ETV4 in pancreatic cancer

描述(申请人提供)：胰腺癌是一种高度侵袭性的恶性肿瘤，是美国癌症相关死亡的第四大原因。尽管我们最近在了解这种疾病的分子进展方面取得了一些进展，但它仍然不清楚 了解是什么让这种癌症如此具有侵袭性和难以捉摸。为了取得进一步的进展，我们需要识别新的基因靶点，并描述它们在胰腺癌病理生物学中的作用机制。ETV4是一种转录因子，在多种恶性肿瘤中过表达，并被证明具有功能参与。然而，到目前为止，还没有研究系统地研究它在胰腺癌中的意义。我们的初步研究首次表明，ETV4在大多数胰腺癌细胞中过表达。 ETV4的沉默抑制了胰腺癌细胞的生长。此外，ETV4的下调与减少迁移、侵袭和增加细胞间的相互作用有关。基于这些有希望的观察，我们假设ETV4是胰腺癌生长和恶性表型的关键决定因素。我们计划在两个具体目标上检验这一假设。在特定的目标I中，我们将通过ETV4在低致瘤性和ETV4不表达的细胞系(BxPC3)中的异位过表达和在高致瘤性和ETV4高表达的胰腺癌细胞系(Colo357)中的沉默来检测ETV4在胰腺癌细胞中的病理学意义。这将为研究ETV4在胰腺癌发病机制中的作用提供信息。在特定的目的II，我们将通过免疫组织化学(IHC)分析ETV4在人胰腺肿瘤和正常胰腺组织中的表达和亚细胞定位。这一目的将支持我们的实验数据的临床相关性，并提供关于ETV4在人类胰腺肿瘤中表达的发生率以及与肿瘤分期和分级的任何关联的信息。综上所述，这一试点项目中提出的研究将提供关于ETV4在胰腺癌中的功能和发病率的足够的初步数据。这一结果将为进一步研究ETV4在胰腺癌中异常表达和功能的机制奠定基础。该项目的长期目标是开发一种基于ETV4的新的治疗干预方法，以成功地管理这种致命的恶性肿瘤。

DESCRIPTION (provided by applicant): Pancreatic cancer is a highly aggressive malignancy and the fourth leading cause of cancer related death in the United States. Despite some recent progress in our understanding of the molecular progression of this disease, it is still not clearly understood what makes this cancer so aggressive and elusive. To make further progress, we need to identify novel gene targets and delineate their mechanisms of action in pancreatic cancer pathobiology. ETV4 is a transcription factor, which is overexpressed in multiple malignancies and has been shown to exhibit functional participation. However, no study so far has systematically examined its significance in pancreatic cancer. Our preliminary studies demonstrate, for the first time, that ETV4 is over- expressed in majority of pancreatic cancer cell lines and tumor tissues, and silencing of ETV4 suppresses growth of pancreatic cancer cells. Furthermore, ETV4 downregulation is associated with decreased migration, invasion and increased cell-cell interaction. Based on these promising observations, we hypothesize that ETV4 is a key determinant of pancreatic cancer growth and malignant phenotype. We plan to test this hypothesis in two specific aims. In specific aim I, we will examine the pathological significance of ETV4 in pancreatic cancer cells through its ectopic overexpression in a poorly-tumorigenic and ETV4-nonexpressing cell line (BxPC3), and silencing in a highly tumorigenic and ETV4-overexpressing pancreatic cancer cell line (Colo357). This aim will provide the information on the functional role of ETV4 in pancreatic cancer pathogenesis. In specific aim II, we will investigate the expression and sub-cellular localization of ETV4 in human pancreatic tumors and normal pancreatic tissues by performing immunohistochemical (IHC) analysis. This aim will support the clinical relevance of our experimental data and provide the information on the incidence of ETV4 expression in human pancreatic tumors and any association with tumor -stage and -grade. Taken together, the studies proposed in this pilot project will provide sufficien preliminary data on the function and incidence of ETV4 in pancreatic cancer. The resulting outcome will form the bases for future investigations to further define the mechanisms underlying the aberrant expression and functions of ETV4 in pancreatic cancer. Long -term goal of this project is to develop a novel ETV4-based therapeutic intervention approach for successful management of this lethal malignancy.