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, the underlying mechanisms of dysregulation of CISH/STAT pathway in oral squamous cell carcinoma (OSCC) remains unknown. Here, we report that CISH protein is significantly downregulated in OSCC patients and its levels are inversely correlated with miR-944 expression. We identified the CISH protein, which modulates STAT3 activity, as a direct target of miR-944. The miR-944-mediated CISH functions are crucial in regulating STAT3 activity, pro-inflammation molecules secretion (such as CCL3, CCL5, IL-1Ra and IL-1β), migration and invasive potential in OSCC cells. Furthermore, the expression of miR-944 was significantly induced by the 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and co-expressed with its host gene TP63. Taken together, miR-944/CISH/STAT3 may have therapeutic potential for the treatment of OSCC.
