Citation
- Authors: Krohler T. et al.
- Year: 2019
- Journal: Cancers 11 1754
- Applications: in vitro / DNA / jetPEI-Hepatocyte
- Cell types:
- Name: Hep G2
Description: Human hepatocarcinoma cells - Name: Huh7
Description: Human hepatocarcinoma cells
Known as: Huh7, Huh 7 - Name: PLC/PRF/5
Description: Human hepatocellular carcinoma cell line.
Known as: PLC-PRF-5; PLC PRF 5; PLC/PRF5; PLCPRF5; PLC-8024; PLC8024; PLC; Alexander cells; Alexander; Primary Liver Carcinoma/Poliomyelitis Research Foundation/5.
- Name: Hep G2
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.