Epithelial–mesenchymal transition during oncogenic transformation induced by hexavalent chromium involves reactive oxygen species-dependent mechanism in lung epithelial cells

• Published in: Toxicology and applied pharmacology Vol. 269; no. 1; pp. 61 - 71
• Main Authors: Ding, Song-Ze, Yang, Yu-Xiu, Li, Xiu-Ling, Michelli-Rivera, Audrey, Han, Shuang-Yin, Wang, Lei, Pratheeshkumar, Poyil, Wang, Xin, Lu, Jian, Yin, Yuan-Qin, Budhraja, Amit, Hitron, Andrew J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15-05-2013; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Biological and medical sciences; Cadherins - genetics; Cadherins - metabolism; Cancer signaling; Carcinogenesis, carcinogens and anticarcinogens; CARCINOGENS; Carcinogens, Environmental - toxicity; CATALASE; Catalase - metabolism; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Shape - drug effects; Cell Transformation, Neoplastic - chemically induced; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Chemical agents; Chemical and industrial products toxicology. Toxic occupational diseases; CHROMIUM; Chromium - toxicity; COLONY FORMATION; DNA; DNA DAMAGES; Dose-Response Relationship, Drug; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelial-Mesenchymal Transition - drug effects; Epithelial–mesenchymal transition; Gene Expression Regulation, Neoplastic - drug effects; Hexavalent chromium; Histone; Humans; Lung Neoplasms - chemically induced; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; LUNGS; Medical sciences; MESSENGER-RNA; Metals and various inorganic compounds; METASTASES; METHYLATION; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); NEOPLASMS; Oncogenic transformation; ONCOGENIC TRANSFORMATIONS; OXYGEN; Reactive Oxygen Species - metabolism; Respiratory Mucosa - drug effects; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; RNA, Messenger - metabolism; Signal Transduction - drug effects; Snail Family Transcription Factors; Toxicology; Transcription Factors - metabolism; Tumors; Vimentin - metabolism; Hexavalent chromium; Epithelial–mesenchymal transition; Oncogenic transformation; Cancer signaling; Histone; Epithelial cells; Oxidative stress; Reactive oxygen species; Lung; Transition metal; Malignant tumor; Cell transformation; Respiratory system; Carcinogenesis; In vitro; Signal transduction; Epithelial-mesenchymal transition; Epithelial cell; Epithelial mesenchymal transition; Mechanism of action; Chromium VI; Cancer
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2013.03.006

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.
Epithelial–mesenchymal transition during oncogenic transformation induced by hexavalent chromium involves reactive oxygen species-dependent mechanisms in lung epithelial cells. [Display omitted]
•We study if Cr(VI) might induce EMT and invasion in epithelial cells.•Cr(VI) induces EMT by altering E-cadherin and vimentin expression.•It also increases cell invasion and promotes oncogenic transformation.•Catalase reduces Cr(VI)-induced EMT, invasion and transformation.