PPAR-gamma regulation of micro RNA metabolism in colon cancer

PPAR-γ对结肠癌微小RNA代谢的调节

• 批准号: 7404582
• 负责人: E. AUBREY THOMPSON
• 金额: $ 7.55万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-10 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7404582
• 关键词: 2,4-thiazolidinedione; Accounting; Acromegaly; Age; Agonist; Anchorage-Independent Growth; Apoptosis; Attenuated; Azoxymethane; Cell Cycle; Cells; Chemoprevention; Chemopreventive Agent; Cholangiocarcinoma; Coin; Colon; Colon Carcinoma; Condition; Data; Down-Regulation; Epithelial Cells; Event; Gene Chips; Gene Expression; Gene Targeting; Genes; Genomics; Genus Cola; Glioblastoma; Goals; Growth; Human; Knock-out; Maintenance; Mediating; Messenger RNA; Metabolism; MicroRNAs; Mus; Numbers; Oncogenic; PPAR gamma; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phenotype; Play; Primary carcinoma of the liver cells; Process; Property; Protein Overexpression; Rate; Regulation; Reporting; Repression; Resistance; Risk; Rodent; Role; Secondary to; Staging; Testing; Thiazolidinediones; Thinking; Transgenic Organisms; Tumor Suppression; Ulcerative Colitis; Withdrawal; cancer cell; carcinogenesis; cohort; colon cancer cell line; colon carcinogenesis; insight; loss of function mutation; matrigel; novel; prevent; response; senescence; small hairpin RNA; tumor

DESCRIPTION (provided by applicant): Peroxisome proliferator-activated receptor-gamma (PPAR?) is a potent suppressor of early stage colon carcinogenesis, and therefore a particularly attractive target for colon cancer chemoprevention. A number of studies have shown that activation of PPAR? in colon cancer cells inhibits proliferation and induces differentiation, suggesting that the tumor-suppressive effects of PPAR? are due to the ability to revert the transformation of early stage colon cancer cells. However, the mechanism that accounts for this process is unknown. We have recently completed a genomic profile of a battery of PPAR? sensitive and resistant human colon cancer cell lines. Our data reveal that reversion of the transformed phenotype is associated with inhibition of micro RNA (miR) metabolism. Specifically, PPAR? inhibits expression of Dicer1, which catalyzes the rate limiting step in conversion of inactive 75nt pre-miRs to active 21-23nt miRs. Downregulation of Dicer1 by PPAR? is associated with inhibition of maturation of a known oncogenic micro RNA, mir21. Recent data indicate that maintenance of the transformed phenotype may depend upon expression of colon cancer specific miRs (so-called oncomirs). Our observation that PPAR? inhibits Dicer1 expression suggests that the tumor suppressive effects of PPAR? may result from inhibition of oncomir-dependent processes that are required for maintenance of the transformed phenotype. To test this hypothesis, we will determine if knockdown of Dicer1 inhibits transformation in early stage colon cancer cells. We determine if overexpression of Dicer1 blocks the tumor suppressive effects of PPAR?, and we will test the hypothesis that some subset of PPAR? target genes are regulated secondary to repression of Dicer1 and inhibition of miR metabolism. Elucidation of this novel mechanism will provide fundamental new insight into our understanding of how PPAR? suppresses tumor formation, how miR metabolism is regulated in the colon, and how specific oncomirs contribute to transformation of colonic epithelial cells. Furthermore, we will identify a cohort of PPAR?/Dicer1 target mRNAs and miRs that may be essential for maintenance of the transformed state and therefore potential new targets for colon cancer chemoprevention.

描述（由申请人提供）： 过氧化物酶体增殖物激活的受体伽马（PPAR？）是早期结肠癌发生的有效抑制剂，因此是结肠癌化学预防的特别有吸引力的靶标。许多研究表明PPAR的激活？在结肠癌细胞中抑制增殖并诱导分化，表明PPAR的肿瘤抑制作用？由于能够恢复早期结肠癌细胞的转化。但是，解释这一过程的机制尚不清楚。我们最近完成了一组PPAR的基因组轮廓？敏感和抗性的人类结肠癌细胞系。我们的数据表明，转化的表型的逆转与抑制微RNA（miR）代谢有关。具体来说，PPAR？抑制DICER1的表达，这会催化速率限制步骤在不活跃的75nt Pre-Mirs转换为活性21-23nt miRs中。 PPAR下调DICER1？与抑制已知的致癌微RNA的成熟相关，miR21。最近的数据表明，转化的表型的维持可能取决于结肠癌特异性miR的表达（所谓的oncomirs）。我们观察到PPAR？抑制DICER1表达表明PPAR的肿瘤抑制作用？可能是由于抑制了维持转化表型所需的oncomir依赖性过程而引起的。为了检验这一假设，我们将确定DICER1的敲低是否抑制了早期结肠癌细胞中的转化。我们确定DICER1的过表达是否阻止了PPAR的肿瘤抑制作用？我们将测试PPAR的某些子集的假设？靶基因受抑制和抑制miR代谢的抑制作用。阐明这种新型机制将为我们对PPAR的理解提供基本的新见解？抑制肿瘤的形成，如何在结肠中调节miR代谢以及特定的吞吐量如何有助于结肠上皮细胞的转化。此外，我们将确定一组PPAR？/dicer1靶标mRNA和miR，这可能对于维持转化状态至关重要，因此可能是结肠癌化学预防的潜在新目标。