PI-3K/Akt pathway-dependent cyclin D1 expression is responsible for arsenite-induced human keratinocyte transformation.
PI-3K/Akt pathway-dependent cyclin D1 expression is responsible for arsenite-induced human keratinocyte transformation.
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DOI：
10.1289/ehp.10403
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发表时间：
2008-01
影响因子：
10.4
通讯作者：
Huang C
中科院分区：
文献类型：
--
作者：
Ouyang W;Luo W;Zhang D;Jian J;Ma Q;Li J;Shi X;Chen J;Gao J;Huang C
长期暴露于砷会导致人类皮肤癌。然而，亚砷酸盐诱发人类皮肤癌的确切机制仍有待确定。在这项研究中，我们研究了PI-3 K/Akt/cyclin D1在砷暴露后人角质形成细胞转化中的潜在作用。我们采用软琼脂法检测砷暴露对细胞的转化活性，并采用裸鼠移植瘤模型检测砷诱导转化细胞的成瘤性。我们使用显性负突变体和基因敲低的方法来阐明参与这一过程的信号通路。我们的研究结果表明，反复长期暴露的HaCat细胞亚砷酸盐引起细胞转化，在软琼脂中的锚定非依赖性生长所示。这些转化细胞的致瘤性在裸鼠中得到证实。用砷处理细胞还诱导PI-3 K和Akt的显著激活，这是负责由砷暴露诱导的锚定非依赖性细胞生长。此外，我们的数据还表明，细胞周期蛋白D1是一个重要的下游分子参与PI-3 K/Akt介导的细胞转化后，砷暴露的基础上，抑制细胞周期蛋白D1的表达由PI-3 K，和Akt，或者在HaCat细胞中通过其特异性siRNA敲低细胞周期蛋白D1的表达导致锚定受损-As_2O_3诱导HaCat细胞独立生长。我们的研究结果表明，PI-3 K/Akt介导的细胞周期蛋白D1的表达至少是一个关键事件牵连在砷人类皮肤致癌作用。
Long-term exposure of arsenite leads to human skin cancer. However, the exact mechanisms of arsenite-induced human skin carcinogenesis remain to be defined. In this study, we investigated the potential role of PI-3K/Akt/cyclin D1in the transformation of human keratinocytic cells upon arsenite exposure. We used the soft agar assay to evaluate the cell transformation activity of arsenite exposure and the nude mice xenograft model to determine the tumorigenesis of arsenite-induced transformed cells. We used the dominant negative mutant and gene knockdown approaches to elucidate the signaling pathway involved in this process. Our results showed that repeated long-term exposure of HaCat cells to arsenite caused cell transformation, as indicated by anchorage-independent growth in soft agar. The tumorigenicity of these transformed cells was confirmed in nude mice. Treatment of cells with arsenite also induced significant activation of PI-3K and Akt, which was responsible for the anchorage-independent cell growth induced by arsenite exposure. Furthermore, our data also indicated that cyclin D1 is an important downstream molecule involved in PI-3K/Akt–mediated cell transformation upon arsenite exposure based on the facts that inhibition of cyclin D1 expression by dominant negative mutants of PI-3K, and Akt, or the knockdown of the cyclin D1 expression by its specific siRNA in the HaCat cells resulted in impairing of anchorage-independent growth of HaCat cells induced by arsenite. Our results demonstrate that PI-3K/Akt–mediated cyclin D1 expression is at least one key event implicated in the arsenite human skin carcinogenic effect.
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影响因子：
4.3
作者：
Huang, CS;Ke, QD;Shi, XL
通讯作者：
Shi, XL
影响因子：
10.4
作者：
Centeno JA;Mullick FG;Martinez L;Page NP;Gibb H;Longfellow D;Thompson C;Ladich ER
通讯作者：
Ladich ER
影响因子：
3.8
作者：
Cooper, KL;Myers, TA;Hudson, LG
通讯作者：
Hudson, LG
影响因子：
11.2
作者：
Asanuma, H;Torigoe, T;Sato, N
通讯作者：
Sato, N
影响因子：
8
作者：
Li, JX;Tang, MS;Huang, C
通讯作者：
Huang, C