Overexpression of miR-203 sensitizes paclitaxel (Taxol)-resistant colorectal cancer cells through targeting the salt-inducible kinase 2 (SIK2)

Tumour Biol. 2016 Sep;37(9):12231-12239. doi: 10.1007/s13277-016-5066-2. Epub 2016 May 28.


MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression through the endogenous RNA interference machinery. Treatments with combination of chemotherapy with surgery are essential for advanced-stage colorectal cancer. However, the development of chemoresistance is a major obstacle for clinical application of anticancer drugs. In this study, we report a miR-203-SIK2 axis that involves in the regulation of Taxol sensitivity in colon cancer cells. MiR-203 is downregulated in human colon tumor specimens and cell lines compared with their normal counterparts. We report miR-203 is correlated with Taxol sensitivity: overexpression of miR-203 sensitizes colon cancer cells and the Taxol-resistant cells display downregulated miR-203 compared with Taxol-sensitive cells. We identify SIK2 as a direct target of miR-203 in colorectal cancer cells. Overexpression of miR-203 complementary pairs to the 3' untranslated region (UTR) of SIK2, leading to the sensitization of Taxol resistant cells. In addition, miR-203 and the salt-inducible kinase 2 (SIK2) are reverse expressed in human colorectal tumors. Finally, we demonstrate recovery of SIK2 by overexpression of SIK2-desensitized Taxol-resistant cells, supporting the miR-203-mediated sensitization to Taxol, is through the inhibition of SIK2. In general, our study will provide mechanisms of the microRNA-based anti-tumor therapy to develop anti-chemoresistance drugs.

Keywords: Chemosensitivity; Colorectal cancer; MicroRNA-203; SIK2; Taxol resistance.

MeSH terms

  • 3' Untranslated Regions / genetics
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Blotting, Western
  • Caco-2 Cells
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Neoplastic*
  • HT29 Cells
  • Humans
  • Immunohistochemistry
  • MicroRNAs / genetics*
  • Paclitaxel / pharmacology*
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction


  • 3' Untranslated Regions
  • Antineoplastic Agents, Phytogenic
  • MIRN203 microRNA, human
  • MicroRNAs
  • salt-inducible kinase-2, human
  • Protein Serine-Threonine Kinases
  • Paclitaxel