The mRNA-binding Protein TTP/ZFP36 in Hepatocarcinogenesis and Hepatocellular Carcinoma.
Tarek KröhlerSonja M KesslerKevan HosseiniMarkus ListAhmad BarghashSonika PatialStephan LaggaiKatja GemperleinJohannes HaybaeckRolf MüllerVolkhard HelmsMarcel H SchulzJessica HoppstädterPerry J BlackshearAlexandra K KiemerPublished in: Cancers (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.
Keyphrases
- wild type
- binding protein
- high fat diet induced
- poor prognosis
- oxidative stress
- risk factors
- insulin resistance
- endothelial cells
- signaling pathway
- fatty acid
- type diabetes
- adipose tissue
- squamous cell carcinoma
- gene expression
- machine learning
- long non coding rna
- young adults
- skeletal muscle
- microbial community
- big data
- high fat diet
- weight loss
- artificial intelligence
- drug induced
- diabetic rats
- transcription factor
- peripheral blood
- deep learning
- cell proliferation