PPAR-gamma regulation of micro RNA metabolism in colon cancer

描述（由申请人提供）： 过氧化物酶体增殖物激活受体-γ（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点。许多研究表明，激活的过氧化物酶体增殖物激活受体？在结肠癌细胞抑制增殖和诱导分化，这表明，肿瘤抑制作用的过氧化物酶体增殖物激活受体？是由于能够逆转早期结肠癌细胞的转化。然而，解释这一过程的机制尚不清楚。我们最近完成了一组过氧化物酶体增殖物激活受体的基因组图谱？敏感和耐药的人结肠癌细胞系。我们的数据显示，转化表型的逆转与微RNA（miR）代谢的抑制有关。具体来说，PPARs？抑制Dicer 1的表达，Dicer 1催化无活性的75 nt pre-miR转化为活性的21- 23 nt miR的限速步骤。Dicer 1通过PPAR下调？与已知致癌微小RNA mir 21成熟的抑制有关。最近的数据表明，转化表型的维持可能取决于结肠癌特异性miR（所谓的oncomir）的表达。我们观察到，PPAR？抑制Dicer 1表达表明，肿瘤抑制作用的过氧化物酶体增殖物激活受体？可能是由于抑制了维持转化表型所需的oncomir依赖性过程。为了验证这一假设，我们将确定Dicer 1的敲低是否抑制早期结肠癌细胞的转化。我们确定Dicer 1的过表达是否阻断了PPAR？的肿瘤抑制作用，我们将检验一个假设，即某些PPAR亚型？靶基因的调节继发于Dicer 1的阻遏和miR代谢的抑制。阐明这一新的机制将提供根本的新见解，我们如何理解过氧化物酶体增殖物激活受体？抑制肿瘤形成，miR代谢如何在结肠中调节，以及特异性oncomir如何促进结肠上皮细胞的转化。此外，我们将确定一个PPAR？/ Dicer 1靶向可能对维持转化状态至关重要的mRNA和miR，因此是结肠癌化学预防的潜在新靶点。

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.