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

引用

Acta Pharmaceutica Sinica B 2019年第3期9卷 484-495页

作者： Linlin Chang Yan Hu Yingying Fu Tianyi Zhou Jun You Jiamin Du Lin Zheng Ji Cao Meidan Ying Xiaoyang Dai Dan Su Qiaojun He Hong Zhu Bo Yang Zhejiang Province Key Laboratory of Anti-Cancer Drug Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China Zhejiang Cancer Hospital Hangzhou310022China

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： Slug c-Met Drug resistance Ovarian cancer xl184

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