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 具有耐药性表型的复发经常在高级浆液卵巢癌（HGSOC）中， 妇科恶性肿瘤中最致命的。但是，负责复发的分子机械和 HGSOC中的抗性表型仍在发展，迫切需要克服治疗性抗性 和预后不良。在这种情况下，将microRNA-195（miR-195）建立为关键分子调节药物 HGSOC中的耐药性很大。我们最近报道了miR -195在HGSOC中表达不足 MICU1，其异位表达显着降低了卵巢的克隆生长，迁移和入侵 癌细胞。使用卵巢癌的小鼠模型，我们报道了miR-195重新表达 减少肿瘤的生长，增加肿瘤加倍的时间，并增强肿瘤的总体存活率 老鼠。然而，尚未阐明miR-195在HGSOC耐药性中的作用。 有趣的是，我们的内部分析表明，miR-195可以靶向Wnt7a，这是Wnt/β-catenin的关键配体 单，在HGSOC中被上调，在正常卵巢中未检测到。 Wnt/β-catenin在卵巢中单身 癌症与具有抗药性表型的癌细胞中的茎状特性有关。此外，我们 在我们的初步数据中证明，miR-195在Wnt/β-catenin信号通路中对MiR-195进行负调节 HGSOC细胞。基于这些结果，我们假设MiR-195在HGSOC中的表达不足为 负责Wnt7a耐药性表型的上调和演变。我们将使用特定的目标 以下要检验假设并实现总体目标；目标1：调查mir-195的作用 耐药卵巢癌的表达。目标2：评估miR-195对转移和药物的影响 使用Auroliposom介导的miR-195递送系统的卵巢癌模型中的灵敏度。成功的 该项目的完成将建立MiR-195作为HGSOC耐药性的调节剂，并可能 可以通过miR-195递送或靶向Wnt7a来克服它的可翻译策略以抑制Wnt/β- Catenin途径。