Post-transcriptional control during chronic inflammation and cancer: a focus on AU-rich elements

Abstract

A considerable number of genes that code for AU-rich mRNAs including cytokines, growth factors, transcriptional factors, and certain receptors are involved in both chronic inflammation and cancer. Overexpression of these genes is affected by aberrations or by prolonged activation of several signaling pathways. AU-rich elements (ARE) are important cis-acting short sequences in the 3'UTR that mediate recognition of an array of RNA-binding proteins and affect mRNA stability and translation. This review addresses the cellular and molecular mechanisms that are common between inflammation and cancer and that also govern ARE-mediated post-transcriptional control. The first part examines the role of the ARE-genes in inflammation and cancer and sequence characteristics of AU-rich elements. The second part addresses the common signaling pathways in inflammation and cancer that regulate the ARE-mediated pathways and how their deregulations affect ARE-gene regulation and disease outcome.

Fig. 1

ARE-genes in inflammation-cancer crosstalk. Infectious agents or their products, such as endotoxin, and chronic irritations stimulate inflammatory and immune system cells such as the macrophages to release pro-inflammatory cytokines. Many of these cytokines are encoded by AU-rich mRNAs. In a chronic inflammation setting, several signaling pathways that lead to stabilization of ARE-mRNAs are continually activated leading to sustained production of the cytokines. In a cancer-associated microenvironment, these cytokines can promote the several processes that underlie cancer, including tumor growth, resistance to apoptosis, angiogenesis, invasion and metastasis. In turn, tumor cells themselves can release chemokines and other mediators that amplify the inflammatory response by attracting further inflammatory cells and stimulating further ARE-gene expression of cytokines and growth factors. Conditions in the tumor microenvironment such as hypoxia can also trigger the expression of ARE-mRNAs of pro-inflammatory cytokines, chemokines, and growth factors

Fig. 2

Common signaling pathways in inflammation and cancer including those regulating ARE-gene expression and mRNA stability. Microbial stimuli, inflammatory and tumor inducers, and ARE-gene products themselves such as certain growth factors and pro-inflammatory cytokines trigger a number of signaling pathways. One of those is the p38 MAPK pathway that leads to phosphorylation and inactivation of the activity of the RNA decay-promoting proteins such as TTP and KSRP. This results in stabilization of ARE-mRNAs that are involved in chronic inflammation and cancer. The RNA-binding stabilizing protein, HuR, is able to compete with the RNA-binding proteins such as TTP and AUF1 for the same mRNA targets; however, it can also act independently on mRNA targets for promoting mRNA stabilization