Abstract
Hepatic lipid deposition and inflammation represent risk factors for hepatocellular carcinoma (HCC). The mRNA-binding protein tristetraprolin (TTP, gene name ZFP36) has been suggested as a tumor suppressor in several malignancies, but it increases insulin resistance. The aim of this study was to elucidate the role of TTP in hepatocarcinogenesis and HCC progression. Employing liver-specific TTP-knockout (lsTtp-KO) mice in the diethylnitrosamine (DEN) hepatocarcinogenesis model, we observed a significantly reduced tumor burden compared to wild-type animals. Upon short-term DEN treatment, modelling early inflammatory processes in hepatocarcinogenesis, lsTtp-KO mice exhibited a reduced monocyte/macrophage ratio as compared to wild-type mice. While short-term DEN strongly induced an abundance of saturated and poly-unsaturated hepatic fatty acids, lsTtp-KO mice did not show these changes. These findings suggested anti-carcinogenic actions of TTP deletion due to effects on inflammation and metabolism. Interestingly, though, investigating effects of TTP on different hallmarks of cancer suggested tumor-suppressing actions: TTP inhibited proliferation, attenuated migration, and slightly increased chemosensitivity. In line with a tumor-suppressing activity, we observed a reduced expression of several oncogenes in TTP-overexpressing cells. Accordingly, ZFP36 expression was downregulated in tumor tissues in three large human data sets. Taken together, this study suggests that hepatocytic TTP promotes hepatocarcinogenesis, while it shows tumor-suppressive actions during hepatic tumor progression.
Highlights
Hepatocellular carcinoma (HCC), the predominant form of liver cancer, is the second most common cause of cancer-related death worldwide [1,2]
The tumor incidence was significantly lower in DEN-treated lsTtp-KO animals compared to DEN-treated wild type animals (Figure 1A), while there was no statistical difference regarding tumor incidence between the genotypes in the sham-treated groups
We were able to confirm a downregulation of TTP in hepatocellular carcinoma (HCC) tissues and tumor suppressor functions of TTP
Summary
Hepatocellular carcinoma (HCC), the predominant form of liver cancer, is the second most common cause of cancer-related death worldwide [1,2]. The initiation and progression of cancer are provoked by a dysregulated expression of proteins controlling diverse cellular phenotypes: cell cycle, differentiation, apoptosis, angiogenesis, and cell invasiveness [6]. Biosynthesis of these proteins is strongly regulated by the concentrations of their respective mRNAs in the cytoplasm, which depend on both mRNA synthesis and degradation. The cytoplasmic stability of many mRNAs is controlled by mRNA-binding proteins (RBPs), some of which have been shown to be deregulated in HCC.
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