Mechanisms of UV-induced skin carcinogenesis

描述(申请人提供)：暴露在阳光的紫外线(UV)成分是非黑色素瘤皮肤癌的主要原因，皮肤癌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，但紫外线致癌的机制尚不清楚。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变；2)ERBB2‘S抑制蛋白酶抑制剂血栓反应蛋白1及其上调基质金属蛋白酶刺激角质形成细胞侵袭和血管生成，导致恶性进展。该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调控细胞周期进展和DNA损伤检查点的分子机制，并确定ERBB2如何导致皮肤癌进展。这些研究将使用我们为ERBB2在皮肤中的抑制和遗传消融开发的模型。这些研究完成后，将揭示紫外线照射后细胞周期调节和检查点控制的基本机制，以及ERBB2调节DNA损伤后细胞周期停滞和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的作用机制，并为皮肤癌的治疗干预提供新的靶点。 在美国，每年确诊的100多万皮肤癌中，大部分都是紫外线照射造成的。这项拟议的研究将揭示紫外线照射诱发皮肤癌的基本分子机制。这项拟议研究的成功完成将有助于开发旨在治疗或预防皮肤癌的新疗法。

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.