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

描述（由申请人提供）：UVB辐射是一种完全的皮肤致癌物，启动信号通路和突变，促进癌前光化性角化病（AKs）和皮肤鳞状细胞癌（cSCCs）的形成。AKs和cSCCs在有阳光照射史的老年人中非常常见，并且这些病变的发病率预计在未来会上升。人类cSCCs的常见突变包括p53的功能丧失突变和Ras的功能获得突变。在人类AKs和cSCCs中，与非病变表皮细胞相比，src家族酪氨酸激酶（SFKs）在病变细胞中被激活，表明SFKs促进皮肤癌；这与SFK Fyn是人类角化细胞中致癌Ras的效应物的观察结果一致。对人类cSCCs和AKs的分析一致显示Srcasm水平下降，表明Srcasm下调可能是肿瘤形成的必要条件。我们之前的数据显示，Fyn下调p53，诱导K14-Fyn Y528F转基因小鼠癌前病变和cSCCs的自发形成。这些癌前病变和cscs在组织学和分子水平上与人类相似。在这些小鼠中，提高Srcasm水平可使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了Srcasm，这些小鼠皮肤中的p53水平显著降低。最近的数据显示，uvb治疗Srcasm阴性小鼠在5周内产生类似于人类AKs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重建的人类皮肤中发挥重要作用。促进Fyn活性可以增强uvb诱导的信号传导和DNA损伤，而增加srm水平可以抑制uvb诱导的DNA损伤和皮肤癌。降低Fyn应能抑制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。局部应用小分子激酶抑制剂靶向这些小鼠模型中促进肿瘤形成的激酶，导致这些肿瘤的消退，这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损伤和皮肤癌的认识。这项工作也将提供新的候选分子，可以改善局部治疗AKs和cSCCs的患者。

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.