Molecular pathogenesis of UVB-induced skin cancer

描述（由申请人提供）：大多数人类癌症起源于皮肤，这些恶性肿瘤超过了所有其他癌症的总和。在美国每年诊断出大约一百万新的非黑色素瘤皮肤癌（NSMC），包括基底细胞癌（BCC）和鳞状细胞癌（SCC）。太阳UVB辐射是NMSC的主要已知原因。UVB的致癌作用是DNA直接结构变化的结果，如环丁烷嘧啶二聚体和6-4光产物，导致C到T和CC到TT转换形式的突变（UVB签名突变）。NMSC具有不同且独特的突变（SCC的情况下的p53和BCC的情况下的ptc和p53），其在这些肿瘤的生长中达到顶峰。对散发性皮肤癌的遗传基础的了解来自于与遗传性皮肤肿瘤综合征相关的特殊基因或遗传位点的鉴定。虽然UVB直接参与两种类型的NMSC的诱导，但有趣的是，相同的致癌物产生独特类型的肿瘤。在已知的人类细胞周期蛋白基因中，只有细胞周期蛋白D1已经令人信服地与肿瘤发生有关。细胞周期蛋白D1在包括人NMSC在内的多种人上皮癌中扩增或过表达。此外，皮肤中细胞周期蛋白D1的靶向过表达增强了小鼠化学致癌作用。我们先前已经表明，在UVB诱导SKH-1无毛小鼠SCC和ptc+/-敲除小鼠BCC期间，细胞周期蛋白D1发生进行性积累。综上所述，很可能在携带p53突变的细胞中细胞周期蛋白D1过表达对于SCC的诱导是关键的，而在携带ptc突变的细胞中其过表达对于BCC是重要的。细胞周期蛋白D1过表达的机制之一涉及p38 MAP激酶的激活。UVB诱导皮肤中p38 MAP激酶及其下游通路在这项提案中，我们将测试的假设，即皮肤暴露于UVB后，细胞信号（p38 MAP激酶）的改变，或者有独特的影响，每种肿瘤类型和/或汇聚在共享的下游基因（细胞周期蛋白D1）的表达途径，协调特定的突变（p53和ptch）的后果，有助于UVB诱导的NMSC的分子发病机制，SCC和BCC。我们将在p53+/-、p53-/-和ptc+/-小鼠中确定UVB诱导的通过p38 MAP激酶导致细胞周期蛋白D1过表达的共享信号通路;确定细胞周期蛋白D1过表达和p53丢失在NMSCs发病机制中的关系;确定细胞周期蛋白D1在NMSC肿瘤发生过程中积累的机制，并评估基因过表达的细胞周期蛋白D1对NMSC发育的影响，p53-/-和PTC+/-小鼠。我们的动物模型为评估UVB诱导的SCC和BCC的分子发病机制提供了一种创新的方法，并有助于创建预防/治疗人类NMSC的新方法。

DESCRIPTION (provided by applicant): The majority of all human cancers originate in the skin and these malignancies exceed all others combined. Approximately one million new non-melanoma skin cancers (NSMC) including basal cell carcinomas (BCCs) and squamous cell carcinoma (SCCs) are diagnosed in the United States annually. Solar UVB radiation is the major known cause of NMSCs. The carcinogenic effects of UVB are the result of direct structural changes in DNA such as cyclobutane pyrimidine dimers and 6-4 photoproducts leading to mutations in the form of C to T and CC to TT transitions (UVB signature mutations). NMSCs harbor different and distinct mutations (p53 in the case of SCCs and ptc & p53 in the case of BCCs), which culminate in the growth of these neoplasms. Insight into the genetic basis of sporadic skin cancers has come from the identification of special genes or genetic loci that relate to inherited skin tumor syndromes. Although UVB is directly involved in the induction of both types of NMSCs, it is intriguing that an identical carcinogen yields unique types of tumors. Among known human cyclin genes, only cyclin D1 has been convincingly implicated in oncogenesis. Cyclin D1 is amplified or overexpressed in a variety of human epithelial cancers including human NMSCs. In addition, targeted overexpression of cyclin D1 in skin enhances murine chemical carcinogenesis. We have previously shown that progressive accumulation of cyclin D1 occurs during UVB induction of SCCs in SKH-1 hairless and BCCs in ptc+/- knockout mice. Taken together, it is likely that cyclin D 1 overexpression in cells carrying p53 mutations is critical for induction of SCCs whereas its overexpression in cells carrying ptc mutations is important for BCCs. One of the mechanisms by which cyclin D1 is overexpressed involves activation of p38 MAP kinase. UVB induces p38 MAP kinase and its downstream pathway in skin. In this proposal we will test the hypothesis that alterations in cell signaling (p38 MAP kinase) following skin exposure to UVB either have unique effects for each tumor-type and/or converge on shared downstream gene (cyclin D1) expression pathways that coordinate the consequences of specific mutations (p53 and ptch) that contribute to the molecular pathogenesis of UVB-induced NMSCs, both SCCs and BCCs. We will determine UVB-induced shared signaling pathways leading to overexpression of cyclin D1 via p38 MAP kinase in p53+/-, p53-/- and ptc+/- mice; define the relationship between cyclin D1 overexpression and p53 loss in the pathogenesis of NMSCs; define the mechanism whereby cyclin D1 accumulates during NMSCs tumorigenesis and assess the effect of genetically overexpressed cyclin D1 on NMSCs development in p53-/- and ptc+/- mice. Our animal models offer an innovative approach for assessing the molecular pathogenesis of UVB-induced SCCs and BCCs and could help create novel approaches to the prevention/treatment of human NMSCs.