Role of eIF3f in Pancreatic Cancer

eIF3f 在胰腺癌中的作用

基本信息

批准号：
7440416
负责人：
Jiaqi Shi
金额：
$ 7.55万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7440416
关键词：
Address Alleles Apoptosis Apoptotic Binding Biological Markers Caenorhabditis elegans Cancer Etiology Cell Proliferation Cessation of life Complex Data Detection Development Drosophila melanogaster Ductal Epithelial Cell Early Diagnosis Ectopic Expression Embryo Etiology Eukaryotic Initiation Factor-3 Figs - dietary Genes Goals Heterogeneous-Nuclear Ribonucleoprotein K Human In Vitro Lead Malignant neoplasm of pancreas Molecular Molecular Target Mouse-ear Cress Mus Neoplastic Cell Transformation Pancreas Pathway interactions Pilot Projects Play Protein Biosynthesis Protein Overexpression Proteins Public Health Quantum Dots Regulation Ribonucleoproteins Ribosomal RNA Ribosomes Role SCID Mice Signal Pathway Specimen Staging Stimulus Survival Rate Technology Tissue Microarray Translations Xenograft procedure cancer cell caspase-3 cell growth cell transformation human AKAP13 protein in vivo knock-down mouse model novel novel diagnostics pancreatic neoplasm small hairpin RNA therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Regulation of protein synthesis is fundamentally important for the control of cell growth and proliferation. The eukaryotic initiation factor 3 (eIF3) is a multi-protein complex that plays an important role in translation. Deletion of certain eIF3 subunit is embryonic lethal in mouse. eIF3f is the p47 subunit of eIF3 complex and is highly conserved in Drosophila melanogaster, C. elegans, and Arabidopsis thaliana. This pilot project investigates the hypothesis that decreased eIF3f expression contributes to pancreatic cancer development by deregulating translation and apoptosis. The expression of eIF3f is significantly decreased in pancreatic cancer. Loss of eIF3f gene allele was observed in pancreatic cancer specimens. eIF3f was also shown to be a negative regulator of translation. Ectopic expression of eIF3f inhibits translation, cell proliferation and induces apoptosis in pancreatic cancer cells. However, no one has studied the direct role of eIF3f in pancreatic neoplasm. Pancreatic cancer has a five year survival rate under 5% because of late detection. Our long term goal is to develop novel biomarkers for early diagnosis and to identify new molecular targets for treatment of pancreatic cancer. To address our hypothesis, the following specific aims will be pursued: (1) To determine if decreased eIF3f contributes to pancreatic neoplastic transformation in vitro and in vivo. eIF3f expression will be knocked down using eIF3f shRNA lentiviral construct in immortal normal human pancreatic ductal epithelial cells to assess the ability of eIF3f to transform these cells in vitro and in the xenograft SCID mouse model. Quantitative immunolabeling analysis of eIF3f protein will be performed using novel Quantum Dot technology on tissue microarrays to define the expression of eIF3f in different stages of pancreatic cancer. (2) To characterize the molecular mechanism by which eIF3f inhibits translation and induces apoptosis. The function of eIF3f as a regulatory non-core subunit of eIF3 is not known. Our preliminary data suggest that eIF3f is a negative regulator of translation. Overexpression of eIF3f leads to reduced ribosomes and rRNA degradation. In this aim, we will investigate the molecular mechanism by which eIF3f regulates rRNA degradation, translation and apoptosis. This proposal will contribute to the exploration of novel molecular pathways and better understanding of the etiology of pancreatic cancer. Characterization of this important new signaling pathway will lead to identification of new biomarkers and therapeutic targets for pancreatic cancer. PUBLIC HEALTH RELEVANCE: Role of eIF3f in Pancreatic Cancer. Pancreatic cancer is the fourth leading cause of cancer death. This proposal will contribute to the exploration of novel molecular pathways and better understanding of the etiology of pancreatic cancer. Characterization of this important new signaling pathway will lead to identification of new diagnostic biomarkers and therapeutic targets for pancreatic cancer.

描述（由申请人提供）：蛋白质合成的调节对于细胞生长和增殖的控制至关重要。真核起始因子 3 (eIF3) 是一种多蛋白复合物，在翻译中发挥重要作用。某些 eIF3 亚基的缺失会导致小鼠胚胎死亡。 eIF3f 是 eIF3 复合物的 p47 亚基，在果蝇、线虫和拟南芥中高度保守。该试点项目研究了这样的假设：eIF3f 表达减少通过解除翻译和细胞凋亡的调控而导致胰腺癌的发生。 eIF3f 的表达在胰腺癌中显着降低。在胰腺癌样本中观察到 eIF3f 基因等位基因丢失。 eIF3f 也被证明是翻译的负调节因子。 eIF3f 的异位表达会抑制胰腺癌细胞的翻译、细胞增殖并诱导细胞凋亡。然而，没有人研究过 eIF3f 在胰腺肿瘤中的直接作用。由于发现较晚，胰腺癌的五年生存率低于 5%。我们的长期目标是开发用于早期诊断的新型生物标志物，并确定治疗胰腺癌的新分子靶点。为了实现我们的假设，我们将追求以下具体目标：（1）确定 eIF3f 减少是否有助于体外和体内胰腺肿瘤转化。使用 eIF3f shRNA 慢病毒构建体在永生的正常人胰腺导管上皮细胞中敲低 eIF3f 表达，以评估 eIF3f 在体外和异种移植 SCID 小鼠模型中转化这些细胞的能力。将使用新型量子点技术在组织微阵列上对 eIF3f 蛋白进行定量免疫标记分析，以确定 eIF3f 在胰腺癌不同阶段的表达。 (2)表征eIF3f抑制翻译并诱导细胞凋亡的分子机制。 eIF3f 作为 eIF3 的非核心调节亚基的功能尚不清楚。我们的初步数据表明 eIF3f 是翻译的负调节因子。 eIF3f 的过度表达会导致核糖体减少和 rRNA 降解。为此，我们将研究eIF3f调节rRNA降解、翻译和凋亡的分子机制。该提案将有助于探索新的分子途径并更好地了解胰腺癌的病因。这一重要的新信号通路的表征将导致胰腺癌新生物标志物和治疗靶点的鉴定。公共卫生相关性：eIF3f 在胰腺癌中的作用。胰腺癌是癌症死亡的第四大原因。该提案将有助于探索新的分子途径并更好地了解胰腺癌的病因学。这一重要的新信号通路的表征将导致胰腺癌新诊断生物标志物和治疗靶点的鉴定。