Tristetraprolin Promotes Hepatic Inflammation and Tumor Initiation but Restrains Cancer Progression to Malignancy
| Autor: | Michelangelo Foti, Olivia Bejuy, Christine Maeder, Marta Correia de Sousa, Monika Gjorgjieva, Claudio De Vito, Laura Rubbia-Brandt, Dobrochna Dolicka, Margot Fournier, Cyril Sobolewski, Didier J. Colin, Flavien Berthou, Perry J. Blackshear |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Liver Cirrhosis Male HNF4α hepatocyte nuclear factor 4 alpha Carcinogenesis Tristetraprolin Datasets as Topic GEPIA Gene Expression Profiling Interactive Analysis Tumor initiation ddc:616.07 DMSO dimethyl sulfoxide LTTPKO liver-specific tristetraprolin knockout mice Mice 0302 clinical medicine Liver Neoplasms Experimental GSEA gene set enrichment analysis Fibrosis Non-alcoholic Fatty Liver Disease hemic and lymphatic diseases 5-AZA 5-aza-2'deoxycytidine EGR1 early growth response 1 TSA trichostatin A heterocyclic compounds Diethylnitrosamine TGFβ transforming growth factor beta RNA-Seq Original Research TCGA the cancer genome atlas ICC intrahepatic cholangiocarcinoma MCD methionine and choline-deficient GEO gene expression omnibus TTP tristetraprolin Liver Neoplasms Gastroenterology NASH respiratory system Prognosis HNF4A Gene Expression Regulation Neoplastic UTR untranslated region Liver FLX floxed allele 030211 gastroenterology & hepatology Female medicine.symptom Hepatocyte dedifferentiation EMT epithelial-mesenchymal transition therapeutics NASH nonalcoholic steatohepatitis Liver Cancer Carcinoma Hepatocellular IL6 interleukin 6 Primary Cell Culture ARE adenylate-uridylate-rich element Down-Regulation Inflammation TUNEL terminal deoxynucleotidyl transferase dUTP nick end labeling 03 medical and health sciences VLDL very low density lipoprotein Cell Line Tumor MPH mouse primary hepatocyte medicine TMA tissue microarray Animals Humans ddc:612 neoplasms AUBPs AUBP adenylate-uridylate-rich element binding protein EV empty vector Hepatology business.industry Cancer DMEM Dulbecco modified Eagle medium Oncogenes medicine.disease Survival Analysis 030104 developmental biology Hepatocyte nuclear factor 4 alpha siRNA small interfering RNA Cancer cell Cancer research Hepatocytes FCS fetal calf serum NAFLD nonalcoholic fatty liver disease business HCC hepatocellular carcinoma SD standard deviation DEN diethylnitrosamine |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology (2020) |
| ISSN: | 2352-345X |
| Popis: | Background & Aims Tristetraprolin (TTP) is a key post-transcriptional regulator of inflammatory and oncogenic transcripts. Accordingly, TTP was reported to act as a tumor suppressor in specific cancers. Herein, we investigated how TTP contributes to the development of liver inflammation and fibrosis, which are key drivers of hepatocarcinogenesis, as well as to the onset and progression of hepatocellular carcinoma (HCC). Methods TTP expression was investigated in mouse/human models of hepatic metabolic diseases and cancer. The role of TTP in nonalcoholic steatohepatitis and HCC development was further examined through in vivo/vitro approaches using liver-specific TTP knockout mice and a panel of hepatic cancer cells. Results Our data demonstrate that TTP loss in vivo strongly restrains development of hepatic steatosis and inflammation/fibrosis in mice fed a methionine/choline-deficient diet, as well as HCC development induced by the carcinogen diethylnitrosamine. In contrast, low TTP expression fostered migration and invasion capacities of in vitro transformed hepatic cancer cells likely by unleashing expression of key oncogenes previously associated with these cancerous features. Consistent with these data, TTP was significantly down-regulated in high-grade human HCC, a feature further correlating with poor clinical prognosis. Finally, we uncover hepatocyte nuclear factor 4 alpha and early growth response 1, two key transcription factors lost with hepatocyte dedifferentiation, as key regulators of TTP expression. Conclusions Although TTP importantly contributes to hepatic inflammation and cancer initiation, its loss with hepatocyte dedifferentiation fosters cancer cells migration and invasion. Loss of TTP may represent a clinically relevant biomarker of high-grade HCC associated with poor prognosis. Graphical abstract |
| Databáze: | OpenAIRE |
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