title: Overexpression of miR-203 sensitizes paclitaxel (Taxol)-resistant colorectal cancer cells through targeting the salt-inducible kinase 2 (SIK2).
abstract: 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.
authors.affiliation: Department of Anesthesia, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, 130033, China.
authors.forename: Yingyi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Anesthesia, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, 130033, China.
authors.forename: Sujie
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of General Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, 130033, China.
authors.forename: Xuebo
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Ultrasonography, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, 130033, China.
authors.forename: Meihan
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, 130033, China.
authors.forename: Cuiying
authors.initials: C
authors.lastname: Mao
authors.affiliation: Department of General Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, 130033, China. fangxuedong@medmail.com.cn.
authors.forename: Xuedong
authors.initials: X
authors.lastname: Fang
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D035683:MicroRNAs / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020413:3' Untranslated Regions; D000972:Antineoplastic Agents, Phytogenic; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; C551842:salt-inducible kinase-2, human; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel
keywords: Chemosensitivity; Colorectal cancer; MicroRNA-203; SIK2; Taxol resistance