Role of miR-195 in Chemo-Resistant Ovarian Cancer

miR-195 在化疗耐药性卵巢癌中的作用

• 批准号: 10640540
• 负责人: Shailendra Kumar Dhar Dwivedi
• 金额: $ 16.95万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2023-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10640540
• 关键词: 3' Untranslated Regions; 3-Dimensional; Adopted; Animal Model; Antineoplastic Agents; Binding Sites; Biological Assay; Calcium; Cancer Model; Cancer Patient; Carboplatin; Cells; Cellular Spheroids; Chemoresistance; Cisplatin; Data; Down-Regulation; Drug resistance; Ectopic Expression; Endothelial Cells; Endowment; Evolution; Fibroblasts; Formulation; Growth; Homing; Human; Immunofluorescence Immunologic; Implant; In Situ Nick-End Labeling; Invaded; Ligands; Luciferases; Maintenance; Malignant Conversion; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; MicroRNAs; Mitochondria; Modeling; Molecular; Mus; Mutate; Neoplasm Metastasis; Ovary; PECAM1 gene; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Prognosis; Property; Proteins; Publishing; Recurrence; Recurrent Malignant Neoplasm; Reporting; Resistance; Role; Sampling; Scheme; Serous; Signal Pathway; Signal Transduction; Small Interfering RNA; System; Techniques; Testing; Therapeutic; Time; Tissue Microarray; Toxic effect; Transfection; Treatment Failure; Tumor Volume; Up-Regulation; WNT7A gene; Western Blotting; Xenograft Model; beta catenin; cancer cell; cancer drug resistance; cancer recurrence; cancer stem cell; cancer therapy; drug sensitivity; in silico; in vivo; migration; mortality; mouse model; novel; overexpression; patient response; stem; therapy outcome; therapy resistant; translatable strategy; tumor; tumor growth; tumor progression; uptake

Abstract Recurrence with drug resistance phenotype is frequent in high-grade serous ovarian cancer (HGSOC), the deadliest among gynecologic malignancies. However, molecular machineries responsible for recurrence and resistant phenotype in HGSOC are still evolving and urgently needed to overcome the therapeutic resistance and poor prognosis. In this context, establishing microRNA-195 (miR-195) as a critical molecule regulating drug resistance in HGSOC is significant. We recently reported that miR‐195 is under‐expressed in HGSOC, targets MICU1, and that its ectopic expression significantly reduces the clonal growth, migration, and invasion of ovarian cancer cells. Using a mouse model of ovarian cancer, we reported that miR-195 re-expression significantly reduces tumor growth, increases tumor doubling times, and enhances the overall survival of the tumor-bearing mouse. However, the role of miR-195 in drug resistance of HGSOC has not been elucidated. Interestingly, our in-silico analyses reveal that miR-195 can target WNT7A, a key ligand for the Wnt/β-catenin singling, which is upregulated in HGSOC and not detected in normal ovaries. Wnt/β-catenin singling in ovarian cancer is associated with stem-like properties in cancer cells with drug-resistant phenotype. Furthermore, we demonstrate in our preliminary data that miR-195 negatively regulates in Wnt/β-catenin signaling pathway in HGSOC cells. Based on these results, we hypothesize that the under-expression of miR-195 in HGSOC is responsible for WNT7A upregulation and evolution of the drug resistance phenotype. We will use specific aims below to test the hypothesis and accomplish overall objectives; Aim 1: Investigating the role of miR-195 expression in drug-resistant ovarian cancer. Aim 2: Evaluate the effect of miR-195 on metastasis and drug sensitivity in an ovarian cancer model using auroliposome mediated miR-195 delivery system. Successful completion of the project will establish miR-195 as a regulator of drug resistance in HGSOC and a potentially translatable strategy to overcome it either by miR-195 delivery or by targeting the WNT7A to inhibit the WNT/β- catenin pathway.

抽象的 耐药表型复发在高级别浆液性卵巢癌 (HGSOC) 中很常见， 妇科恶性肿瘤中最致命的。然而，分子机制负责复发和 HGSOC 中的耐药表型仍在不断发展，迫切需要克服治疗耐药性 且预后不良。在此背景下，将 microRNA-195 (miR-195) 确立为关键分子调节药物 HGSOC 中的阻力是显着的。我们最近报道 miR-195 在 HGSOC 中表达不足，目标 MICU1，其异位表达显着降低卵巢的克隆生长、迁移和侵袭 癌细胞。使用卵巢癌小鼠模型，我们报告 miR-195 重新表达显着 减少肿瘤生长，增加肿瘤倍增时间，并提高荷瘤者的总体生存率 老鼠。然而，miR-195在HGSOC耐药中的作用尚未阐明。 有趣的是，我们的计算机分析表明 miR-195 可以靶向 WNT7A，Wnt7A 是 Wnt/β-连环蛋白的关键配体 singleing，它在 HGSOC 中上调，但在正常卵巢中未检测到。卵巢中的 Wnt/β-连环蛋白单向 癌症与具有耐药表型的癌细胞的干细胞样特性有关。此外，我们 我们的初步数据表明，miR-195 在 Wnt/β-catenin 信号通路中负向调节 HGSOC 细胞。基于这些结果，我们假设 HGSOC 中 miR-195 的表达不足是 负责 WNT7A 上调和耐药表型的进化。我们将使用特定的目标 下面测试假设并实现总体目标；目标 1：研究 miR-195 的作用 在耐药性卵巢癌中的表达。目标2：评估miR-195对转移和药物的影响 使用金脂体介导的 miR-195 递送系统的卵巢癌模型的敏感性。成功的 该项目的完成将确立 miR-195 作为 HGSOC 耐药性的调节剂，并有可能成为 通过传递 miR-195 或靶向 WNT7A 抑制 WNT/β- 来克服它的可翻译策略 连环蛋白途径。