Hu Antigen R (HuR) Protein Structure, Function and Regulation in Hepatobiliary Tumors

Abstract

Hu antigen R (HuR) is a 36-kDa ubiquitous member of the ELAV/Hu family of RNA-binding proteins (RBPs), which plays an important role as a post-transcriptional regulator of specific RNAs under physiological and pathological conditions, including cancer. Herein, we review HuR protein structure, function, and its regulation, as well as its implications in the pathogenesis, progression, and treatment of hepatobiliary cancers. In particular, we focus on hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), tumors where the increased cytoplasmic localization of HuR and activity are proposed, as valuable diagnostic and prognostic markers. An overview of the main regulatory axes involving HuR, which are associated with cell proliferation, invasion, metastasis, apoptosis, and autophagy in HCC, is provided. These include the transcriptional, post-transcriptional, and post-translational modulators of HuR function, in addition to HuR target transcripts. Finally, whereas studies addressing the relevance of targeting HuR in CCA are limited, in the past few years, HuR has emerged as a potential therapeutic target in HCC. In fact, the therapeutic efficacy of some pharmacological inhibitors of HuR has been evaluated, in early experimental models of HCC. We, further, discuss the major findings and future perspectives of therapeutic approaches that specifically block HuR interactions, either with post-translational modifiers or cognate transcripts in hepatobiliary cancers.

Human antigen R: Exploring its inflammatory response impact and significance in cardiometabolic disorders

“…It is one of the best‐characterized RBPs among its family, consisting of HuB, HuC, and HuD (Schultz et al, 2020). The latter is mainly expressed in the nervous system, while HuR is widely expressed in the respiratory, gastrointestinal tract, and endocrine tissue, encoded by the ELAVL1 gene (Lachiondo‐Ortega et al, 2022). Hu proteins selectively bind with high affinity to mRNAs that bear ARE in their 3′ UTR, such as cytokines with a short half‐life, tumor‐promoting genes, and growth factor mRNAs resulting in the modification of their expression either by increasing transcripts' stability, varying the translation, or carrying out both actions (Chen et al, 2001; Lal et al, 2004).…”

Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan

“…It also occurs through active regulation of Sirt1 (AROS). Finally, increasing Hu antigen R (HuR) and decreasing p53 can prevent cellular senescence but inhibit tumor suppression [ 106 , 107 , 108 ]. It has also demonstrated the ability to improve biological parameters of kidney aging [ 109 ] and improves arterial aging by reducing media thickness, inflammation, fibrosis, and oxidative stress through increasing SIRT1, AMPK, and PGC1α, SOD1, and SOD2 expression, as well as decreasing NADH oxidase 2 and 4 [ 110 , 111 ].…”

Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan

“…Anti-metastatic and anti-cancer properties are notoriously associated with resveratrol, as it has the ability to suppress tumour proliferation and unnecessary cellular division [88]. Interestingly, resveratrol has the ability to mimic caloric restriction (CR) in a similar fashion associated with the SIRT1 pathway to extend longevity, particularly through increased telomerase activity, FoxO3a, active regulator of Sirt1 (AROS), but conversely increased Hu antigen R (HuR) and decreased p53, which can be implicated in the prevention of cellular senescence but inhibition of tumour suppression abilities [89][90][91]. It has demonstrated the ability to improve biological parameters of kidney aging [92] and additionally improves arterial aging by reducing media thickness, inflammation, fibrosis, and oxidative stress, increased SIRT1, AMPK, and PGC1 expression, SOD1 and 2, and decreased NADH oxidase 2 and 4 [93,94].…”