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

描述（由申请人提供）：癌症是一种由体细胞基因组改变引起的疾病，它是遗传改变的积累，驱动肿瘤发生。此外，一个正在发育的肿瘤细胞获得这些基因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引起的DNA损伤，角化细胞已经发展出复杂的途径来应对紫外线辐射引起的DNA损伤。最近，我们提供了第一个遗传学证据，证明CCAAT/增强子结合蛋白1 （C/EBP1）是碱性亮氨酸拉链转录因子家族的成员，通过利用表皮靶向消融C/EBP1的小鼠作为上皮肿瘤抑制因子。这些小鼠对UVB和致癌物诱导的鳞状乳头状瘤的发展高度敏感，这些良性皮肤肿瘤显示出高度加速的恶性进展为鳞状细胞癌。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中C/EBP1表达弱或减弱。总之，这些发现表明C/EBP1通过维持基因组在皮肤癌中的抑瘤功能。我们假设C/EBP1表达的减少或消融导致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/EBP1的缺失如何导致恶性肿瘤进展率的增加，重点关注C/EBP1在DNA损伤诱导的G1检查点中的作用。为了实现这一目标，我们的目标是：1)描述C/EBP1在DNA损伤诱导的G1检查点中发挥作用的分子机制；2)为C/EBP1消融后基因组不稳定性/突变表型增加提供分子证据。

DESCRIPTION (provided by applicant): 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 1 (C/EBP1), 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/EBP1. 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/EBP1. Together these findings suggest a tumor suppressor function of C/EBP1 in skin cancer through maintenance of the genome. We hypothesize that reduced or ablated expression of C/EBP1 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/EBP1 contributes to an increased rate of malignant tumor progression focusing on the role of C/EBP1 in the DNA damage- induced G1 checkpoint. To address this objective we aim to 1) delineate the molecular mechanism through which C/EBP1 functions in the DNA damaged-induced G1 checkpoint and 2) provide molecular evidence for increased genome instability/mutator phenotype in response to C/EBP1 ablation. . PUBLIC HEALTH RELEVANCE: Understanding how C/EBP1 influences the rate of cancer progression and the acquisition of mutations will provide further insights to the mechanisms of carcinogen- and UVB-induced skin cancer as well as numerous cancers where C/EBP1 expression is diminished. Recent analysis of the genomes from human cancers discovered that mutations in specific cancer associated genes can vary dramatically within a give tumor type and suggest the identification of the origin of genomic point mutations may be a more effective strategy for cancer treatment than targeting a specific cancer gene as mutations in other essential genes will be enhanced and selected by the mutator phenotype. Drugs that target point mutation genetic instability may delay the accumulation of mutations and subsequently prevent cancer onset.