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Mechanisms of UV-induced skin carcinogenesis

紫外线诱发皮肤癌的机制

基本信息

批准号：
7528761
负责人：
LAURA A HANSEN
金额：
$ 30.49万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7528761
关键词：
Ablation Apoptosis Biological Biological Process Cancer Etiology Carcinogenesis Mechanism Cell Cycle Arrest Cell Cycle Checkpoint Cell Cycle Progression Cell Cycle Regulation Cells DNA Damage DNA Repair DNA damage checkpoint Data Development ERBB2 gene Ectopic Expression Event Exposure to Genetic Goals Growth Health Human Inherited Intervention Investigation Knockout Mice Knowledge MMP9 gene Maintenance Malignant - descriptor Malignant Neoplasms Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Modeling Molecular Mus Mutagenesis Mutation Orphan Pathway interactions Phase Phosphatidylinositols Phosphorylation Phosphotransferases Physiological Protease Inhibitor Proto-Oncogene Proteins c-akt Proto-Oncogenes Receptor Protein-Tyrosine Kinases Regulation Research Risk Role Signal Pathway Signal Transduction Skin Skin Cancer Skin Carcinogenesis Skin Carcinoma Skin Neoplasms Squamous cell carcinoma Staging Sunlight System TP53 gene Testing Therapeutic Intervention Thrombospondin 1 Tumor Angiogenesis Tumor Cell Invasion UV induced United States Up-Regulation angiogenesis base cancer diagnosis carcinogenesis daughter cell design erbB-2 Receptor in vivo keratinocyte migration mouse model novel novel strategies prevent programs receptor-mediated signaling research study resistance mechanism response skin cancer prevention therapy design tumor tumor initiation tumor progression ultraviolet ultraviolet irradiation upstream kinase

项目摘要

DESCRIPTION (provided by applicant): Exposure to the ultraviolet (UV) component of sunlight is the major cause of nonmelanoma skin cancer, the most common form of cancer in the United States. Despite its significance for human health, however, the mechanisms through which UV causes cancer are not well understood. One potential mechanism for skin carcinogenesis involves the UV-induced activation of Erbb2, a proto-oncogene and orphan receptor tyrosine kinase. Our preliminary data reveal novel mechanisms through which Erbb2 contributes to skin carcinogenesis at multiple stages, both during tumor development and progression. Our central hypotheses are 1) that Erbb2 promotes cell cycle progression and thus increases UV-induced skin carcinogenesis by dampening DNA damage response checkpoints and 2) that Erbb2's suppression of proteinase inhibitor Thrombospondin 1 and its upregulation of matrix metalloproteinases stimulate keratinocyte invasion and angiogenesis, leading to malignant progression. The long-term objective of this application is to understand the biological functions of Erbb2 during carcinogenesis and the mechanisms through which Erbb2 acts. Studies are proposed to reveal the biological significance of Erbb2 in skin tumor development and progression, to determine the molecular mechanisms by which Erbb2 regulates cell cycle progression and a DNA damage checkpoint through Cdc25a, and to determine how Erbb2 causes skin cancer progression. These studies will use models that we have developed for both the inhibition and genetic ablation of Erbb2 in the skin. Upon completion, these studies will reveal the basic mechanisms of cell cycle regulation and checkpoint control following UV exposure as well as novel mechanisms through which Erbb2 regulates cell cycle arrest after DNA damage and promotes malignant progression. This research will provide a comprehensive analysis of the importance of Erbb2 in skin carcinogenesis, will elucidate novel mechanisms through which Erbb2 acts, and will provide new targets for therapeutic intervention during skin carcinogenesis. Ultraviolet irradiation is the cause of most of the more than one million skin cancers diagnosed in the United States each year. The proposed research will reveal basic molecular mechanisms responsible for the induction of skin cancer in response to ultraviolet irradiation. Successful completion of the proposed research will allow for the development of novel therapies designed to treat or prevent skin cancer.

描述（由申请人提供）：暴露于阳光的紫外线（UV）成分是导致非黑色素瘤皮肤癌的主要原因，这是美国最常见的癌症形式。然而，尽管紫外线对人类健康具有重要意义，但其致癌机制尚不清楚。皮肤癌发生的一个潜在机制涉及紫外线诱导Erbb2的激活，Erbb2是一种原癌基因和孤儿受体酪氨酸激酶。我们的初步数据揭示了Erbb2在肿瘤发生和发展的多个阶段参与皮肤癌变的新机制。我们的主要假设是：1)Erbb2通过抑制DNA损伤反应检查点促进细胞周期进程，从而增加紫外线诱导的皮肤癌发生；2)Erbb2抑制蛋白酶抑制剂血小板反应蛋白1及其上调基质金属蛋白酶刺激角质细胞侵袭和血管生成，导致恶性进展。这项应用的长期目标是了解Erbb2在癌变过程中的生物学功能以及Erbb2的作用机制。研究旨在揭示Erbb2在皮肤肿瘤发生发展中的生物学意义，确定Erbb2通过Cdc25a调控细胞周期进程和DNA损伤检查点的分子机制，确定Erbb2如何导致皮肤癌进展。这些研究将使用我们开发的模型来抑制和基因消融皮肤中的Erbb2。一旦完成，这些研究将揭示紫外线照射后细胞周期调控和检查点控制的基本机制，以及Erbb2调节DNA损伤后细胞周期阻滞和促进恶性进展的新机制。本研究将全面分析Erbb2在皮肤癌变中的重要性，阐明Erbb2作用的新机制，并为皮肤癌变过程中的治疗干预提供新的靶点。