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GEO help: Mouse over screen elements for information. |
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Status |
Public on Dec 10, 2021 |
Title |
Loss of RNF43/ZNRF3 predisposes to Hepatocellular carcinoma by impairing liver regeneration and altering liver fat metabolism |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
The homologous E3 ubiquitin ligases RNF43/ZNRF3 negatively regulate WNT signalling activation. Recently, both genes have been found mutated in several types of cancers. Specifically, loss-of-function mutations result in adenoma formation in mouse small intestine. However, their role in liver pathology and cancer has not been explored yet. Here, we describe that hepatocyte-specific deletion of Rnf43/Znrf3 results in altered lipid metabolism and steatohepatitis, in the absence of exogenous dietary fat supplementation, with a remarkable increase in unsaturated lipids. Upon liver injury, Rnf43/Znrf3 deletion results in impaired hepatocyte regeneration and liver cancer, subsequent to an imbalance between differentiation and proliferation. Using three different liver organoid models (hepatocyte-, hepatoblast- and ductal cell-derived organoids) we demonstrate that the hepatocyte differentiation defects and the lipid metabolic alterations are, at least in part, cell-autonomous. Remarkably, hepatocellular carcinoma patients with mutations in either or both genes or in other WNT pathway components also present altered hepatic lipid metabolism and non-alcoholic steatohepatitis (NASH) profiles. Our findings imply that hyperactivation of WNT signaling through the RNF43/ZNRF3 module predisposes to liver cancer by impairing hepatocyte differentiation and altering the lipid metabolic ground-state of the liver. Both mechanisms combined facilitate the progression towards malignancy. Our findings might aid on the management of those RNF43/ZNRF3 or WNT mutated individuals at risk of developing fatty liver and/or liver cancer.
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Overall design |
RNAseq of mouse livers WT (24 samples) and KO (24 samples) for Rnf43 and Znrf3 and with chronic damage (11 samples), partial hepatectomy (12 samples) at different time points or without damage (25 samples)
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Contributor(s) |
Mastrogiovanni G, Huch M |
Citation(s) |
35039505 |
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Submission date |
Jun 24, 2019 |
Last update date |
Dec 20, 2024 |
Contact name |
Meritxell Huch |
E-mail(s) |
huch@mpi-cbg.de
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Organization name |
Max Planck Institute of Molecular Cell Biology and Genetics
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Street address |
Pfotenhauerstrasse 108
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City |
Dresden |
ZIP/Postal code |
01307 |
Country |
Germany |
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Platforms (2) |
GPL18480 |
Illumina HiSeq 1500 (Mus musculus) |
GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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Samples (48)
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GSM3902372 |
Liver, R&Z_KO_CD_4d_2 |
GSM3902373 |
Liver, R&Z_KO_CD_50d_1 |
GSM3902374 |
Liver, R&Z_KO_CD_50d_2 |
GSM3902375 |
Liver, R&Z_KO_CD_170d_1 |
GSM3902376 |
Liver, R&Z_KO_CD_170d_2 |
GSM3902377 |
Liver, R&Z_WT_7M_1 |
GSM3902378 |
Liver, R&Z_WT_7M_2 |
GSM3902379 |
Liver, R&Z_WT_7M_3 |
GSM3902380 |
Liver, R&Z_WT_CD_4d_1 |
GSM3902381 |
Liver, R&Z_WT_CD_4d_2 |
GSM3902382 |
Liver, R&Z_WT_CD_50d_1 |
GSM3902383 |
Liver, R&Z_WT_CD_170d_1 |
GSM3902384 |
Liver, R&Z_WT_CD_170d_2 |
GSM5392296 |
Liver, R&Z_WT_3M_3 |
GSM5392297 |
Liver, R&Z_WT_3M_4 |
GSM5392298 |
Liver, R&Z_WT_3M_5 |
GSM5392299 |
Liver, R&Z_KO_3M_1 |
GSM5392300 |
Liver, R&Z_KO_3M_2 |
GSM5392301 |
Liver, R&Z_KO_3M_3 |
GSM5392302 |
Liver, R&Z_KO_1M_1 |
GSM5392303 |
Liver, R&Z_KO_1M_2 |
GSM5392304 |
Liver, R&Z_KO_1M_3 |
GSM5392305 |
Liver, R&Z_KO_1M_4 |
GSM5392306 |
Liver, R&Z_WT_1M_3 |
GSM5392307 |
Liver, R&Z_WT_1M_4 |
GSM5392308 |
Liver, R&Z_WT_1M_1 |
GSM5392309 |
Liver, R&Z_WT_1M_2 |
GSM5392310 |
Liver, R&Z_KO_7M_3 |
GSM5392311 |
Liver, R&Z_KO_7M_4 |
GSM5392312 |
Liver, R&Z_KO_7M_5 |
GSM5392313 |
Liver, R&Z_WT_7M_2 |
GSM5392314 |
Liver, R&Z_WT_7M_3 |
GSM5392315 |
Liver, R&Z_WT_7M_4 |
GSM5392316 |
Liver, R&Z_KO_PHx_21d_3 |
GSM5392317 |
Liver, R&Z_KO_PHx_7d_1 |
GSM5392318 |
Liver, R&Z_KO_PHx_7d_2 |
GSM5392319 |
Liver, R&Z_KO_PHx_7d_3 |
GSM5392320 |
Liver, R&Z_KO_PHx_21d_1 |
GSM5392321 |
Liver, R&Z_KO_PHx_21d_2 |
GSM5392322 |
Liver, R&Z_WT_PHx_7d_1 |
GSM5392323 |
Liver, R&Z_WT_PHx_7d_2 |
GSM5392324 |
Liver, R&Z_WT_PHx_7d_3 |
GSM5392325 |
Liver, R&Z_WT_PHx_21d_1 |
GSM5392326 |
Liver, R&Z_WT_PHx_21d_2 |
GSM5392327 |
Liver, R&Z_WT_PHx_21d_3 |
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Relations |
BioProject |
PRJNA550396 |
SRA |
SRP211826 |
Supplementary file |
Size |
Download |
File type/resource |
GSE133213_CountFile.csv.gz |
1.1 Mb |
(ftp)(http) |
CSV |
GSE133213_RAW.tar |
2.3 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
Processed data are available on Series record |
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