MiR-139-5p reverses CD44+/CD133+-associated multidrug resistance by downregulating NOTCH1 in colorectal carcinoma cells
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Ke Xu1, Ke Shen2, Xin Liang2, Yueqi Li2, Norio Nagao3, Jiyu Li4, Jianwen Liu2, Peihao Yin1
1Central Laboratory, Putuo Hospital and Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China
2State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, PR China
3Department of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, 727-0023, Japan
4Department of general surgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China
Peihao Yin, email: [email protected]
Jianwen Liu, email: [email protected]
Jiyu Li, email: [email protected]
Keywords: colorectal cancer, miR-139-5p, NOTCH1, drug resistance
Received: February 18, 2016 Accepted: September 25, 2016 Published: October 12, 2016
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.
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