title: MicroRNA-520g confers drug resistance by regulating p21 expression in colorectal cancer.
abstract: Development of drug resistance is one of the major causes of colorectal cancer recurrence, yet mechanistic understanding and therapeutic options remain limited. Here, we show that expression of microRNA (miR)-520g is correlated with drug resistance of colon cancer cells. Ectopic expression of miR-520g conferred resistance to 5-fluorouracil (5-FU)- or oxaliplatin-induced apoptosis in vitro and reduced the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. Further studies indicated that miR-520g mediated drug resistance through down-regulation of p21 expression. Moreover, p53 suppressed miR-520g expression, and deletion of p53 up-regulated miR-520g expression. Inhibition of miR-520g in p53(-/-) cells increased their sensitivity to 5-FU treatment. Importantly, studies of patient samples indicated that expression of miR-520g correlated with chemoresistance in colorectal cancer. These findings indicate that the p53/miR-520g/p21 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of miR-520g or restoration of p21 expression may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, especially in those with mutant p53.
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, Department of Genetics, Cell Biology, and Anatomy.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases.
authors.forename: Liying
authors.initials: L
authors.lastname: Geng
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Talmon
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, Department of Genetics, Cell Biology, and Anatomy, Department of Biochemistry and Molecular Biology and Fred & Pamela Buffett Cancer Center, and jjwang@unmc.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005472:Fluorouracil / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009154:Mutation; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C575048:MIRN520 microRNA, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; D005472:Fluorouracil
keywords: 5-FU; Apoptosis; Colorectal Cancer; Drug Resistance; MicroRNA (miRNA); miR-520g; p21; p53