The IL-6/STAT3 pathway via miR-21 is involved in the neoplastic and metastatic properties of arsenite-transformed human keratinocytes

• Arsenite evokes IL-6 secretion and induces inflammation of human keratinocytes.
• IL-6 autocrine activates STAT3 signaling and up-regulates miR-21expression
• MiR-21 regulated by STAT3 is involved in arsenite-induced epithelial-mesenchymal transition (EMT) and promotes migration and invasion.

Inflammation and microRNAs are involved in human skin cancer; however, their molecular mechanisms remain unclear. Further, a concern in skin cancer research is the identification of biomarkers for early diagnosis and accurate prognosis. To explore new biomarkers of chemical exposure in risk assessment of chemical carcinogenesis and arsenite-induced skin cancer, we investigated the roles of interleukin-6 (IL-6) regulation of microRNA-21 (miR-21), functioning via activation of signal transducers and activators of transcription 3 (STAT3), in neoplastic and metastatic properties of immortalized human keratinocytes (HaCaT cells) transformed by arsenite. In HaCaT cells, arsenite caused increases of IL-6 and miR-21 levels and activation of STAT3, which induced the epithelial-mesenchymal transition (EMT). Blocking IL-6 with anti-IL-6 antibody inhibited the activation of STAT3 and increases of miR-21 levels. Knock-down of STAT3 by siRNA blocked the increases of miR-21. In arsenite-transformed HaCaT (HaCaT-30T) cells, down-regulation of STAT3 by siRNA blocked the process of EMT and decreased their neoplastic properties and migratory capacity, effects that were antagonized by over-expression of miR-21.Thus, the IL-6/STAT3 pathway via miR-21 is involved in EMT, neoplastic properties, and migratory capacity of arsenite-transformed HaCaT cells. The results may lead to development of biomarkers for early diagnosis and accurate prognosis of arsenite-induced skin cancer.