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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：
7845318
负责人：
LAURA A HANSEN
金额：
$ 2.98万
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 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7845318
关键词：
Ablation Adenovirus Infections Affect American Animal Welfare Apoptosis Bibliography Biological Biological Assay Biological Process Biotechnology Blinded Blood capillaries Cancer Etiology Carcinogenesis Mechanism Cell Culture Techniques Cell Cycle Arrest Cell Cycle Progression Cell Cycle Regulation Cell Line Cells Chronic Coculture Techniques Conditioned Culture Media Country DNA Damage DNA Repair DNA damage checkpoint Data Development Dose ERBB2 gene Ectopic Expression Endothelial Cells Ensure Environment Environmental Impact Epidermal Growth Factor Receptor Equipment Exposure to Extracellular Matrix Figs - dietary Gene Expression Genetic Health Human IACUC In Vitro Inflammation International Journals Length Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Matrix Metalloproteinases Measures Microscopic Modeling Molecular Molecular Carcinogenesis Orphan PI3K/AKT Pathology Phase Phosphorylation Principal Investigator Protease Inhibitor Proto-Oncogene Proteins c-akt Proto-Oncogenes Publications Receptor Protein-Tyrosine Kinases Research Research Ethics Committees Research Personnel Resources Sampling Signal Transduction Skin Skin Cancer Skin Carcinogenesis Skin Carcinoma Skin Neoplasms Solid Staging Sunlight System Text Therapeutic Intervention Thrombospondin 1 Time Tube Tumor Cell Invasion UV induced Ultraviolet Rays United States United States National Institutes of Health Up-Regulation Vertebrates Work abstracting angiogenesis capillary experience expiration human subject keratinocyte migration novel programs research study response tumor tumor progression ultraviolet ultraviolet irradiation

项目摘要

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.

暴露于阳光的紫外线（UV）成分是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。尽管它对人类健康的重要性，但是，紫外线导致癌症的机制还没有得到很好的理解。皮肤癌发生的一个潜在机制涉及Erbb2（一种原癌基因和孤儿受体酪氨酸激酶）的UV诱导活化。我们的初步数据揭示了Erbb2在肿瘤发展和进展的多个阶段促进皮肤癌发生的新机制。我们的中心假设是：1）Erbb2促进细胞周期进程，从而增加紫外线诱导的皮肤癌发生，抑制DNA损伤应答检查点，和2）Erbb2对蛋白酶抑制剂血小板反应蛋白1的抑制及其对基质金属蛋白酶的上调刺激角质形成细胞侵袭和血管生成，导致恶性进展。本申请的长期目标是了解Erbb2在肿瘤发生过程中的生物学功能。癌症发生和Erbb2作用的机制。本研究旨在揭示Erbb2在皮肤肿瘤发生发展中的生物学意义，确定Erbb2调控细胞周期进程和DNA损伤的分子机制通过Cdc25a检查点，并确定Erbb2如何导致皮肤癌进展。这些研究将使用我们开发的用于抑制和基因消融皮肤中Erbb2的模型。完成后，这些研究将揭示紫外线暴露后细胞周期调控和检查点控制的基本机制，以及Erbb2在DNA损伤后调节细胞周期阻滞并促进恶性进展的新机制。这项研究将全面分析Erbb2在皮肤癌发生中的重要性，阐明Erbb2作用的新机制，并为皮肤癌发生过程中的治疗干预提供新靶点。