title: Arsenite-mediated promotion of anchorage-independent growth of HaCaT cells through placental growth factor.
abstract: Various cancers including skin cancer are increasing in 45 million people exposed to arsenic above the World Health Organization's guideline value of 10 μg l(-1). However, there is limited information on key molecules regulating arsenic-mediated carcinogenesis. Our fieldwork in Bangladesh demonstrated that levels of placental growth factor (PlGF) in urine samples from residents of cancer-prone areas with arsenic-polluted drinking water were higher than those in urine samples from residents of an area that was not polluted with arsenic. Our experimental study in human nontumorigenic HaCaT skin keratinocytes showed that arsenite promoted anchorage-independent growth with increased expression and secretion of PlGF, a ligand of vascular endothelial growth factor receptor1 (VEGFR1), and increased VEGFR1/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) activities. The arsenite-mediated promotion of anchorage-independent growth was strongly inhibited by PlGF depletion with decreased activities of the PlGF/VEGFR1/MEK/ERK pathway. Moreover, arsenite proteasome-dependently degrades metal-regulatory transcription factor-1 (MTF-1) protein, resulting in a decreased amount of MTF-1 protein binding to the PlGF promoter. MTF-1 negatively controlled PlGF transcription in HaCaT cells, resulting in increased PlGF transcription. These results suggest that arsenite-mediated MTF-1 degradation enhances the activity of PlGF/VEGFR1/MEK/ERK signaling, resulting in promotion of the malignant transformation of keratinocytes. Thus, this study proposed a molecular mechanism for arsenite-mediated development of skin cancer.
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan; Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan; Voluntary Body for International Health Care in Universities, Nagoya, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yajima
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan; Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan; Voluntary Body for International Health Care in Universities, Nagoya, Japan.
authors.forename: Mayuko Y
authors.initials: MY
authors.lastname: Kumasaka
authors.affiliation: Voluntary Body for International Health Care in Universities, Nagoya, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Ohnuma
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan; Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan; Voluntary Body for International Health Care in Universities, Nagoya, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Ohgami
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Naito
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka-1000, Bangladesh.
authors.forename: Hossain U
authors.initials: HU
authors.lastname: Shekhar
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Omata
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan; Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan; Voluntary Body for International Health Care in Universities, Nagoya, Japan; Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka-1000, Bangladesh. Electronic address: katomasa@med.nagoya-u.ac.jp.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
mesh_terms: D000818:Animals; D001151:Arsenic / Q000737:chemistry / Q000633:toxicity*; D020261:Arsenic Poisoning / Q000378:metabolism*; D018053:Arsenites / Q000737:chemistry* / Q000652:urine; D001459:Bangladesh; D002448:Cell Adhesion; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D004785:Environmental Pollutants; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000187:drug effects; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism / Q000502:physiology* / Q000652:urine; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced*; D014556:Urine / Q000737:chemistry; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000652:urine
chemical_list: D018053:Arsenites; D004785:Environmental Pollutants; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D014874:Water Pollutants, Chemical; D000072483:Placenta Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D020930:MAP Kinase Kinase Kinases; D046988:Proteasome Endopeptidase Complex; C015001:arsenite; D001151:Arsenic