The role of KLF5 in GI epithelial homeostasis and disease

KLF5 在胃肠道上皮稳态和疾病中的作用

• 批准号: 7888558
• 负责人: JONATHAN P KATZ
• 金额: $ 33.13万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7888558
• 关键词: Adhesions; Anoikis; Apoptosis; Basal Cell; Benign; Binding; Biological; Biological Assay; Breast; Carcinogens; Cells; Colon Carcinoma; Complex; Cyclin D1; Data; Disease; Dysplasia; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Esophageal; Esophageal Diseases; Esophageal Intraepithelial Neoplasia; Esophageal Squamous Cell; Esophagus; Event; Extinction (Psychology); Extracellular Matrix; Foundations; Future; Gastroesophageal reflux disease; Gastrointestinal tract structure; Genetic Models for Cancer; Genetic Transcription; Growth Factor Receptors; Homeostasis; Human; Immigration; In Vitro; Integrins; Intestines; Link; Luciferases; Malignant - descriptor; Malignant Squamous Cell Neoplasm; Malignant neoplasm of esophagus; Malignant neoplasm of prostate; Mediating; Mesenchymal; Modeling; Molecular; Mus; Nucleic Acid Regulatory Sequences; Pathway interactions; Proliferating; Property; Prostate; Proteins; Receptor Signaling; Regulation; Reporter; Reporting; Research; Research Design; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Testing; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; Tumor Cell Invasion; United States; Yang; Zinc Fingers; adenoma; angiogenesis; cancer cell; carcinogenesis; chromatin immunoprecipitation; gastrointestinal epithelium; genetic regulatory protein; in vivo; in vivo Model; insight; integrin-linked kinase; keratinocyte; migration; nitrosobenzylmethylamine; notch protein; novel; overexpression; promoter; public health relevance; transcription factor; tumor; tumor initiation; tumorigenesis; two-dimensional; Adhesions; Anoikis; Apoptosis; Basal Cell; Benign; Binding; Biological; Biological Assay; Breast; Carcinogens; Cells; Colon Carcinoma; Complex; Cyclin D1; Data; Disease; Dysplasia; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Esophageal; Esophageal Diseases; Esophageal Intraepithelial Neoplasia; Esophageal Squamous Cell; Esophagus; Event; Extinction (Psychology); Extracellular Matrix; Foundations; Future; Gastroesophageal reflux disease; Gastrointestinal tract structure; Genetic Models for Cancer; Genetic Transcription; Growth Factor Receptors; Homeostasis; Human; Immigration; In Vitro; Integrins; Intestines; Link; Luciferases; Malignant - descriptor; Malignant Squamous Cell Neoplasm; Malignant neoplasm of esophagus; Malignant neoplasm of prostate; Mediating; Mesenchymal; Modeling; Molecular; Mus; Nucleic Acid Regulatory Sequences; Pathway interactions; Proliferating; Property; Prostate; Proteins; Receptor Signaling; Regulation; Reporter; Reporting; Research; Research Design; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Testing; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; Tumor Cell Invasion; United States; Yang; Zinc Fingers; adenoma; angiogenesis; cancer cell; carcinogenesis; chromatin immunoprecipitation; gastrointestinal epithelium; genetic regulatory protein; in vivo; in vivo Model; insight; integrin-linked kinase; keratinocyte; migration; nitrosobenzylmethylamine; notch protein; novel; overexpression; promoter; public health relevance; transcription factor; tumor; tumor initiation; tumorigenesis; two-dimensional

DESCRIPTION (provided by applicant): Kr¿ppel-like factor 5 (KLF5; IKLF; BTEB2), a zinc-finger transcription factor with pro-proliferative properties in vitro, is expressed in proliferating cells of gastrointestinal tract epithelia, including the basal cells of the esophagus. The interplay of these cells with the extracellular matrix (ECM) is critical to their function, and we have shown that Klf5 regulates proliferation in esophageal epithelial cells through the epidermal growth factor receptor (EGFR). In novel preliminary data, we demonstrate that Klf5 increases migration via the integrin- linked kinase (ILK) in primary esophageal keratinocytes in culture. Given these findings, Klf5 is an excellent candidate to orchestrate esophageal epithelial cell proliferation and migration in vivo. However, despite significant evidence of a pro-proliferative role for KLF5 in non-transformed epithelial cells, KLF5 inhibits proliferation, promotes anoikis, and decreases invasion of esophageal squamous cancer cells. KLF5 is also deleted or down-regulated in human breast and prostate cancers, as well as intestinal adenomas from mice and humans. In epithelial cancer cells, KLF5 protein undergoes more rapid degradation than in non- transformed epithelial cells. These findings suggest that extinction of KLF5 function may be important for carcinogenesis. In fact, KLF5 has been suggested to have tumor suppressive functions in human breast, prostate, esophageal, and colon cancers. This dichotomous role for KLF5 is not unique, as divergent functions have been reported for other factors, such as TGF?, Notch, and KLF4. Here, we will investigate the role of KLF5 in normal and transformed esophagus by testing the following hypotheses: (1) KLF5 is a critical regulator of proliferation, differentiation, and migration in transit amplifying cells of the esophagus; and (2) loss of KLF5 is a key step in malignant transformation in the esophagus. We will test these hypotheses through the following interrelated Specific Aims. In Specific Aim 1, we will investigate the role of KLF5 in esophageal epithelial homeostasis by: (a) evaluating integrin, integrin-linked kinase (ILK), and epidermal growth factor receptor (EGFR) signaling in non-transformed keratinocytes with overexpression or suppression of KLF5; (b) studying the transcriptional regulation of EGFR and ILK by KLF5; (c) examining mice with transgenic expression of Klf5 in the esophagus. In Specific Aim 2, we will determine the function of KLF5 during esophageal tumorigenesis by: (a) examining the regulation of the integrin, ILK, and EGFR pathways by KLF5 in transformed esophageal squamous cells; and (b) evaluating dysplasia and tumor formation in mice with transgenic expression of Klf5 in esophagus which have been treated with the carcinogen NMBA or crossed with ED-L2/cyclin D1 transgenic mice, an established genetic cancer model. Overall, an understanding of the pathways regulated by KLF5 in esophageal epithelia will provide a framework to understand the molecular events underlying esophageal diseases, both benign and malignant. PUBLIC HEALTH RELEVANCE: Diseases of the esophagus, such as gastroesophageal reflux disease and esophageal cancer, are among the most common ailments in the United States and throughout the world, and these diseases result from dysregulation of normal epithelial homeostasis. Thus, an appreciation of the molecular mechanisms, including the specific factors and complex signaling arrays, which govern normal esophageal proliferation and differentiation is critical to the understanding of esophageal diseases, both benign and malignant. The research proposed in this application aims to elucidate these factors and signaling pathways through studies of the key regulatory protein KLF5.

描述（应用程序提供）：kr¿ppel样因子5（KLF5； IKLF； BTEB2）是一种体外促增殖特性的锌指转录因子，在胃肠道上皮细胞的增殖细胞中表达，包括食管的基本细胞。这些细胞与细胞外基质（ECM）的相互作用对其功能至关重要，我们已经表明，KLF5通过表皮生长因子受体（EGFR）调节食管上皮细胞的增殖。新的初步数据，我们证明了KLF5通过培养原代食管角质形成细胞中的整合素链接激酶（ILK）增加迁移。鉴于这些发现，KLF5是在体内编排食道上皮细胞增殖和迁移的绝佳候选者。然而，尽管有明显的证据表明KLF5在非转化的上皮细胞中具有促分化作用，但KLF5抑制了增殖，促进了厌氧菌并降低了食管鳞状癌细胞的侵袭。 KLF5在人类乳房和前列腺癌以及小鼠和人类的肠道腺瘤中也被删除或下调。在上皮癌细胞中，KLF5蛋白比非转化的上皮细胞更快地降解。这些发现表明，KLF5功能的扩展对于癌变可能很重要。实际上，已经建议KLF5在人乳房，前列腺，食管和结肠癌中具有抑制肿瘤功能。 KLF5的这种二分作用并非唯一，因为已经报道了其他因素（例如TGF？，Notch和KLF4）的发散功能。在这里，我们将通过检验以下假设来研究KLF5在正常和转化的食道中的作用：（1）KLF5是食管的传输扩增细胞中增殖，分化和迁移的关键调节剂； （2）损失KLF5是我们将通过以下相互关联的特定目的测试这些假设的关键步骤。在特定的目标1中，我们将研究KLF5在食管上皮稳态中的作用：（a）评估整联蛋白，整联蛋白连接激酶（ILK）和表皮生长因子受体（EGFR）信号在非转化的角膜生体中具有过度表达或抑制性Klf5的非转化角质细胞中的作用； （b）通过KLF5研究EGFR和ILK的转录调控； （c）检查食管中KLF5的转基因表达的小鼠。在特定的目标2中，我们将通过以下方式确定食管过程中KLF5的功能：（a）检查整联蛋白，ILK和EGFR途径在转化的食管鳞状细胞中； （b）在食管中评估具有KLF5的转基因表达的小鼠中的发育不良和肿瘤形成，这些小鼠已用癌变NMBA治疗或用ED-L2/Cyclin D1转基因小鼠（一种既定的遗传癌模型）交叉。总体而言，对食管上皮亚中KLF5调节的途径的理解将提供一个框架，以了解良性和恶性的食管疾病的分子事件。公共卫生相关性：食道疾病，例如胃食管反射疾病和食管癌，是美国和全世界最常见的疾病之一，这些疾病是由于正常的上皮稳态失调而引起的。这是对分子机制的欣赏，包括控制正常的食管增殖和分化的特定因素和复杂信号阵列，对于理解良性和恶性食管疾病的理解至关重要。该应用程序中提出的研究旨在通过研究关键调节蛋白KLF5的研究来阐明这些因素和信号通路。