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质在上皮细胞中以组织特异性、分化相关性和环境依赖性方式进行严格调节。大多数疾病状态，包括癌症，涉及偏离正常生理学，并且总是伴随着细胞分化途径和角蛋白调节的畸变。除了普遍存在和至关重要的结构支持作用外，最近发现角蛋白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，在基底细胞癌和相关的基底细胞样皮肤肿瘤中，两种伴侣角蛋白（角蛋白17和角蛋白5）具有重要的调节作用。本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，我们将试图定义角蛋白17通过其增强Gli 2过表达、肿瘤易感性皮肤角质形成细胞中选择的细胞因子和趋化因子的表达的分子机制。在目标2中，我们将试图确定角蛋白5中的两种变体（Gly 138 Glu和Asp 197 Glu）增加发生基底细胞癌的风险的机制。在目标3中，我们将探讨角蛋白17是否影响组成性表达人乳头瘤病毒16的E6和E7癌蛋白的转基因小鼠中产生的皮肤和宫颈肿瘤，然后研究角蛋白依赖性调节肿瘤生长的机制是否与基底细胞癌和基底细胞样皮肤肿瘤中发现的机制相同。对肿瘤细胞结构和调控的新决定因素的机械见解可能会导致在对抗癌症的斗争中识别新的治疗靶点。 公共卫生相关性：角蛋白是上皮细胞中主要的中间产物形成蛋白，以组织特异性、分化相关性和环境依赖性的方式进行严格调节;因此，角蛋白表达的改变在临床上可用于表征癌症的细胞起源和诊断肿瘤分期。最近的两项研究表明，角蛋白与人类和转基因小鼠模型中基底细胞癌和相关基底细胞样皮肤肿瘤的风险和生长特性有关。该项目建立在这些努力的基础上，旨在了解选择角蛋白对肿瘤性质的影响的细胞和分子机制基础。

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. PUBLIC HEALTH RELEVANCE: Keratins, the major intermediate filament-forming proteins occurring in epithelia, undergo tight regulation in a tissue-specific, differentiation-related, and context-dependent fashion; accordingly, alterations in keratin expression are useful clinically to typify the cellular origin of cancers and diagnose tumor stage. Two very recent studies implicate keratin proteins in the risk towards, and growth properties of, basal cell carcinoma and related basaloid skin tumors in the human and in a transgenic mouse model. This project builds upon these efforts and seeks to understand the cellular and molecular mechanistic basis of the impact of select keratin proteins on the properties of tumors.