Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2
Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2
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DOI：
10.1016/j.freeradbiomed.2008.05.020
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发表时间：
2008-09-01
影响因子：
7.4
通讯作者：
Waalkes, Michael P.
中科院分区：
文献类型：
--
作者：
Pi, Jingbo;Diwan, Bhalchandra A.;Waalkes, Michael P.
砷是一种众所周知的人类皮肤致癌物，但其致癌机制尚不清楚。转录因子 Nrf2 介导的抗氧化反应代表了一种关键的细胞防御机制，新出现的数据表明 Nrf2 的组成型激活有助于恶性表型。在现在的学习中当成仙了。将非致瘤性人角质形成细胞系（HaCaT）连续暴露于环境相关水平的无机亚砷酸盐（100 nM）28周，发生恶性转化，接种裸鼠后形成高度侵袭性鳞状细胞癌。为了研究所涉及的机制，在这些砷转化细胞（称为 As-TM）中评估了一系列广泛的转化生物标志物。除了基质金属蛋白酶-9 (MMP-9) 的分泌增加之外，As-TM 细胞中一系列鳞状分化和皮肤角化的标志物，包括角蛋白-1、角蛋白-10、外皮蛋白和兜甲蛋白，也显着升高。此外，As-TM细胞表现出细胞内谷胱甘肽增加、Nrf2及其靶基因表达升高以及普遍的凋亡抗性。与 As-TM 细胞中 Nrf2 基础活性增加相反，急性暴露于高剂量亚砷酸盐或叔丁基羟基醌诱导的 Nrf2 介导的抗氧化反应减弱。在 As-TM 细胞中观察到的多种恶性转化生物标志物，包括 MMP-9 和细胞角蛋白，可能受 NFf2 调节，这一发现表明，组成型 Nrf2 激活可能与砷皮肤癌发生有关。在 As-TM 细胞中观察到，Nrf2 响应氧化应激源而激活减弱，再加上获得性细胞凋亡抵抗，可能会增加可传播氧化 DNA 损伤和突变/DNA 损伤事件固定的可能性。 (c) 2008 Elsevier Inc. 保留所有权利。
Arsenic is a well-known human skin carcinogen but the underlying mechanisms of carcinogenesis are unclear. Transcription factor Nrf2-mediated antioxidant response represents a critical cellular defense mechanism, and emerging data suggest that constitutive activation of Nrf2 contributes to malignant phenotype. In the present study when an immortalized. nontumorigenic human keratinocyte cell line (HaCaT) was continuously exposed to an environmentally relevant level of inorganic arsenite (100 nM) for 28 weeks, malignant transformation occurred as evidenced by the formation of highly aggressive squamous cell carcinoma after inoculation into nude mice. To investigate the mechanisms involved, a broad array of biomarkers for transformation were assessed in these arsenic-transformed cells (termed As-TM). In addition to increased secretion of matrix metalloproteinase-9 (MMP-9), a set of markers for squamous differentiation and skin keratinization, including keratin-1, keratin-10, involucrin, and loricrin, were significantly elevated in As-TM cells. Furthermore, As-TM cells showed increased intracellular glutathione and elevated expression of Nrf2 and its target genes, as well as generalized apoptotic resistance. In contrast to increased basal Nrf2 activity in As-TM cells, a diminished Nrf2-mediated antioxidant response induced by acute exposure to high doses of arsenite or tert-butyl hydroxyquinone occurred. The findings that multiple biomarkers for malignant transformation observed in As-TM cells, including MMP-9 and cytokeratins, are potentially regulated by NFf2 suggest that Constitutive Nrf2 activation may be involved in arsenic carcinogenesis of skin. The weakened Nrf2 activation in response to oxidative stressors observed in As-TM cells, coupled with acquired apoptotic resistance, would potentially have increased the likelihood of transmittable oxidative DNA damage and fixation of mutational/DNA damage events. (c) 2008 Elsevier Inc. All rights reserved.