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Prostaglandin E₂ Induces the Expression of IL-1 in Colon Cancer Cells¹

Department of Surgery and Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202

PGE₂ has been shown to exert pro-oncogenic effects in colorectal neoplasia through producing autocrine or paracrine growth factors. In the present study, we demonstrate that PGE₂ induced the expression of IL-1 in colon cancer cells, which plays critical roles in tumor metastasis and neoangiogenesis in a variety of cancers. PGE₂ increased the levels of both IL-1 mRNA and protein, suggesting a positive feedback loop between the IL-1 pathway and PGE₂ signaling. Mechanistically, PGE₂ induced the expression of IL-1 at both transcriptional and posttranscriptional levels. PGE₂ stimulated the transcriptional activity of the IL-1 promoter and significantly stabilized IL-1 mRNA. Moreover, we show that IL-1 enhanced colorectal neoplasia, stimulating cell migration and neoangiogenesis. Knockdown of the expression of IL-1 by small-interfering RNA resulted in a reduction of vascular endothelial growth factor secretion in colon cancer cells and an inhibition of tube formation by HUVECs. Thus, our results suggest that PGE₂ induces the expression of proinflammatory cytokine IL-1, which may potentially enhance the proneoplastic actions of the cyclooxygenase-2/PGE₂ signaling pathway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grants DK-065615 (to H.S.) and DK-64593 (to H.S.).

² Address correspondence and reprint requests to Dr. Hongmiao Sheng, Department of Surgery, Indiana University, Indianapolis, IN 46202. E-mail address: hsheng{at}iupui.edu

³ Abbreviations used in this paper: COX-2, cyclooxygenase-2; KO, knockout; C_T, cycle threshold; VEGF, vascular endothelial growth factor; PKA, protein kinase A; ARE, adenosine uridine-rich element; UTR, untranslated region; siRNA, small-interfering RNA; DRB, 5,6,-dichlorobenzimidazole riboside; GPCR, G protein-coupled receptor; CRE, cAMP responsive element; EP, E-prostanoid.