title: miR-23a promotes cisplatin chemoresistance and protects against cisplatin-induced apoptosis in tongue squamous cell carcinoma cells through Twist.
abstract: Tongue squamous cell carcinoma (TSCC) is one of the most common head and neck cancers. Cisplatin is effective as a single agent or in combination with other drugs for the treatment of TSCC. Treatment with cisplatin-based chemotherapy has been found to improve the prognosis of patients with TSCC. However, one of the most important clinical issues of cisplatin-based TSCC chemotherapy is the intrinsic/acquired chemoresistance to cisplatin. Increased expression of miR-23a reportedly promotes cisplatin chemoresistance in TSCC cells. High expression of Twist is also associated with cancer chemoresistance and poor prognosis of TSCC patients. In the present study, we explored the interaction between miR-23a and Twist in TSCC cells, and assessed its impact on TSCC chemoresistance to cisplatin. miR-23a and/or Twist were overexpressed or knocked down in SCC-4 and Tca8113 human TSCC cells. The expression levels of miR-23a and Twist were determined. The half maximal inhibitory concentration (IC50) of cisplatin and cell apoptosis rate under cisplatin treatment were used as measures of cisplatin chemoresistance. Overexpression of miR-23a in both SCC-4 and Tca8113 cells markedly increased Twist expression, c-Jun N-terminal kinase (JNK) activity and the half maximal inhibitory concentration (IC50) of cisplain, and decreased cisplatin-induced apoptosis, all of which was abolished by knockdown of Twist or selective JNK inhibitor SP600125. On the other hand, knockdown of miR-23a significantly decreased Twist expression, JNK activity and IC50 of cisplain, and increased cisplatin-induced apoptosis, all of which was completely reversed by overexpression of Twist. In conclusion, the present study for the first time demonstrates that miR-23a promotes cisplatin chemoresistance and protects cisplatin-induced apoptosis in TSCC cells through inducing Twist expression by a JNK-dependent mechanism. It adds new insights into the molecular mechanisms underlying TSCC chemoresistance.
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.
authors.forename: Fusen
authors.initials: F
authors.lastname: Peng
authors.affiliation: Department of Head and Neck Surgery, Hunan Provincial Tumor Hospital, Changsha, Hunan, P.R. China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Loudi Central Hospital, Loudi, Hunan, P.R. China.
authors.forename: Youhong
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Head and Neck Surgery, Hunan Provincial Tumor Hospital, Changsha, Hunan, P.R. China.
authors.forename: Pingqing
authors.initials: P
authors.lastname: Tan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D014062:Tongue Neoplasms / Q000235:genetics / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D002945:Cisplatin