The Role of Cul4A in Genome Stability and Cancer Development

Cul4A 在基因组稳定性和癌症发展中的作用

基本信息

批准号：
8676461
负责人：
LIANG YOU
金额：
$ 28.45万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-09 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676461
关键词：
13q34 9p21 Bladder CDKN2A gene Cancer Etiology Cell Cycle Cell Cycle Arrest Cell Cycle Regulation Cell Line Cell Proliferation Cells Chromosomes Clinical Crocidolite Asbestos DNA amplification Developing Countries Development Diagnosis Drug resistance Esophageal Europe Event Excision Gene Amplification Genes Genetic Models Genome Stability Genomics Goals Head and neck structure Human Human Development Incidence Injection of therapeutic agent Intervention Knock-out Knockout Mice Lung Malignant Neoplasms Malignant Pleural Mesothelioma Mediating Mesothelioma Modality Modeling Molecular Molecular Genetics Mus Mutation Oncogene Activation Oncogenes Oncogenic Patients Phenotype Play Pleural Post-Translational Protein Processing Primary carcinoma of the liver cells Protein p53 Proteins Proto-Oncogenes Radiation therapy Recombinant Cytokines Resistance Role Staging Stomach Testing Therapeutic Agents Tissues Transgenic Mice Tumor Cell Line Tumor Suppressor Genes Tumor Suppressor Proteins United States base cancer cell carcinogenesis cell growth chemotherapy cullin 4A drug discovery functional loss gain of function in vivo knock-down malignant breast neoplasm mouse model novel therapeutics oncoprotein p21 overexpression small hairpin RNA therapeutic target tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): In human malignances, DNA amplification leading to oncogene activation represents one of the major forms of genomic alterations that plays a causative role in tumorigenesis. The amplified genes may be viewed as primary oncogenic targets in the development of human cancer. The gain-of-function effect of gene amplification makes them ideal therapeutic targets for cancer. Amplification of ch13q34, the region that Cullin 4A (Cul4A) resides in, is amplified in several human cancers, including breast and hepatocellular cancer. The amplification of this region has also been observed in a variety of human cancers including esophageal, gastric, head and neck, bladder, small cell and non-small cell cancers. Since such the amplification involves multiple genes, the identification of the functional target has been difficult. To date, the study on the potential oncogenic role of Cul4A has been limited. Our hypothesis is that Cul4A is the key cancer-causing oncogene in this amplified region. In our preliminary study, we have identified frequent Cul4A amplification and overexpression in malignant pleural mesothelioma cell lines and tumors. Knockdown of Cul4A by shRNA leads to increased p21 protein, and subsequently induces cell cycle arrest and inhibits mesothelioma cell growth. Forced expression of Cul4A decreases p21 protein and promotes cell growth. The molecular genetics of mesothelioma are relatively homogenous, e.g., homozygous deletion of 9p21 (contains the INK4a/ARF locus) was found in more than 70% of mesothelioma tumors[12], thus make mesothelioma an unique model to study the mechanisms of human carcinogenesis. Currently, there is no Cul4A transgenic mouse tumor model available. The following specific aims outline our detailed plan to prove our hypothesis. To determine the role of Cul4A amplification in mesothelioma, we plan to perform additional Cul4A knockdown and overexpression study using more mesothelioma cell lines (Specific Aim 1). To elucidate the potential mechanisms through which Cul4A is a proto-oncogene, we have the detailed plan on the important Cul4A-related cell cycle and genome stability analysis (Specific Aim 2). To evaluate the potential oncogenic role of Cul4A in vivo and mimic the human mesothelioma, we have generated a conditional Cul4A transgenic mouse model and we plan to cross this model with three conditional tumor suppressor knockout models (Specific Aim 3). The specific aims to test our hypothesis: In aim 1, Investigate the role of Cul4A in human mesothelioma cell lines and tissues. We plane to investigate and validate the role of Cul4A in mesothelioma cell lines with amplification in the 13q34 region by knocking-down Cul4A and investigate the effects of enhanced Cul4A expression in normal and mesothelioma cell lines. In addition, we plan to determine the role of Cul4A amplification in large number of mesothelioma tissues; In aim 2, the goal is to investigate the potential mechanisms through which Cul4A plays an oncogenic role. We plan to investigate the mechanisms through which Cul4A regulates cell proliferation and genome stability; In aim 3, we plan to elucidate the role of Cul4A in mesothelioma development using knockout and transgenic mouse models. We have generated a Cul4A transgenic mouse model. We are now ready to use the Cul4A transgenic mice to test our hypothesis that Cul4A is an oncogene.

描述（由申请人提供）：在人类恶性肿瘤中，导致癌基因激活的DNA扩增代表了在肿瘤发生中起因作用的主要基因组改变的主要形式。扩增的基因可能被视为人类癌症发展中的主要致癌靶标。基因扩增的功能效果使它们成为癌症的理想治疗靶标。 CH13Q34的扩增是Cullin 4a（Cul4a）所在的区域，包括在包括乳腺癌和肝细胞癌在内的几种人类癌症中。在各种人类癌症中也观察到了该区域的扩增，包括食管，胃，头颈，膀胱，小细胞和非小细胞癌。由于这种扩增涉及多个基因，因此很难识别功能靶标。迄今为止，关于CUL4A潜在的致癌作用的研究一直受到限制。我们的假设是CUL4A是该扩增区域中致癌的关键致癌癌基因。在我们的初步研究中，我们已经确定了恶性胸膜间皮瘤细胞系和肿瘤中频繁的CUL4A扩增和过表达。 SHRNA敲低CUL4A会导致P21蛋白增加，并随后诱导细胞周期停滞并抑制间皮瘤细胞的生长。 CUL4A的强制表达降低了P21蛋白并促进细胞生长。间皮瘤的分子遗传学相对均匀，例如，在超过70％的间皮瘤肿瘤中发现了9p21的纯合缺失（包含Ink4a/arf基因座）[12]，从而使间皮瘤成为研究人类癌作用机制的独特模型。当前，没有CUL4A转基因小鼠肿瘤模型可用。以下具体目的概述了我们证明我们的假设的详细计划。为了确定CUL4A扩增在间皮瘤中的作用，我们计划使用更多间皮瘤细胞系进行其他CUL4A敲低和过表达研究（特定的AIM 1）。为了阐明CUL4A是原始癌基因的潜在机制，我们制定了有关重要CUL4A相关细胞周期和基因组稳定性分析的详细计划（特定目标2）。为了评估Cul4a在体内的潜在致癌作用，并模仿人间皮瘤，我们产生了一个条件的Cul4a转基因小鼠模型，我们计划将该模型与三个条件抑制肿瘤抑制器敲除模型（特定AIM 3）交叉。具体目的是检验我们的假设：在AIM 1中，研究CUL4A在人间皮瘤细胞系和组织中的作用。我们通过敲击降低的CUL4A并研究了正常和间皮瘤细胞系中CUL4A表达增强的效果，从而在13q34区域进行了调查和验证CUL4A在间皮瘤细胞系中具有扩增和扩增的作用。此外，我们计划确定Cul4a扩增在大量间皮瘤组织中的作用。在AIM 2中，目标是研究CUL4A发挥致癌作用的潜在机制。我们计划研究CUL4A调节细胞增殖和基因组稳定性的机制。在AIM 3中，我们计划使用敲除和转基因小鼠模型阐明CUL4A在间皮瘤发育中的作用。我们已经生成了CUL4A转基因小鼠模型。现在，我们准备使用CUL4A转基因小鼠来测试我们的假设CUL4A是癌基因。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

YAP1 regulates ABCG2 and cancer cell side population in human lung cancer cells.

DOI：
10.18632/oncotarget.13686
发表时间：
2017-01-17
期刊：
Oncotarget
影响因子：
0
作者：
Dai Y;Liu S;Zhang WQ;Yang YL;Hang P;Wang H;Cheng L;Hsu PC;Wang YC;Xu Z;Jablons DM;You L
通讯作者：
You L

Lung tumourigenesis in a conditional Cul4A transgenic mouse model.

条件性 Cul4A 转基因小鼠模型中的肺肿瘤发生

DOI：
10.1002/path.4352
发表时间：
2014-06
期刊：
JOURNAL OF PATHOLOGY
影响因子：
7.3
作者：
Yang, Yi-Lin;Hung, Ming-Szu;Wang, Yang;Ni, Jian;Mao, Jian-Hua;Hsieh, David;Au, Alfred;Kumar, Atul;Quigley, David;Fang, Li Tai;Yeh, Che-Chung;Xu, Zhidong;Jablons, David M.;You, Liang
通讯作者：
You, Liang

An alternative way to initiate Notch1 signaling in non-small cell lung cancer.

DOI：
10.3978/j.issn.2218-6751.2013.12.06
发表时间：
2014-06
期刊：
Translational lung cancer research
影响因子：
4
作者：
Yi-lin Yang;D. Jablons;L. You
通讯作者：
Yi-lin Yang;D. Jablons;L. You

YAP promotes erlotinib resistance in human non-small cell lung cancer cells.

DOI：
10.18632/oncotarget.10458
发表时间：
2016-08-09
期刊：
Oncotarget
影响因子：
0
作者：
Hsu PC;You B;Yang YL;Zhang WQ;Wang YC;Xu Z;Dai Y;Liu S;Yang CT;Li H;Hu B;Jablons DM;You L
通讯作者：
You L

Analysis of lung tumor initiation and progression in transgenic mice for Cre-inducible overexpression of Cul4A gene.

Cre 诱导的 Cul4A 基因过表达转基因小鼠肺肿瘤的发生和进展分析