MicroRNA and AU-rich element regulation of prostaglandin synthesis

Many lines of evidence demonstrate that prostaglandins play an important role in cancer, and enhanced synthesis of prostaglandin E₂ (PGE₂) is often observed in various human malignancies often associated with poor prognosis. PGE₂ synthesis is initiated with the release of arachidonic acid by phospholipase enzymes, where it is then converted into the intermediate prostaglandin prostaglandin H₂ (PGH₂) by members of the cyclooxygenase family. The synthesis of PGE₂ from PGH₂ is facilitated by three different PGE synthases, and functional PGE₂ can promote tumor growth by binding to four EP receptors to activate signaling pathways that control cell proliferation, migration, apoptosis, and angiogenesis. An integral method of controlling gene expression is by posttranscriptional mechanisms that regulate mRNA stability and protein translation. Messenger RNA regulatory elements typically reside within the 3′ untranslated region (3′UTR) of the transcript and play a critical role in targeting specific mRNAs for posttranscriptional regulation through microRNA (miRNA) binding and adenylate- and uridylate-rich element RNA-binding proteins. In this review, we highlight the current advances in our understanding of the impact these RNA sequence elements have upon regulating PGE₂ levels. We also identify various RNA sequence elements consistently observed within the 3′UTRs of the genes involved in the PGE₂ pathway, indicating these binding sites for miRNAs and RNA-binding proteins to be central regulators of PGE₂ synthesis and function. These findings may provide a rationale for the development of new therapeutic approaches to control tumor growth and metastasis promoted by elevated PGE₂ levels.