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Post-Transcriptional Regulation in Colorectal Cancer

结直肠癌的转录后调控

基本信息

批准号：
8515341
负责人：
DAN ALAN DIXON
金额：
$ 28.57万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
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：
2009-09-21 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8515341
关键词：
3&apos Untranslated Regions Adult American Apoptosis Area Attenuated Binding Cancer Biology Cancer Cell Growth Cancer Etiology Cessation of life Characteristics Clinical Colon Carcinoma Colonic Neoplasms Colorectal Colorectal Cancer Defect ERG gene Effectiveness Elements Epigenetic Process Epithelial Cells Event Gastrointestinal tract structure Gene Expression Gene Silencing Genes Genetic Transcription Growth Growth Factor HuR protein Incidence Inflammation Inflammation Mediators Intestines Knockout Mice Lead Malignant Neoplasms Mediating Messenger RNA Molecular Molecular Target Molecular Weight Mus Neoplasm Metastasis Oncogenic Outcome Play Post-Transcriptional Regulation Prevention strategy Proliferating Proto-Oncogenes RNA Degradation RNA-Binding Proteins Role TIS11 protein Testing Therapeutic Therapeutic Intervention Transcript Transgenic Mice Viral angiogenesis base cancer cell cell transformation cis acting element design improved in vivo inhibitor/antagonist intestinal epithelium mRNA Decay mRNA Stability metaplastic cell transformation mortality mouse model neoplastic cell novel overexpression public health relevance therapeutic target treatment strategy tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer is a leading cause of cancer mortality among adults. Commonly observed in colon cancer cells and tumors is overexpression of many growth- and inflammation-associated immediate-early response genes. A critical point in controlling the expression of these factors in normal intestinal epithelium occurs through post-transcriptional mechanisms that regulate mRNA decay. The two primary RNA-binding proteins associated with post-transcriptional regulation are the mRNA stability factor Hu antigen R (HuR) and the mRNA decay factor tristetraprolin (TTP). Both of these factors bind AU-rich mRNA elements (ARE) present in a majority of cancer-associated immediate-early response gene transcripts and target the mRNA for stabilization or rapid decay. However, a characteristic feature observed in colon cancer cells and tumors is overexpression of the stability factor HuR and loss of expression of the decay factor TTP. These combined defects allow for stabilization and overexpression of cancer-associated growth factors. Based on these observations we hypothesize that loss of post-transcriptional regulation promotes intestinal epithelial cell tumorigenesis by selectively stabilizing AU-rich element containing-mRNA transcripts. The following specific aims are proposed to test this hypothesis. Specific Aim 1: Determine whether altered expression of the mRNA stability factor HuR and the mRNA decay factor TTP can promote intestinal cell transformation and tumorigenesis. Under Aim 1 we will determine whether HuR overexpression and TTP loss play a causal role in promoting epithelial cell transformation and tumorigenesis through a mechanism of defective rapid mRNA decay and cancer-associated gene overexpression. Specific Aim 2: Determine the ability of low-molecular- weight inhibitors of HuR and viral-mediated delivery of TTP to impact colon cancer cell growth and gene expression. The emphasis of this aim is to investigate the therapeutic potential of targeting HuR-mediated mRNA stabilization. Specific Aim 3: Determine if HuR overexpression and TTP loss in the murine gastrointestinal tract promotes cancer-associated gene expression and tumorigenesis in vivo. In this Specific Aim we will determine the in vivo significance of HuR overexpression and TTP loss in promoting intestinal tumorigenesis. Specific Aim 4: Determine the molecular events in colon cancer cells and tumors that promote HuR overexpression and silencing of TTP expression. Under this aim, we will determine the mechanisms promoting HuR expression and TTP gene silencing in colon cancer. This study will enhance our understanding of colorectal cancer biology and lead to the identification of novel molecular targets, which will improve current treatment and prevention strategies.

描述（由申请人提供）：结直肠癌是成人癌症死亡的主要原因。在结肠癌细胞和肿瘤中通常观察到许多生长和炎症相关的立即早期反应基因的过表达。控制这些因子在正常肠上皮中表达的关键点是通过调节mRNA衰变的转录后机制发生。与转录后调节相关的两种主要RNA结合蛋白是mRNA稳定因子Hu抗原R（HuR）和mRNA衰变因子tristetraprolin（TTP）。这两种因子结合存在于大多数癌症相关的立即早期反应基因转录物中的富含AU的mRNA元件（ARE），并靶向mRNA以稳定或快速衰减。然而，在结肠癌细胞和肿瘤中观察到的特征性特征是稳定因子HuR的过表达和衰变因子TTP的表达丧失。这些组合的缺陷允许癌症相关生长因子的稳定和过度表达。基于这些观察结果，我们推测，转录后调控的损失，促进肠上皮细胞肿瘤的发生，通过选择性地稳定AU丰富的元素含有mRNA转录。为检验这一假设，提出了以下具体目标。具体目标1：确定mRNA稳定因子HuR和mRNA衰减因子TTP的表达改变是否可以促进肠细胞转化和肿瘤发生。在目标1下，我们将确定HuR过表达和TTP损失是否通过缺陷性快速mRNA衰减和癌症相关基因过表达的机制在促进上皮细胞转化和肿瘤发生中发挥因果作用。具体目标二：确定HuR的低分子量抑制剂和病毒介导的TTP递送影响结肠癌细胞生长和基因表达的能力。这一目标的重点是研究靶向HuR介导的mRNA稳定的治疗潜力。具体目标3：确定小鼠胃肠道中HuR过表达和TTP丢失是否促进体内癌症相关基因表达和肿瘤发生。在这个特定的目标，我们将确定在体内的意义，HuR过表达和TTP损失，促进肠道肿瘤的发生。具体目标4：确定结肠癌细胞和肿瘤中促进HuR过表达和TTP表达沉默的分子事件。在此目标下，我们将确定促进HuR表达和TTP基因沉默在结肠癌中的机制。这项研究将增强我们对结直肠癌生物学的理解，并导致新的分子靶点的鉴定，这将改善目前的治疗和预防策略。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The roles of TTP and BRF proteins in regulated mRNA decay.

DOI：
10.1002/wrna.28
发表时间：
2011-01
期刊：
WILEY INTERDISCIPLINARY REVIEWS-RNA
影响因子：
7.3
作者：
Sanduja, Sandhya;Blanco, Fernando F.;Dixon, Dan A.
通讯作者：
Dixon, Dan A.

Genetic polymorphisms in RNA binding proteins contribute to breast cancer survival.

DOI：
10.1002/ijc.27789
发表时间：
2013-02-01
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Upadhyay, Rohit;Sanduja, Sandhya;Kaza, Vimala;Dixon, Dan A.
通讯作者：
Dixon, Dan A.

Hu antigen R is required for NOX-1 but not NOX-4 regulation by inflammatory stimuli in vascular smooth muscle cells.

DOI：
10.1097/hjh.0000000000000801
发表时间：
2016-02
期刊：
Journal of hypertension
影响因子：
4.9
作者：
Aguado A;Fischer T;Rodríguez C;Manea A;Martínez-González J;Touyz RM;Hernanz R;Alonso MJ;Dixon DA;Briones AM;Salaices M
通讯作者：
Salaices M

MicroRNA and AU-rich element regulation of prostaglandin synthesis.