Transcriptional Repression of MMP7 by FXR in Intestinal Epithelial Cells

FXR 对肠上皮细胞中 MMP7 的转录抑制

基本信息

批准号：
10085614
负责人：
Guofeng Xie
金额：
--
依托单位：
BALTIMORE VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10085614
关键词：
Agonist Antibodies Antibody Therapy ApcMin/+ mice Apoptosis Attenuated Bile Acids Biological Assay Cancer Etiology Cell Proliferation Cessation of life Chemoprevention Clinical Clinical Data Colon Colon Carcinoma Colonic Neoplasms Colonoscopy Colorectal Cancer Data Disease Disease Progression Dominant-Negative Mutation Elements Epithelial Cells Extracellular Matrix Fecal occult blood Genes Genetic Transcription Goals Growth Human Image In Vitro Intestinal Cancer Intestinal Neoplasms Intestines Knowledge Light Luciferases Matrilysin Molecular Morbidity - disease rate Mutation Analysis Neoplasm Metastasis Nuclear Receptors Outcome Patient Noncompliance Receptor Activation Regulatory Element Rodent Model Role Seminal Signal Transduction Testing Transcription Initiation Site Transcription Repressor Tumor Cell Invasion Tumor Suppressor Proteins United States Veterans WNT Signaling Pathway Work Xenograft Model Xenograft procedure adenoma advanced disease base cancer cell cancer chemoprevention chromatin immunoprecipitation collagenase colon cancer progression colorectal cancer screening effective therapy efficacy testing fexaramine gene repression in vivo in vivo Model inhibiting antibody innovation intestinal epithelium knock-down member mortality mouse model mutant new therapeutic target novel overexpression pre-clinical promoter public health relevance receptor screening targeted treatment therapeutic target transcription factor tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Colon cancer remains a leading cause of morbidity and mortality in Veterans because therapy for metastatic disease has limited efficacy. Our long-term goal is to develop innovative, effective, and safe therapies by targeting pivotal signal transduction molecules underlying colon cancer progression. The Farnesoid X Receptor (FXR), a member of the nuclear receptor superfamily of bile acid-activated transcription factors, appears to be such a pivotal molecule. FXR is a tumor suppressor whose expression is strikingly reduced in colon cancer; in rodent models of intestinal neoplasia FXR deficiency increases adenoma size and number. FXR regulates cell proliferation, apoptosis, and Wnt signaling but the molecular mechanisms underlying its tumor-suppressive actions are incompletely understood. Our short-term goal is to fill this gap in knowledge. Recently, we made the seminal observation that matrix metalloproteinase 7 (MMP7) is an FXR target gene. MMP7, a collagenase that degrades extracellular matrix, is over-expressed in most colon tumors and enhances cell proliferation, tumor invasion, and metastasis. Our preliminary data show that FXR is a transcriptional repressor for MMP7; decreased FXR levels correlate with increased MMP7 expression in normal intestine and colon cancer. Also, we found that activating FXR in human colon cancer cells attenuates MMP7 expression, as well as xenograft growth and invasion. Based on these novel findings we propose the paradigm-shifting central hypothesis that FXR activation inhibits colon cancer progression by repressing MMP7 gene transcription. To test this hypothesis we propose three Specific Aims: Aim 1. Test the hypothesis that FXR is a direct transcriptional repressor of MMP7 and identify the MMP7 FXR responsive element. Aim 2. Test the hypothesis that activating intestinal FXR selectively down-regulates MMP7 expression, thereby inhibiting tumor growth in vivo. Aim 3. Test the hypothesis that neutralizing anti-MMP7 antibody attenuates colon cancer progression in vivo. Overall impact: We will reveal a novel role for FXR as a transcriptional repressor of MMP7 and identify a new mechanism whereby FXR suppresses colon cancer cell proliferation and disease progression. Moreover, we will demonstrate the clinical potential of using fexaramine, an intestine-selective FXR agonist, for chemo- prevention and anti-MMP7 antibody for advanced disease.

描述（由申请人提供）：结肠癌仍然是退伍军人发病和死亡的主要原因，因为转移性疾病的治疗效果有限，我们的长期目标是通过靶向结肠癌进展的关键信号转导分子来开发创新、有效和安全的疗法。受体 (FXR) 是胆汁酸激活转录因子核受体超家族的成员，FXR 似乎是一种肿瘤抑制因子，其在结肠癌啮齿动物模型中的表达显着降低。 FXR 缺乏会增加腺瘤的大小和数量，但其肿瘤抑制作用的分子机制尚不完全清楚。基质金属蛋白酶 7 (MMP7) 是 FXR 靶基因的开创性观察，MMP7 是一种降解细胞外基质的胶原酶，在大多数结肠肿瘤中过度表达并增强细胞增殖，我们的初步数据表明，FXR 是 MMP7 的转录抑制因子；FXR 水平降低与正常肠癌和结肠癌中 MMP7 表达增加相关。此外，我们发现激活人结肠癌细胞中的 FXR 会减弱 MMP7 表达。基于这些新发现，我们提出了范式转变的中心假设：FXR 激活通过抑制 MMP7 基因来抑制结肠癌进展。为了测试这一假设，我们提出了三个具体目标：目标 1. 测试 FXR 是 MMP7 的直接转录抑制因子的假设，并鉴定 MMP7 FXR 响应元件目标 2. 测试激活肠道 FXR 选择性下调 MMP7 的假设。目标 3. 检验中和抗 MMP7 抗体可在体内减弱结肠癌进展的假设：我们将。揭示了 FXR 作为 MMP7 转录抑制因子的新作用，并确定了 FXR 抑制结肠癌细胞增殖和疾病进展的新机制。此外，我们将证明使用 fexaramine（一种肠道选择性 FXR 激动剂）用于化疗的临床潜力。预防和针对晚期疾病的抗 MMP7 抗体。