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Open AccessArticle

The mRNA-binding Protein TTP/ZFP36 in Hepatocarcinogenesis and Hepatocellular Carcinoma

Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66123 Saarbrücken, Germany
Institute of Pharmacy, Department of Pharmacology for Natural Sciences, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany
Department for Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarland Informatics Campus, 66123 Saarbrücken, Germany
Big Data in BioMedicine Group, Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany
School of Electrical Engineering and Information Technology, German Jordanian University, Amman 11180, Jordan
Center for Bioinformatics, Saarland University, 66123 Saarbrücken, Germany
The Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, 66123 Saarbrücken, Germany
Department of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, 39106 Magdeburg, Germany
Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck 6020, Austria
Institute of Pathology, Medical University of Graz, Graz 8036, Austria
Cluster of Excellence in Multimodal Computing and Interaction, Saarland Informatics Campus, 66123 Saarbrücken, Germany
Institute for Cardiovascular Regeneration, Goethe-University Hospital, 60590 Frankfurt, Germany
German Centre for Cardiovascular Research (DZHK), Partner site Rhine-Main, 60590 Frankfurt, Germany
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(11), 1754;
Received: 13 October 2019 / Revised: 4 November 2019 / Accepted: 5 November 2019 / Published: 8 November 2019
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. View Full-Text
Keywords: liver cancer; NASH; chemoresistance; NEAT1; HepG2; Huh7; BCL2; MYC; VEGFA; flow cytometry liver cancer; NASH; chemoresistance; NEAT1; HepG2; Huh7; BCL2; MYC; VEGFA; flow cytometry
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Kröhler, T.; Kessler, S.M.; Hosseini, K.; List, M.; Barghash, A.; Patial, S.; Laggai, S.; Gemperlein, K.; Haybaeck, J.; Müller, R.; Helms, V.; Schulz, M.H.; Hoppstädter, J.; Blackshear, P.J.; Kiemer, A.K. The mRNA-binding Protein TTP/ZFP36 in Hepatocarcinogenesis and Hepatocellular Carcinoma. Cancers 2019, 11, 1754.

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