Deciphering the Tissue Specificity of MEN1 Related Tumorigenesis

破译 MEN1 相关肿瘤发生的组织特异性

• 批准号: 8532864
• 负责人: Richard N Kitsis
• 金额: $ 32.57万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532864
• 关键词: Accounting; Address; Age-Months; Alleles; Apoptosis; Apoptosis Inhibitor; Applications Grants; Binding; Binding Sites; Biological; Cell Cycle; Cells; ChIP-on-chip; ChIP-seq; Characteristics; DNA Binding; Development; Endocrine; Event; Exocrine pancreas; Experimental Designs; Gene Expression Profile; Genes; Germ Lines; Goals; Hereditary Malignant Neoplasm; Histocompatibility Testing; Informatics; Islets of Langerhans; Link; Malignant Neoplasms; Mammary Tumorigenesis; Menin; MicroRNAs; Modeling; Multiple Endocrine Neoplasia Type 1; Mus; Mutate; Nature; Organ; Pancreas; Parathyroid gland; Pathway interactions; Pattern; Phenotype; Play; Proteins; Regulation; Research; Role; Site; Specificity; Syndrome; Testing; Thyroid Gland; Tissues; Transcript; Tumor Suppressor Genes; Tumor Suppressor Proteins; Wild Type Mouse; carcinogenesis; cell type; genome wide association study; genome-wide; insight; mortality; novel; operation; prevent; promoter; research study; survivorship; transcription factor; transcriptome sequencing; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Our research application is addressing PQ8: "Why do certain mutational events promote cancer phenotypes in some tissues and not in others?" The goal of our proposed research is to identify factors responsible for tissue-selective tumorigenesis following inactivation of a tumor suppressor gene. Multiple Endocrine Neoplasia type 1 (MEN1), a familial cancer syndrome characterized by tissue-restricted tumorigenesis, provides a unique and tractable model with which to accomplish this goal. Bi-allelic inactivation of Men1, a ubiquitously expressed tumor suppressor encoding the transcription factor menin, is required for tumorigenesis in MEN1. Our experiments using Cre-lox deletion of Men1 demonstrates that differential inactivation of Men1 in various tissues does not explain the tissue restricted nature of tumors in MEN1. Rather, additional factors are required to enhance or suppress tumorigenesis in tissues that have lost Men1. For example, homozygous deletion of Men1 in all cells of the pancreas results in tumors in the endocrine tissue but not exocrine tissue of the same organ. Given that inactivation of Men1 is tightly linked to MEN1, we postulate that operation of these modulating factors is regulated by loss of menin. Our central hypothesis is that loss of menin differentially regulates expression of factors that influence carcinogenesis in various tissues so as to generate the tissue restricted characteristic of tumor formation in MEN1. To test this hypothesis, we propose to undertake both unbiased, genome wide screens and candidate approaches to identify relevant factors. Aim 1 employs ChIP- Seq and RNA-Seq respectively to identify DNA binding sites for menin that are differentially occupied and transcriptomes that are differentially expressed in tissues that develop MEN1 tumors versus those that do not. Specifically, we will compare tissues from the endocrine pancreas (develops tumors) versus the exocrine pancreas (does not develop tumors). Aim 2 will validate these findings in the parathyroid gland, a second site of tumor development in MEN1. Aim 3 will explore the role of the candidate protein ARC, an apoptosis inhibitor and cell cycle promoter that has already been implicated in mammary carcinogenesis. Our preliminary studies show that ARC is up-regulated by deletion of Men1 in the endocrine pancreas and parathyroid gland, but not in the exocrine pancreas. Moreover, ChIP-CHIP studies suggest that menin binds to the promoter of nol3, the gene encoding ARC. Taken together, these studies will provide novel and important insights into why tumors develop in some tissues and not in others following loss of a tumor suppressor gene.

描述（由申请人提供）：我们的研究申请正在解决PQ8：“为什么某些突变事件会促进某些组织中而不是其他组织中的癌症表型？”我们提出的研究的目的是确定肿瘤抑制基因失活后，负责组织选择性肿瘤发生的因素。多内分泌肿瘤1型（MEN1）是一种以组织限制性肿瘤发生为特征的家族性癌症综合征，提供了一个独特且可拖延的模型，可以实现这一目标。 Men1的Men1的Bi-calillic灭活是Men1中肿瘤发生的普遍表达的肿瘤抑制器。我们使用MEN1的CRE-LOX缺失的实验表明，各种组织中MEN1的差异失活并不能解释MEN1中肿瘤的组织性质。相反，需要其他因素来增强或抑制失去MEN1的组织中的肿瘤发生。例如，在胰腺的所有细胞中，MEN1的纯合缺失导致内分泌组织中的肿瘤，而不是外分泌组织 相同的器官。鉴于Men1的失活与Men1紧密相关，我们假设这些调节因子的运行受到Menin的损失的调节。我们的中心假设是，Menin的丧失调节了影响各种组织中癌变的因素的表达，从而产生了MEN1中肿瘤形成的组织受限特征。为了检验这一假设，我们建议采用公正的基因组宽筛查和候选方法来识别相关因素。 AIM 1分别采用芯片SEQ和RNA-SEQ，以鉴定Menin的DNA结合位点，而Menin差异占据，并且在发生MEN1肿瘤的组织中与不相比的转录组差异表达。具体而言，我们将比较内分泌胰腺（发展肿瘤）的组织与外分泌胰腺（不发展肿瘤）。 AIM 2将在甲状旁腺中验证这些发现，甲状旁腺是MEN1肿瘤发育的第二个部位。 AIM 3将探讨候选蛋白弧的作用，候选蛋白弧是已经与乳腺癌发生有关的凋亡抑制剂和细胞周期启动子。我们的初步研究表明，在内分泌胰腺和甲状旁腺中MEN1的缺失是由ARC上调的，但在外分泌胰腺中却没有上调。此外，芯片芯片研究表明，梅宁与编码弧的基因Nol3的启动子结合。综上所述，这些研究将提供新颖而重要的见解，说明为什么在某些组织中肿瘤发生在某些组织中，而不是在肿瘤抑制基因丧失后而不是在其他组织中发展的。