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

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide with few and poorly efficient therapeutic options. Adenylate–uridylate-rich-element-binding proteins (AUBPs) are potent post-transcriptional regulators of gene expression, whose alterations have been associated with the development of chronic liver diseases (e.g., fatty liver disease) and their progression toward HCC. Emerging evidence indicates that T-Cell-restricted intracellular antigen-1 (TIA1), an AUBP regulating mRNA translation, promotes HCC. Herein, we further characterize TIA1’s functions in hepatic cancer cells by identifying an entire set of oncogenes and tumor suppressors under TIA1’s influence, thus suggesting a dual role in hepatocarcinogenesis. In agreement, using in vivo models, we found that contrary to our observations in HCC cells, TIA1 can exert a tumor suppressive function and refrain from hepatic steatosis and fibrosis. Finally, TIA1 expression is reduced in human HCC. Our study provides new insights regarding the role for TIA1 in HCC and questions the current concept of TIA1 as a strict tumor promoter. 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.