The role of EP4 in fibronectin-induced human lung cancer cell growth

描述（由申请人提供）：在美国，超过90%的肺癌是在烟草相关和其他慢性肺部疾病患者中检测到的。这些疾病的特征是肺细胞外基质的含量和组成的改变。慢性肺病中高表达的一种基质糖蛋白是纤维连接蛋白（Fn），我们坚信肺中Fn含量的相对增加可能促进肺癌的发生。与这一观点一致的是，我们报道了Fn刺激非小细胞肺癌（NSCLC）增殖并减少细胞凋亡，提示Fn可能有助于促进肿瘤生长和存活。进一步的研究表明，这些作用与促癌基因COX-2的表达增加和肺癌细胞有丝分裂原PGE2的分泌有关。最近，我们发现Fn的刺激作用可以通过其诱导EP4（一种介导其有丝分裂作用的PGE2受体）表达的能力而增强。根据我们的初步数据，我们假设除了诱导COX-2的表达和PGE2的生物合成外，Fn与其整合素5(1)受体结合可激活PI3-K/Akt/GSK-3激酶信号通路，诱导转录因子AP-2，进而导致EP4受体表达增加，从而增强PGE2在肿瘤细胞中的有丝分裂作用。这一假设将在以下具体目标中进行检验。目的1：探讨EP4在Fn诱导的肺癌细胞增殖中的作用，确定Fn上调EP4表达的细胞分子机制。目的2：利用已建立的k-ras突变相关肺癌模型和Lewis肺癌（LLC）小鼠模型，确定Fn/(5(1)和EP4受体在肺癌发生实验模型中的作用。

DESCRIPTION (provided by applicant): In the U.S., over 90% of lung cancers are detected in patients with tobacco-related and other chronic lung disorders. These disorders are characterized by alterations in the content and composition of the lung extracellular matrix. One matrix glycoprotein highly expressed in chronic lung disease is fibronectin (Fn), and we firmly believe that relative increases in the content of Fn in lung might promote lung carcinogenesis. Consistent with this idea, we have reported that Fn stimulates non small cell lung carcinoma (NSCLC) proliferation and reduces apoptosis suggesting that Fn may serve to promote tumor growth and survival. Further work revealed that these effects were related to increased expression of the pro-oncogene COX-2 and secretion of PGE2, a mitogen for lung carcinoma cells. More recently, we found that the stimulatory effect of Fn could be enhanced by its ability to induce the expression of EP4, a PGE2 receptor that mediates its mitogenic effects. Based on our preliminary data, we hypothesize that, in addition to inducing COX-2 expression and PGE2 biosynthesis, Fn binding to its integrin (5(1 receptor leads to activation of PI3-K/Akt/GSK-3 kinase signaling and induction of the transcription factor AP-2 which, in turn, leads to increased EP4 receptor expression thereby enhancing the mitogenic effect of PGE2 in tumor cells in vitro and in vivo. This hypothesis will be tested in the following specific aims. Aim 1: Explore the role of EP4 in Fn-induced lung carcinoma cell proliferation, and determine the cellular and molecular mechanism(s) by which Fn upregulates EP4 expression. Aim 2: Determine the role of Fn/(5(1 and EP4 receptors in experimental models of lung carcinogenesis using established model of lung carcinogenesis related to k-ras mutation and Lewis Lung Carcinoma (LLC) mouse models. This research program will be accompanied by comprehensive didactic sessions and strengthened by mentor/ collaborators and consultants that will enhance the investigator's skills and promote an independent career in academia.