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%的肺癌是在患有与烟草有关的疾病和其他慢性肺部疾病的患者中发现的。这些疾病的特征在于肺细胞外基质的含量和组成的改变。纤维连接蛋白（Fn）是慢性肺疾病中高表达的一种基质糖蛋白，我们坚信肺中Fn含量的相对增加可能促进肺癌的发生。与此一致，我们已经报道了Fn刺激非小细胞肺癌（NSCLC）增殖并减少凋亡，这表明Fn可能有助于促进肿瘤生长和存活。进一步的研究表明，这些作用与原癌基因考克斯-2的表达增加和肺癌细胞有丝分裂原PGE 2的分泌增加有关。最近，我们发现Fn的刺激作用可以通过其诱导EP 4表达的能力来增强，EP 4是一种介导其促有丝分裂作用的PGE 2受体。基于我们的初步数据，我们假设，除了诱导考克斯-2表达和PGE 2生物合成外，Fn与其整合素β 1受体的结合导致PI 3-K/Akt/GSK-3激酶信号传导的激活和转录因子AP-2的诱导，这反过来导致EP 4受体表达的增加，从而增强PGE 2在体外和体内肿瘤细胞中的促有丝分裂作用。这一假设将在以下具体目标中得到检验。 目标1：探讨EP 4在Fn诱导的肺癌细胞增殖中的作用，并探讨Fn上调EP 4表达的细胞和分子机制。 目标二：利用已建立的与k-ras突变相关的肺癌发生模型和刘易斯肺癌（LLC）小鼠模型，探讨Fn/β_1和EP_4受体在肺癌发生实验模型中的作用。 该研究计划将伴随着全面的教学会议，并通过导师/合作者和顾问加强，这将提高研究者的技能，促进学术界的独立职业生涯。

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.