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TG-interacting factor mediates arsenic-induced malignant transformation of keratinocytes via c-Src/EGFR/AKT/FOXO3A and redox signalings

  • Inorganic Compounds
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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.

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Acknowledgments

This work was supported in part by Grants from the National Science Council (Taipei, Taiwan; NSC98-2320-B-006-008-MY3; NSC101-2320-B-006-034; NSC102-2320-B-006-017) and by a Grant from Health and Welfare surcharge of tobacco products, Ministry of Health and Welfare (MOHW103-TD-B-111-05).

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The authors state no conflict of interest.

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Authors and Affiliations

  1. Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan

    Zi-Miao Liu, Hong-Yu Tseng, Bi-Wen Yeh & Huei-Sheng Huang

  2. Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    Bi-Wen Yeh & Wen-Jeng Wu

  3. Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Bi-Wen Yeh & Wen-Jeng Wu

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  1. Zi-Miao Liu
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Correspondence to Huei-Sheng Huang.

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Fig. S1 Low-dose ATO increased cellular migration abilities of NIH3T3. NIH3T3 fibroblasts were pretreated with various doses or ATO for 48 h as indicated, then the cellular migration abilities were analyzed by migration assay as described in “Materials and methods” (PDF 80 kb)

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Liu, ZM., Tseng, HY., Yeh, BW. et al. TG-interacting factor mediates arsenic-induced malignant transformation of keratinocytes via c-Src/EGFR/AKT/FOXO3A and redox signalings. Arch Toxicol 89, 2229–2241 (2015). https://doi.org/10.1007/s00204-014-1445-x

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