The role of Fyn and Srcasm in UVB-induced cutaneous neoplasia

描述（由申请人提供）：UVB辐射是皮肤的完全致癌物，并启动促进癌前光化性角化病（AK）和皮肤鳞状细胞癌（cSCC）形成的信号通路和突变。AK和cSCC在有日光暴露史的老年人中非常常见，预计这些病变的发生率在未来会上升。人cSCC中的常见突变包括p53中的功能丧失突变和Ras中的功能获得突变。在人AK和cSCC中，与非病变表皮相比，Src家族酪氨酸激酶（SFK）在病变细胞中被激活，表明SFK促进皮肤癌;这与SFK Fyn是人角质形成细胞中致癌Ras的效应子的观察结果一致。人cSCC和AK的分析一致地显示降低的Srcasm水平，表明Srcasm下调可能是瘤形成所必需的。 我们先前的数据表明，Fyn下调p53并诱导K14-Fyn Y 528 F转基因小鼠中癌前病变和cSCC的自发形成。这些癌前病变和cSCC在组织学和分子水平上类似于它们的人类对应物。在这些小鼠中提高Srcasm水平使Fyn激酶活性正常化，恢复p53，并抑制肿瘤形成。我们在小鼠中基因删除Srcasm，这些小鼠皮肤中的p53水平显著降低。最近的数据显示，Srcasm无效小鼠的UVB治疗在5周内产生类似于人AK的癌前病变。总之，这些数据表明Fyn和Srcasm形成了调节皮肤癌的信号联系。 本提案的主要目标是证明Fyn和Srcasm在小鼠模型和基因工程改造的重建人类皮肤中发挥重要的Fyn作用。促进Fyn活性应增强UVB诱导的信号传导和DNA损伤，而增加Srcasm水平应抑制UVB诱导的DNA损伤和皮肤癌。减少Fyn应该抑制Ras诱导的皮肤癌。在这些研究中，我们将展示Fyn和Srcasm如何调节导致皮肤癌的信号通路。在这些小鼠模型中，用局部应用的小分子激酶抑制剂靶向负责促进肿瘤形成的激酶，导致这些肿瘤消退，表明这些分子可能具有治疗人类病变的潜力。 通过本研究计划获得的数据将进一步加深我们对SFKs和Srcasm如何调节UVB诱导的DNA损伤和皮肤癌发生的认识。这项工作还将提供新的候选分子，可以改善局部治疗，以治疗患者的AK和cSCC。

DESCRIPTION (provided by applicant): UVB radiation is a complete carcinogen for skin and initiates signaling pathways and mutations that promote the formation of precancerous actinic keratoses (AKs) and cutaneous squamous cell carcinomas (cSCCs). Both AKs and cSCCs are very common in older individuals with a history of sun-exposure, and the incidence of these lesions is expected to rise in the future. Common mutations in human cSCCs include loss-of-function mutations in p53 and gain-of-function mutations in Ras. In human AKs and cSCCs, Src-family tyrosine kinases (SFKs) are activated in lesional cells compared with non- lesional epidermis, suggesting that SFKs promote skin cancer; this is consistent with the observation that the SFK Fyn is an effector of oncogenic Ras in human keratinocytes. Analysis of human cSCCs and AKs consistently shows decreased Srcasm levels suggesting that Srcasm downregulation may be necessary for neoplasia. Our previous data show that Fyn downregulates p53 and induces the spontaneous formation of precancerous lesions and cSCCs in K14-Fyn Y528F transgenic mice. These precancerous lesions and cSCCs resemble their human counterparts at the histologic and molecular levels. Raising Srcasm levels in these mice normalizes Fyn kinase activity, restores p53, and inhibits tumor formation. We genetically deleted Srcasm in mice and these mice have markedly reduced p53 levels in skin. Recent data show that UVB-treatment of Srcasm null mice produces precancerous lesions that resemble human AKs in 5 weeks. Together, these data show that Fyn and Srcasm form a signaling nexus that regulates skin cancer. The primary goal of this proposal is to demonstrate that Fyn and Srcasm play important Fyn in murine models and in genetically engineered, reconstituted human skin. Promoting Fyn activity should enhance UVB-induced signaling and DNA damage while increasing Srcasm levels should inhibit UVB-induced DNA damage and skin cancer. Decreasing Fyn should inhibit Ras-induced skin cancer. In these studies, we will show how Fyn and Srcasm regulate signaling pathways that contribute to skin cancer. Targeting the kinases responsible for promoting neoplasia in these mouse models with topically applied small molecule kinase inhibitors results in regression of these tumors, suggesting that such molecules may have potential in treating human lesions. The data obtained through this research proposal will further our knowledge of how SFKs and Srcasm regulate UVB-induced DNA damage and skin carcinogenesis. This work will also provide new candidate molecules that may improve topical therapies to treat AKs and cSCCs in patients.