ETV4 in pancreatic cancer

ETV4在胰腺癌中的作用

• 批准号: 8364769
• 负责人: Seema Singh
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-10 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364769
• 关键词: Area; Attention; Behavior; Biological Markers; Biology; Cancer Etiology; Cancer cell line; Cell Communication; Cell Line; Cells; Cessation of life; Curative Surgery; Data; Development; Diagnosis; Diagnostic; Diagnostic Neoplasm Staging; Disease; Disease Management; Disease Progression; Down-Regulation; ETV4 gene; Exhibits; Future; Gene Targeting; Genes; Genetically Engineered Mouse; Genome; Goals; Growth; Human; In Vitro; Incidence; Investigation; Knowledge; Lead; Life Expectancy; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Molecular; Molecular Target; Neoplasm Metastasis; Newly Diagnosed; Normal tissue morphology; Oncogenic; Outcome; Pancreas; Pathogenesis; Patients; Pilot Projects; Play; Reporting; Role; Sampling; Series; Staging; Stratification; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Tumor Tissue; Tumor stage; United States; Woman; advanced disease; anticancer research; base; cancer type; carcinogenesis; clinically relevant; established cell line; in vivo; innovation; malignant phenotype; men; migration; mouse model; new therapeutic target; novel; outcome forecast; overexpression; pancreatic cancer cells; pancreatic neoplasm; prognostic; therapeutic target; transcription factor; treatment strategy; tumor; tumor progression; tumorigenic; vector

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. PUBLIC HEALTH RELEVANCE: Pancreatic cancer has the worst prognosis among all cancers thus underscoring the need to identify novel molecular targets that could lead to the development of more effective diagnostic and treatment strategies. The proposed pilot studies will provide novel information on the pathological role of ETV4 in pancreatic cancer and support its clinical relevance as a therapeutic target. The resulting information, in long term, will be useful for better disease management and thus enhance the life expectancy of patients diagnosed with this devastating and lethal malignancy.

描述（由申请人提供）：胰腺癌是一种高度侵略性的恶性肿瘤，是美国与癌症相关死亡的第四个主要原因。尽管我们对这种疾病的分子进展的了解最近有所进步，但它仍然不清楚 了解是什么使这种癌症如此激进和难以捉摸。为了取得进一步的进步，我们需要确定新颖的基因靶标，并描述其在胰腺癌病理学中的作用机理。 ETV4是转录因子，在多种恶性肿瘤中过表达，已显示出表现出功能参与。但是，到目前为止，还没有系统地检查了其在胰腺癌中的重要性。我们的初步研究首次证明，在大多数胰腺癌细胞中，ETV4表达过多 线和肿瘤组织以及ETV4的沉默抑制胰腺癌细胞的生长。此外，ETV4下调与迁移，侵袭和细胞相互作用增加有关。基于这些有希望的观察结果，我们假设ETV4是胰腺癌生长和恶性表型的关键决定因素。我们计划以两个具体目标来检验这一假设。在特定的目标I中，我们将通过肿瘤肿瘤和ETV4-荷尼抗压细胞系（BXPC3）中的异位过表达在胰腺癌细胞中检查ETV4的病理意义，并在高度肿瘤的和ETV4（ETV4）过表达的胰腺癌细胞系（CoLoReatic pancreatic Cell Line（Colo）中的静止状态（CoLorigenic）。该目标将提供有关ETV4在胰腺癌发病机理中功能作用的信息。在特定的目标II中，我们将通过进行免疫组织化学（IHC）分析来研究ETV4在人胰腺肿瘤和正常胰腺组织中的表达和细胞局部定位。该目标将支持我们的实验数据的临床相关性，并提供有关人类胰腺肿瘤中ETV4表达发生率以及与肿瘤阶段和 - 级别的任何关联的信息。综上所述，该试点项目中提出的研究将提供有关胰腺癌中ETV4功能和发生率的足够初步数据。结果结果将构成未来研究的基础，以进一步定义胰腺癌中ETV4异常表达和功能的基础机制。该项目的长期目标是开发一种基于ETV4的新型治疗干预方法，以成功地管理这种致命的恶性肿瘤。 公共卫生相关性：胰腺癌在所有癌症中的预后最糟糕，因此强调了鉴定新的分子靶标的需求，这可能导致更有效的诊断和治疗策略。拟议的试点研究将提供有关ETV4在胰腺癌中的病理作用的新信息，并支持其作为治疗靶点的临床相关性。从长远来看，最终的信息将有助于更好的疾病管理，从而提高诊断为这种毁灭性和致命性恶性肿瘤的患者的预期寿命。