文献类型：期刊文献

英文题名：MiR-139-5p reverses CD44+/CD133+-associated multidrug resistance by downregulating NOTCH1 in colorectal carcinoma cells

作者：Xu, Ke[1,2];Shen, Ke[3,4];Liang, Xin[3,4];Li, Yueqi[3,4];Nagao, Norio[5];Li, Jiyu[6];Liu, Jianwen[3,4];Yin, Peihao[1,2]

机构：[1]Shanghai Univ Tradit Chinese Med, Putuo Hosp, Cent Lab, Shanghai 200062, Peoples R China;[2]Shanghai Univ Tradit Chinese Med, Intervent Canc Inst Chinese Integrat Med, Shanghai 200062, Peoples R China;[3]East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[4]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[5]Prefectural Univ Hiroshima, Dept Life & Environm Sci, Shobara 7270023, Japan;[6]Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Gen Surg, Shanghai 200072, Peoples R China

年份：2016

卷号：7

期号：46

起止页码：75118

外文期刊名：ONCOTARGET

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000389632800054)】；

基金：This work was supported by the National Natural Science Foundation of China (No. 81502540, 81502600 and 81503434) and the Fundamental Research Fund for the Central Universities of China (No. 222201514333).

语种：英文

外文关键词：colorectal cancer; miR-139-5p; NOTCH1; drug resistance

摘要：MiRNAs may promote or inhibit tumor recurrence and drug resistance. MiR-139-5p is reportedly downregulated in colorectal cancer patient samples, but it is unknown whether and how miR-139-5p regulates drug resistance. Cancer stem cells (CSCs) are postulated to be important promoters of multiple drug resistance (MDR). In this study, we established a MDR cell model which strongly expressed the CSC-associated biomarkers CD44 and CD133. MiR-139-5p expression was reduced in MDR cell lines, while overexpression of miR-139-5p reversed CD44+/CD133+-associated MDR. We also identified NOTCH1, an important protein for stem cell maintenance and function, as a direct target of miR-139-5p, both in vitro and in a knockout mouse model. Notch1 expression was upregulated in tumor samples and inversely correlated with expression of miR-139-5p. Silencing NOTCH1 exerted an effect similar to overexpression of miR-139-5p by inhibiting the CD44+ and CD133+ population and reversing the drug-resistant phenotype. In conclusion, miR-139-5p downregulated NOTCH1 signaling to reverse CD44+/CD133+-associated MDR in colorectal cancer cells. Given this insight into the miRNA regulation of MDR, miR-139-5p could be a promising therapeutic target for colorectal cancer therapy.