title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA; Institute of Respiratory Diseases, Department of Pulmonary Medicine, First Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, China; Respiratory Medicine, The 4th Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, China.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA; Institute of Respiratory Diseases, Department of Pulmonary Medicine, First Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, China; Liaoning Cancer Hospital and Institute, Shenyang, Liaoning Province, China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA.
authors.forename: Yongju
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA.
authors.forename: Chitra
authors.initials: C
authors.lastname: Thakur
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA.
authors.forename: Bailing
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Qiu
authors.affiliation: Institute of Respiratory Diseases, Department of Pulmonary Medicine, First Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, China. Electronic address: hwzhao2007@yahoo.com.
authors.forename: Hongwen
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA. Electronic address: fchen@wayne.edu.
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
mesh_terms: D001151:Arsenic / Q000633:toxicity*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049308:Dioxygenases; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D056466:Histone Demethylases; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D049308:Dioxygenases; D056466:Histone Demethylases; C466777:RIOX2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048670:MAP Kinase Kinase 4; D001151:Arsenic
keywords: Arsenic; JNK; Mdig; Metalloid; STAT3