
Zdroj: Journal of hepatology [J Hepatol] 2017 Nov; Vol. 67 (5), pp. 979-990. Date of Electronic Publication: 2017 Jun 22.
DOI: 10.1016/j.jhep.2017.06.015
Abstrakt: Background & Aims: We investigated the functional role and clinical significance of stearoyl-CoA desaturase-1 (SCD1) mediated endoplasmic reticulum (ER) stress in regulating liver tumor-initiating cells (T-ICs) and sorafenib resistance, with the aim of developing a novel therapeutic strategy against hepatocellular carcinomas (HCCs).
Methods: We evaluated the clinic-pathological relevance of SCD1 and its correlation with sorafenib resistance in large cohorts of HCC clinical samples by qPCR and immunohistochemical analyses. Lentiviral-based overexpression and knockdown approaches were performed to characterize the functional roles of SCD1 in regulating liver T-ICs and sorafenib resistance. Molecular pathways mediating the phenotypic alterations were identified through RNA sequencing analysis and functional rescue experiments. The combinatorial effect of SCD1 inhibition and sorafenib was tested using a patient-derived tumor xenograft (PDTX) model.
Results: SCD1 overexpression was found in HCC, which was associated with shorter disease-free survival (p = 0.008, log rank test). SCD1 was found to regulate the populations of liver T-ICs; while its suppression by a SCD1 inhibitor suppressed liver T-ICs and sorafenib resistance. Interestingly, SCD1 was markedly upregulated in our established sorafenib-resistant PDTX model, and its overexpression predicts the clinical response of HCC patients to sorafenib treatment. Suppression of SCD1 forces liver T-ICs to differentiate via ER stress-induced unfolded protein response, resulting in an enhanced sensitivity to sorafenib. The PDTX#1 model, combined with sorafenib treatment and a novel SCD1 inhibitor (SSI-4), showed a maximal growth suppressive effect.
Conclusions: SCD1-mediated ER stress regulates liver T-ICs and sorafenib sensitivity. Targeting SCD1 alone or in combination with sorafenib might be a novel personalized medicine against HCC. Lay summary: In this study, SCD1 was found to play a critical role in regulating liver tumor-initiating cells and sorafenib resistance through the regulation of ER stress-mediated differentiation. Targeting SCD1 in combination with sorafenib may be a novel therapeutic strategy against liver cancer.
(Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: