MicroRNA-21 activation of Akt via PTEN is involved in the epithelial-mesenchymal transition and malignant transformation of human keratinocytes induced by arsenite

MicroRNAs are involved in the epithelial-mesenchymal transition (EMT) and malignant transformation of cells. However, the molecular mechanisms remain unclear. In seeking new biomarkers of chemical exposure in the risk assessment of arsenite-induced skin cancer, the function of microRNA-21 (miR-21) in the regulation of serine/threonine kinase (Akt) activation was investigated. Akt suppresses phosphatase and tensin homolog (PTEN) and is involved in neoplastic and metastatic properties of arsenite-transformed human keratinocyte (T-HaCaT) cells. In HaCaT cells, arsenite caused an increase of miR-21 levels and a decrease of PTEN, which activated Akt signaling and induced the EMT. On inhibiting miR-21, the levels of PTEN were increased, and activation of Akt was blocked. Knock-down of PTEN by siRNA enhanced the activation of Akt. The effects of an miR-21 inhibitor on Akt activation were antagonized by PTEN siRNA. In T-HaCaT cells, blocking the activation of Akt by LY294002 inhibited the EMT. Moreover, the effects of an miR-21 mimic on the EMT and the neoplastic capacity, invasion, and metastasis of T-HaCaT cells were antagonized by LY294002. T-HaCaT transfected with PTEN plasmids showed decreased Akt activation and E-cadherin expression and increased vimentin levels. Thus, activation of Akt, controlled by miR-21/PTEN, is involved in the EMT, and thereby affects the neoplastic, invasion, and migratory capacities of T-HaCaT cells. The results point to the potential use of miR-21 as a biomarker for skin cancer and as a target for cancer prevention and treatment.