The Role of C/EBPa in Genome Stability and Tumor Progression

癌症是由体细胞中的基因组改变引起的疾病，并且是遗传改变的积累驱动肿瘤发生。此外，正是发育中的肿瘤细胞获得这些遗传改变的速度最终决定了癌症的发生。人类皮肤经常受到太阳辐射诱导的DNA损伤，角质形成细胞已经开发出复杂的途径来响应UVB诱导的DNA损伤。最近，我们提供了第一个遗传证据CCAAT/增强子结合蛋白α（C/EBPalpha），一个成员的碱性亮氨酸拉链家族的转录因子，作为一个上皮肿瘤抑制因子，通过利用小鼠表皮靶向消融C/EBPalpha。这些小鼠对UVB和致癌物诱导的鳞状乳头状瘤发展高度敏感，并且这些良性皮肤肿瘤显示出恶性进展为鳞状细胞癌的高度加速的速率。人皮肤鳞状细胞癌和基底细胞癌以及小鼠皮肤鳞状细胞癌显示C/EBPalpha的弱表达或消除的表达。总之，这些发现表明C/EBPalpha通过维持基因组在皮肤癌中具有肿瘤抑制功能。我们假设C/EBPalpha表达的减少或消除导致DNA损伤诱导的G1检查点受损，导致体细胞突变的积累并促进皮肤癌的进展。本提案的总体目标是了解C/EBPalpha的丢失如何导致恶性肿瘤进展率增加，重点关注C/EBPalpha在DNA损伤诱导的G1检查点中的作用。为了解决这一目标，我们的目标是1）描绘的分子机制，通过它的C/EBPalpha功能的DNA损伤诱导的G1检查点和2）提供分子证据增加基因组不稳定性/增变表型响应C/EBPalpha消融。

Cancer is a disease that arises from genomic alterations in somatic cells and it is the accumulation of genetic alterations that drives tumorigenesis. Moreover, it is the rate at which a developing tumor cell acquires these genetic alterations that ultimately determines the onset of cancer. Human skin is routinely subjected to DNA damage induced by solar radiation and keratinocytes have developed intricate pathways to response to UVB-induced DNA damage. Recently, we provided the first genetic evidence CCAAT/enhancer binding protein alpha (C/EBPalpha), a member of the basic leucine zipper family of transcription factors, functions as an epithelial tumor suppressor through utilization of mice with an epidermal-targeted ablation of C/EBPalpha. These mice are highly susceptible to UVB- and carcinogen-induced squamous papilloma development and these benign skin tumors display a highly accelerated rate of malignant progression to squamous cell carcinomas. Human skin squamous cell carcinomas and basal cell carcinomas as well as mouse skin squamous carcinomas display weak or ablated expression of C/EBPalpha. Together these findings suggest a tumor suppressor function of C/EBPalpha in skin cancer through maintenance of the genome. We hypothesize that reduced or ablated expression of C/EBPalpha results in an impaired DNA damage-induced G1 checkpoint, resulting in the accumulation of somatic mutations and promoting skin cancer progression. The overall objective of this proposal is to understand how the loss of C/EBPalpha contributes to an increased rate of malignant tumor progression focusing on the role of C/EBPalpha in the DNA damageinduced G1 checkpoint. To address this objective we aim to 1) delineate the molecular mechanism through which C/EBPalpha functions in the DNA damaged-induced G1 checkpoint and 2) provide molecular evidence for increased genome instability/mutator phenotype in response to C/EBPalpha ablation.