Arsenite-Mediated Promotion of Anchorage-Independent Growth of HaCaT Cells through Placental Growth Factor

Ichiro Yajima, Mayuko Y. Kumasaka, Shoko Ohnuma, Nobutaka Ohgami, Hisao Naito, Hossain U. Shekhar, Yasuhiro Omata, Masashi Kato

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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 μgl-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.

Original languageEnglish
Pages (from-to)1147-1156
Number of pages10
JournalJournal of Investigative Dermatology
Volume135
Issue number4
DOIs
Publication statusPublished - 20-04-2015

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Intercellular Signaling Peptides and Proteins
Extracellular Signal-Regulated MAP Kinases
Cells
Arsenic
Vascular Endothelial Growth Factor A
Transcription Factors
Growth
Metals
Skin
Skin Neoplasms
Mitogen-Activated Protein Kinase Kinases
Transcription
Keratinocytes
MAP Kinase Kinase Kinases
Urine
Proteasome Endopeptidase Complex
Mitogen-Activated Protein Kinases
Drinking Water
Bangladesh
arsenite

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Yajima, Ichiro ; Kumasaka, Mayuko Y. ; Ohnuma, Shoko ; Ohgami, Nobutaka ; Naito, Hisao ; Shekhar, Hossain U. ; Omata, Yasuhiro ; Kato, Masashi. / Arsenite-Mediated Promotion of Anchorage-Independent Growth of HaCaT Cells through Placental Growth Factor. In: Journal of Investigative Dermatology. 2015 ; Vol. 135, No. 4. pp. 1147-1156.
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Arsenite-Mediated Promotion of Anchorage-Independent Growth of HaCaT Cells through Placental Growth Factor. / Yajima, Ichiro; Kumasaka, Mayuko Y.; Ohnuma, Shoko; Ohgami, Nobutaka; Naito, Hisao; Shekhar, Hossain U.; Omata, Yasuhiro; Kato, Masashi.

In: Journal of Investigative Dermatology, Vol. 135, No. 4, 20.04.2015, p. 1147-1156.

Research output: Contribution to journalArticle

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AU - Yajima, Ichiro

AU - Kumasaka, Mayuko Y.

AU - Ohnuma, Shoko

AU - Ohgami, Nobutaka

AU - Naito, Hisao

AU - Shekhar, Hossain U.

AU - Omata, Yasuhiro

AU - Kato, Masashi

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AB - Various cancers including skin cancer are increasing in 45 million people exposed to arsenic above the World Health Organization's guideline value of 10 μgl-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.

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