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Open AccessArticle

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

1
Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66123 Saarbrücken, Germany
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Institute of Pharmacy, Department of Pharmacology for Natural Sciences, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany
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Department for Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarland Informatics Campus, 66123 Saarbrücken, Germany
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Big Data in BioMedicine Group, Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany
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School of Electrical Engineering and Information Technology, German Jordanian University, Amman 11180, Jordan
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Center for Bioinformatics, Saarland University, 66123 Saarbrücken, Germany
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The Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
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Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
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Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, 66123 Saarbrücken, Germany
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Department of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, 39106 Magdeburg, Germany
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Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck 6020, Austria
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Institute of Pathology, Medical University of Graz, Graz 8036, Austria
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Cluster of Excellence in Multimodal Computing and Interaction, Saarland Informatics Campus, 66123 Saarbrücken, Germany
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Institute for Cardiovascular Regeneration, Goethe-University Hospital, 60590 Frankfurt, Germany
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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; https://doi.org/10.3390/cancers11111754
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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