Mechanisms of UVA-induced skin cancer

描述（由申请人提供）：本研究的长期目标是确定皮肤癌发病机制中基因-环境相互作用的分子/细胞基础。非黑色素瘤皮肤癌的主要环境风险因素是阳光中的紫外线（UV）辐射，包括UVB和UVA。虽然UVA具有与UVB不同的物理和生物靶点，但UVA对皮肤癌易感性的贡献及其分子基础尚不清楚。该提案中的初步数据表明，人类和小鼠皮肤癌的关键抑制因子是PTEN（10号染色体上缺失的磷酸酶和张力蛋白同源物）。在表皮角质形成细胞中，PTEN转录被UVA显著下调，而表皮中PTEN的靶向缺失加速皮肤癌变。虽然对皮肤肿瘤发生敏感性增强的确切机制尚不清楚，但该提案中的初步数据表明，PTEN丢失可能会损害DNA损伤的修复和检查点。所提出的实验的中心假设是UVA诱导的PTEN转录下调抑制DNA修复和DNA损伤检查点，从而增加皮肤癌易感性。该建议的总体目标是确定UVA诱导的PTEN下调的分子机制和后果。具体目的是（1）检验PTEN下调抑制响应于低水平UV照射的DNA修复和DNA损伤检查点的假设;（2）阐明对于UVA诱导的PTEN转录下调至关重要的上游调节物;和（3）分析体内皮肤癌易感性中PTEN下调的后果。这些实验将为UVA对皮肤致癌作用的分子和细胞基础提供新的见解。这些知识可以用来制定更好的策略来预防和治疗皮肤癌。

DESCRIPTION (provided by applicant): The long-term goal of this research is to determine the molecular/cellular basis for the gene- environment interactions in the pathogenesis of skin cancer. The major environmental risk factor for non-melanoma skin cancer is ultraviolet (UV) radiation in sunlight including UVB and UVA. Although UVA has different physical and biological targets from UVB, the UVA contribution to skin cancer susceptibility and its molecular basis is unclear. Preliminary data within this proposal demonstrate that a critical suppressor for human and mouse skin cancer is PTEN (phosphatase and tensin homologue deleted on chromosome 10). In epidermal keratinocytes, PTEN transcription is significantly down-regulated by UVA, whereas targeted deletion of PTEN in the epidermis accelerates skin carcinogenesis. Although the precise mechanisms responsible for the enhanced susceptibility to skin tumorigenesis are unknown, preliminary data within this proposal show that PTEN loss may impair repair and checkpoints in response to DNA damage. The central hypothesis of the proposed experiments is that UVA-induced down-regulation of PTEN transcription inhibits DNA repair and DNA damage checkpoints and thus increases skin cancer susceptibility. The overall aim of this proposal is to determine the molecular mechanisms and consequences of UVA-induced PTEN down-regulation. The specific aims are to (1) test the hypothesis that PTEN down-regulation inhibits DNA repair and DNA damage checkpoints in response to low-level UV irradiation; (2) elucidate upstream regulators critical for UVA-induced down-regulation of PTEN transcription; and (3) analyze the consequences of PTEN down- regulation in skin cancer susceptibility in vivo. These experiments will provide new insights into the molecular and cellular basis for the UVA contribution to skin carcinogenesis. This knowledge can be used to develop better strategies to prevent and treat skin cancer.