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: 9110901
• 负责人: John T. Seykora
• 金额: $ 33.2万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110901
• 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; TP53 gene; 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 辐射是一种完全的皮肤致癌物，并启动信号通路和突变，促进癌前光化性角化病 (AK) 和皮肤鳞状细胞癌 (cSCC) 的形成。 AK 和 cSCC 在有日晒史的老年人中都很常见，预计这些病变的发病率将来会上升。人类 cSCC 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 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 会促进皮肤癌；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。对人类 cSCC 和 AK 的分析一致显示 Srcasm 水平降低，表明 Srcasm 下调可能是肿瘤形成所必需的。 我们之前的数据表明，Fyn 下调 p53 并诱导 K14-Fyn Y528F 转基因小鼠自发形成癌前病变和 cSCC。这些癌前病变和鳞状细胞癌在组织学和分子水平上类似于人类的对应物。提高这些小鼠中的 Srcasm 水平可以使 Fyn 激酶活性正常化、恢复 p53 并抑制肿瘤形成。我们从小鼠体内基因删除了 Srcasm，这些小鼠皮肤中的 p53 水平显着降低。最近的数据显示，对 Srcasm 缺失小鼠进行 UVB 治疗，5 周内会产生类似于人类 AK 的癌前病变。这些数据共同表明，Fyn 和 Srcasm 形成了调节皮肤癌的信号连接。 该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着重要的 Fyn 作用。促进 Fyn 活性应增强 UVB 诱导的信号传导和 DNA 损伤，同时增加 Srcasm 水平应抑制 UVB 诱导的 DNA 损伤和皮肤癌。减少 Fyn 应该可以抑制 Ras 诱发的皮肤癌。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，通过局部应用小分子激酶抑制剂来靶向促进肿瘤形成的激酶，可导致这些肿瘤消退，这表明此类分子可能具有治疗人类病变的潜力。 通过这项研究计划获得的数据将进一步加深我们对 SFK 和 Srcasm 如何调节 UVB 诱导的 DNA 损伤和皮肤癌发生的了解。这项工作还将提供新的候选分子，可以改善患者 AK 和 cSCC 的局部治疗。

项目成果

Launch of the new letter category: 'mouse mutants with absent/minimal skin phenotype'.

推出新的字母类别：“具有缺失/最小皮肤表型的小鼠突变体”。

• DOI: 10.1111/exd.12307
• 发表时间: 2014
• 期刊: Experimental dermatology
• 影响因子: 3.6
• 作者: Rendl,Michael;Sundberg,John;Seykora,John;Luger,Thomas;Paus,Ralf;Trier-Mork,Thomas
• 通讯作者: Trier-Mork,Thomas