mRNA Post-Transcriptional Regulation by AU-Rich Element-Binding Proteins in Liver Inflammation and Cancer

Abstract

AU-rich element-binding proteins (AUBPs) represent important post-transcriptional regulators of gene expression. AUBPs can bind to the AU-rich elements present in the 3’-UTR of more than 8% of all mRNAs and are thereby able to control the stability and/or translation of numerous target mRNAs. The regulation of the stability and the translation of mRNA transcripts by AUBPs are highly complex processes that occur through multiple mechanisms depending on the cell type and the cellular context. While AUBPs have been shown to be involved in inflammatory processes and the development of various cancers, their important role and function in the development of chronic metabolic and inflammatory fatty liver diseases (FLDs), as well as in the progression of these disorders toward cancers such as hepatocellular carcinoma (HCC), has recently started to emerge. Alterations of either the expression or activity of AUBPs are indeed significantly associated with FLDs and HCC, and accumulating evidence indicates that several AUBPs are deeply involved in a significant number of cellular processes governing hepatic metabolic disorders, inflammation, fibrosis, and carcinogenesis. Herein, we discuss our current knowledge of the roles and functions of AUBPs in liver diseases and cancer. The relevance of AUBPs as potential biomarkers for different stages of FLD and HCC, or as therapeutic targets for these diseases, are also highlighted.

HuR Protein in Hepatocellular Carcinoma: Implications in Development, Prognosis and Treatment

“…Hu-antigen R (HuR) or ELAV (embryonic lethal, abnormal vision Drosophila)-like protein 1 (ELAVL1) is a ubiquitously expressed RNA-binding post-transcriptional regulator, which contains three highly conserved RNA binding domains and belongs to the RNA recognition motif (RRM) superfamily [ 1 , 2 ]; RRM-1 and -2 bind to AU-rich elements (AREs), while RRM3, by binding to the mRNA poly(A) tail, mediates canonical RNA interactions and exists a dimerization interface localized on the α-helical face of RRM3. Significantly, HuR binds to a U-rich sequence, usually located within the 3’ untranslated region (UTR) of the target mRNAs and regulates directly or indirectly their stability, translation, and nucleo-cytoplasmic translocation [ 3 , 4 ].…”

Metabolic Reprogramming of Liver Fibrosis

“…This is especially true in a background of metabolic disorders where a tight regulation is required to control the intrinsic and microenvironmental mechanisms that affect the cell fate decisions [ 117 , 119 ]. In this regard, many RBPs have been already described as essential, not only in the regulation of HSCs metabolic reprogramming, but also in the general mechanism of fibrosis [ 117 , 123 , 125 , 126 ].…”

“…AU-rich element-binding proteins (AUBPs) are a class of RBPs that, by binding to the 3′-UTR of mRNAs, can cause either their degradation, stabilization, or translational inhibition. AUBPs have been described as key actors in pathological processes such as NASH and fibrosis, since the expression of several AUBPs was strongly altered in patients that were suffering from these diseases (reviewed by [ 126 ]).…”

“…Another member from the AUBPs family with a relevant role in the HSCs activity is the RBP tristetraprolin (TTP, also known as zinc finger protein 36 homolog/ZFP36) [ 126 ] ( Figure 2 ). The ubiquitous TTP is one of the best-studied RBPs that is involved in the regulation of the cytoplasmic mRNA fate [ 138 ].…”

Mir-21 Suppression Promotes Mouse Hepatocarcinogenesis

“…Besides well-known mutations associated with HCC (e.g., TERT , TP53 , MYC , WNT , CTNNB1 , CCND1 , PTEN , [ 1 , 2 ]), numerous other mechanisms are deregulated and contribute to the development and heterogeneity of HCC, including DNA methylation events, chromatin structure changes, and post-transcriptional regulation of cancer-related factors by non-coding RNAs (e.g., microRNAs (miRNAs), long non-coding RNAs), or RNA-binding proteins [ 4 , 5 , 6 , 7 ]. Akin to genetic mutations, these non-genomic alterations can strongly affect the tumor microenvironment, the immune response, and the expression/activity of cancer-related factors (e.g., tumor suppressors or oncogenes), thereby markedly affecting disease development [ 1 , 8 ].…”