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.
Arch Toxicol. 2015 Dec;89(12):2229-41. doi: 10.1007/s00204-014-1445-x. Epub 2014 Dec 24.
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.
无机砷是一种众所周知的人类致癌物。慢性暴露于无机砷会增加某些癌症和非致癌性疾病的风险，例如人类的皮肤损伤。然而，其作用模式尚未得到充分阐明。在本研究中，HaCaT 细胞（一种永生化的非致瘤性人角质形成细胞）连续暴露于低剂量三价砷（三氧化二砷，0.1 和 0.2 μM）至少 4 周。我们证明低剂量砷可以刺激 HaCaT 细胞的恶性转化，包括细胞增殖增加、上皮-间充质转化标志物改变、基质金属蛋白酶激活、侵袭伪足形成、迁移/侵袭活性和锚定非依赖性生长。令人惊讶的是，低剂量砷还可以通过涉及 NADPH 氧化酶超氧化物产生的 c-Src/EGFR/AKT/FOXO3A 信号转导，转录性地上调 TG 相互作用因子（TGIF）的表达。此外，TGIF 的稳定过表达也可以诱导 HaCaT 细胞的恶性转化。用其特异性 shRNA 敲低 TGIF 可消除砷诱导的效应。总之，我们认为 TGIF 在低剂量砷诱导的 HaCaT 细胞恶性转化中起重要作用，该过程受 c-Src/EGFR/AKT/FOXO3A 途径和氧化还原信号的调节。
