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MicroRNA-25 regulates chemoresistance-associated autophagy in breast cancer cells, a process modulated by the natural autophagy inducer isoliquiritigenin

文献类型:期刊文献

英文题名:MicroRNA-25 regulates chemoresistance-associated autophagy in breast cancer cells, a process modulated by the natural autophagy inducer isoliquiritigenin

作者:Wang, Zhiyu[1,2];Wang, Neng[2];Liu, Pengxi[1];Chen, Qianjun[1];Situ, Honglin[1];Xie, Ting[3];Zhang, Jianxing[1];Peng, Cheng[4];Lin, Yi[1];Chen, Jianping[2]

第一作者:Wang, Zhiyu

机构:[1]Guangdong Prov Hosp Chinese Med, Dept Mammary Dis, Guangzhou, Guangdong, Peoples R China;[2]Univ Hong Kong, Sch Chinese Med, Pokfulam, Hong Kong, Peoples R China;[3]Guangzhou Univ Chinese Med, Clin Collage 2, Guangdong Prov Hosp Chinese Med, Dept Dermatol, Guangzhou, Guangdong, Peoples R China;[4]Chengdu Univ Tradit Chinese Med, Deapartment Pharmacol, Chengdu, Peoples R China

第一机构:Guangdong Prov Hosp Chinese Med, Dept Mammary Dis, Guangzhou, Guangdong, Peoples R China

通讯机构:[1]Univ Hong Kong, Sch Chinese Med, Pokfulam, Hong Kong, Peoples R China.

年份:2014

卷号:5

期号:16

起止页码:7013-7026

外文期刊名:ONCOTARGET

收录:WOS:【SCI-EXPANDED(收录号:WOS:000347920100040)】;

基金:This work was supported by the Health and Medical Research Fund (HMRF) of Hong Kong (Project no: 11121951), Seed funding programme for basic research of the university of Hong Kong (Project no: 201211159095), Small project funding of the university of Hong Kong (Project no: 201209176138) and Prestigious herbalist Lin Yi's experience inheritance project supported by state administration of Traditional Chinese Medicine of China (Project no: 12BMaa03). The authors would like to express their gratitude to Mr. Keith Wong, Ms. Cindy Lee and Mr. Alex Shi for providing technical support.

语种:英文

外文关键词:Autophagy; Drug resistance; miRNA-25; ULK1; Isoliquiritigenin; Breast cancer

摘要:Recent findings have revealed that dysregulated miRNAs contribute significantly to autophagy and chemoresistance. Pharmacologically targeting autophagy-related miRNAs is a novel strategy to reverse drug resistance. Here, we report a novel function of isoliquiritigenin (ISL) as a natural inhibitor of autophagy-related miR-25 in killing drug-resistant breast cancer cells. ISL induced chemosensitization, cell cycle arrest and autophagy, but not apoptosis, in MCF-7/ADR cells. ISL also promoted the degradation of the ATP-binding cassette (ABC) protein ABCG2 primarily via the autophagy-lysosome pathway. More importantly, miRNA 3.0 array experiments identified miR-25 as the main target of ISL in triggering autophagy flux. A mechanistic study validated that miR-25 inhibition led to autophagic cell death by directly increasing ULK1 expression, an early regulator in the autophagy induction phase. miR-25 overexpression was demonstrated to block ISL-induced autophagy and chemosensitization. Subsequent in vivo experiments showed that ISL had chemosensitizing potency, as revealed by an increase in LC3-II staining, the downregulation of ABCG2, a reduction in miR-25 expression and the activation of the miR-25 target ULK1. Overall, our results not only indicate that ISL acts as a natural autophagy inducer to increase breast cancer chemosensitivity, but also reveal that miR-25 functions as a novel regulator of autophagy by targeting ULK1.

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