title: WP1066 sensitizes oral squamous cell carcinoma cells to cisplatin by targeting STAT3/miR-21 axis.
abstract: Accumulating evidence reveals that activation of STAT3 and miR-21 contributes to chemoresistance in multiple tumors. We examined the expression of STAT3 and miR-21 in 43 oral squamous cell carcinoma (OSCC) tumors and classified them into cisplatin sensitive or resistant group. Tca8113 and Tca8113/DDP cells were treated with cisplatin (DDP), WP1066 (STAT3 inhibitor) or in combination. MTT, colony formation, wound healing, 3-D culture, and transwell chamber assays were used to evaluate the malignant phenotype of OSCC cells. We evaluated the effect of WP1066 on the expression of STAT3 and miR-21. A Tca8113/DDP OSCC xenograft tumor model was established to evaluate the therapeutic effect of WP1066 in combination with DDP. The expression of STAT3/miR-21 was significantly increased in DDP-resistant OSCC samples and Tca8113/DDP cells compared to its parental cell. Treatment of DDP combined with WP1066 efficiently inhibited Tca8113 and Tca8113/DDP cell proliferation, migration and invasion. STAT3 mediated OSCC cell survival and DDP resistance through upregulating the expression of miR-21 and downregulating miR-21 downstream targets, including PTEN, TIMP3 and PDCD4. WP1066 plus DDP treatment could inhibit Tca8113 and Tca8113/DDP cell growth by inhibiting STAT3 phosphorylation and miR-21 expression. These results indicated that STAT3/miR-21 axis could be a candidate therapeutic target for OSCC chemoresistance.
authors.affiliation: The Department of Otorhinolaryngology and Maxillofacial Oncology; Tianjin Medical University Cancer Institute &Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute; National Clinical Research Center of Cancer; Tianjin 300060, P.R. China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Tianjin Research Center of Basic Medical Science, Tianjin Medical University, Tianjin 300070, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ren
authors.affiliation: The Department of Otorhinolaryngology and Maxillofacial Oncology; Tianjin Medical University Cancer Institute &Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute; National Clinical Research Center of Cancer; Tianjin 300060, P.R. China.
authors.forename: Aiqin
authors.initials: A
authors.lastname: Liu
authors.affiliation: The Department of Otorhinolaryngology and Maxillofacial Oncology; Tianjin Medical University Cancer Institute &Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute; National Clinical Research Center of Cancer; Tianjin 300060, P.R. China.
authors.forename: Rui
authors.initials: R
authors.lastname: Jin
authors.affiliation: Department of Pathology, the third affiliated hospital, Guangzhou medical university, Guangzhou 510150, P.R. China.
authors.forename: Qingping
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: The Department of Otorhinolaryngology and Maxillofacial Oncology; Tianjin Medical University Cancer Institute &Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute; National Clinical Research Center of Cancer; Tianjin 300060, P.R. China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: The Department of Otorhinolaryngology and Maxillofacial Oncology; Tianjin Medical University Cancer Institute &Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute; National Clinical Research Center of Cancer; Tianjin 300060, P.R. China.
authors.forename: Lingping
authors.initials: L
authors.lastname: Kong
authors.affiliation: The Department of Otorhinolaryngology and Maxillofacial Oncology; Tianjin Medical University Cancer Institute &Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute; National Clinical Research Center of Cancer; Tianjin 300060, P.R. China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Department of Otorhinolaryngology and Maxillofacial Oncology; Tianjin Medical University Cancer Institute &Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute; National Clinical Research Center of Cancer; Tianjin 300060, P.R. China.
authors.forename: Lun
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; D011725:Pyridines; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D020032:Tyrphostins; C519885:WP1066; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D002945:Cisplatin