5 maart 2022: Bron: UMC Utrecht en EMBO journal

Augustus 2020 al ontdekten onderzoekers aan de Nederlandse UMC universiteit - Utrecht dat wanneer kankerremmende eiwitten (met name in het RNF43 gen) door een mutatie gedeeltelijk of geheel worden uitgeschakeld deze kankerremmende eiwitten kunnen veranderen in kankerstimulerend. Het UMC brachten in hun persbericht over deze studie gedaan in gekweekte mini-darmen (darmorganoïden) met deze titel: Kankermutatie zet remmend eiwit om in gaspedaal . Dit onderzoek is dus nog in een beginnende fase van laboratorium onderzoek tot dierstudies. Maar toch wel belangrijk. 

Afgelopen januari 2022 blijkt wat de Utrechtse onderzoekers vonden ook op te treden bij leverproblemen / leverkanker. Conclusie van een studie:  "RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state" (vertaling via google translate: RNF43 / ZNRF3-verlies maakt vatbaar voor hepatocellulair carcinoom door leverregeneratie te belemmeren en de metabolische grondtoestand van leverlipiden te veranderen). Deze leverstudies zijn uitgebreid en tot in detail beschreven in een studierapport. Zie onder dit artikel. Met lange referentielijst gerelateerd aan dit onderwerp. 

In de Utrechtse studie (abstract onderaan dit artikel) wordt grafisch weergegeven hoe dit mechanisme werkt en er wordt ook in video uitgelegd hoe dit mechanisme werkt:

The Wnt pathway-antagonising tumor suppressor RNF43 is frequently lost in human malignancies. Identification of a distinct class of patient-derived RNF43 truncating mutations that drive Wnt receptor/β-catenin target expression in a ligand-independent manner may impact on current cancer treatment schemes.

  • Expression of C-terminally-truncated RNF43 increases β-catenin-mediated transcription in the absence of Wnt ligands.
  • Truncated RNF43 retains destruction complex components CK1 and AXIN at the plasma membrane.
  • CK1α-mediated phosphorylation of the cytosolic tail of truncated RNF43 activates intracellular Wnt signaling.
  • Oncogenic RNF43 induces TP53-dependent epithelial growth arrest in human colon organoids, and decreases sensitivity to anti-Wnt-based therapy.


Wnt/β-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 β-catenin-mediated transcription, despite exhibiting retained Wnt receptor downregulation. These mutations interfere with a 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 β-catenin turnover and propelling ligand-independent 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.


RNF43/ZNRF3 negatively regulate WNT signalling. Both genes are mutated in several types of cancers, however, their contribution to liver disease is unknown. Here we describe that hepatocyte-specific loss of Rnf43/Znrf3 results in steatohepatitis and in increase in unsaturated lipids, in the absence of dietary fat supplementation. Upon injury, Rnf43/Znrf3 deletion results in defective hepatocyte regeneration and liver cancer, caused by an imbalance between differentiation/proliferation. Using hepatocyte-, hepatoblast- and ductal cell-derived organoids we demonstrate that the differentiation defects and lipid alterations are, in part, cell-autonomous. Interestingly, ZNRF3 mutant liver cancer patients present poorer prognosis, altered hepatic lipid metabolism and steatohepatitis/NASH signatures. Our results imply that RNF43/ZNRF3 predispose to liver cancer by controlling the proliferative/differentiation and lipid metabolic state of hepatocytes. Both mechanisms combined facilitate the progression towards malignancy. Our findings might aid on the management of those RNF43/ZNRF3 mutated individuals at risk of developing fatty liver and/or liver cancer.


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