TY  - JOUR
A1  - Kröhler, Tarek
A1  - Keßler, Sonja
A1  - Hosseini, Kevan
A1  - List, Markus
A1  - Barghash, Ahmad
A1  - Patial, Sonika
A1  - Laggai, Stephan
A1  - Gemperlein, Katja
A1  - Haybäck, Johannes
A1  - Müller, Rolf
A1  - Helms, Volkhard
A1  - Schulz, Marcel Holger
A1  - Hoppstädter, Jessica
A1  - Blackshear, Perry J.
A1  - Kiemer, Alexandra Kathrin
T1  - The mRNA-binding protein TTP/ZFP36 in hepatocarcinogenesis and hepatocellular carcinoma
T2  - Cancers
N2  - 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.
KW  - liver cancer
KW  - NASH
KW  - chemoresistance
KW  - NEAT1
KW  - HepG2
KW  - Huh7
KW  - BCL2
KW  - MYC
KW  - VEGFA
KW  - flow cytometry
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/51833
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-518336
SN  - 2072-6694
N1  - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
VL  - 11
IS  - 11, Art. 1754
SP  - 1
EP  - 19
PB  - MDPI
CY  - Basel
ER  -