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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.
AuthorsXuan Zhou, Yu Ren, Aiqin Liu, Lei Han, Kailiang Zhang, Shasha Li, Peng Li, Ping Li, Chunsheng Kang, Xudong Wang, Lun Zhang
JournalOncology reports (Oncol Rep) Vol. 31 Issue 5 Pg. 2173-80 (May 2014) ISSN: 1791-2431 [Electronic] Greece
PMID24676554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Apoptosis Regulatory Proteins
  • IL6 protein, human
  • Interleukin-6
  • Ki-67 Antigen
  • MIRN21 microRNA, human
  • MicroRNAs
  • PDCD4 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Pyridines
  • RNA-Binding Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • TIMP3 protein, human
  • Tissue Inhibitor of Metalloproteinase-3
  • Tyrphostins
  • WP1066
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Matrix Metalloproteinase 2
Topics
  • Animals
  • Apoptosis (drug effects)
  • Apoptosis Regulatory Proteins (biosynthesis)
  • Carcinoma, Squamous Cell (drug therapy)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Humans
  • Interleukin-6 (metabolism)
  • Ki-67 Antigen (biosynthesis)
  • Matrix Metalloproteinase 2 (biosynthesis)
  • Mice
  • Mice, Nude
  • MicroRNAs (antagonists & inhibitors, biosynthesis)
  • Mouth Neoplasms (drug therapy)
  • PTEN Phosphohydrolase (biosynthesis)
  • Proto-Oncogene Proteins c-bcl-2 (biosynthesis)
  • Pyridines (pharmacology)
  • RNA-Binding Proteins (biosynthesis)
  • STAT3 Transcription Factor (antagonists & inhibitors, biosynthesis)
  • Tissue Inhibitor of Metalloproteinase-3 (biosynthesis)
  • Tyrphostins (pharmacology)
  • Xenograft Model Antitumor Assays

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