RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state

RNF43/ZNRF3 negatively regulates WNT signaling. 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 an 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.

Circ_0000190 sponges miR-382-5p to suppress cell proliferation and motility and promote cell death by targeting ZNRF3 in gastric cancer

This study was to explore the role of circRNA_0000190 (circ_0000190) in gastric cancer (GC) progression. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were applied to measure RNA and protein expression. 5-Ethynyl-2′-deoxyuridine (EdU) assay and cell counting kit-8 (CCK8) assay were implemented to analyze cell proliferation ability.
Transwell assays were conducted to analyze cell motility.
Cell ferroptosis was assessed using commercial kit. The target relationship between microRNA-382-5p (miR-382-5p) and circ_0000190 or zinc and ring finger 3 (ZNRF3) was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay.
Murine xenograft model was used to analyze the function of circ_0000190 in GC progression in vivo. Circ_0000190 was down-regulated in GC tissues and cell lines.
Low expression of circ_0000190 predicted dismal prognosis in GC patients. Circ_0000190 overexpression inhibited the proliferation, migration and invasion and promoted Erastin- or ras selective lethal 3 (RSL3)-mediated ferroptosis in GC cells. MiR-382-5p was a target of circ_0000190, and circ_0000190 suppressed GC progression partly via serving as miR-382-5p sponge.
ZNRF3 was a target of miR-382-5p, and miR-382-5p accelerated the proliferation, motility and restrained the ferroptosis of GC cells partly via regulating ZNRF3.
Circ_0000190 overexpression restrained xenograft tumor growth in vivo. Collectively, Circ_0000190 suppressed GC progression via miR-382-5p-dependent regulation of ZNRF3.

The RSPO-LGR4/5-ZNRF3/RNF43 module in liver homeostasis, regeneration and disease

WNT/β-catenin signaling plays pivotal roles during liver development, homeostasis and regeneration. Likewise, its deregulation disturbs metabolic liver zonation and is responsible for the development of a large number of hepatic tumors. Liver fibrosis, which has become a major health burden for the society and a hallmark of non-alcoholic-steatohepatitis (NASH), can also be promoted by WNT/β-catenin signaling.
Upstream regulatory mechanisms controlling hepatic WNT/β-catenin activity may constitute targets for the development of novel therapies addressing these life-threatening conditions.
The RSPO-LGR4/5-ZNRF3/RNF43 module is fine-tuning WNT/β-catenin signaling in several tissues and is essential for hepatic WNT/β-catenin activity.
In this review article, we recapitulate the role of the RSPO-LGR4/5-ZNRF3/RNF43 module during liver development, homeostasis, metabolic zonation, regeneration and disease. We further discuss the controversy around LGR5 as a liver stem cell marker.

RNF43/ZNRF3 negatively regulates taste tissue homeostasis and positively regulates dorsal lingual epithelial tissue homeostasis

Taste bud cells are renewed throughout life in a process requiring innervation. Recently, we reported that R-spondin substitutes for neuronal input for taste cell regeneration. R-spondin amplifies WNT signaling by interacting with stem-cell-expressed E3 ubiquitin ligases RNF43/ZNRF3 (negative regulators of WNT signaling) and G-protein-coupled receptors LGR4/5/6 (positive regulators of WNT signaling).
Therefore, we hypothesized that RNF43/ZNRF3 may serve as a brake, controlled by gustatory neuron-produced R-spondin, for regulating taste tissue homeostasis. Here, we show that mice deficient for Rnf43/Znrf3 in KRT5-expressing epithelial stem/progenitor cells (RZ dKO) exhibited taste cell hyperplasia; in stark contrast, epithelial tissue on the tongue degenerated. WNT signaling blockade substantially reversed all these effects in RZ dKO mice.
Furthermore, innervation becomes dispensable for taste cell renewal in RZ dKO mice.
We thus demonstrate important but distinct functions of RNF43/ZNRF3 in regulating taste versus lingual epithelial tissue homeostasis.

Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse

Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate prognostic biomarkers.
We analyze 1,844 localized (1,289) or mCRPC (555) tumors and quantify the prevalence of 113 somatic driver single nucleotide variants (SNVs), copy number aberrations (CNAs), and structural variants (SVs) in each state. One-third are significantly more prevalent in mCRPC than expected while a quarter are less prevalent.
Mutations in AR and its enhancer are more prevalent in mCRPC, as are those in TP53, MYC, ZNRF3 and PRKDC. ZNRF3 loss is associated with decreased ZNRF3 mRNA abundance, WNT, cell cycle & PRC1/2 activity, and genomic instability.
ZNRF3 loss, RNA downregulation and hypermethylation are prognostic of metastasis and overall survival, independent of clinical and pathologic indices.
These data demonstrate a strategy for identifying biomarkers of localized cancer aggression, with ZNRF3 loss as a predictor of metastasis in prostate cancer.

Ub and Dub of RNF43/ZNRF3 in the WNT signalling pathway

The E3 ubiquitin ligases RING finger protein 43 (RNF43) and zinc and RING finger 3 (ZNRF3) have received great attention for their critical role in regulating WNT signalling during adult stem cell homeostasis. By promoting the turnover of WNT receptors, Frizzled and LRP5/6, RNF43 and ZNRF3 ensure that proper levels of WNT activity are maintained in stem cells.
The molecular mechanism of RNF43/ZNRF3 activity is beginning to emerge from several recent studies, yet little is known about the regulation of RNF43/ZNRF3 at the post-translational level.
A study in this issue of EMBO Reports identifies the deubiquitinating enzyme USP42 as a key regulator of WNT signalling, which acts by antagonizing the ubiquitin-dependent clearance of RNF43/ZNRF3 induced by R-spondins (Giebel et al, 2021).

Low Protein Expression of both ATRX and ZNRF3 as Novel Negative Prognostic Markers of Adult Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a rare malignancy that is associated with a dismal prognosis. Pan-genomic studies have demonstrated the involvement of ATRX and ZNRF3 genes in adrenocortical tumorigenesis.
Our aims were to evaluate the protein expression of ATRX and ZNRF3 in a cohort of 82 adults with ACC and to establish their prognostic value.
Two pathologists analyzed immuno-stained slides of a tissue microarray. The low protein expression of ATRX and ZNRF3 was associated with a decrease in overall survival (OS) (p = 0.045, p = 0.012, respectively). The Cox regression for ATRX protein expression of >1.5 showed a hazard ratio (HR) for OS of 0.521 (95% CI 0.273-0.997; p = 0.049) when compared with ≤1.5; for ZNRF3 expression >2, the HR for OS was 0.441 (95% CI, 0.229-0.852; p = 0.015) when compared with ≤2. High ATRX and ZNRF3 protein expressions were associated with optimistic recurrence-free survival (RFS) (p = 0.027 and p = 0.005, respectively).

Human E3 ubiquitin-protein ligase ZNRF3 (ZNRF3)

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The Cox regression of RFS showed an HR of 0.332 (95%CI, 0.111-0.932) for ATRX expression >2.7 (p = 0.037), and an HR of 0.333 (95%CI, 0.140-0.790) for ZNRF3 expression >2 (p = 0.013). In conclusion, low protein expression of ATRX and ZNRF3 are negative prognostic markers of ACC; however, different cohorts should be evaluated to validate these findings.

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