Carcinogenic metalloid arsenic induces expression of mdig oncogene through JNK and STAT3 activation.

Environmental or occupational exposure to arsenic, a chemical element classified as metalloid, has been associated with cancer of the lung, skin, bladder, liver, etc. Mdig (mineral dust-induced gene) is a newly identified oncogene linked to occupational lung diseases and lung cancer. It is unclear whether mdig is also involved in arsenic-induced malignant transformation of the lung cells. By using human bronchial epithelial cells and human lung cancer cell lines, we showed that arsenic was able to induce expression of mdig. We further demonstrated that this mdig induction by arsenic was partially dependent on the JNK and STAT3 signaling pathways. Disruption of the JNK or STAT3 by either chemical inhibitors or siRNAs diminished arsenic-induced accumulation of mdig mRNA and protein. Furthermore, we also showed that microRNA-21 (miR-21) and Akt were down-stream effectors of the JNK and STAT3 signaling pathways in arsenic-induced mdig expression. Transfection of the cells with anti-miR-21 or pre-treatment of the cells with Akt inhibitor blunted mdig induction by arsenic. Clinically, the levels of mdig can be applied to predict the disease progression, the first progression (FP), in non-small cell lung cancer (NSCLC) patients. Taken together, our data suggest that mdig may play important roles on the pathogenesis of arsenic-induced lung cancer and that JNK and STAT3 signaling pathways are essential in mediating arsenic-induced mdig expression.