The acquisition of cancer stem cell-like properties and neoplastic transformation of human keratinocytes induced by arsenite involves epigenetic silencing of let-7c via Ras/NF-κB

• Arsenite decreases levels of let-7 family members.
• The Ras/NF-κB signal pathway is inhibited by let-7c.
• Let-7c is involved in arsenite-induced neoplastic transformation by cellular acquisition of CSCs-like properties.

Exposure of humans to inorganic arsenic can cause skin cancer. The acquisition of cancer stem cell-like properties is involved in the initiation of some cancers, and there are changes in let-7 levels in some tumors. The mechanisms of action, however, remain obscure. Here, we report that there are decreased levels of let-7a, let-7b, and let-7c in human keratinocyte HaCaT cells during malignant transformation induced by a low concentration (1.0 μM) of arsenite. The process by which arsenite reduces the level of let-7c apparently involves methylation, for 5-aza-2′-deoxycytidine, an inhibitor of methyltransferases, prevents arsenite-induced hypermethylation, decreases the level of let-7c, and thereby blocks arsenite-induced activation of the Ras/NF-κB signal pathway. Let-7c is an up-stream regulator of the Ras/NF-κB signal pathway and down-regulates activation of this pathway. In arsenite-transformed HaCaT cells, the acquisition of cancer stem cell-like properties is prevented by over-expression of let-7c, and over-expression of let-7c decreases the malignancy of transformed HaCaT cells. Thus, we conclude that epigenetic silencing of let-7c via Ras/NF-κB is involved in the acquisition of cancer stem cell-like properties and neoplastic transformation of HaCaT cells induced by arsenite, which contribute to the tumorigenesis of arsenite.