Deregulated activity of akt in epithelial basal cells induces spontaneous tumors and heightened sensitivity to skin carcinogenesis
Deregulated activity of akt in epithelial basal cells induces spontaneous tumors and heightened sensitivity to skin carcinogenesis
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DOI：
10.1158/0008-5472.can-07-2564
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发表时间：
2007-11-15
期刊：
影响因子：
11.2
通讯作者：
DiGiovanni, John
中科院分区：
文献类型：
--
作者：
Segrelles, Carmen;Lu, Jerry;DiGiovanni, John
磷脂酰肌醇-3-激酶(PI3K)/PTEN/Akt通路的异常激活导致细胞增殖增加和细胞凋亡减少，与包括癌症在内的多种人类病理过程有关。我们以前的数据表明，Akt介导的信号转导在小鼠皮肤癌变系统中是一个必不可少的媒介，在肿瘤的促进和进展阶段都是如此。此外，Akt的过表达还能够通过转录和转录后过程转化角质形成细胞。在这里，我们报告了在牛角蛋白K5启动子作用下，AM(WtAkt)或结构性活性Akt1(MyrAkt)在复层上皮基底层表达增加的后果。这些小鼠在表皮增殖和分化方面表现出变化。此外，Akt表达水平最高的转基因小鼠随着年龄的增长会发生多个器官的自发性上皮性肿瘤。此外，wt4kt和myrAkt转基因系对肿瘤促进剂12-O-十四烷基佛波醇-13-乙酸酯(TPA)的表皮增殖作用均表现出高度的敏感性，并对两阶段皮肤癌的发生具有较高的敏感性。最后，对两阶段癌变的敏感性增强与TPA治疗后更持久的增殖反应以及Akt下游信号通路的持续变化和细胞周期调节蛋白的升高有关。总之，这些数据为Akt信号在体内上皮癌发生中的重要作用提供了直接支持，特别是在肿瘤促进阶段。
Aberrant activation of the phosphoinositide-3-kinase (PI3K)/ PTEN/Akt pathway, leading to increased proliferation and decreased apoptosis, has been implicated in several human pathologies including cancer. Our previous data have shown that Akt-mediated signaling is an essential mediator in the mouse skin carcinogenesis system during both the tumor promotion and progression stages. In addition, overexpression of Akt is also able to transform keratinocytes through transcriptional and posttranscriptional processes. Here, we report the consequences of the increased expression of AM (wtAkt) or constitutively active Akt1 (myrAkt) in the basal layer of stratified epithelia using the bovine keratin K5 promoter. These mice display alterations in epidermal proliferation and differentiation. In addition, transgenic mice with the highest levels of Akt expression developed spontaneous epithelial tumors in multiple organs with age. Furthermore, both wt4kt and myrAkt transgenic lines displayed heightened sensitivity to the epidermal proliferative effects of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and heightened sensitivity to two-stage skin carcinogenesis. Finally, enhanced susceptibility to two-stage carcinogenesis correlated with a more sustained proliferative response following treatment with TPA as well as sustained alterations in Akt downstream signaling pathways and elevations in cell cycle regulatory proteins. Collectively, the data provide direct support for an important role for Akt signaling in epithelial carcinogenesis in vivo, especially during the tumor promotion stage.