Keratins as novel determinants of tumor biology

描述(由申请人提供)：I型和II型角蛋白基因及其蛋白在上皮细胞中经历组织特异性、分化相关和上下文相关的严格调控。大多数疾病状态，包括癌症，涉及到偏离正常生理，并总是伴随着细胞分化途径和角蛋白调节的异常。除了结构支持的普遍和至关重要的作用外，角蛋白蛋白最近被发现影响上皮细胞中的几个关键信号通路。最近的两项研究指出，两种配对角蛋白蛋白，角蛋白17和角蛋白5，在基底细胞癌和相关的基底细胞样皮肤肿瘤中具有重要的调节作用。该项目旨在确定这些角蛋白与皮肤肿瘤发生之间的机制联系，并探索其是否适用于其他上皮组织。我们对这个项目的具体目标如下。在目标1中，我们将试图确定角蛋白17通过增强Gli2过度表达的、易于肿瘤的皮肤角质形成细胞中特定细胞因子和趋化因子的表达的分子机制(S)。在目标2中，我们将试图确定角蛋白5的两个变异(Gly138Glu和Asp197Glu)通过其增加发生基底细胞癌的风险的机制(S)。在目标3中，我们将探索角蛋白17是否影响从人乳头瘤病毒16E6和E7癌蛋白组成的转基因小鼠产生的皮肤和宫颈肿瘤，然后研究角蛋白依赖的肿瘤生长调节机制(S)是否与在基底细胞癌和基底细胞样皮肤肿瘤中发现的相同。对肿瘤细胞结构和调控的新决定因素获得的机械洞察力可能导致在抗癌斗争中识别新的治疗靶点。

DESCRIPTION (provided by applicant): Type I and type II keratin genes and their proteins undergo a tight regulation in a tissue-specific, differentiation-related, and context-dependent fashion in epithelial cells. Most disease states, including cancer, involve a departure from normal physiology and are invariably accompanied by aberrations in cellular differentiation pathways and keratin regulation. In addition to a ubiquitous and critically important role of structural support, keratin proteins were recently found to impact several key signaling pathways in epithelia. Two recent studies point to a significant modulatory role for two partner keratin proteins, keratin 17 and keratin 5, in basal cell carcinoma and related basaloid skin tumors. This project aims at defining the mechanistic link between these keratins and tumorigenesis in skin, and explore whether it applies to other epithelial tissues. Our specific aims for this project will be as follows. In Aim 1, we will seek to define the molecular mechanism(s) through which keratin 17 enhances the expression of select cytokines and chemokines in Gli2-overexpressing, tumor-prone skin keratinocytes. In Aim 2, we will seek to define the mechanism(s) through which two variants in keratin 5 (Gly138Glu and Asp197Glu) enhance the risk of developing basal cell carcinoma. In Aim 3, we will explore whether keratin 17 impacts the skin and cervical tumors arising in transgenic mice constitutively expressing the E6 and E7 oncoproteins from human papillomavirus 16, and then investigate whether the mechanism(s) underlying keratin-dependent modulation of tumor growth are the same as those uncovered in basal cell carcinoma and basaloid skin tumors. The mechanistic insight acquired about novel determinants of tumor cell architecture and regulation may lead to the identification of new therapeutic targets in the fight against cancer.