Basal Cell Carcinoma:Molecular Pathogenesis & Prevention

描述（由申请人提供）：非黑色素瘤皮肤癌（NMSC）包括基底细胞癌（BCC）和鳞状细胞癌（SCC），它们是人类最常见的恶性肿瘤类型。每年有超过一百万美国人发展一种或多种这些肿瘤，BCC占NMSC的75%以上。因此，基底细胞癌是一个主要的公共卫生问题，也是该国发病率和医疗保健费用不断上升的主要原因。太阳紫外线B（UVB）的环境暴露是诱发基底细胞癌的主要危险因素。现在已知这些肿瘤发展的分子基础与包括patched（PTCH）在内的hedgehog信号通路中的突变有关。Sonic Hedgehog（SHH）和Smoothened（SMO）。此外，还建立了基底细胞癌的动物模型。已经开发了补丁杂合敲除小鼠，其提供了用于探索UVB诱导的BCC的分子发病机制的系统。已知皮肤暴露于UVB驱动对表皮角质形成细胞的增殖刺激，并且酶鸟氨酸脱羧酶（ODC）的诱导是起始细胞的增强生长和克隆扩增的主要贡献者。UVB暴露也会增强皮肤中的氧化应激。这伴随着可诱导ODC和增加角质形成细胞增殖的活性氧（ROS）的产生增加。在这个建议中，我们将测试的假设，如增加ODC表达和氧化应激的细胞增殖的因素是至关重要的UVB诱导的BCC。我们已经开发了一种新的修改补丁+/-杂合子小鼠，其中ODC过表达（ptch +I-/ODC TgN）。这些小鼠在20周龄时加速了显微镜下BCC样肿瘤的自发发展，并且在30周内暴露于UVB下可见BCC。我们将利用这种动物模型，通过评估ODC过度表达的作用，通过评估细胞周期调控改变的影响和通过测量氧化应激来探索IVB诱导的BCC的发病机制。这些研究的结果将用于设计创新的药物遗传学方法来化学预防UVB诱导的BCC。通过本提案中的研究，可能会发现可能适用于人群检测的新型抗癌剂。

DESCRIPTION (provided by applicant): Non-melanoma skin cancer (NMSC) includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), which together are the most common type of human malignancy. More than one million Americans develop one or more of these tumors annually and BCCs represent more than 75% of NMSC. Thus BCCs are a major public health problem and a major cause of morbidity and escalating health care costs in this country. Environmental exposure to solar ultraviolet B (UVB) is the major risk factor for the induction of BCCs. The molecular basis underlying the development of these tumors is now known to relate to mutations in the hedgehog signaling pathway including patched (PTCH). sonic hedgehog (SHH) and smoothened (SMO). In addition, an animal model for BCCs. the patched heterozygous knockout mouse, has been developed which provides a system with which to explore the molecular pathogenesis of UVB-induced BCCs. It is known that skin exposure to UVB drives a proliferative stimulus to epidermal keratinocytes and that induction of the enzyme ornithine decarhoxylase (ODC') is a major contributor to the augmented growth and clonal expansion of initiated cells. UVB exposure also enhances oxidant stress in the skin. which is accompanied by increased generation of reactive oxygen species (ROS) that can induce ODC and augment keratinocyte proliferation. In this proposal we will test the hypothesis that factors which enhance cell proliferation such as increased ODC expression and oxidant stress are crucial for UVB induction of BCCs. We have developed a novel modification of patch +/- heterozygous mice in which ODC is overexpressed (ptch +I-/ODC TgN). These mice have accelerated spontaneous development of microscopic BCCs like tumors by the age of 20 weeks and with UVB exposure visible BCCs within 30 weeks. We will utilize this animal model to probe the pathogenesis of IJVB-induced BCCs by assessing the role of over-expression of ODC, by evaluating the effects of altered cell cycle regulation and by measuring oxidant stress. The result of these studies will be used to devise innovative pharmacogenetic approaches to the chemoprevention of UVB-induced BCCs. It is likely that novel anti-carcinogenic agents potentially suitable for testing in the human population could be identified as a result of the studies in this proposal.