title: STAT3 inhibitor WP1066 attenuates miRNA-21 to suppress human oral squamous cell carcinoma growth in vitro and in vivo.
abstract: Abnormalities in signal transducer and activator of transcription 3 (STAT3) are involved in the oncogenesis of oral squamous cell carcinoma (OSCC). MicroRNA-21 (miR-21) is an important gene expression regulator to OSCC. miR-21 induction by STAT3 has been reported in multiple human cancers. In the present study, we found that STAT3 (-/p) expression was positively correlated with miR-21 in 60 OSCC samples. A reporter gene assay showed that miR-21 overexpression was dependent on STAT3 activation. WP1066, a small molecular inhibitor of STAT3, was used to suppress STAT3 expression in OSCC cells. TSCCA and TCA8113 showed reduction in tumor cell proliferation, invasion ability and miR-21 expression by WP1066 treatment. In addition, the expression of miR-21 target proteins [programmed cell death 4 (PDCD4), tissue inhibitor of metalloproteinase 3 (TIMP-3) and phosphatase and tensin homolog (PTEN)] was upregulated. Restored STAT3 expression by IL-6 induced miR-21 overexpression, which further confirmed the correlation between STAT3 and miR-21. WP1066 inhibited tumor growth and induced tumor cell apoptosis in the TSCCA xenograft tumor model. Western blotting and immunohistochemistry staining indicated that STAT3 (-/p), Ki67, Bcl-2 and MMP-2 expressions decreased in the WP1066-treated group; PDCD4, TIMP-3 and PTEN expression increased simulta-neously. The present study provides evidence that targeting STAT3 could regulate OSCC cell growth in a miR-21-dependent manner and WP1066 could be a novel candidate drug to treat OSCC by inhibiting STAT3/miR-21 axis.
authors.affiliation: Department of Otorhinolaryngology and Maxillofacial Oncology, Tianjin Medical University Cancer Institute and Hospital, 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: Department of Otorhinolaryngology and Maxillofacial Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors.forename: Aiqin
authors.initials: A
authors.lastname: Liu
authors.affiliation: Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, P.R. China.
authors.forename: Kailiang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Otorhinolaryngology and Maxillofacial Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Li
authors.affiliation: Tianjin Medical Information Institute, Tianjin 300070, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Otorhinolaryngology and Maxillofacial Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, P.R. China.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Kang
authors.affiliation: Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, Tianjin 300060, P.R. China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Otorhinolaryngology and Maxillofacial Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors.forename: Lun
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009062:Mouth Neoplasms / Q000188:drug therapy*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011725:Pyridines / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis; D020032:Tyrphostins / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D019394:Ki-67 Antigen; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; 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; D020778:Matrix Metalloproteinase 2