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Series GSE133213 Query DataSets for GSE133213
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
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.
 
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)
 
Contributor(s) Mastrogiovanni G, Huch M
Citation(s) 35039505
Submission date Jun 24, 2019
Last update date Feb 08, 2022
Contact name Charles Bradshaw
Organization name University of Cambridge
Department Gurdon Institute
Street address Tennis Court Road
City Cambridge
ZIP/Postal code CB2 1QN
Country United Kingdom
 
Platforms (2)
GPL18480 Illumina HiSeq 1500 (Mus musculus)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
Samples (48)
GSM3902369 Liver, R&Z_KO_7M_1
GSM3902370 Liver, R&Z_KO_7M_2
GSM3902371 Liver, R&Z_KO_CD_4d_1
Relations
BioProject PRJNA550396
SRA SRP211826

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

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 SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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