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

Abstract

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.

The mechanistic basis of arsenicosis: Pathogenesis of skin cancer

“…Recent findings have demonstrated its ability to activate the mineral dust induced gene (MDIG), also known as myc-induced nuclear antigen 53 and nucleolar protein 52 by upregulating JNK and STAT3 pathways. MDIG is an oncogene that has been linked to lung [79], breast, colon, and gastric cancers, esophageal squamous cell, hepatocellular, and renal cell carcinomas, as well as some forms of lymphoma [80]. Evidence also suggests that this metalloid works through Akt (also known as protein kinase B) to promote epithelial to mesenchymal transition (EMT), invasion, and migration of arsenic-transformed bronchial epithelial cells [81].…”

Cutaneous Toxicology of Arsenic

“…The metalloid also activates oncogenes such as the mineral dust-induced gene (MDIG), a gene that has been linked to lung [52], breast, colon, and gastric cancers, esophageal squamous cell, hepatocellular, and renal cell carcinomas, as well as some forms of lymphoma. Enhancement in the JNK and STAT3 pathways is required for this MDIG activation [53].…”

Oxidative Stress, Epigenetics, and Cancer Stem Cells in Arsenic Carcinogenesis and Prevention

“…In our most recent studies, we uncovered an entirely unexplored new mechanism linking arsenic exposure to a compromised DNA repair function. In human bronchial epithelial cells or lung cancer cell line A549 cells, arsenic is potent in inducing mdig expression 45 . By exploring potential interaction partners of the mdig protein, we conducted proteomic analysis of the immunocomplexes from mdig immunoprecipitation and revealed direct interaction of mdig with XRCC5, XRCC6 and DNAPK, the non-homologous end joining (NHEJ) repair complex.…”