ETV4 in pancreatic cancer

描述（由申请人提供）：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。尽管我们对这种疾病的分子进展的理解最近取得了一些进展，但仍然不清楚 是什么让这种癌症如此具有侵略性和难以捉摸。为了取得进一步的进展，我们需要确定新的基因靶点，并描述它们在胰腺癌病理生物学中的作用机制。ETV 4是一种转录因子，在多种恶性肿瘤中过表达，并已显示出功能性参与。然而，到目前为止，还没有研究系统地研究其在胰腺癌中的意义。我们的初步研究首次证实，ETV 4在大多数胰腺癌细胞中过表达 细胞系和肿瘤组织，并且ETV 4的沉默抑制胰腺癌细胞的生长。此外，ETV 4下调与迁移、侵袭减少和细胞-细胞相互作用增加相关。基于这些有希望的观察，我们假设ETV 4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中检验这一假设。在具体目标I中，我们将通过在致瘤性差且ETV 4不表达的细胞系（BxPC 3）中的异位过表达以及在致瘤性高且ETV 4过表达的胰腺癌细胞系（Colo 357）中的沉默来检查ETV 4在胰腺癌细胞中的病理学意义。这一目的将提供ETV 4在胰腺癌发病机制中的功能作用的信息。在具体目标II中，我们将通过进行免疫组织化学（IHC）分析来研究ETV 4在人胰腺肿瘤和正常胰腺组织中的表达和亚细胞定位。这一目标将支持我们的实验数据的临床相关性，并提供关于ETV 4在人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。总之，该试点项目中提出的研究将提供关于ETV 4在胰腺癌中的功能和发病率的初步数据。研究结果将为进一步阐明ETV 4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新的基于ETV 4的治疗干预方法，用于成功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.