Posttranscriptional Regulation of Angiogenesis Through AU-Rich mRNA Degradation: Potential Application in Cancer Therapy

Abstract

Angiogenesis is a finely tuned process that is tightly regulated in time and space by environmental factors (oxygen levels, extracellular matrix, diffusible growth factors, and cytokines). Expression of angiogenesis effectors and regulators is coordinately regulated at both transcriptional and posttranscriptional levels. Accumulating evidence suggests that regulation of mRNA stability plays a pivotal role in this process. Many AU-rich mRNAs encoding cytokines, growth factors, transcriptional factors, and receptors are involved in cancer and inflammation. Overexpression of these mRNAs in tumors is often correlated with deregulation in their mRNA stability. mRNA decay is regulated by cis-regulatory elements represented by the AU-rich elements (AREs) present in the 3′-UTR of target mRNAs and trans-acting ARE-binding proteins (ARE-BPs) that control mRNA degradation by diverse ribonucleases. Competition between ARE-BPs will finally determine whether an mRNA is degraded or stabilized. Regulation of mRNA stability is furthermore controlled by signaling pathways that are often overactive in cancer and impact the function of stabilizing or destabilizing factors. In this review, we present examples of angiogenesis genes regulated through ARE-directed mRNA decay with focus on deregulation of these processes in tumor angiogenesis. We finally comment on the modulation of ARE-BP expression and activity as a potential future application in anti-angiogenic and anti-tumorigenic therapies.