期刊
BRITISH JOURNAL OF CANCER
卷 120, 期 5, 页码 512-521出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41416-018-0373-6
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资金
- Action Against Cancer
- DeAgostini Foundation (Novara, Italy)
- Imperial Biomedical Research Centre (BRC)
- National Institute for Health Research (NIHR)
- Clinical Lecturer Starter Grant - Academy of Medical Sciences (AMS) [SGL013/1021]
- AMS
- Wellcome Trust
- Medical Research Council
- British Heart Foundation
- Arthritis Research UK
- Royal College of Physicians
- Diabetes UK
BACKGROUND: Aberrant activation of Axl is implicated in the progression of hepatocellular carcinoma (HCC). We explored the biologic significance and preclinical efficacy of Axl inhibition as a therapeutic strategy in sorafenib-naive and resistant HCC. METHODS: We evaluated Axl expression in sorafenib-naive and resistant (SR) clones of epithelial (HuH7) and mesenchymal origin (SKHep-1) using antibody arrays and confirmed tissue expression. We tested the effect of Axl inhibition with RNA-interference and pharmacologically with R428 on a number of phenotypic assays. RESULTS: Axl mRNA overexpression in cell lines (n = 28) and RNA-seq tissue datasets (n = 373) correlated with epithelial-to-mesenchymal transition (EMT). Axl was overexpressed in HCC compared to cirrhosis and normal liver. We confirmed sorafenib resistance to be associated with EMT and enhanced motility in both HuH7-SR and SKHep-1-SR cells documenting a 4-fold increase in Axl phosphorylation as an adaptive feature of chronic sorafenib treatment in SKHep-1-SR cells. Axl inhibition reduced motility and enhanced sensitivity to sorafenib in SKHep-1SR cells. In patients treated with sorafenib (n = 40), circulating Axl levels correlated with shorter survival. CONCLUSIONS: Suppression of Axl-dependent signalling influences the transformed phenotype in HCC cells and contributes to adaptive resistance to sorafenib, providing a pre-clinical rationale for the development of Axl inhibitors as a measure to overcome sorafenib resistance.
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