Molecular Studies Of Ovarian Cancer

卵巢癌的分子研究

• 批准号: 6969293
• 负责人: Patrice J. Morin
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6969293
• 关键词: antisense nucleic acid; apoptosis; carcinogenesis; cell adhesion; cisplatin; collagen; drug resistance; extracellular matrix; gene expression; gene mutation; gene targeting; human tissue; membrane proteins; molecular oncology; neoplasm /cancer genetics; ovary neoplasms; phosphatidylinositol 3 kinase; phosphorylation; serial analysis of gene expression; tight junctions

Ovarian cancer is the fifth most common cancer and the fourth leading cause of cancer death among women in the United States. Because of a lack of powerful screening and diagnostic tests, early detection has been difficult. Moreover, the molecular mechanisms important in ovarian cancer initiation, progression, and resistance to chemotherapeutic drugs remain largely unknown. We are using SAGE and other state-of-the-art molecular techniques to identify tumor markers and gain a greater understanding of the molecular pathways involved in ovarian tumorigenesis and cisplatin resistance. The analysis of gene expression in ovarian cancer suggests the involvement of many novel pathways in this disease. We are currently investigating the roles of different pathways using molecular and cellular approaches. Of particular interest is the involvement of claudin proteins and the role of tight junctions in ovarian cancer. Claudin proteins represent a large family of integral membrane proteins crucial for tight junction formation and function. Our SAGE data and follow-up experiments show that a few members of the claudin family are frequently elevated in all primary ovarian cancer subtypes and in many ovarian cancer cell lines but not in non-malignant ovarian cystadenomas. Although normally found at the membrane, these proteins are frequently mislocalized in cancer suggesting abnormal processing and a role in malignancy unrelated to known tight junction function. We are studying the role of these proteins by examining the effects of overexpression of wild type and mutant claudin proteins in ovarian cells. We are also examining the mechanisms of regulation of these proteins through phosphorylation. Our ultimate goal is the development of mechanism-based interventions for ovarian cancer patients. For example, we have recently found an important role for extracellular matrix (ECM) remodeling in the development of drug resistance in ovarian cancer. We have shown that tumor cells can remodel their microenvironment through production of collagen VI and that the presence of collagen VI increases resistance of ovarian cells to chemotherapeutic agents. Inhibition of ECM-cancer cell interactions may therefore provide novel therapeutic opportunities for the development of strategies to circumvent the problem of drug resistance in ovarian cancer. We are currently investigating the mechanisms of cell adhesion-mediated drug resistance (CAM-DR) in ovarian cancer. We are also studying the roles of the phosphatidylinositol 3 kinase/Akt pathway as well as the X-linked inhibitor of apoptosis (XIAP) pathway in ovarian cancer drug resistance using, among other approaches, siRNAs and somatic gene targeting strategies.

卵巢癌是美国女性第五大癌症，也是癌症死亡的第四个主要原因。由于缺乏强大的筛查和诊断测试，很难早期检测。此外，在卵巢癌的开始，进展和对化学治疗药物的抗性中重要的分子机制仍然很大程度上未知。我们正在使用SAGE和其他最先进的分子技术来鉴定肿瘤标记，并对参与卵巢肿瘤发生和顺铂耐药的分子途径有更深入的了解。卵巢癌基因表达的分析表明，许多新途径参与了这种疾病。我们目前正在使用分子和细胞方法研究不同途径的作用。特别令人感兴趣的是克劳丁蛋白的参与以及紧密连接在卵巢癌中的作用。 Claudin蛋白代表了一个大型整体膜蛋白，对于紧密结的形成和功能至关重要。我们的鼠尾草数据和随访实验表明，在所有原发性卵巢癌亚型和许多卵巢癌细胞系中，克劳丁家族的几个成员经常升高，但在非恶性卵巢囊肿瘤中没有升高。尽管通常在膜上发现这些蛋白质，但这些蛋白质经常在癌症中错误地定位，表明处理异常和在与已知紧密连接功能无关的恶性肿瘤中作用。我们正在研究这些蛋白质的作用，通过研究野生型和突变蛋白蛋白在卵巢细胞中的过表达的影响。我们还通过磷酸化检查了这些蛋白质调节的机制。 我们的最终目标是开发基于机制的卵巢癌患者的干预措施。例如，我们最近发现了细胞外基质（ECM）重塑在卵巢癌中耐药性发展中的重要作用。我们已经表明，肿瘤细胞可以通过产生胶原蛋白VI来重塑其微环境，并且胶原蛋白VI的存在增加了卵巢细胞对化学治疗剂的耐药性。因此，抑制ECM-Canter细胞相互作用可能会为制定策略避免卵巢癌耐药性问题提供新的治疗机会。我们目前正在研究卵巢癌中细胞粘附介导的耐药性（CAM-DR）的机制。我们还研究了磷脂酰肌醇3激酶/AKT途径的作用，以及X连锁的凋亡抑制剂（XIAP）途径在卵巢癌耐药性中使用sirNAS和体细胞基因靶向策略的抗卵巢癌耐药性。