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。它代表每年在美国被诊断出的所有癌症中的三分之一以上，其发病率正在上升。尽管它很少转移，但BCC可能是毁灭性的，因为肿瘤可能是局部侵略性的，导致溃疡和毁容。关于BCC肿瘤生物学的生化决定因素，相对较少。 I型角蛋白17（K17）在BCC病变中，无论是在人体皮肤还是相关的转基因小鼠模型中都始终诱导，使其成为体内此类肿瘤的可靠标记。从分子上讲，K17与BCC之间的关联是G17基因启动子的Gli介导的反式激活的直接结果。 GLI家族成员是转录因子和声音刺猬（SHH）信号传导的终端效应子。从遗传上讲，大多数BCC都与编码SHH信号的关键效应的突变有关，从而导致其持续的激活，并在毛囊和表皮中产生过度增殖状态，这有利于肿瘤转化所需的其他“遗传命中”。最近的工作表明，K17在皮肤上皮中发挥了多种功能。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，皮肤上皮症中K17独有的功能的实例是角质形成细胞免受TNFA介导的凋亡的保护，这在循环毛囊中的Anagen（生长）期间表现出来，并且能够刺激MTOR依赖性蛋白质的合成和细胞的生长，以使其在Keratinocycils中的生长迅速造成，从而使对基础的生长进行了迅速的组织。这三个功能中的每一个都代表了肿瘤生物学的关键决定因素。该项目的总体目的是在BCC的成熟的转基因小鼠模型的背景下评估K17的功能贡献。我们将通过交配先前表征的K17 NULL小鼠的交配，其中K17蛋白完全缺少，而转基因小鼠组成型在皮肤的祖细胞角质形成细胞中表达GLI2，并且它们像年轻人一样可重复发展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而非K14）的丧失导致BCC肿瘤生长延迟。在AIM 1中，在没有K17或K14的情况下，宏观，微观，分子和生化结果将用于评估肿瘤生物学。在AIM 2中，我们将利用角质形成细胞原发性来定义体内肿瘤生长明显延迟的细胞和分子基础。特别重点将放在细胞增殖，程序性细胞死亡和蛋白质合成的调节上。总的来说，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略性的决定因素。 项目叙述：基底细胞癌（BCC）是北美最常见的癌症。它代表每年在美国被诊断出的所有癌症中的三分之一以上，其发病率正在上升。尽管它很少转移，但BCC可能是毁灭性的，因为肿瘤可能是局部侵略性的，导致溃疡和毁容。关于BCC肿瘤生物学的生化决定因素，相对较少。一种称为角蛋白17（K17）的细胞骨架蛋白是BCC病变的非常有用的标记。尚未研究其对BCC病变的生长和命运的潜在贡献。 K17通常功能提供机械支持，并参与各种类型的皮肤上皮细胞中编程细胞死亡以及蛋白质合成的调节。所有这些角色代表了肿瘤生物学的关键决定因素。在这项研究中，我们将在完全没有K17蛋白质的情况下研究BCC肿瘤在建立的实验小鼠模型的背景下如何出现。我们希望我们的发现为这些肿瘤的侵略性和反复出现形式的治疗管理带来新的想法。