Basal Cell Carcinoma:Molecular Pathogenesis & Prevention

描述(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)，这两种肿瘤一起是人类最常见的恶性肿瘤类型。每年有100多万美国人患上一种或多种此类肿瘤，基底细胞癌占NMSC的75%以上。因此，BCC是一个重大的公共卫生问题，也是该国发病率和医疗费用不断上升的主要原因。环境暴露于太阳紫外线B(UVB)是诱发基底细胞癌的主要危险因素。目前已知这些肿瘤发生的分子基础与Hedgehog信号通路的突变有关，包括Patted(PTCH)。音速刺猬(SHH)和平滑(SMO)。此外，还建立了BCC的动物模型。已建立了补丁杂合基因敲除小鼠，为探讨UVB诱导的基底细胞癌的分子发病机制提供了一种系统。众所周知，皮肤暴露于中波紫外线可刺激表皮角质形成细胞增殖，而鸟氨酸脱羧酶(ODC‘)的诱导是促进启动细胞生长和克隆性扩增的主要因素。UVB暴露还会增加皮肤中的氧化应激。伴随而来的是可诱导ODC和促进角质形成细胞增殖的活性氧物种(ROS)的增加。在这项建议中，我们将检验一种假设，即促进细胞增殖的因素，如ODC表达增加和氧化应激，是UVB诱导BCC的关键。我们开发了一种新的修饰Patch+/-杂合子小鼠，其中ODC过表达(PTCH+I-/ODC TGN)。这些小鼠在20周大时加速了微小的基底细胞瘤的自发发展，并在30周内暴露于紫外线照射下可见基底细胞癌。我们将利用这个动物模型，通过评估ODC过度表达的作用，通过评估细胞周期调节的改变的影响，以及通过测量氧化应激来探讨IJVB诱导的BCCs的发病机制。这些研究的结果将被用于设计创新的药物遗传学方法，以化学预防UVB诱导的基底细胞癌。根据这项提案中的研究，可能会确定可能适合在人类群体中进行测试的新型抗癌药物。

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.