The Role of VILIP-1 in Development of Skin Tumors

VILIP-1 在皮肤肿瘤发展中的作用

• 批准号: 6993466
• 负责人: ANDRES J KLEIN-SZANTO
• 金额: $ 30.4万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6993466
• 关键词: cell line; chemical carcinogenesis; cyclic AMP; cyclic GMP; gene expression; genetic susceptibility; genetically modified animals; guanosinetriphosphatases; laboratory mouse; neoplasm /cancer genetics; neoplastic process; nerve /myelin protein; radiation carcinogenesis; skin neoplasms; squamous cell carcinoma; transfection; ultraviolet radiation

DESCRIPTION (provided by applicant): Using differential display and other molecular techniques we identified the absence of expression of a gene homologous to the human Visinin-like Protein 1 (VILIP-1) in selected high grade murine squamous cell carcinoma (SCC) and in tumor cell lines. Ectopic expression of VILIP-1 in SCC cell lines resulted in a less aggressive phenotype associated with increased levels of cAMP, decreased cell proliferation and decreased RhoA activation. The central hypothesis to be tested in vivo is that the loss of VILIP-1 expression enhances the malignant phenotype of SCC cells by down-regulating cyclic nucleotide-dependent pathways that include specific tumor-progression-related targets, such as small GTPases, thus constituting an important element in the chain of events leading to the malignant phenotype. Conversely, VILIP-1 expression should increase resistance to skin carcinogenesis by decreasing tumor cell growth and/or inhibiting tumor progression. For this purpose we have designed three specific aims: 1) Examine biological and biochemical mechanisms whereby loss of VILIP-1 expression may lead to increased malignancy. In this experiment, we will study cell proliferation, differentiation, adhesiveness, migration and invasiveness of VILIP-1 transfectants and knocked-down SCC cells in the context of cyclic nucleotide regulation. We will focus on the relative hierarchical role played by cAMP and cGMP, both known to be regulated by VILIP-1, and their participation as possible effectors of small GTPases. 2) We will evaluate the in vivo susceptibility to carcinogenesis in K5-VILIP-1 transgenic mice. These mice should be less susceptible to skin chemical carcinogenesis and will be utilized to evaluate in vivo the mechanism of action of VILIP-1. 3) Investigate the in vivo susceptibility to skin carcinogenesis using a protocol of ultraviolet carcinogenesis in K5-VILEP-1 transgenic mice backcrossed to a SHK-1 background.

描述（由申请人提供）：使用差异显示和其他分子技术，我们鉴定出在选定的高级别鼠鳞状细胞癌（SCC）和肿瘤细胞系。 SCC 细胞系中 VILIP-1 的异位表达导致侵袭性减弱的表型，与 cAMP 水平增加、细胞增殖减少和 RhoA 激活减少相关。体内测试的中心假设是，VILIP-1表达的丧失通过下调环核苷酸依赖性途径来增强鳞状细胞癌细胞的恶性表型，这些途径包括特定的肿瘤进展相关靶标，例如小GTP酶，从而构成导致恶性表型的事件链中的一个重要因素。相反，VILIP-1 表达应通过减少肿瘤细胞生长和/或抑制肿瘤进展来增强对皮肤癌的抵抗力。为此，我们设计了三个具体目标：1) 检查 VILIP-1 表达缺失可能导致恶性肿瘤增加的生物学和生化机制。在本实验中，我们将在环核苷酸调控的背景下研究VILIP-1转染子和敲低的SCC细胞的细胞增殖、分化、粘附、迁移和侵袭性。我们将重点关注 cAMP 和 cGMP 所发挥的相对等级作用（已知两者均受 VILIP-1 调节），以及它们作为小 GTP 酶的可能效应器的参与。 2）我们将评估K5-VILIP-1转基因小鼠体内致癌的易感性。这些小鼠应该不太容易受到皮肤化学致癌作用的影响，并将用于评估 VILIP-1 的体内作用机制。 3) 使用与 SHK-1 背景回交的 K5-VILEP-1 转基因小鼠中的紫外线致癌方案研究体内对皮肤致癌的敏感性。