Novel Suppressors of Pancreatic Cancer

胰腺癌的新型抑制剂

基本信息

批准号：
7891308
负责人：
DAWN E QUELLE
金额：
$ 16.5万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-10 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7891308
关键词：
Address Affect Aneuploidy CDKN2A gene Cancer cell line Cell Line Cells Chromosomal Instability Cytogenetic Analysis DNA Damage Detection Development Disease Early Diagnosis Exhibits Experimental Models Genes Genetically Engineered Mouse Genome Stability Genomic Instability Goals Growth Human Immunohistochemistry In Vitro Knockout Mice Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Messenger RNA Molecular Molecular Cytogenetics Mus Mutation NIH Program Announcements Neoplasm Metastasis Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Pilot Projects Play Protein p53 Proteins Reading Frames Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Staging TP53 gene Testing Tissues Transcript Tumor Suppressor Genes Tumor Suppressor Proteins United States Western Blotting Work anticancer activity base cancer cell cell motility cell type improved in vivo mouse model novel novel strategies overexpression prevent protein expression public health relevance response tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, lethal cancer characterized by extensive genomic instability and aneuploidy. One of the signature alterations of PDAC is inactivation of the p14ARF (Alternative Reading Frame) tumor suppressor. It has been shown that ARF-p53 signaling is disrupted in 50-75% of human cases and plays a critical role in restraining PDAC progression in genetically engineered mouse models of the disease. Importantly, ARF also functions independent of the p53 tumor suppressor to prevent cancer. As such, components of ARF's p53-independent signaling may be disrupted in the remaining 25-50% of PDAC that retain wild type ARF and p53. We recently discovered a novel Partner of ARF (Parf) that is required for ARF signaling in the absence of p53. Parf also acts independent of ARF to maintain genomic stability and restrain the proliferation of multiple cell types, particularly pancreatic cancer lines. The Parf transcript and protein is most highly expressed in the normal pancreas compared to other tissues and there is evidence for its inactivation in human PDAC. These findings support the hypothesis that Parf is a novel tumor suppressor gene that promotes genomic stability and inhibits the malignant progression of pancreatic cancer. Moreover, because Parf exhibits anticancer activities that intersect with ARF as well as other anticancer pathways, we speculate it could be targeted for inactivation in both ARF-positive and ARF-negative tumors. This proposal tests these ideas using molecular approaches and mouse models of PDAC. Aim 1 will determine if inactivation of Parf occurs in advanced stages of PDAC that exhibit increased chromosomal instability. Aim 2 uses novel mouse models to test if Parf normally suppresses PDAC development and/or metastasis in vivo. This work will advance our understanding of the molecular basis of PDAC and result in new experimental models for human pancreatic cancer, thereby facilitating improved detection and treatment of PDAC. These goals directly address key initiatives defined in the program announcement for Pilot Studies in Pancreatic Cancer. PUBLIC HEALTH RELEVANCE: Pancreatic ductal adenocarcinoma (PDAC) is arguably the deadliest of all cancers in the United States due to lack of early detection and ineffective treatments. This study will advance our understanding of the molecular basis of PDAC and provide new experimental models for human pancreatic cancer, thereby facilitating improved detection and treatment of this currently incurable and devastating disease.

描述（由申请人提供）：胰腺导管腺癌（PDAC）是一种高度侵袭性、致命的癌症，其特征是广泛的基因组不稳定性和非整倍性。 PDAC 的标志性改变之一是 p14ARF（替代阅读框）肿瘤抑制因子的失活。研究表明，ARF-p53 信号传导在 50-75% 的人类病例中被破坏，并在该疾病的基因工程小鼠模型中抑制 PDAC 进展中发挥着关键作用。重要的是，ARF 还可以独立于 p53 肿瘤抑制因子发挥预防癌症的作用。因此，ARF 的 p53 独立信号传导成分可能会在保留野生型 ARF 和 p53 的剩余 25-50% 的 PDAC 中被破坏。我们最近发现了一种新的 ARF 伙伴 (Parf)，它是在 p53 缺失的情况下 ARF 信号转导所必需的。 Parf 还独立于 ARF 发挥作用，维持基因组稳定性并抑制多种细胞类型（尤其是胰腺癌细胞系）的增殖。与其他组织相比，Parf 转录物和蛋白质在正常胰腺中表达最高，并且有证据表明其在人 PDAC 中失活。这些发现支持这样的假设：Parf 是一种新型抑癌基因，可促进基因组稳定性并抑制胰腺癌的恶性进展。此外，由于 Parf 表现出与 ARF 以及其他抗癌途径交叉的抗癌活性，我们推测它可以作为 ARF 阳性和 ARF 阴性肿瘤的灭活目标。该提案使用分子方法和 PDAC 小鼠模型来测试这些想法。目标 1 将确定 Parf 失活是否发生在 PDAC 晚期，表现出染色体不稳定性增加。目标 2 使用新型小鼠模型来测试 Parf 是否正常抑制体内 PDAC 发育和/或转移。这项工作将增进我们对 PDAC 分子基础的理解，并产生新的人类胰腺癌实验模型，从而促进改进 PDAC 的检测和治疗。这些目标直接涉及胰腺癌试点研究计划公告中定义的关键举措。公共健康相关性：由于缺乏早期发现和治疗无效，胰腺导管腺癌 (PDAC) 可以说是美国所有癌症中最致命的。这项研究将增进我们对 PDAC 分子基础的理解，并为人类胰腺癌提供新的实验模型，从而促进改善这种目前无法治愈的破坏性疾病的检测和治疗。