Regulation of MMP-9 mRNA stability and tumor growth by alpha3 beta1 integrin

α3β1 整合素对 MMP-9 mRNA 稳定性和肿瘤生长的调节

基本信息

批准号：
8332876
负责人：
C. Michael DiPersio
金额：
$ 23.04万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-26 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8332876
关键词：
Adhesions Binding Biochemical CD29 Antigen Carcinoma Cell Proliferation Cell model Cells Data Development Dominant-Negative Mutation ECM receptor Elements Epidermis Epithelial Epithelial Cells Extracellular Matrix Family Gelatinase B Gene Expression Gene Expression Regulation Generations Genes Genetic Goals Guanosine Triphosphate Phosphohydrolases Health Human Indium Integrins Laminin Link MAP Kinase Gene MAPK14 gene Malignant - descriptor Malignant Neoplasms Matrix Metalloproteinases Mediating Messenger RNA Modeling Molecular Molecular Genetics Molecular Target Mutation Neonatal Neoplasm Metastasis Normal Cell Nude Mice Oncogenic Pathway interactions Phenotype Polyadenylation Publishing Regulation Regulatory Element Research Role Signal Pathway Signal Transduction Signal Transduction Pathway Site-Directed Mutagenesis Specimen Squamous Cell Squamous cell carcinoma Staging System Testing Transcript Tumor Angiogenesis Tumor Cell Invasion Untranslated Regions Variant base cancer cell cancer therapy cell growth data modeling epithelial to mesenchymal transition in vivo keratinocyte mRNA Expression mRNA Stability neoplastic cell novel null mutation receptor research study rho small hairpin RNA therapeutic target tumor tumor growth tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Integrin a3b1 is an extracellular matrix receptor that is expressed in many malignant tumors and has been shown to regulate cellular phenotypes associated with epithelial-to-mesenchymal transition (EMT), such as cell proliferation, survival, and invasion. Expression of matrix metalloproteinase MMP-9 is also linked to malignant tumor growth, where it promotes tumor angiogenesis and cell invasion. a3b1 induces MMP-9 in immortalized keratinocytes (MK cells) through post-transcriptional mRNA stability, and this regulation is acquired during cellular immortalization. However, the mechanisms and signaling pathways whereby a3b1 regulates MMP-9 mRNA stability and their roles in tumor growth and progression are unknown. The goal of the proposed research is to answer these questions by exploiting a panel of a3b1-expressing (i.e. a3 wild type) and a3b1- deficient (i.e., a3-null) MK variants that collectively represent different EMT stages: (1) non-immortalized keratinocytes are isolated from neonatal epidermis; (2) immortalized MK cells harbor a p53-null mutation; (2) transformed MK cells additionally express oncogenic RasV12. Loss of p53 and oncogenic Ras activation are common mutations in squamous cell and other carcinomas. Preliminary data from this model indicate that a3b1 and MMP-9 are required for in vivo tumor growth of MK cells, and identify candidate signaling pathways and mechanisms whereby a3b1 may control MMP-9 mRNA stability. The proposed studies will test the hypotheses that MMP-9 mRNA expression is controlled by specific a3b1-mediated signaling pathways that control mRNA stability, and that these mechanisms control tumor growth in vivo. A combination of molecular, genetic, and biochemical approaches will be used to identify mRNA regulatory elements that control a3b1- dependent mRNA stability, and to elucidate specific signaling pathways or integrin functions that are involved in a3b1-mediated MMP-9 mRNA stability. An in vivo tumorigenesis model will be used to investigate the role of a3b1-dependent regulation of MMP-9 for tumor growth. Finally, the human relevance of these observations will be investigated by testing for a3b1-dependent regulation of MMP-9 in several human carcinoma lines, and by assessing expression of a3b1 and MMP-9 in human tumor specimens.

描述（由申请人提供）：整联蛋白A3B1是一种在许多恶性肿瘤中表达的细胞外基质受体，已被证明可以调节与上皮到间质转变（EMT）相关的细胞表型，例如细胞增殖，存活和入侵。基质金属蛋白酶MMP-9的表达也与恶性肿瘤生长有关，它促进了肿瘤血管生成和细胞浸润。 A3B1通过转录后mRNA稳定性诱导MMP-9在永生化角质形成细胞（MK细胞）中，并且在细胞永生化期间获得了这种调节。但是，A3B1调节MMP-9 mRNA稳定性及其在肿瘤生长和进展中的作用的机制和信号通路尚不清楚。 The goal of the proposed research is to answer these questions by exploiting a panel of a3b1-expressing (i.e. a3 wild type) and a3b1- deficient (i.e., a3-null) MK variants that collectively represent different EMT stages: (1) non-immortalized keratinocytes are isolated from neonatal epidermis; （2）永生的MK细胞带有p53-null突变；（2）转化的MK细胞另外表达致癌RASV12。 p53和致癌性RAS激活的丧失是鳞状细胞和其他癌中的常见突变。来自该模型的初步数据表明，MK细胞体内肿瘤生长需要A3B1和MMP-9，并确定A3B1可能控制MMP-9 mRNA稳定性的候选信号通路和机制。拟议的研究将测试MMP-9 mRNA表达的假设由控制mRNA稳定性的特定A3B1介导的信号通路控制，并且这些机制控制体内肿瘤的生长。分子，遗传和生化方法的组合将用于鉴定控制A3B1依赖的mRNA稳定性的mRNA调节元件，并阐明与A3B1介导的MMP-9 mRNA稳定性有关的特定信号通路或整合素功能。体内肿瘤发生模型将用于研究MMP-9对A3B1依赖性调节在肿瘤生长中的作用。最后，将通过测试几种人类癌系中A3B1依赖的MMP-9调节，以及评估人类肿瘤标本中A3B1和MMP-9的表达来研究这些观察结果的人类相关性。