Molecular Pathogenesis of Ovarian Endometrioid Adenocarc

卵巢子宫内膜样腺癌的分子发病机制

• 批准号: 7173994
• 负责人: KATHLEEN R. CHO
• 金额: $ 5.42万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7173994
• 关键词: adenocarcinoma; athymic mouse; cadherins; cell cycle; endometriosis; enzyme activity; enzyme induction /repression; human tissue; molecular pathology; neoplasm /cancer genetics; ovary neoplasms; phosphorylation; telomerase

Ovarian carcinoma (OvCa) is a major cause of cancer- associated morbidity and mortality for women, yet much remains to be learned about its pathogenesis. Like other cancers, OvCas are thought to arise through a multi-step process in which repeated cycles of somatic mutation and clonal selection produce variant progeny with increasingly aggressive growth properties. The genes mutated in cancer frequently encode proteins that function in conserved signaling pathways. Molecular genetic analyses suggest that the different histologic subtypes of OvCa (e.g., serous, clear cell, mucinous, and endometrioid) may represent distinct disease entities and that OvCa precursor lesions may be subtype specific. Hence, a clearer understanding of OvCa pathogenesis might be more readily attained by focusing molecular genetic studies on distinct OvCa types for defects in cell signaling pathways. The ovarian endometrioid adenocarcinomas (OEAs) share a number of molecular genetic features with uterine endometrioid adenocarcinomas, including frequent mutations of the CTNNB1 gene which encodes beta-catenin (beta-cat), a critical component of the highly conserved Wnt signaling pathway. Previous studies suggest that although the Wnt/beta-cat/Tcf pathway may be defective in a substantial percentage of OEAs, it is only rarely altered in other histologic subtypes of OvCa. This application describes studies that are focused on defining the molecular mechanisms by which Wnt pathway defects contribute to the development and behavior of a specific type of OvCa, namely endometrioid adenocarcinomas. Toward this end, four specific aims are proposed: 1) To complete a comprehensive mutational analysis of genes encoding proteins known to regulate the Wnt/beta-cat/Tcf signaling pathway in a large group of primary OEAs; 2) To characterize expression of candidate downstream genes transcriptionally activated by the beta-cat/Tcf signaling pathway in OEAs with known pathway defects; 3) To examine a spectrum of endometriosis lesions (putative OEA precursors) for defects in beta-cat/Tcf pathway genes, and to determine whether expression of mutant beta-cat results in malignant transformation of immortalized cells derived from endometriosis, and 4) To determine if selected beta-cat/Tcf- activated genes are necessary and/or sufficient for neoplastic transformation by mutant beta-cat in RK3E cells or human cells with relevance to ovarian cancer (immortalized ovarian surface epithelial cells expressing telomerase, or cell lines derived from endometriosis).

卵巢癌（OVCA）是癌症相关的发病率和女性死亡率的主要原因，但有关其发病机理仍有很多待了解。 像其他癌症一样，卵子被认为是通过多步骤的过程产生的，在多步骤过程中，体细胞突变和克隆选择的重复循环产生具有越来越侵略性生长特性的变异后代。 癌症中突变的基因经常编码在保守信号通路中起作用的蛋白质。 分子遗传分析表明，OVCA的不同组织学亚型（例如，浆液，透明细胞，粘液和子宫内膜类药物）可能代表不同的疾病实体，并且OVCA前体病变可能是亚型特异性的。 因此，通过将分子遗传研究集中在不同的OVCA类型上，以使细胞信号传导途径的缺陷将分子遗传研究集中在不同的OVCA类型上，从而更清楚地了解OVCA发病机理。 卵巢子宫内膜类药物腺癌（OEAS）与子宫内膜类药物腺癌共享许多分子遗传特征，包括频繁的CTNNB1基因突变，这些突变编码了beta-catenin（beta-cat）（beta-cat），这是高度保存的Wnt信号通路的重要组成部分。先前的研究表明，尽管Wnt/beta-cat/tcf途径可能在很大一部分OEA中有缺陷，但在OVCA的其他组织学亚型中，它很少改变。该应用描述了重点是定义Wnt途径缺陷有助于特定类型OVCA的发展和行为的分子机制，即子宫内膜类药物腺癌。 为此，提出了四个具体目的：1）完成编码已知蛋白质的基因的全面突变分析，这些蛋白质已知，这些蛋白质已知，这些蛋白质已知，这些蛋白质会在大量的原代OEAS中调节WNT/beta-cat/tcf信号传导途径； 2）表征候选下游基因的表达，该基因由OEA中的β-CAT/TCF信号通路转录激活，并具有已知途径缺陷； 3）检查子宫内膜异位病变（推定的OEA前体）是否存在β-CAT/TCF途径基因的缺陷，并确定突变β-CAT的表达是否导致了来自子宫内膜异位症的永生细胞的恶性转化，以及4）至4）确定所选的β-CAT/TCF激活的基因是必需的，并且/或/或/或足以通过与卵巢癌相关的RK3E细胞或人类细胞中突变β-CAT进行肿瘤转化（不朽的卵巢表面上皮细胞，表达端粒酶或细胞系，或子宫内膜异位症）。