Unraveling the Role of MMP3 in the Cisplatin Resistance of Ovarian Cancer

揭示 MMP3 在卵巢癌顺铂耐药中的作用

基本信息

批准号：
10412430
负责人：
Pablo Elias Vivas-Mejia
金额：
$ 15万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-11 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10412430
关键词：
Agreement Applications Grants Binding Biological Biomedical Research Cancer Etiology Cancer Model Cancer Patient Cancerous Catalytic Domain Cell Extracts Cell Proliferation Cell Survival Cell physiology Cells Cessation of life Chemicals Chemoresistance Cisplatin Clinical Clustered Regularly Interspaced Short Palindromic Repeats Combination Drug Therapy Conditioned Culture Media Data Disease Disease Progression Dose Enzymes Extracellular Matrix Family Genes Goals Hemopexin Immunoprecipitation Implant Intervention Investigation Knock-out Laboratories Link Liposomes Malignant Neoplasms Malignant neoplasm of ovary Mass Spectrum Analysis Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Medical Messenger RNA Mission Molecular Molecular Biology Neoplasm Metastasis Nodule Nude Mice Pathway interactions Patients Peptide Hydrolases Platinum Play Predisposition Process Progression-Free Survivals Proteins Proteomics Public Health Publishing Puerto Rico Quinones RNA RNA Interference Regulation Relapse Research Research Project Grants Resistance Role Science Seminal Signaling Protein Small Interfering RNA Stromelysin 1 Testing The Cancer Genome Atlas Therapeutic Therapeutic Effect Tissue-Specific Gene Expression Toxic effect Tumor Cell Invasion Tumor Weights Western Blotting Woman angiogenesis base cancer cell cancer therapy carcinogenesis chemotherapy data portal design effective therapy experimental study graduate student holistic approach in vivo inhibitor intraperitoneal knock-down mouse model mutant new therapeutic target novel novel therapeutic intervention overexpression programs protein structure response subcutaneous taxane therapeutic target therapy resistant tool transcriptome sequencing trend tumor tumor growth undergraduate student university student

Agreement Applications Grants Binding Biological Biomedical Research Cancer Etiology Cancer Model Cancer Patient Cancerous Catalytic Domain Cell Extracts Cell Proliferation Cell Survival Cell physiology Cells Cessation of life Chemicals Chemoresistance Cisplatin Clinical Clustered Regularly Interspaced Short Palindromic Repeats Combination Drug Therapy Conditioned Culture Media Data Disease Disease Progression Dose Enzymes Extracellular Matrix Family Genes Goals Hemopexin Immunoprecipitation Implant Intervention Investigation Knock-out Laboratories Link Liposomes Malignant Neoplasms Malignant neoplasm of ovary Mass Spectrum Analysis Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Medical Messenger RNA Mission Molecular Molecular Biology Neoplasm Metastasis Nodule Nude Mice Pathway interactions Patients Peptide Hydrolases Platinum Play Predisposition Process Progression-Free Survivals Proteins Proteomics Public Health Publishing Puerto Rico Quinones RNA RNA Interference Regulation Relapse Research Research Project Grants Resistance Role Science Seminal Signaling Protein Small Interfering RNA Stromelysin 1 Testing The Cancer Genome Atlas Therapeutic Therapeutic Effect Tissue-Specific Gene Expression Toxic effect Tumor Cell Invasion Tumor Weights Western Blotting Woman angiogenesis base cancer cell cancer therapy carcinogenesis chemotherapy data portal design effective therapy experimental study graduate student holistic approach in vivo inhibitor intraperitoneal knock-down mouse model mutant new therapeutic target novel novel therapeutic intervention overexpression programs protein structure response subcutaneous taxane therapeutic target therapy resistant tool transcriptome sequencing trend tumor tumor growth undergraduate student university student

展开

项目摘要

Abstract The purpose of this grant application is to promote the excellence in biomedical research of underrepresented graduate and undergraduate students of the University of Puerto Rico Medical Sciences Campus. World-wide, cancer related deaths continue to increase due to their ability to become chemotherapy resistant and metastasize. For women with ovarian cancer, a staggering 70% will become resistant to the front-line therapy, cisplatin. While the mechanism of cisplatin resistance has been extensively studied, no effective treatments have resulted, making such research critical and important. During the search for new therapeutic strategies to reverse these horrendous trends, we identified matrix metalloproteinase 3 (MMP3) to be highly abundant in cisplatin resistant ovarian cancer cells, as compared to responsive ones, using differential gene expression studies. Our seminal findings have further demonstrated that ovarian cancer tumors with high MMP3 levels relapse at a faster rate than those expressing lower levels, further supporting the notion that this enzyme plays a key role in disease progression. MMP3 belongs to the MMPs family of proteolytic enzymes that degrade multiple components of the extracellular matrix (ECM). The protein structure of MMPs includes a catalytic domain and a hemopexin (HPX) domain. Several synthetic and natural MMP inhibitors have been designed to inhibit the catalytic domain of MMPs. However, these studies were abandoned years ago due to the overt toxicities resulting from the non- specific profile of those inhibitors. However, exciting data from our laboratory seeks to reverse these disappointing trends by demonstrating that MMP3-targeting small-interfering RNAs (siRNAs) significantly reduced cell proliferation and the invasiveness ability of cisplatin resistant ovarian cancer cells. We did not observe reduced proliferation or invasiveness when we used an inhibitor that binds to the catalytic domain of the MMP3. Our preliminary results are in agreement with evidence that the HPX domain of MMP3 could binds to proteins connecting the ECM with intracellular molecular pathways. Therefore, we are poised to examine not only the contribution of MMP3 to the cisplatin resistance, but also to identify associated proteins that might contribute to this disease and they themselves represent new therapeutic targets for investigation. Therefore, we plan to test our hypothesis that other regions of MMP3 (HPX domain) interact with proteins promoting cisplatin resistance. Using a combination of molecular biology tools and our extensive and well established ovarian cancer models, we will test this central hypothesis with the following specific aims: (1) determine whether MMP3 in ovarian cancer models mediates susceptibility to the chemotherapy agent cisplatin, (2) identify the protein directly interacting with MMP3 in cisplatin resistant ovarian cancer cells, and (3) determine the biological consequences and therapeutic effects of siRNA-mediated MMP3 targeting in ovarian cancer models. Results of this research project have the potential to provide impact by enhancing understanding of therapy resistance and non-catalytic functions of MMP3 in ovarian cancer.

抽象的该赠款申请的目的是促进代表性不足的生物医学研究的卓越波多黎各大学医学科学校园的研究生和本科生。全世界，癌症与癌症相关的死亡由于能够成为化学疗法的能力而继续增加转移。对于患有卵巢癌的女性，惊人的70％将对前线治疗具有抵抗力，顺铂。尽管已经对顺铂耐药的机制进行了广泛的研究，但没有有效的治疗方法导致这样的研究至关重要。在寻找新的治疗策略以逆转这些可怕的趋势，我们确定基质金属蛋白酶3（MMP3）在顺铂高度丰富与反应迅速的抗卵巢癌细胞相比，使用差异基因表达研究。我们的开创性发现进一步证明，MMP3水平高的卵巢癌肿瘤更快地复发比率比表达较低水平的速度，进一步支持这种酶在疾病中起关键作用的观念进展。 mmp3属于蛋白水解酶的MMP家族，这些酶降解了多个成分细胞外基质（ECM）。 MMP的蛋白质结构包括催化结构域和血压素（HPX）领域。已经设计了几种合成和天然MMP抑制剂，以抑制 MMP。但是，由于非 - 这些抑制剂的特定曲线。但是，我们实验室的令人兴奋的数据试图扭转这些令人失望的趋势通过证明了对MMP3的小互动RNA（siRNA）显着的趋势降低了细胞增殖和抗铂抗卵巢癌细胞的侵袭能力。我们没有当我们使用与结合与催化结构域结合的抑制剂时，观察到降低或侵入性降低 mmp3。我们的初步结果与证据表明MMP3的HPX结构域可能与将ECM与细胞内分子途径连接的蛋白质。因此，我们准备不检查仅MMP3对顺铂耐药性的贡献，但也可以鉴定可能的蛋白质为这种疾病做出贡献，它们本身代表了调查的新治疗靶标。所以，我们计划测试我们的假设，即MMP3的其他区域（HPX结构域）与促进顺铂的蛋白质相互作用反抗。结合分子生物学工具和我们广泛且良好的卵巢癌症模型，我们将以以下特定目的测试此中心假设：（1）确定MMP3是否在卵巢癌模型中，介导对化学疗法剂顺铂的敏感性，（2）鉴定蛋白质在抗顺铂抗性卵巢癌细胞中与MMP3直接相互作用，（3）确定生物学卵巢癌模型中siRNA介导的MMP3靶向的后果和治疗作用。结果该研究项目有可能通过增强对治疗耐药性的理解来提供影响 MMP3在卵巢癌中的非催化功能。