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

Zi Miao Liu, Hong Yu Tseng, Bi Wen Yeh, Wen Jeng Wu, Huei Sheng Huang

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2229-2241
Number of pages13
JournalArchives of Toxicology
Volume89
Issue number12
DOIs
Publication statusPublished - 2015 Dec 1

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Health, Toxicology and Mutagenesis

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