title: MiR-139-5p reverses CD44+/CD133+-associated multidrug resistance by downregulating NOTCH1 in colorectal carcinoma cells.
abstract: 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.
authors.affiliation: Central Laboratory, Putuo Hospital and Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: State 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.
authors.forename: Ke
authors.initials: K
authors.lastname: Shen
authors.affiliation: State 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.
authors.forename: Xin
authors.initials: X
authors.lastname: Liang
authors.affiliation: State 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.
authors.forename: Yueqi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, 727-0023, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Nagao
authors.affiliation: Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China.
authors.forename: Jiyu
authors.initials: J
authors.lastname: Li
authors.affiliation: State 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.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Liu
authors.affiliation: Central Laboratory, Putuo Hospital and Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China.
authors.forename: Peihao
authors.initials: P
authors.lastname: Yin
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D018432:Drug Resistance, Multiple / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D020128:Inhibitory Concentration 50; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C555098:MIRN139 microRNA, human; D035683:MicroRNAs; D051881:Receptor, Notch1
keywords: NOTCH1; colorectal cancer; drug resistance; miR-139-5p