Molecular Studies Of Ovarian Cancer

卵巢癌的分子研究

基本信息

批准号：
7592009
负责人：
Patrice J. Morin
金额：
$ 149.42万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Our previous data has clearly implicated members of the claudin family in ovarian tumorigenmesis. In this fiscal year, we have made significant progress in identifying the mechanisms of claudin-3 and -4 regulation as well as the possible roles these proteins may have in ovarian cancer progression. We have shown that both claudin -3 and claudin-4 are phosphorylated in ovarian cancer cells (by PKA and PKC, respectively) and that this phosphorylation has significant functional consequences. Indeed, we have shown that this phosphorylation can contribute to the dismantlement of tight junctions in ovarian cancer. In addition, we have also continued our work investigating the mechanisms regulating the CLDN3 and CLDN4 promoters. We have found that these promoters are highly affected by DNA methylation and histone acetylation and that they require the SP1 transcription factor for activity. We are currently identifying enhancers that may be important in the co-regulation of CLDN3 and CLDN4. We are also studying claudin-7, another claudin that involved in ovarian cancer. We have now demonstrated that claudin-7 is expressed in a large number of ovarian tumors and that it may have roles in survival and cell invasion. Drug resistance represent a major clinical problem in the treatment of ovarian cancer, but the exact mechanisms involved in the development of resistance are unclear. In this fiscal year, we have use microarrays to identify gene differentially expressed in our model of ovarian cancer drug resistance. We have identified several interesting candidate genes and pathways that may be involved in this phenomenon. We are hoping that a better understanding of the mechanisms leading to drug resistance may suggest approaches for alternative therapies or for strategies aimed at reversing drug resistance.

我们以前的数据清楚地暗示了克劳丁家族的成员在卵巢肿瘤中。在这个财政年度，我们在确定Claudin -3和-4调节的机制方面取得了重大进展，以及这些蛋白质可能在卵巢癌进展中具有的可能作用。我们已经表明，Claudin -3和Claudin -4均在卵巢癌细胞中磷酸化（分别为PKA和PKC），并且这种磷酸化具有显着的功能后果。确实，我们已经表明，这种磷酸化可以导致卵巢癌紧密连接的拆除。此外，我们还继续研究调节CLDN3和CLDN4启动子的机制。我们发现这些启动子受DNA甲基化和组蛋白乙酰化的高度影响，并且需要SP1转录因子才能进行活性。我们目前正在识别可能在CLDN3和CLDN4的共同调节中很重要的增强剂。我们还研究Claudin-7，这是另一种涉及卵巢癌的克劳丁。现在，我们已经证明了Claudin-7在大量卵巢肿瘤中表达，并且可能在生存和细胞侵袭中具有作用。耐药性代表了治疗卵巢癌的主要临床问题，但抗药性发展的确切机制尚不清楚。在这个财政年度，我们使用微阵列来鉴定在卵巢癌耐药性模型中差异表达的基因。我们已经确定了可能与这种现象有关的几个有趣的候选基因和途径。我们希望对导致耐药性的机制有更好的理解可以提出替代疗法或旨在逆转耐药性的策略的方法。