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The mRNA-binding Protein TTP/ZFP36 in Hepatocarcinogenesis and Hepatocellular Carcinoma.
Kröhler, Tarek Kessler, Sonja M Hosseini, Kevan List, Markus Barghash, Ahmad Patial, Sonika Laggai, Stephan Gemperlein, Katja Haybaeck, Johannes Müller, Rolf
Kröhler, Tarek
Kessler, Sonja M
Hosseini, Kevan
List, Markus
Barghash, Ahmad
Patial, Sonika
Laggai, Stephan
Gemperlein, Katja
Haybaeck, Johannes
Müller, Rolf
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2019-11-08
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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.
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Cancers (Basel). 2019 Nov 8;11(11). pii: cancers11111754. doi: 10.3390/cancers11111754.
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en
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2072-6694
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Attribution-NonCommercial-ShareAlike 4.0 International