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.

摘要 高级别浆液性卵巢癌（HGSOC）经常复发并伴有耐药表型， 是妇科恶性肿瘤中最致命的然而，负责复发的分子机制和 HGSOC中的耐药表型仍在发展，迫切需要克服治疗耐药性 预后差。在此背景下，将microRNA-195（miR-195）确定为关键分子调节药物， HGSOC中的抗性是显著的。我们最近报道，miR-195在HGSOC中表达不足，靶向 MICU 1的异位表达显著降低了卵巢癌细胞的克隆生长、迁移和侵袭， 癌细胞使用小鼠卵巢癌模型，我们报道了miR-195的重新表达显著地抑制了卵巢癌的发生。 减少肿瘤生长，增加肿瘤倍增时间，并提高荷瘤患者的总体存活率。 老鼠.然而，miR-195在HGSOC耐药性中的作用尚未阐明。 有趣的是，我们的计算机模拟分析显示，miR-195可以靶向WNT 7A，WNT/β-catenin的关键配体， 单一化，在HGSOC中上调，在正常卵巢中未检测到。卵巢中Wnt/β-catenin的单一表达 癌症与具有耐药表型的癌细胞中的干细胞样性质有关。而且我们 在我们的初步数据中证明，miR-195在Wnt/β-catenin信号通路中负调控， HGSOC细胞。基于这些结果，我们假设miR-195在HGSOC中的低表达是由于 负责WNT 7A上调和耐药性表型的演变。我们将使用特定的目标 目的1：研究miR-195的作用 在耐药卵巢癌中的表达。目的2：评估miR-195对肿瘤转移和药物治疗的影响 使用金脂质体介导的miR-195递送系统在卵巢癌模型中的敏感性。成功 该项目的完成将确立miR-195作为HGSOC耐药性的调节剂，并可能成为HGSOC的潜在靶点。 通过miR-195递送或通过靶向WNT 7A以抑制WNT/β-半乳糖苷酶， 连环蛋白途径