title: Epithelial-mesenchymal transition during oncogenic transformation induced by hexavalent chromium involves reactive oxygen species-dependent mechanism in lung epithelial cells.
abstract: Hexavalent chromium [Cr(VI)] is an important human carcinogen associated with pulmonary diseases and lung cancer. Exposure to Cr(VI) induces DNA damage, cell morphological change and malignant transformation in human lung epithelial cells. Despite extensive studies, the molecular mechanisms remain elusive, it is also not known if Cr(VI)-induced transformation might accompany with invasive properties to facilitate metastasis. We aimed to study Cr(VI)-induced epithelial-mesenchymal transition (EMT) and invasion during oncogenic transformation in lung epithelial cells. The results showed that Cr(VI) at low doses represses E-cadherin mRNA and protein expression, enhances mesenchymal marker vimentin expression and transforms the epithelial cell into fibroblastoid morphology. Cr(VI) also increases cell invasion and promotes colony formation. Further studies indicated that Cr(VI) uses multiple mechanisms to repress E-cadherin expression, including activation of E-cadherin repressors such as Slug, ZEB1, KLF8 and enhancement the binding of HDAC1 in E-cadherin gene promoter, but DNA methylation is not responsible for the loss of E-cadherin. Catalase reduces Cr(VI)-induced E-cadherin and vimentin protein expression, attenuates cell invasion in matrigel and colony formation on soft agar. These results demonstrate that exposure to a common human carcinogen, Cr(VI), induces EMT and invasion during oncogenic transformation in lung epithelial cells and implicate in cancer metastasis and prevention.
authors.affiliation: Department of Internal Medicine, Henan Provincial People's Hospital, Zhengzhou University, Wei-Wu Road, Zhengzhou, Henan 450000, PR China. dingsongze@hotmail.com
authors.forename: Song-Ze
authors.initials: SZ
authors.lastname: Ding
authors.forename: Yu-Xiu
authors.initials: YX
authors.lastname: Yang
authors.forename: Xiu-Ling
authors.initials: XL
authors.lastname: Li
authors.forename: Audrey
authors.initials: A
authors.lastname: Michelli-Rivera
authors.forename: Shuang-Yin
authors.initials: SY
authors.lastname: Han
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Poyil
authors.initials: P
authors.lastname: Pratheeshkumar
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Lu
authors.forename: Yuan-Qin
authors.initials: YQ
authors.lastname: Yin
authors.forename: Amit
authors.initials: A
authors.lastname: Budhraja
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hitron
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002857:Chromium / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D002274:Carcinogens, Environmental; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014746:Vimentin; D002857:Chromium; C074702:chromium hexavalent ion; D002374:Catalase