Ras activation pathways in UVR-induced epidermal transformation

UVR诱导表皮转化中的Ras激活途径

• 批准号: 8244396
• 负责人: PATRICIA S LORENZO
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244396
• 关键词: Acute; Affect; Apoptosis; Biology; Carcinogens; Cell Death; Cells; Chemoprevention; Chemopreventive Agent; Cicatrix; Country; Development; Diagnosis; Drug Delivery Systems; Elements; Epidermal Growth Factor Receptor; Epidermis; Exposure to; Frequencies; Goals; Homeostasis; Human; In Vitro; Incidence; Knock-out; Knockout Mice; Knowledge; Lead; MAP Kinase Gene; MAPK8 gene; Malignant - descriptor; Malignant Neoplasms; Mediating; Mitogen-Activated Protein Kinases; Molecular; Molecular Target; Morbidity - disease rate; Mus; Mutation; Neoplasm Metastasis; Oncogenic; Operative Surgical Procedures; Oxidative Stress; Pathway interactions; Predisposition; Prevention; Protocols documentation; Role; Signal Transduction; Signaling Molecule; Skin; Skin Cancer; Skin Carcinogenesis; Squamous cell carcinoma; Testing; Therapeutic; Transactivation; Transgenic Mice; Transgenic Organisms; Ultraviolet Rays; Up-Regulation; aging population; base; cell type; dosage; extracellular; in vivo; keratinocyte; mouse model; novel; novel strategies; overexpression; ras Oncogene; ras Proteins; response; skin squamous cell carcinoma; tumor; tumor progression; tumorigenesis; tumorigenic

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.

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诊断的恶性肿瘤，由于暴露于太阳能紫外线辐射（UVR）和人口老化，其发病率正在上升。尽管大多数SCC通过手术成功治疗，但由于疤痕和毁容，它们仍然代表了发病率明显的原因。更重要的是，一定比例的肿瘤可以转移，没有量身定制的治疗方法。因此，有必要对皮肤SCC的启动，促进和进展中扰动的机制进行更完整的了解，以开发用于预防和治疗这种恶性肿瘤的新方法。大部分SCC显示了蛋白质RA的过度激活。不幸的是，RAS是一种难以捉摸的分子，可在药理上抑制药理，并且由于其多种功能，它对于健康细胞而言无法承受这种抑制作用，它可能太毒性了。因此，在SCC中找到参与致癌性RAS途径的上游和下游元素可能会发现更适合化学预防和治疗的靶标。来自我们实验室的研究表明，RASGRP1通过激活RAS的能力在皮肤肿瘤发生中的作用，并支持这样的概念，即通过增强细胞外信号刺激RasGRP1可能有助于对皮肤中恶性转化和肿瘤进展所必需的激活RAS的剂量。鉴于UVR是与皮肤SCC相关的最相关的致癌，因此该提案的目的是阐明RasGRP1在UVR诱导的肿瘤发生中的潜在参与。 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.合并的结果应该为我们的假设提供了强有力的检验，即rasgrp1对于表皮中UVR的致瘤作用是必需的，并为对RasgRP1的新药物的进一步研究奠定了基础，这可能在化学预防和皮肤SCC的治疗中有用。 公共卫生相关性：该应用研究与皮肤鳞状细胞癌（SCC）相关的分子途径，这些途径可能导致预防和治疗的新方法。太阳能紫外线辐射（UVR）是皮肤SCC中的主要致癌因子，已知会影响Ras，Ras是在皮肤稳态中具有重要作用的分子。实际上，大部分皮肤SCC具有异常的RAS激活。因此，它代表了癌症治疗剂的有吸引力的分子靶标。不幸的是，RAS不容易吸毒，因此努力已被重定向到其他分子，这些分子在Ras Oncogene的上游或下游作用。该提案的目的是测试新型Ras激活剂-RASGRP1-在UVR诱导的皮肤肿瘤发生中的参与。我们对皮肤SCC的角质形成细胞生物学和小鼠模型的发现支持了这些研究。如果我们的研究成功完成，它们将影响知识，这可能会导致皮肤癌（包括化学预防）的治疗方法更好。