Molecular pathogenesis of UVB-induced skin cancer

描述(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，每年大约有一百万新的非黑色素瘤皮肤癌(NSMC)被诊断出来，包括基底细胞癌(BCC)和鳞状细胞癌(SCCs)。太阳UVB辐射是NMSCs的主要已知原因。UVB的致癌作用是由于DNA的直接结构变化，如环丁烷、嘧啶二聚体和6-4光产物，导致C到T和CC到TT的突变(UVB特征突变)。NMSCs具有不同和不同的突变(在SCC中为P53，在BCC中为PTC和P53)，最终导致这些肿瘤的生长。对散发性皮肤癌的遗传学基础的洞察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。尽管UVB直接参与了两种类型的NMSCs的诱导，但有趣的是，相同的致癌物会产生独特的肿瘤类型。在已知的人类细胞周期蛋白基因中，只有细胞周期蛋白D1与肿瘤的发生有关。细胞周期蛋白D1在包括人NMSCs在内的多种人类上皮性肿瘤中被扩增或过表达。此外，细胞周期蛋白D1在皮肤中的定向过表达增强了小鼠的化学致癌作用。我们先前已经证明，在UVB诱导SKH-1无毛小鼠的SCCs和PTC+/-基因敲除小鼠的BCC过程中，细胞周期蛋白D1的进行性积累发生。综上所述，细胞周期蛋白D 1在携带P53突变的细胞中的过度表达可能是诱导鳞状细胞癌的关键，而其在携带PTC突变的细胞中的过度表达对基底细胞癌是重要的。细胞周期蛋白D1过表达的机制之一是激活p38MAPK。UVB在皮肤中诱导p38MAPK及其下游通路。在这项建议中，我们将测试一种假设，即皮肤暴露于UVB后，细胞信号转导(p38 MAP激酶)的变化对每种肿瘤类型具有独特的影响和/或汇聚在共同的下游基因(细胞周期蛋白D1)表达途径上，这些途径协调了特定突变(P53和PTCH)的后果，这些突变有助于UVB诱导的NMSCs(SCC和BCC)的分子发病。我们将在P53+/-、P53-/-和PTC+/-小鼠中确定UVB诱导的共同信号通路导致细胞周期蛋白D1过表达；明确细胞周期蛋白D1过表达与P53缺失在NMSCs发病机制中的关系；确定细胞周期蛋白D1在NMSCs发生过程中积聚的机制，并评估基因过表达细胞周期蛋白D1对P53-/-和PTC+/-小鼠NMSCs发育的影响。我们的动物模型为评估UVB诱导的SCCs和BCCs的分子发病机制提供了一种创新的方法，并有助于为人类NMSCs的预防/治疗创造新的方法。

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.