MicroRNA-520g confers drug resistance by regulating p21 expression in colorectal cancer

J Biol Chem. 2015 Mar 6;290(10):6215-25. doi: 10.1074/jbc.M114.620252. Epub 2015 Jan 23.


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.

Keywords: 5-FU; Apoptosis; Colorectal Cancer; Drug Resistance; MicroRNA (miRNA); miR-520g; p21; p53.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Drug Resistance, Neoplasm / genetics*
  • Fluorouracil / therapeutic use
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • Humans
  • Mice
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics*
  • Mutation
  • Organoplatinum Compounds / therapeutic use
  • Oxaliplatin
  • Tumor Suppressor Protein p53 / genetics
  • Xenograft Model Antitumor Assays


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • MIRN520 microRNA, human
  • MicroRNAs
  • Organoplatinum Compounds
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Oxaliplatin
  • Fluorouracil