title: Oncogenic transformation of human lung bronchial epithelial cells induced by arsenic involves ROS-dependent activation of STAT3-miR-21-PDCD4 mechanism.
abstract: Arsenic is a well-documented human carcinogen. The present study explored the role of the onco-miR, miR-21 and its target protein, programmed cell death 4 (PDCD4) in arsenic induced malignant cell transformation and tumorigenesis. Our results showed that treatment of human bronchial epithelial (BEAS-2B) cells with arsenic induces ROS through p47phox, one of the NOX subunits that is the key source of arsenic-induced ROS. Arsenic exposure induced an upregulation of miR-21 expression associated with inhibition of PDCD4, and caused malignant cell transformation and tumorigenesis of BEAS-2B cells. Indispensably, STAT3 transcriptional activation by IL-6 is crucial for the arsenic induced miR-21 increase. Upregulated miR-21 levels and suppressed PDCD4 expression was also observed in xenograft tumors generated with chronic arsenic exposed BEAS-2B cells. Stable shut down of miR-21, p47phoxor STAT3 and overexpression of PDCD4 or catalase in BEAS-2B cells markedly inhibited the arsenic induced malignant transformation and tumorigenesis. Similarly, silencing of miR-21 or STAT3 and forced expression of PDCD4 in arsenic transformed cells (AsT) also inhibited cell proliferation and tumorigenesis. Furthermore, arsenic suppressed the downstream protein E-cadherin expression and induced β-catenin/TCF-dependent transcription of uPAR and c-Myc. These results indicate that the ROS-STAT3-miR-21-PDCD4 signaling axis plays an important role in arsenic -induced carcinogenesis.
authors.affiliation: Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: Poyil
authors.initials: P
authors.lastname: Pratheeshkumar
authors.affiliation: Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: Young-Ok
authors.initials: YO
authors.lastname: Son
authors.affiliation: Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: Sasidharan Padmaja
authors.initials: SP
authors.lastname: Divya
authors.affiliation: Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001151:Arsenic / Q000633:toxicity*; D001980:Bronchi / Q000378:metabolism* / Q000473:pathology; D001984:Bronchial Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; C114487:PDCD4 protein, human; D012334:RNA, Neoplasm; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D001151:Arsenic