Identification of CD55 as a downstream factor of EP4 receptor signaling in colorectal cancer cells
Prostaglandin E2 (PGE2) signaling through the E-type prostanoid 4 (EP4) receptor has been implicated in the initiation and progression of colorectal cancer (CRC); however, specific downstream factors have yet to be defined. We herein identified decay-accelerating factor, also known as CD55, as a novel CRC-associated downstream factor of the EP4 receptor. The integration of transcriptomic profiling of PGE2-stimulated human CRC HCA-7 cells with analyses of cancer genomic databases predicted CD55 as an EP4 receptor-linked candidate. Inhibitor-based experiments on EP4 receptor-expressing HCA-7 cells showed that the induction of CD55 after a PGE2 stimulation required the EP4 receptor and Gi protein, whereas protein kinase A signaling was dispensable. In combination with a toxicogenomic database analysis, p38 mitogen-activated protein kinase (MAPK) was identified as the predominant effector connecting the EP4 receptor to CD55 upregulation. A single-cell RNA-seq re-analysis of human CRC tissues showed CD55 upregulation and p38 MAPK-related gene set enrichment in epithelial cells expressing the EP4 receptor, supporting the conservation of this induction mechanism in clinical specimens. Collectively, these results delineate a PGE2/EP4 receptor/Gi protein/p38 MAPK signaling axis that induces CD55 expression in CRC model cells and epithelial tumor cells, providing mechanistic insights into the prostanoid-driven immune evasion of human CRC.
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