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MiR-944/CISH mediated inflammation via STAT3 is involved in oral cancer malignance by cigarette smoking

The cytokine-inducible Src homology 2-containing protein (CISH) is an endogenous suppressors of signal transduction and activator of transcription (STAT) and acts as a key negative regulator of inflammatory cytokine responses. Downregulation of CISH has been reported to associate with increased acti...

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Detalles Bibliográficos
Autores principales: Peng, Hsuan-Yu, Hsiao, Jenn-Ren, Chou, Sung-Tau, Hsu, Yuan-Ming, Wu, Guan-Hsun, Shieh, Yi-Shing, Shiah, Shine-Gwo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505767/
https://www.ncbi.nlm.nih.gov/pubmed/32961483
http://dx.doi.org/10.1016/j.neo.2020.08.005
Descripción
Sumario:The cytokine-inducible Src homology 2-containing protein (CISH) is an endogenous suppressors of signal transduction and activator of transcription (STAT) and acts as a key negative regulator of inflammatory cytokine responses. Downregulation of CISH has been reported to associate with increased activation of STAT and enhanced inflammatory pathways. However, whether microRNAs (miRNAs) play a crucial role in CISH/STAT regulation in oral squamous cell carcinoma (OSCC) remains unknown. The expression of CISH on OSCC patients was determine by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Specific targeting by miRNAs was determined by software prediction, luciferase reporter assay, and correlation with target protein expression. The functions of miR-944 and CISH were accessed by transwell migration and invasion analyses using gain- and loss-of-function approaches. Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR were used to evaluate the pro-inflammation cytokines expression under the miR-944, CISH, NNK or combinations treatment. We found that the CISH protein, which modulates STAT3 activity, as a direct target of miR-944. CISH protein was significantly down-regulated in OSCC patients and cell lines and its level was inversely correlated with miR-944 expression. The miR-944-induced STAT3 phosphorylation, pro-inflammation cytokines secretion, migration and invasion were abolished by CISH restoration, suggesting that the oncogenic activity of miR-944 is CISH dependent. Furthermore, tobacco extract (NNK) may contribute to miR-944 induction and STAT3 activation. Antagomir-mediated inactivation of miR-944 prevented the NNK-induced STAT3 phosphorylation and pro-inflammation cytokines secretion. Altogether, these data demonstrate that NNK-induced miR944 expression plays an important role in CISH/STAT3-mediated inflammatory response and activation of tumor malignancy.