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

Fyn 和 Srcasm 在 UVB 诱导的皮肤肿瘤中的作用

• 批准号: 8513948
• 负责人: John T. Seykora
• 金额: $ 31.21万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513948
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accounting; Actinic keratosis; Adverse effects; Age; Aging; Biological; Boxing; Cancerous; Carcinogens; Cells; Cessation of life; Cutaneous; DNA Damage; Data; Dermatologic; Development; Down-Regulation; Epidermis; Event; Exhibits; Fluorouracil; Future; Gap Junctions; Genetic; Genetic Engineering; Goals; Histologic; Histology; Human; Human Engineering; Hyperplasia; Imiquimod; In Vitro; Incidence; Individual; Knockout Mice; Knowledge; Lesion; Malignant Neoplasms; Mitogen-Activated Protein Kinases; Modeling; Molecular; Monitor; Mus; Mutation; Neoplasms; Office Visits; Oncogenic; Pathway interactions; Patients; Phosphotransferases; Photography; Play; Population; Premalignant; Prevention; Protein Tyrosine Kinase; Protein-Serine-Threonine Kinases; Recording of previous events; Research Proposals; Role; Side; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Skin tanning; Squamous cell carcinoma; Sun Exposure; Testing; Topical agent; Topical application; Transgenes; Transgenic Mice; Tumor Suppressor Proteins; UVB induced; Ulcer; Ultraviolet B Radiation; Visit; Western Blotting; Work; Xenograft procedure; base; cost; gain of function mutation; improved; in vivo; keratinocyte; kinase inhibitor; loss of function mutation; mortality; mouse model; notch protein; overexpression; reconstitution; research study; skin irritation; skin lesion; skin squamous cell carcinoma; small molecule; src-Family Kinases; tumor

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.

描述（由申请人提供）：UVB辐射是皮肤的完整致癌物，并启动信号通路和突变，促进癌前活化性角膜结构（AKS）和皮肤鳞状细胞癌（CSCC）的形成。 AK和CSCC在具有阳光暴露史的老年人中都很普遍，并且这些病变的发生率预计将来会上升。人CSCC中的常见突变包括p53的功能丧失突变以及RAS的功能获得突变。在人AK和CSCC中，与非洗脱表皮相比，在病变细胞中激活了SRC家庭酪氨酸激酶（SFKS），这表明SFK促进了皮肤癌。这与SFK FYN是人角质形成细胞中致癌Ras的效应因子的观察结果一致。对人CSCC和AK的分析始终显示出降低的SRCASM水平，这表明SRCASM下调对于肿瘤可能是必需的。 我们先前的数据表明，FYN下调了p53并诱导癌前病变和CSCC在K14-FYN Y528F转基因小鼠中的自发形成。这些癌前病变和CSCC在组织学和分子水平上类似于其人类对应物。这些小鼠中的SRCASM水平提高了FYN激酶活性，恢复p53并抑制肿瘤的形成。我们在小鼠中遗传缺失的SRCASM，这些小鼠显着降低了皮肤的p53水平。最近的数据表明，SRCASM无效小鼠的UVB治疗会产生与人类AK相似的癌性病变。总之，这些数据表明，FYN和SRCASM形成了调节皮肤癌的信号通道。 该提案的主要目的是证明Fyn和Srcasm在鼠模型以及基因工程，重建的人类皮肤中发挥重要作用。促进FYN活性应增强UVB诱导的信号传导和DNA损伤，同时增加SRCASM水平应抑制UVB诱导的DNA损伤和皮肤癌。减少FYN应抑制RAS诱导的皮肤癌。在这些研究中，我们将展示FYN和SRCASM如何调节有助于皮肤癌的信号通路。在这些小鼠模型中，靶向负责促进肿瘤的激酶具有局部施用的小分子激酶抑制剂会导致这些肿瘤的消退，这表明这种分子可能具有治疗人病变的潜力。 通过该研究提案获得的数据将进一步了解SFK和SRCASM如何调节UVB诱导的DNA损伤和皮肤致癌作用。这项工作还将提供新的候选分子，这些分子可以改善患者中AKS和CSCC的局部疗法。