title: miR-139-5p sensitizes colorectal cancer cells to 5-fluorouracil by targeting NOTCH-1.
abstract: Multidrug resistance (MDR), a phenomenon that often occurs with drug treatment and is characterized by relapse or attenuation of drug efficacy, is almost unavoidable in colorectal cancer (CRC) patients receiving 5-fluorouracil (5-FU)-based chemotherapy. MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression. Our previous study has identified miR-139-5p as a potential tumor suppressor in CRC, but its role in chemoresistance of CRC has not been elucidated. In this study, we demonstrated that miR-139-5p was down-regulated either in CRC tumors receiving chemotherapy or in 5-FU-resistant CRC cell lines (HCT-8/5-FU and HCT-116/5-FU). Ectopic expression of miR-139-5p sensitized CRC cells to 5-FU by increasing 5-FU-induced apoptosis. In addition, miR-139-5p inhibited the expression of the miR-139-5p target gene NOTCH-1 and its downstream molecules MRP-1 and BCL-2, two key MDR-associated genes. Furthermore, silencing NOTCH-1 expression promoted the chemotherapeutic effects of 5-FU, and up-regulation of NOTCH-1 abrogated miR-139-5p-mediated sensitization to 5-FU in LoVo and HCT-116 cells. Taken together, our data indicate a new role of miR-139-5p/NOTCH-1 pathway in the drug resistance of CRC cells to 5-FU, which may be a promising therapeutic target for the anti-MDR treatment of CRC.
authors.affiliation: Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China; Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China.
authors.forename: Heyong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China.
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China.
authors.forename: Zehua
authors.initials: Z
authors.lastname: Bian
authors.affiliation: Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China.
authors.forename: Surui
authors.initials: S
authors.lastname: Yao
authors.affiliation: Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China; Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China. Electronic address: wxsytsg@126.com.
authors.forename: Qingjun
authors.initials: Q
authors.lastname: You
authors.affiliation: Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China. Electronic address: hzhwxsy@126.com.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Huang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C555098:MIRN139 microRNA, human; D035683:MicroRNAs; D051881:Receptor, Notch1; D005472:Fluorouracil
keywords: Chemoresistance; Colorectal cancer; NOTCH-1; miR-139-5p