Genetic ablation of CCAAT/Enhancer binding protein α in epidermis reveals its role in suppression of epithelial tumorigenesis
Genetic ablation of CCAAT/Enhancer binding protein α in epidermis reveals its role in suppression of epithelial tumorigenesis
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DOI：
10.1158/0008-5472.can-07-0139
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发表时间：
2007-07-15
期刊：
影响因子：
11.2
通讯作者：
Smart, Robert C.
中科院分区：
文献类型：
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作者：
Loomis, Kari D.;Zhu, Songyun;Smart, Robert C.
CCAAT/增强子结合蛋白α (C/EBP α)是一种基本的亮氨酸拉链转录因子，可抑制细胞周期进程并调节各种细胞类型的分化。C/EBP α在急性髓性白血病（AmL）中因突变而失活，被认为是AmL中的一种人类肿瘤抑制因子。尽管C/EBP α突变未在AML以外的恶性肿瘤中观察到，但C/EBP α的表达显著降低发生在许多人类上皮性癌症中，包括肺癌、肝癌、子宫内膜癌、皮肤癌和乳腺癌，这表明C/EBP α可能具有肿瘤抑制功能。然而，由于上皮肿瘤中缺乏C/EBP α突变以及小鼠模型系统中C/EBP α缺失的致死效应，缺乏C/EBP α作为上皮肿瘤抑制因子的直接证据。为了研究C/EBP α在上皮性肿瘤发展中的功能，我们制造了一只表皮特异性C/EBP α敲除小鼠。表皮特异性C/EBP敲除小鼠存活下来，表皮角质细胞增殖、分化或凋亡均未出现可检测到的异常，表明C/EBP α对于正常的表皮稳态是必不可少的。尽管如此，表皮特异性C/EBP(x敲除小鼠对涉及致癌Ras的皮肤肿瘤发展高度敏感。这些小鼠显示出肿瘤潜伏期减少，肿瘤发病率、多样性、生长速度和恶性进展速度显著增加。C/EBP α半合子小鼠表现出中等增强的肿瘤表型。我们的结果表明，C/EBP α的表达降低。有助于抑制肿瘤细胞增殖。C/EBP α被认为通过抑制E2F活性来阻断细胞周期进程。我们观察到C/EBPa阻断ras诱导的和表皮生长因子诱导的角化细胞中的E2F活性，并阻断ras诱导的细胞转化和细胞周期进程。我们的研究表明，C/EBP α对于表皮稳态是不可或缺的，并提供了遗传证据，证明C/EBP α是上皮肿瘤发生的抑制因子。
CCAAT/enhancer binding protein alpha (C/EBP alpha) is a basic leucine zipper transcription factor that inhibits cell cycle progression and regulates differentiation in various cell types. C/EBP alpha is inactivated by mutation in acute myeloid leukemia (AmL) and is considered a human tumor suppressor in AML. Although C/EBP alpha mutations have not been observed in malignancies other than AML, greatly diminished expression of C/EBP alpha occurs in numerous human epithelial cancers including lung, liver, endometrial, skin, and breast, suggesting a possible tumor suppressor function. However, direct evidence for C/EBP alpha as an epithelial tumor suppressor is lacking due to the absence of C/EBP alpha mutations in epithelial tumors and the lethal effect of C/EBP alpha deletion in mouse model systems. To examine the function of C/EBP alpha in epithelial tumor development, an epidermal-specific C/EBP alpha knockout mouse was generated. The epidermal-specific C/EBPa knockout mice survived and displayed no detectable abnormalities in epidermal keratinocyte proliferation, differentiation, or apoptosis, showing that C/EBP alpha is dispensable for normal epidermal homeostasis. In spite of this, the epidermal-specific C/EBP(x knockout mice were highly susceptible to skin tumor development involving oncogenic Ras. These mice displayed decreased tumor latency and striking increases in tumor incidence, multiplicity, growth rate, and the rate of malignant progression. Mice hemizygous for C/EBP alpha displayed an intermediate-enhanced tumor phenotype. Our results suggest that decreased expression of C/EBP alpha. contributes to deregulation of tumor cell proliferation. C/EBP alpha had been proposed to block cell cycle progression through inhibition of E2F activity. We observed that C/EBPa blocked Ras-induced and epidermal growth factor-induced E2F activity in keratinocytes and also blocked Ras-induced cell transformation and cell cycle progression. Our study shows that C/EBP alpha is dispensable for epidermal homeostasis and provides genetic evidence that C/EBP alpha is a suppressor of epithelial tumorigenesis.