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

• 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
• 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

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.

摘要 这项拨款申请的目的是促进优秀的生物医学研究的代表性不足 波多黎各大学医学院的研究生和本科生。在世界范围内， 癌症相关的死亡继续增加，这是由于它们具有变得耐化疗的能力， 转移对于患有卵巢癌的女性来说，惊人的70%会对一线治疗产生抗药性， 顺铂虽然顺铂耐药的机制已被广泛研究，但没有有效的治疗方法。 结果，使这样的研究至关重要。在寻找新的治疗策略，以扭转 这些可怕的趋势，我们确定了基质金属蛋白酶3（MMP 3）在顺铂中高度丰富 耐药卵巢癌细胞，与响应的，使用差异基因表达研究。我们 开创性的发现进一步证明，MMP 3水平高的卵巢癌肿瘤复发速度更快， 比那些表达较低水平的人，进一步支持这种酶在疾病中起关键作用的观点。 进展MMP 3属于MMPs家族的蛋白水解酶，其降解细胞中的多种组分。 细胞外基质（ECM）。MMPs的蛋白质结构包括催化结构域和血红素结合蛋白（HPX） 域已经设计了几种合成的和天然的MMP抑制剂来抑制MMP的催化结构域。 MMPs然而，这些研究在几年前就被放弃了，因为这些研究的结果是由非- 这些抑制剂的具体特征。然而，来自我们实验室的令人兴奋的数据试图扭转这些趋势。 令人失望的趋势，通过证明MMP 3靶向小干扰RNA（siRNA）显着 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 当我们使用结合到细胞的催化结构域的抑制剂时， MMP3。我们的初步结果与MMP 3的HPX结构域可以结合到 连接ECM与细胞内分子通路的蛋白质。因此，我们准备审查不 我们不仅要研究MMP 3对顺铂耐药的作用，还要鉴定可能与顺铂耐药相关的蛋白质。 有助于这种疾病，它们本身代表了研究的新治疗靶点。因此，我们认为， 我们计划验证我们的假设，即MMP 3的其他区域（HPX结构域）与促进顺铂的蛋白质相互作用 阻力使用分子生物学工具和我们广泛而完善的卵巢 在癌症模型中，我们将用以下具体目标来检验这个中心假设：（1）确定MMP 3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 在顺铂耐药卵巢癌细胞中直接与MMP 3相互作用，和（3）确定生物学活性， siRNA介导的MMP 3靶向卵巢癌模型的结果和治疗效果。结果 该研究项目有可能通过提高对治疗抵抗的理解而产生影响。 MMP 3在卵巢癌中的非催化功能