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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., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Arsenic is well established as a human carcinogen, but the molecular mechanisms leading to arsenic-induced carcinogenesis are complex and elusive. It is not been determined if the epithelial-mesenchymal transition (EMT) contributes to carcinogen-induced malignant transformation and subsequent tumor formation. We have found that, during the neoplastic transformation induced in human bronchial epithelial (HBE) cells by a low concentration (1.0μM) of arsenite, the cells undergo an EMT and show enhanced invasion and migration. With longer times for transformation of HBE cells, there was increased miR-21 expression. Further, during the transformation of HBE cells, inhibition of miR-21 with an miR-21 inhibitor increased levels of PDCD4, an inhibitor of neoplastic transformation; reduced Twist1, a transcription factor involved in cell differentiation; and inhibited cell invasion and migration. In addition, PDCD4 interacted with Twist1 and inhibited its expression function, which is involved in arsenite-induced EMT. Thus, miR-21, acting on PDCD4, which interacts with Twist1 and represses the expression of Twist1, contributes to the EMT induced by arsenite. These observations add to an understanding of the processes involved in arsenite-induced carcinogenesis., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

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 (1.0μM) 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., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Arsenite is an established human carcinogen, and arsenite-induced inflammation contributes to malignant transformation of cells, but the molecular mechanisms by which cancers are produced remain to be established. The present results showed that, evoked by arsenite, secretion of interleukin-6 (IL-6), a pro-inflammatory cytokine, led to the activation of STAT3, a transcription activator, and to increased levels of a microRNA, miR-21. Blocking IL-6 with anti-IL-6 antibody and inhibiting STAT3 activation reduced miR-21 expression. For human bronchial epithelial cells, cultured in the presence of anti-IL-6 antibody for 3days, the arsenite-induced EMT and malignant transformation were reversed. Thus, IL-6, acting on STAT3 signaling, which up-regulates miR-21in an autocrine manner, contributes to the EMT induced by arsenite. These data define a link from inflammation to EMT in the arsenite-induced malignant transformation of HBE cells. This link, mediated through miRNAs, establishes a mechanism for arsenite-induced lung carcinogenesis., (© 2013.)

Evidence for arsenite-induced lung cancer in humans is strong, but the molecular mechanisms by which arsenite causes cancer remain to be established. Angiogenesis is a fundamental characteristic of cancer and is necessary in its multi-step progression. In this investigation, the mechanism for arsenite-induced angiogenesis was evaluated. Tumors formed from human bronchial epithelial (HBE) cells transformed by arsenite developed new blood vessels, which were prevented by the knockdown of miR-21, and cultures of human umbilical vein endothelial cells (HUVEC) exposed to arsenite developed endothelial tubes, a characteristic of angiogenesis. Also found in transformed HBE cells were up-regulation of a microRNA, miR-21, and increased levels of vascular endothelial growth factor (VEGF), which promotes angiogenesis. Down-regulation of miR-21 in these cells inhibited the arsenite-induced increases of VEGF levels. Thus, we conclude that arsenite induces tumor angiogenesis through processes mediated by miR-21., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Arsenic is a well established human carcinogen that causes diseases of the lung. Some studies have suggested a link between inflammation and lung cancer; however, it is unknown if arsenite-induced inflammation causally contributes to arsenite-caused malignant transformation of cells. In this study, we investigated the molecular mechanisms underlying inflammation during neoplastic transformation induced in human bronchial epithelial (HBE) cells by chronic exposure to arsenite. The results showed that, on acute or chronic exposure to arsenite, HBE cells over-expressed the pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1β (IL-1β). The data also indicated that HIF-2α was involved in arsenite-induced inflammation. Moreover, IL-6 and IL-8 were essential for the malignant progression of arsenite-transformed HBE cells. Thus, these experiments show that HIF-2α mediates arsenite-induced inflammation and that such inflammation is involved in arsenite-induced malignant transformation of HBE cells. The results provide a link between the inflammatory response and the acquisition of a malignant transformed phenotype by cells chronically exposed to arsenite and thus establish a previously unknown mechanism for arsenite-induced carcinogenesis., (© 2013.)