STAT3 inhibitor WP1066 attenuates miRNA-21 to suppress human oral squamous cell carcinoma growth in vitro and in vivo
STAT3 inhibitor WP1066 attenuates miRNA-21 to suppress human oral squamous cell carcinoma growth in vitro and in vivo
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STAT3 抑制剂 WP1066 减弱 miRNA-21 以抑制人口腔鳞状细胞癌的体外和体内生长
DOI：
10.3892/or.2014.3114
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发表时间：
2014-05-01
期刊：
影响因子：
4.2
通讯作者：
Zhang, Lun
中科院分区：
文献类型：
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作者：
Zhou, Xuan;Ren, Yu;Zhang, Lun
信号转导子和转录激活子3（STAT 3）异常参与口腔鳞状细胞癌（OSCC）的发生。microRNA-21（miR-21）是口腔鳞癌发生发展的重要基因调控因子。已经在多种人类癌症中报道了STAT 3对miR-21的诱导。在本研究中，我们发现STAT 3（-/p）表达与miR-21在60例OSCC中呈正相关。报告基因分析显示miR-21过表达依赖于STAT 3激活。用小分子STAT 3抑制剂WP 1066抑制口腔鳞癌细胞中STAT 3的表达。TSCCA和TCA 8113显示通过WP1066处理的肿瘤细胞增殖、侵袭能力和miR-21表达降低。此外，miR-21靶蛋白[程序性细胞死亡4（PDCD 4）、金属蛋白酶组织抑制剂3（TIMP-3）和磷酸酶和张力蛋白同源物（PTEN）]的表达上调。通过IL-6诱导miR-21过表达恢复STAT 3表达，进一步证实了STAT 3与miR-21之间的相关性。WP1066在TSCCA异种移植肿瘤模型中抑制肿瘤生长并诱导肿瘤细胞凋亡。Western blotting和免疫组织化学染色显示，WP1066处理组STAT 3（-/p）、Ki 67、Bcl-2和MMP-2表达降低，PDCD 4、TIMP-3和PTEN表达增加。本研究表明，STAT 3可以通过miR-21依赖性方式调控OSCC细胞的生长，WP1066可能通过抑制STAT 3/miR-21轴成为治疗OSCC的新候选药物。
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.