Role of NFAT and NFAT-Induced Genes in Carcinoma

项目摘要/摘要 本申请的目的是确定NFAT转录因子 促进乳腺癌细胞侵袭性迁移。具体地说，我们将重点介绍受刺激的信号通路 通过NFAT诱导的促进侵入性迁移的基因。上一资助期的研究 研究表明，NFAT在癌细胞中是一个关键的转录因子，因为它促进了癌细胞的运动和侵袭 癌细胞的数量。我们发现6‘4整合素是一种重要的上游调控机制 也发表了Akt/PKB和GSK-3在NFAT调控中的作用。鲜为人知的是， 然而，关于NFAT诱导的基因阵列，以及这些基因如何反过来控制侵袭性 迁移。最近发表的和初步的研究提供了证据，COX-2(环氧合酶-2)是 NFAT诱导的促进肿瘤侵袭的基因。我们进一步鉴定了两个细胞家族 表面受体、趋化因子受体和Glypicans(硫酸乙酰肝素蛋白多糖)由 NFAT，研究表明它们促进了侵入性迁移。我们提出了NFAT的假设 通过诱导旁分泌和自分泌信号通路促进侵袭性迁移 配体、趋化因子受体和Glypicans是这种表型的关键调节因子。已经接近完成了 关于NFAT在癌症中诱导的基因性质的知识匮乏，我们的研究采取了 基于发现的方法来识别、表征和详细研究分子机制 NFAT诱导的转录反应调节癌细胞信号转导。我们的总体假设将 在两个具体目标上进行测试：- 在AIM 1中，我们将测试NFAT在乳腺中诱导的趋化因子受体和趋化因子的贡献 癌细胞。我们将确定趋化因子受体包括CXCR-2，CCR-2，XCR-1和 CXCR4及其配体在NFAT介导的侵袭中的作用，以及旁分泌和自分泌信号的作用。 在AIM 2中，我们将确定NFAT诱导GPC6表达的机制。我们会 确定NFAT和GPC6在体外和体内如何促进侵袭性迁移，并研究 GPC6与WNT信号协同的机制。 这些研究的结果将为NFAT的机制提供重要的新见解 通过诱导关键靶基因来调节癌细胞的侵袭性迁移。我们预料到 我们NFAT研究的继续将在该领域提供重要的新信息，因为它们将突出 调控癌症进展的新机制。还有一种可能性是，我们的 研究将为肿瘤进展的治疗干预措施的未来发展提供依据。

Project Summary/Abstract The objective of this application is to define the mechanisms by which the NFAT transcription factor promotes breast cancer cell invasive migration. Specifically, we will focus on the signaling pathways stimulated by genes induced by NFAT and which promote invasive migration. Studies in the previous funding period showed that NFAT is a critical transcription factor in cancer cells as it promotes both the motility and invasion of carcinoma cells. We showed that the ¿6¿4 integrin is one important upstream regulatory mechanism leading to NFAT activation, and also published the role of Akt/PKB and GSK-3 in NFAT regulation. Little is known, however, concerning the array of genes induced by NFAT, and how in turn these genes control invasive migration. Recent published and preliminary studies have provided evidence that COX-2 (cyclooxygenase-2) is an NFAT-induced gene which promotes carcinoma invasion. We have further identified two families of cell surface receptors, chemokine receptors and glypicans (heparan sulfate proteoglycans) which are induced by NFAT, and studies show that they promote invasive migration. We propose the hypothesis that NFAT promotes invasive migration by inducing paracrine and autocrine signaling pathways whereby both chemokine ligands, chemokine receptors and glypicans are critical modulators of this phenotype. There is near complete paucity of knowledge concerning the nature of genes induced by NFAT in cancer, and our studies take a discovery-based approach to identify, characterize and investigate in detail the molecular mechanisms by which transcriptional responses induced by NFAT modulate cancer cell signaling. Our overall hypothesis will be tested in 2 specific Aims.:- In AIM 1 we will test the contribution chemokine receptors and chemokines induced by NFAT in breast cancer cells. We will determine the contribution of chemokine receptors including CXCR-2, CCR-2, XCR-1 and CXCR4 and their ligands in NFAT-mediated invasion, and the role of paracrine and autocrine signaling. In AIM 2, we will determine the mechanism by which NFAT induces glypican-6 (GPC6) expression. We will determine how NFAT and GPC6 promote invasive migration in vitro and in vivo, and investigate the mechanisms by which GPC6 collaborates with Wnt signaling. The results of these studies will provide important new insights into the mechanisms by which NFAT modulates cancer cell invasive migration through induction of critical target genes. We anticipate that continuation of our NFAT studies will provide important new information in the field because they will highlight new mechanisms of modulation of cancer progression. There is also the potential that the outcome of our studies will provide for the future development of therapeutic interventions for tumor progression.