TIA1 Loss Exacerbates Fatty Liver Disease but Exerts a Dual Role in Hepatocarcinogenesis

Abstract

Alterations in specific RNA-binding protein expression/activity importantly contribute to the development of fatty liver disease (FLD) and hepatocellular carcinoma (HCC). In particular, adenylate–uridylate-rich element binding proteins (AUBPs) were reported to control the post-transcriptional regulation of genes involved in both metabolic and cancerous processes. Herein, we investigated the pathophysiological functions of the AUBP, T-cell-restricted intracellular antigen-1 (TIA1) in the development of FLD and HCC. Analysis of TIA1 expression in mouse and human models of FLD and HCC indicated that TIA1 is downregulated in human HCC. In vivo silencing of TIA1 using AAV8-delivered shRNAs in mice worsens hepatic steatosis and fibrosis induced by a methionine and choline-deficient diet and increases the hepatic tumor burden in liver-specific PTEN knockout (LPTENKO) mice. In contrast, our in vitro data indicated that TIA1 expression promoted proliferation and migration in HCC cell lines, thus suggesting a dual and context-dependent role for TIA1 in tumor initiation versus progression. Consistent with a dual function of TIA1 in tumorigenesis, translatome analysis revealed that TIA1 appears to control the expression of both pro- and anti-tumorigenic factors in hepatic cancer cells. This duality of TIA1′s function in hepatocarcinogenesis calls for cautiousness when considering TIA1 as a therapeutic target or biomarker in HCC.

Multiple functions of stress granules in viral infection at a glance

“…For instance, the deficiency of G3BP1 leads to abnormal synaptic plasticity, calcium homeostasis in neurons, and increases apoptotic cell death (Zekri et al, 2005;Martin et al, 2013). TIA-1 knockout (KO) mice worsen hepatic steatosis and fibrosis (Dolicka et al, 2022) and dysregulate expression of lipid storage and membrane dynamics factors in nervous tissue (Heck et al, 2014). In the case of viral infections, in G3BP1 KO cells, the replication efficiency of mammalian orthoreovirus (MRV) is significantly improved (Carroll et al, 2014).…”