Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells

HFCAS OpenIR

	Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells
其他题名	Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells
	2019
发表期刊	ACTA PHARMACEUTICA SINICA B
ISSN	2211-3835
摘要	Metastasis-associated drug resistance accounts for high mortality in ovarian cancer and remains to be a major barrier for effective treatment. In this study, SKOV3/T4, a metastatic subpopulation of ovarian cancer SKOV3 cells, was enriched to explore potential interventions against metastatic associated drug resistance. Quantitative genomic and functional analyses were performed and found that slug was significantly increased in the SKOV3/T4 subpopulation and contributed to the high resistance of SKOV3/T4. Further studies showed that slug activated c-Met in a ligand-independent manner due to elevated levels of fibronectin and provoked integrin a V function, which was confirmed by the significant correlation of slug and p-Met levels in 121 ovarian cancer patient samples. Intriguingly, c-Met inhibitor(s) exhibited greatly enhanced anti-cancer effects in slug-positive ovarian cancer models both in vitro and in vivo. Additionally, IHC analyses revealed that slug levels were highly correlated with reduced survival of ovarian cancer patients. Taken together, this study not only uncovers the critical roles of slug in drug resistance in ovarian cancer but also highlights a promising therapeutic strategy by targeting the noncanonical activation of c-Met in slug-positive ovarian cancer patients with poor prognosis. (C) 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
其他摘要	Metastasis-associated drug resistance accounts for high mortality in ovarian cancer and remains to be a major barrier for effective treatment.In this study,SKOV3/T4,a metastatic subpopulation of ovarian cancer SKOV3 cells,was enriched to explore potential interventions against metastaticassociated drug resistance.Quantitative genomic and functional analyses were performed and found that slug was significantly increased in the SKOV3/T4 subpopulation and contributed to the high resistance of SKOV3/T4.Further studies showed that slug activated c-Met in a ligand-independent manner due to elevated levels of fibronectin and provoked integrin α V function,which was confirmed by the significant correlation of slug and p-Met levels in 121 ovarian cancer patient samples.Intriguingly,c-Met inhibitor(s) exhibited greatly enhanced anti-cancer effects in slug-positive ovarian cancer models both in vitro and in vivo.Additionally,IHC analyses revealed that slug levels were highly correlated with reduced survival of ovarian cancer patients.Taken together,this study not only uncovers the critical roles of slug in drug resistance in ovarian cancer but also highlights a promising therapeutic strategy by targeting the noncanonical activation of c-Met in slug-positive ovarian cancer patients with poor prognosis.
关键词	EPITHELIAL-MESENCHYMAL TRANSITION TUMOR-GROWTH HETEROGENEITY AMPLIFICATION CONTRIBUTES PROGRESSION CARCINOMA REVEALS PATHWAY SNAIL Slug c-Met Drug resistance Ovarian cancer XL184
收录类别	CSCD
语种	英语
资助项目	[National Natural Science Foundation for Distinguished Young Scholar of China] ; [National Natural Science Foundation of China] ; [Zhejiang Provincial Natural Science Foundation]
CSCD记录号	CSCD:6517507
引用统计
文献类型	期刊论文
条目标识符	http://ir.hfcas.ac.cn:8080/handle/334002/49272
专题	中国科学院合肥物质科学研究院
推荐引用方式 GB/T 7714	. Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells[J]. ACTA PHARMACEUTICA SINICA B,2019,9.
APA	(2019).Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells.ACTA PHARMACEUTICA SINICA B,9.
MLA	"Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells".ACTA PHARMACEUTICA SINICA B 9(2019).