Prostaglandin E2 Regulates the Complement Inhibitor CD55/Decay-accelerating Factor in Colorectal Cancer

Abstract

Cyclooxygenase-derived prostaglandin E 2 (PGE 2 ) stimulates tumor progression by modulating several proneoplastic pathways. The mechanisms by which PGE 2 promotes tumor growth and metastasis through stimulation of cell migration, invasion, and angiogenesis have been fairly well characterized. Much less is known, however, about the molecular mechanisms responsible for the immunosuppressive effects of PGE 2 . We identified PGE 2 target genes and subsequently studied their biologic role in colorectal cancer cells. The complement regulatory protein decay-accelerating factor (DAF or CD55) was induced following PGE 2 treatment of LS174T colon cancer cells. Analysis of PGE 2 -mediated activation of the DAF promoter employing 5-deletion luciferase constructs suggests that regulation occurs at the transcriptional level via a cyclic AMP/ protein kinase A-dependent pathway. Nonsteroidal antiinflammatory drugs blocked DAF expression in HCA-7 colon cancer cells, which could be restored by the addition of exogenous PGE 2 . Finally, we observed an increase in DAF expression in the intestinal mucosa of Apc Min؉/؊ mice treated with PGE 2 in vivo. In summary, these results indicate a novel immunosuppressive role for PGE 2 in the development of colorectal carcinomas.

Regulation of the Helicobacter pylori Cellular Receptor Decay-accelerating Factor

“…An affect H. pylori-induced IL-8 production, 3 a response that has previously been shown to be dependent on MAPK signaling (44). Therefore, these findings are not consistent with a model of DAF autoregulation in H. pyloriinfected gastric epithelial cells.…”

“…Although the mechanism through which NOD1 induces activation of p38 remains unclear (56), there are several mechanisms by which p38 may promote increased DAF expression. Activation of p38 can transactivate the transcription factor CREB, which has previously been shown to transcriptionally up-regulate DAF in intestinal epithelial cells (41,42,44). Alternatively, daf mRNA transcript stability has been shown to be increased by activation of p38 in monocytic cell lines (57).…”

“…The daf promoter contains a B response element, and activation of NF-B leads to the up-regulation of DAF in response to proinflammatory stimuli (41)(42)(43)(44). To define the role of NF-B in H. pylori-induced DAF expression, MKN28 cells were transiently transfected with constructs that express either a dominant-negative IB␣ or dominant-negative IB kinase ␤ as well as a NF-B-responsive luciferase reporter construct.…”

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

“…COX-2/PGE 2 signaling plays critical roles in neoangiogenesis; homozygous deletion of EP 2 R significantly reduces the number and size of intestinal polyps in APC ⌬716 mice that is associated with a reduction of VEGF expression, suggesting that PGE 2 /EP 2 signaling is critical for increased levels of VEGF in intestinal neoplasm (19 4 receptors are coupled to stimulatory G (G s ) proteins and signal through increased cAMP, whereas the EP 3 R is coupled to inhibitory G (G i ) proteins which inhibit the generation of cAMP. PGE 2 stimulates the transcription of a number of genes through the cAMP/PKA pathway where the cAMP responsive element (CRE) within the promoter plays critical roles (13,41). The CRE consists of an 8-bp palindrome (TGACGTCA) and is typically found within 100 nt of the TATA box.…”

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

“…53 The Mut construct was generated by sitedirected mutagenesis using the QuickChange kit (Stratagene, La Jolla, CA, USA) to mutate the C at c.-198 to G using the WT DAF promoter construct as a template. The mutant sequence was verified using an ABI Prism 3100 automated sequencer before further evaluation.…”