title: Gene 33/Mig6 inhibits hexavalent chromium-induced DNA damage and cell transformation in human lung epithelial cells.
abstract: Hexavalent Chromium [Cr(VI)] compounds are human lung carcinogens and environmental/occupational hazards. The molecular mechanisms of Cr(VI) carcinogenesis appear to be complex and are poorly defined. In this study, we investigated the potential role of Gene 33 (ERRFI1, Mig6), a multifunctional adaptor protein, in Cr(VI)-mediated lung carcinogenesis. We show that the level of Gene 33 protein is suppressed by both acute and chronic Cr(VI) treatments in a dose- and time-dependent fashion in BEAS-2B lung epithelial cells. The inhibition also occurs in A549 lung bronchial carcinoma cells. Cr(VI) suppresses Gene 33 expression mainly through post-transcriptional mechanisms, although the mRNA level of gene 33 also tends to be lower upon Cr(VI) treatments. Cr(VI)-induced DNA damage appears primarily in the S phases of the cell cycle despite the high basal DNA damage signals at the G2M phase. Knockdown of Gene 33 with siRNA significantly elevates Cr(VI)-induced DNA damage in both BEAS-2B and A549 cells. Depletion of Gene 33 also promotes Cr(VI)-induced micronucleus (MN) formation and cell transformation in BEAS-2B cells. Our results reveal a novel function of Gene 33 in Cr(VI)-induced DNA damage and lung epithelial cell transformation. We propose that in addition to its role in the canonical EGFR signaling pathway and other signaling pathways, Gene 33 may also inhibit Cr(VI)-induced lung carcinogenesis by reducing DNA damage triggered by Cr(VI).
authors.affiliation: Department of Pathology, School of Medicine, New York Medical College, Valhalla, NY, USA.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Pathology, School of Medicine, New York Medical College, Valhalla, NY, USA.
authors.forename: Cen
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Pathology, School of Medicine, New York Medical College, Valhalla, NY, USA.|Brander Cancer Research Institute, School of Medicine, New York Medical College, Valhalla, NY, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Pathology, School of Medicine, New York Medical College, Valhalla, NY, USA.|Brander Cancer Research Institute, School of Medicine, New York Medical College, Valhalla, NY, USA.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Darzynkiewicz
authors.affiliation: Department of Pathology, School of Medicine, New York Medical College, Valhalla, NY, USA.
authors.forename: Dazhong
authors.initials: D
authors.lastname: Xu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D015153:Blotting, Western; D002274:Carcinogens, Environmental / Q000494:pharmacology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D002857:Chromium / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D047468:Immunoprecipitation; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015162:Micronucleus Tests; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002274:Carcinogens, Environmental; C484017:ERRFI1 protein, human; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D002857:Chromium; C074702:chromium hexavalent ion
keywords: DNA damage; Gene 33/Mig6; carcinogenesis; chromium; lung