Furin and the Etiopathogenesis of UV-Induced Skin Cancer

弗林蛋白酶和紫外线诱发的皮肤癌的发病机制

• 批准号: 7795923
• 负责人: ANDRES J KLEIN-SZANTO
• 金额: $ 36.21万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795923
• 关键词: Biological Process; Biomedical Engineering; Cell Proliferation; Complementary DNA; Development; Early Diagnosis; Enzymes; Epidermis; Experimental Animal Model; Family; Growth; Growth Factor; Growth Factor Receptors; Growth and Development function; Human; Impairment; Lead; MMP11 gene; Malignant Neoplasms; Matrix Metalloproteinases; Modeling; Mus; Pathogenesis; Peptide Hydrolases; Peptides; Physiological; Play; Predisposition; Premalignant; Process; Proprotein Convertase 2; Proprotein Convertases; Proteins; Protocols documentation; Public Health Applications Research; Relative (related person); Role; Series; Skin; Skin Cancer; Skin Carcinogenesis; Skin Neoplasms; Squamous cell carcinoma; Substrate Specificity; Testing; Transgenic Animals; Transgenic Mice; Transgenic Model; Transgenic Organisms; UV Radiation Exposure; UV carcinogenesis; UV induced; Ultraviolet Rays; base; cancer cell; carcinogenesis; design; in vivo; inhibitor/antagonist; keratinocyte; mouse model; neoplastic; neoplastic cell; overexpression; public health relevance; receptor; research study; synergism; tumor; tumor growth

DESCRIPTION (provided by applicant): Furin is a protein processing enzyme of the family of proprotein convertases (PCs), which has a significant role in cancer etiopathogenesis. In this application, we propose to investigate the function of furin during skin tumor development, focusing on the early and late changes that take place after UV exposure of the mouse skin. PACE4, another related PC, has been shown to have a role in murine tumor cell invasiveness by activating relevant proteases. Furin is also able to enhance cell proliferation in human precancerous and cancer cells by activating growth factor and growth factor receptors, such as IGF-R1. The lack of a mouse model to study the function of furin during carcinogenesis prompted us to design a series of experiments using transgenic mice to facilitate the better understanding of this prominent PC in the etiopathogenesis of skin cancer. Our objective in this proposal is to determine the mechanisms by which furin contributes to tumor development alone or in combination with PACE4 using transgenic mice overexpressing PCs. Two aims have been designed to this effect: First we will determine if the targeted in vivo overexpression of furin alone will enhance the development of experimental skin cancer induced by UV. We shall investigate the simultaneous in vivo overexpression of PACE4 and furin using bigenic mice in order to establish the possible cooperation of the 2 PCs in skin carcinogenesis. Substrate- specificity will be evaluated in keratinocyte cultures derived from monogenic (K5-PACE4 and K5-Furin) as well as from bigenic mice (K5-PACE4/Furin). These experiments will clarify the significance of furin's pro-proliferative effect and whether its pro-invasive effects are the same or different from PACE4's predominant pro-invasive function. In addition, this specific aim will determine whether the combination of both PCs have an enhancing effect on any or both of these biological processes. Second, we will also determine if PC inhibition blocks tumor growth and development in transgenic models. Crossing monogenic PC transgenic mice as well as double transgenics K5-Furin/PACE4 with K5-PDX and K5-PC-Propeptide transgenic mice expressing either the cDNA of a competitive PC peptide inhibitor or that of the physiological inhibitors of PCs, we will determine if inhibition of PCs alters the formation of skin tumors induced by UV carcinogenesis. PUBLIC HEALTH RELEVANCE: This application will use modern experimental animal models to dissect the function of proprotein convertases, enzymes that activate relevant cancer-associated biomolecules, during the early formation and growth of squamous cell carcinomas, one of the most common cancers of the human skin. The proposed studies will lead to the identification of mechanisms involved in the origination of cancer that could be of great practical value in its early diagnosis and treatment.

描述（由申请人提供）：Furin是一种蛋白质加工酶的蛋白质加工酶（PCS），在癌症疗法发生中具有重要作用。在此应用中，我们建议研究皮肤肿瘤发育过程中FURIN的功能，重点关注小鼠皮肤紫外线暴露后发生的早期和晚期变化。 PACE4是另一个相关的PC，已证明通过激活相关蛋白酶在鼠肿瘤细胞的侵袭性中起作用。 FURIN还能够通过激活生长因子和生长因子受体（例如IGF-R1）来增强人癌细胞和癌细胞中的细胞增殖。缺乏小鼠模型来研究癌过程中弗林的功能，促使我们设计了一系列使用转基因小鼠的实验，以促进对皮肤癌的病情发生中对该突出的PC的更好理解。我们在该提案中的目标是确定FURIN单独使用过表达PC的转基因小鼠与PACE4相结合的机制。已经设计了两个目的是为了这一效果：首先，我们将确定靶向的体内过度表达是否单独使用FURIN，从而增强紫外线诱导的实验性皮肤癌的发展。我们将使用临后小鼠同时研究PACE4和FURIN的体内过度表达，以确定皮肤癌变中2个PC的可能合作。底物特异性将在源自单基因（K5-PACE4和K5-氟林）以及bigenic小鼠（K5-PACE4/Furin）的角质形成细胞培养物中进行评估。这些实验将阐明Furin促增殖作用的重要性，以及其促侵入性效应是否与PACE4的主要促侵入性功能相同或不同。此外，这一特定目的将决定这两种PC的组合是否对这些生物过程中的任何或两个都有增强的影响。其次，我们还将确定PC抑制是否会阻断转基因模型中的肿瘤生长和发育。 Crossing monogenic PC transgenic mice as well as double transgenics K5-Furin/PACE4 with K5-PDX and K5-PC-Propeptide transgenic mice expressing either the cDNA of a competitive PC peptide inhibitor or that of the physiological inhibitors of PCs, we will determine if inhibition of PCs alters the formation of skin tumors induced by UV carcinogenesis.公共卫生相关性：本应用将使用现代的实验动物模型来剖析普罗蛋白转化酶的功能，即激活相关癌症相关的生物分子的酶，在鳞状细胞癌的早期形成和生长中，这是人类皮肤最常见的癌症之一。拟议的研究将导致鉴定癌症起源的机制，这些机制在早期诊断和治疗中可能具有巨大的实际价值。