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 simultaneously. 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.