Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/75687
Title: Stearoyl-CoA desaturase regulates sorafenib resistance via modulation of ER stress-induced differentiation
Authors: Ma, MKF
Lau, EYT 
Leung, DHW 
Lo, J 
Ho, NPY 
Cheng, LKW
Ma, S
Lin, CH
Copland, JA
Ding, J
Lo, RCL
Ng, IOL
Lee, TKW 
Keywords: ER stress
HCC
SCD1
Sorafenib
T-ICs
Issue Date: 2017
Publisher: Elsevier
Source: Journal of hepatology, 2017, v. 67, no. 5, p. 979-990 How to cite?
Journal: Journal of hepatology 
Abstract: 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.
URI: http://hdl.handle.net/10397/75687
ISSN: 0168-8278
EISSN: 1600-0641
DOI: 10.1016/j.jhep.2017.06.015
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