Ras activation pathways in UVR-induced epidermal transformation

描述（由申请人提供）：皮肤鳞状细胞癌（SCC）是西方国家第二常见的诊断恶性肿瘤，由于暴露于太阳紫外线辐射（UVR）和人口老龄化的增加，其发病率正在上升。虽然大多数SCC通过手术成功治疗，但由于疤痕和毁容，它们仍然是导致显著发病率的原因。更重要的是，有一定比例的肿瘤会转移，对此没有专门的治疗方法。因此，有必要收集一个更完整的了解机制扰动的启动，促进和发展的皮肤鳞状细胞癌，以开发新的方法来预防和治疗这种恶性肿瘤。大部分SCC显示Ras蛋白的超活化;不幸的是，Ras是一种难以抑制的分子，并且由于其多种功能，它可能对健康细胞毒性太大，无法承受这种抑制。因此，发现参与癌基因Ras途径的上游和下游元件，在SCC可能揭示一个更适合的化学预防和治疗的目标。我们实验室的研究已经证明了RasGRP 1通过其激活Ras的能力在皮肤肿瘤发生中的作用，并支持这样的概念，即通过增强的细胞外信号刺激RasGRP 1可能有助于皮肤恶性转化和肿瘤进展所需的激活Ras的剂量。鉴于UVR是与皮肤SCC相关的最相关的致癌物，本提案的目标是阐明RasGRP 1在UVR诱导的肿瘤发生中的潜在参与。使用小鼠模型和体外方法的组合，我们提出了以下目标：（1）确定RasGRP 1在角质形成细胞对UVR的急性反应中的作用，以及（2）使用RasGRP 1敲除和K5.RasGRP1转基因小鼠模型确定RasGRP 1在UVR诱导的皮肤癌变中的需求。综合结果应提供一个强有力的测试，我们的假设，RasGRP 1是所需的UVR在表皮中的致瘤作用，并设置了基础，为进一步研究新的药物靶向RasGRP 1，可能是有用的化学预防和治疗皮肤SCC。 公共卫生相关性：本申请研究了与皮肤鳞状细胞癌（SCC）相关的分子途径，可能导致预防和治疗的新方法。太阳紫外线辐射（UVR）是皮肤SCC的主要致癌因素，已知其影响Ras，Ras是一种在皮肤稳态中具有重要作用的分子。事实上，大部分皮肤SCC具有Ras的异常激活;因此，它代表了癌症治疗的有吸引力的分子靶标。不幸的是，Ras不容易被药物化，因此人们将努力转向Ras癌基因上游或下游的其他分子。该提案的目标是测试一种新的Ras激活剂-RasGRP 1-在紫外线诱导的皮肤肿瘤发生中的参与。这些研究得到了我们对角质形成细胞生物学和皮肤SCC小鼠模型的研究结果的支持。如果我们的研究成功完成，它们将影响可能导致更好的皮肤癌治疗方法的知识，包括化学预防。

DESCRIPTION (provided by applicant): Cutaneous squamous cell carcinoma (SCC) is the second most common diagnosed malignancy in Western countries, and its incidence is rising due to increased exposure to solar ultraviolet radiation (UVR) and population aging. While most SCC are successfully treated by surgery, they still represents a cause of significant morbidity due to scarring and disfigurement. More importantly, a percentage of tumors can metastasize, for which there are no tailored treatments. Thus, there is a need to gather a more complete understanding of the mechanisms perturbed in the initiation, promotion and progression of cutaneous SCC in order to develop new approaches for prevention and treatment of this malignancy. A large fraction of SCC shows hyperactivation of the protein Ras; unfortunately, Ras is an elusive molecule to inhibit pharmacologically, and due to its multiple functions, it may be too toxic for healthy cells to withstand such inhibition. Thus, finding upstream and downstream elements that participate in the oncogenic Ras pathways in SCC may reveal a more amenable target for chemoprevention and therapy. Studies from our lab have demonstrated a role for RasGRP1 in skin tumorigenesis through its ability to activate Ras, and support the concept that stimulation of RasGRP1 by intensified extracellular signals could contribute to the dosage of activated Ras necessary for malignant transformation and tumor progression in the skin. Given the fact that UVR is the most relevant carcinogen associated to cutaneous SCC, the goal of this proposal is to elucidate the potential participation of RasGRP1 in UVR-induced tumorigenesis. Using a combination of mouse models and in vitro approaches, we proposed the following aims: (1) Define the role of RasGRP1 in the acute response of keratinocytes to UVR, and (2) Determine the requirement for RasGRP1 in UVR-induced skin carcinogenesis, using a RasGRP1 knockout and a K5.RasGRP1 transgenic mouse models. The combined results should provide a strong test for our hypothesis that RasGRP1 is required for the tumorigenic effects of UVR in the epidermis, and set the basis for further studies on new drugs targeted to RasGRP1 that could be useful in chemoprevention and treatment of cutaneous SCC. PUBLIC HEALTH RELEVANCE: This application investigates molecular pathways relevant to cutaneous squamous cell carcinoma (SCC) that could lead to novel approaches for prevention and treatment. The solar UV radiation (UVR) is a major carcinogenic factor in cutaneous SCC and is known to affect Ras, a molecule with important roles in skin homeostasis. In fact, a large proportion of cutaneous SCC possesses aberrant activation of Ras; as such, it represents an attractive molecular target for cancer therapeutics. Unfortunately, Ras is not easily druggable, so efforts have been redirected to other molecules that act upstream or downstream of the Ras oncogene. The goal of the proposal is to test the participation of a novel Ras activator -RasGRP1- in UVR-induced skin tumorigenesis. The studies are supported by our findings on keratinocyte biology and mouse models of cutaneous SCC. If our studies are successfully completed, they will impact the knowledge that could lead to better approaches for treatment in skin cancer, including chemoprevention.