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Peroxisome Proliferator-Activated Receptor- Induces Cell Proliferation by a Cyclin E1–Dependent Mechanism and Is Up-regulated in Thyroid Tumors

¹ Department of Pathology, University of Chicago School of Medicine, University of Chicago Cancer Research Center, Chicago, Illinois and ² Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Todd G. Kroll, 5841 South Maryland Avenue, AMB P323 (MC1089), Chicago, IL 60637. Phone: 773-702-3017; Fax: 773-834-5251; E-mail: tkroll{at}bsd.uchicago.edu.

Key Words: PPAR • nuclear receptors • thyroid cancer • cell proliferation • cyclin E1

Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that have been implicated in multiple physiologic processes including cancer. Here, we determine that PPAR induces cell proliferation through a novel cyclin E1–dependent mechanism and is up-regulated in many human thyroid tumors. The expression of PPAR was induced coordinately with proliferation in primary human thyroid cells by the activation of serum, thyroid-stimulating hormone/cyclic AMP, or epidermal growth factor/mitogen-activated protein kinase mitogenic signaling pathways. Engineered overexpression of PPAR increased thyroid cell number, the incorporation of bromodeoxyuridine, and the phosphorylation of retinoblastoma protein by 40% to 45% in just 2 days, one usual cell population doubling. The synthetic PPAR agonist GW501516 augmented these PPAR proliferation effects in a dose-dependent manner. Overexpression of PPAR increased cyclin E1 protein by 9-fold, whereas knockdown of PPAR by small inhibitory RNA reduced both cyclin E1 protein and cell proliferation by 2-fold. Induction of proliferation by PPAR was abrogated by knockdown of cyclin E1 by small inhibitory RNA in primary thyroid cells and by knockout of cyclin E1 in mouse embryo fibroblasts, confirming a cyclin E1 dependence for this PPAR pathway. In addition, the mean expression of native PPAR was increased by 2-fold to 5-fold (P < 0.0001) and correlated with that of the in situ proliferation marker Ki67 (R = 0.8571; P = 0.02381) in six different classes of benign and malignant human thyroid tumors. Our experiments identify a PPAR mechanism that induces cell proliferation through cyclin E1 and is regulated by growth factor and lipid signals. The data argue for systematic investigation of PPAR antagonists as antineoplastic agents and implicate altered PPAR–cyclin E1 signaling in thyroid and other carcinomas. [Cancer Res 2008;68(16):6578–86]