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：
10620830
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/10620830
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 Proliferating 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 Transfection Tumor Cell Invasion Tumor Weights Western Blotting Woman angiogenesis 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

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.

抽象的这项拨款申请的目的是促进代表性不足的生物医学研究的卓越发展波多黎各大学医学科学校区的研究生和本科生。全世界，由于癌症具有对化疗产生耐药性的能力，因此与癌症相关的死亡人数持续增加转移。对于患有卵巢癌的女性，高达 70% 的女性会对一线治疗产生耐药性，顺铂。虽然顺铂耐药机制已被广泛研究，但尚无有效的治疗方法结果，使得此类研究变得至关重要且重要。在寻找新的治疗策略以逆转鉴于这些可怕的趋势，我们发现顺铂中基质金属蛋白酶 3 (MMP3) 含量很高使用差异基因表达研究，将耐药性卵巢癌细胞与反应性卵巢癌细胞进行比较。我们的开创性的发现进一步证明，MMP3水平高的卵巢癌肿瘤复发速度更快率高于表达水平较低的酶，进一步支持了这种酶在疾病中发挥关键作用的观点进展。 MMP3 属于 MMP 蛋白水解酶家族，可降解多种成分细胞外基质（ECM）。 MMP 的蛋白质结构包括催化结构域和血红素结合蛋白 (HPX) 领域。几种合成和天然 MMP 抑制剂已被设计用于抑制 MMP 的催化结构域 MMP。然而，由于非药物引起的明显毒性，这些研究几年前就被放弃了。这些抑制剂的具体特征。然而，我们实验室的令人兴奋的数据试图扭转这些通过证明靶向 MMP3 的小干扰 RNA (siRNA) 显着降低趋势，结果令人失望降低顺铂耐药卵巢癌细胞的细胞增殖和侵袭能力。我们没有当我们使用与催化结构域结合的抑制剂时，观察到增殖或侵袭性降低基质金属蛋白酶3。我们的初步结果与 MMP3 的 HPX 结构域可以结合的证据一致连接 ECM 与细胞内分子途径的蛋白质。因此，我们准备检查不不仅研究了 MMP3 对顺铂耐药性的贡献，而且还鉴定了可能的相关蛋白它们对这种疾病有贡献，它们本身就代表了新的研究治疗靶点。所以，我们计划检验我们的假设，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完善的卵巢癌症模型中，我们将测试这个中心假设，具体目标如下：（1）确定MMP3是否在卵巢癌模型中介导对化疗药物顺铂的敏感性，(2) 鉴定蛋白质直接与顺铂耐药卵巢癌细胞中的 MMP3 相互作用，以及 (3) 确定生物学 siRNA 介导的 MMP3 靶向在卵巢癌模型中的后果和治疗效果。结果该研究项目有可能通过增强对治疗耐药性的理解来产生影响 MMP3 在卵巢癌中的非催化功能。