title: TG-interacting factor mediates arsenic-induced malignant transformation of keratinocytes via c-Src/EGFR/AKT/FOXO3A and redox signalings.
abstract: Inorganic arsenic is well known as a carcinogen in human beings. Chronic exposure to inorganic arsenic increases risks of developing some cancers and non-carcinogenic diseases, such as skin lesions in humans. However, the modes of action are not well elucidated. In the present study, HaCaT cells, an immortalized non-tumorigenic human keratinocyte, were continuously exposed to low-dose trivalent arsenic (arsenic trioxide, 0.1 and 0.2 μM) for at least 4 weeks. We proved that low-dose arsenic could stimulate malignant transformation of HaCaT cells, including increase of cellular proliferation, epithelial-to-mesenchymal transition markers alteration, matrix metalloproteinases activation, invadopodia formation, migration/invasion activities, and anchorage-independent growth. Surprisingly, low-dose arsenic could also transcriptionally increase TG-interacting factor (TGIF) expression via c-Src/EGFR/AKT/FOXO3A signaling involving superoxide production from NADPH oxidase. Moreover, stable overexpression of TGIF could also induce malignant transformation of HaCaT cells. Knockdown of TGIF with its specific shRNA abolished the arsenic-induced effects. Taken together, we suggest that TGIF plays an important role in low-dose arsenic-induced malignant transformation of HaCaT cells, which is regulated by c-Src/EGFR/AKT/FOXO3A pathway and redox signaling.
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
authors.forename: Zi-Miao
authors.initials: ZM
authors.lastname: Liu
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Tseng
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.|Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Bi-Wen
authors.initials: BW
authors.lastname: Yeh
authors.affiliation: Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wen-Jeng
authors.initials: WJ
authors.lastname: Wu
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. huanghs@mail.ncku.edu.tw.
authors.forename: Huei-Sheng
authors.initials: HS
authors.lastname: Huang
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction / Q000187:drug effects; D010087:Oxides / Q000008:administration & dosage / Q000633:toxicity*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D001152:Arsenicals; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D010087:Oxides; D012097:Repressor Proteins; C097504:TGIF1 protein, human; D066246:ErbB Receptors; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D051057:Proto-Oncogene Proteins c-akt; D000077237:Arsenic Trioxide
keywords: AKT; Arsenic; Keratinocyte; Superoxide; TGIF