Keratin proteins and non-melanoma skin tumors

角蛋白和非黑色素瘤皮肤肿瘤

• 批准号: 7387372
• 负责人: Pierre Coulombe
• 金额: $ 16.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7387372
• 关键词: Alleles; Apoptosis; Basal Cell; Basal cell carcinoma; Biochemical; Biology; Carcinoma; Cell Proliferation Regulation; Characteristics; Cytoskeletal Proteins; Ear Neoplasms; Epidermis; Epithelial Cells; Epithelium; Erinaceidae; Exploratory/Developmental Grant; Family member; Funding; Genes; Genetic; Growth; Hair follicle structure; Human; Incidence; Injury; Intermediate Filament Proteins; Keratin; Knockout Mice; Laboratories; Lead; Lesion; Light; Malignant Neoplasms; Mechanics; Mediating; Microscopic; Molecular; Mus; Mutation; Names; Neoplasm Metastasis; Neoplastic Cell Transformation; North America; Nuts; Outcome; Partner in relationship; Pattern; Phase; Plant Roots; Population; Process; Property; Protein Biosynthesis; Proteins; Qualifying; Regulation; Role; Seeds; Signal Transduction; Skin; Skin Neoplasms; Skin Tissue; Testing; Therapeutic; Tissues; Transactivation; Transgenic Mice; Transgenic Organisms; Tumor Biology; Tumor Tissue; Ulcer; Work; Zinc Fingers; base; cancer diagnosis; cell growth; experience; human FRAP1 protein; in vivo; keratin 14, K14; keratinocyte; melanoma; mouse model; neoplastic cell; novel; progenitor; promoter; transcription factor; tumor; tumor growth; young adult

DESCRIPTION (provided by applicant): Basal cell carcinoma (BCC) is the most frequent cancer in North America. It represents more than one-third of all cancers diagnosed in the U.S. every year, and its incidence is on the rise. Whereas it rarely metastasizes, BCC can be devastating in that tumors can be locally aggressive, leading to ulceration and disfigurement. There is relatively little known about the biochemical determinants of BCC tumor biology. The type I keratin 17 (K17) is consistently induced in BCC lesions, whether in human skin or in relevant transgenic mouse models, making it a reliable marker of this type of tumor in vivo. Molecularly, the association between K17 and BCC is the direct result of Gli-mediated transactivation of the K17 gene promoter. Gli family members are transcription factors and terminal effectors of sonic hedgehog (Shh) signaling. Genetically, most BCCs are associated with mutations at loci encoding key effectors of Shh signaling, resulting in its sustained activation, and creating a hyperproliferative state in hair follicles and epidermis that is conducive to the additional "genetic hits" required for neoplastic transformation. Recent work has shown that K17 serves multiple functions in skin epithelia. Like other keratins and all other intermediate filament proteins, K17 provides structural support. Examples of functions that are so far unique to K17 in skin epithelia are the protection of keratinocytes against TNFa-mediated apoptosis, which is manifested during the anagen (growth) phase in cycling hair follicles, and an ability to stimulate mTOR- dependent protein synthesis and cell growth in keratinocytes called upon to sustain rapid tissue growth, as occurs following tissue injury. Each of these three functions represents a key determinant of tumor biology. The overall objective of this project is to assess the functional contribution of K17 in the context of a well-established transgenic mouse model of BCC. We will do so by mating previously characterized K17 null mice, in which the K17 protein is completely missing, with transgenic mice that constitutively express Gli2 in progenitor keratinocytes of the skin, and which reproducibly develop BCC skin tumors as young adults. Mice carrying a null allele in K14 will provide a suitable reference for those studies. We have strong preliminary evidence indicating that loss of K17 (nut not K14) results in a delay in BCC tumor growth. In Aim 1, macroscopic, microscopic, molecular and biochemical outcomes will be used to assess tumor biology in the absence of either K17 or K14. In Aim 2, we will exploit keratinocyte primary to define the cellular and molecular basis for the apparent delay in tumor growth in vivo. A particular emphasis will be placed on the regulation of cell proliferation, programmed cell death, and protein synthesis. Altogether, the proposed studies will shed light on the role of keratins as determinants of the growth and aggressiveness of non-melanoma skin tumors. Project Narrative: Basal cell carcinoma (BCC) is the most frequent cancer in North America. It represents more than one-third of all cancers diagnosed in the U.S. every year, and its incidence is on the rise. Whereas it rarely metastasizes, BCC can be devastating in that tumors can be locally aggressive, leading to ulceration and disfigurement. There is relatively little known about the biochemical determinants of BCC tumor biology. A cytoskeletal protein named keratin 17 (K17) serves as a very useful marker for BCC lesions. Its potential contribution to the growth and fate of BCC lesions has not yet been examined. K17 normally functions to provide mechanical support, and participates in the regulation of programmed cell death as well as protein synthesis, in various types of skin epithelial cells. All of these roles represent key determinants of tumor biology. In this study, we will examine how BCC tumors fare in the complete absence of K17 protein in the context of an established experimental mouse model. We hope that our findings lead to new ideas for the therapeutic management of aggressive and recurring forms of these tumors.

描述（由申请人提供）：基底细胞癌（BCC）是北美最常见的癌症。它占美国每年诊断出的所有癌症的三分之一以上，并且其发病率正在上升。虽然它很少转移，但BCC可能是毁灭性的，因为肿瘤可以局部侵袭，导致溃疡和毁容。关于BCC肿瘤生物学的生物化学决定因素知之甚少。I型角蛋白17（K17）在BCC病变中一致地被诱导，无论是在人皮肤中还是在相关的转基因小鼠模型中，使其成为这种类型的肿瘤的体内可靠标记物。分子上，K17和BCC之间的关联是Gli介导的K17基因启动子反式激活的直接结果。Gli家族成员是转录因子和音刺猬信号传导的末端效应子。在遗传上，大多数BCC与编码Shh信号传导的关键效应子的基因座处的突变相关，导致其持续活化，并在毛囊和表皮中产生过度增殖状态，这有助于肿瘤转化所需的额外“遗传命中”。最近的研究表明，K17在皮肤上皮细胞中具有多种功能。像其他角蛋白和所有其他中间丝蛋白一样，K17提供结构支持。到目前为止，皮肤上皮中K17特有的功能的实例是保护角质形成细胞免受TNF α介导的细胞凋亡，这在周期性毛囊的生长期（生长）期间表现出来，以及刺激角质形成细胞中的mTOR依赖性蛋白质合成和细胞生长的能力，所述角质形成细胞被要求维持快速组织生长，如组织损伤后发生的。这三种功能中的每一种都代表了肿瘤生物学的关键决定因素。该项目的总体目标是在一个完善的BCC转基因小鼠模型的背景下评估K17的功能贡献。我们将通过将先前表征的K17缺失小鼠（其中K17蛋白完全缺失）与在皮肤的前体角质形成细胞中组成型表达Gli2的转基因小鼠交配来实现这一点，所述转基因小鼠在年轻成人时可重复地发展BCC皮肤肿瘤。在K14中携带无效等位基因的小鼠将为这些研究提供合适的参考。我们有强有力的初步证据表明，K17（nut而不是K14）的缺失导致BCC肿瘤生长延迟。在目标1中，在不存在K17或K14的情况下，将使用肉眼、显微镜、分子和生化结果评估肿瘤生物学。在目标2中，我们将利用角质形成细胞的主要定义在体内肿瘤生长的明显延迟的细胞和分子基础。将特别强调细胞增殖，程序性细胞死亡和蛋白质合成的调节。总而言之，拟议的研究将阐明角蛋白作为非黑色素瘤皮肤肿瘤生长和侵袭性决定因素的作用。 基底细胞癌（BCC）是北美最常见的癌症。它占美国每年诊断出的所有癌症的三分之一以上，并且其发病率正在上升。虽然它很少转移，但BCC可能是毁灭性的，因为肿瘤可以局部侵袭，导致溃疡和毁容。关于BCC肿瘤生物学的生物化学决定因素知之甚少。一种名为角蛋白17（K17）的细胞骨架蛋白是BCC病变的一个非常有用的标志物。其对基底细胞癌病变的生长和转归的潜在作用尚未研究。K17通常在各种类型的皮肤上皮细胞中起提供机械支持的作用，并参与调节程序性细胞死亡以及蛋白质合成。所有这些角色都代表了肿瘤生物学的关键决定因素。在这项研究中，我们将研究如何BCC肿瘤的票价在完全缺乏K17蛋白的背景下，建立实验小鼠模型。我们希望我们的发现为这些肿瘤的侵袭性和复发性形式的治疗管理带来新的想法。