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Loss of RNF43/ZNRF3 predisposes to Hepatocellular carcinoma by impairing liver regeneration and altering liver fat metabolism

ABSTRACT: Loss of RNF43/ZNRF3 predisposes to Hepatocellular carcinoma by impairing liver regeneration and altering liver fat metabolism

PROVIDER: PRJNA550396 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14862200.fastq.gz	Fastqsanger.gz
	SRR14862201.fastq.gz	Fastqsanger.gz
	SRR14862202.fastq.gz	Fastqsanger.gz
	SRR14862203.fastq.gz	Fastqsanger.gz
	SRR14862204.fastq.gz	Fastqsanger.gz

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Loss of RNF43/ZNRF3 predisposes to Hepatocellular carcinoma by impairing liver regeneration and altering liver fat metabolism

Project description: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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Expression data from HepG2 cells before and after RNF43 knockdown

Project description:It has been demonstrated that Ring finger protein 43 (RNF43) is overexpressed in colorectal cancer and mediates cancer cell proliferation. We found that RNF43 was frequently overexpressed in HCC, and knockdown of RNF43 could induce apoptosis and inhibit proliferation, invasion, colony formation and xenograft growth of HCC cells. Suggesting that RNF43 is involved in tumorigenesis and progression of HCC. We used microarrays to profile gene expression patterns before and after RNF43 knockdown, and identified differentially expressed genes during this process. HepG2 cells were transfected with RNF43 siRNA or negative control siRNA in triplicate. Forty-eight hours after transfection, total RNA was extracted,labeled and hybridized to HG-U133 Plus 2.0 arrays.

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RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer

Project description:Wnt/b-catenin signaling is a primary pathway for stem cell maintenance during tissue renewal and a frequent target for mutations in cancer. Impaired Wnt receptor endocytosis due to loss of the ubiquitin ligase RNF43 gives rise to Wnt-hypersensitive tumors that are susceptible to anti-Wnt-based therapy. Contrary to this paradigm, we identify a class of RNF43 truncating cancer mutations that induce b-catenin-mediated transcription, despite exhibiting retained Wnt receptor downregulation. These mutations interfere with an ubiquitin-independent suppressor role of the RNF43 cytosolic tail that involves casein kinase-1 (CK1) binding and phosphorylation. Mechanistically, truncated RNF43 variants trap CK1 at the plasma membrane, thereby preventing b-catenin turnover and propelling ligandindependent target gene transcription. Gene editing of human colon stem cells shows that RNF43 truncations cooperate with p53 loss to drive a niche-independent program for self-renewal and proliferation. Moreover, these RNF43 variants confer decreased sensitivity to anti-Wnt-based therapy. Our data demonstrate the relevance of studying patient-derived mutations for understanding disease mechanisms and improved applications of precision medicine.

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Transcriptional response to PORCN inhibition using an orthotopic model of RNF43 mutant pancreatic adenocarcinoma (HPAF-II)

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Transcriptional response to PORCN inhibition using a subcutaneous model of RNF43 mutant pancreatic adenocarcinoma (HPAF-II)

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