MicroRNA‑301a/ZNRF3/wnt/β‑catenin signal regulatory crosstalk mediates glioma progression

MicroRNA (miR)‑mediated mRNA and multiple signaling pathway dysregulations have been extensively implicated in several cancer types, including gliomas.
Although previous studies have reported that miR‑301a acts as an oncogene, the underlying mechanisms of miR‑301a in the initiation and progression of glioma remain unknown. The present study aimed to investigate the involvement of miR‑301a‑mediated signaling pathway dysregulation in glioma.
The results identified that miR‑301a was significantly upregulated in gliomas and was associated with a poor prognosis based on The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases.
Moreover, zinc and ring finger 3 (ZNRF3) exerted a critical role in the miR‑301a‑mediated effects on the malignant phenotype, such as by affecting proliferation and apoptosis.
Mechanistically, the TOP/FOP luciferase assay, western blotting and immunofluorescence results demonstrated that miR‑301a knockdown inhibited the wnt/β‑catenin signaling pathway, at least partially via ZNRF3, while ZNRF3 was a direct functional target of miR‑301a, as indicated by luciferase reporter assay and western blot analysis.
Furthermore, ZNRF3 could in turn repress miR‑301a expression, which was dependent on the wnt pathway. Collectively, the present study identified a novel miR‑301a/ZNRF3/wnt/β‑catenin signaling feedback loop that serves critical roles in glioma tumorigenesis, and that may represent a potential therapeutic target.

ZNRF3 Regulates Collagen-Induced Arthritis Through NF-kB and Wnt Pathways

Although the E3 ubiquitin ligase Zinc and ring finger 3 (ZNRF3) negatively regulates the Wnt signaling pathway, its function in rheumatoid arthritis (RA) is elusive. Here, the effects and the mechanism of ZNRF3 on a mouse model of collagen-induced arthritis (CIA) and human fibroblast-like synoviocytes (FLS) obtained from RA patients were determined. Our results showed that ZNRF3 was highly expressed in tissues and FLSs compared to trauma patients.
Lentivirus-mediated silencing of ZNRF3 induced apoptosis decreased cell viability and significantly attenuated inflammation in RA-FLSs via tumor necrosis-α (TNF-α).
Additionally, silencing of ZNRF3 reduced knee joint damage and also decreased the level of TNF-α, IL-1β, and IL-6 in the CIA mouse model.
These effects were mediated by the crosstalk between Wnt and NF-κB pathways in RA-FLS.

The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer.

A hallmark of Spemann’s organizer function is its expression of Wnt antagonists that regulate axial embryonic patterning. Here we identify the tumor suppressor Protein tyrosine phosphatase receptor-type kappa (Ptprk), as a Wnt inhibitor of the Spemann organizer.
We show that PTPRK acts via the transmembrane E3 ubiquitin ligase ZNRF3, a negative regulator of Wnt signaling promoting Wnt receptor degradation, which is also expressed in the organizer.
Deficiency of ptprk increases Wnt signaling, leading to reduced expression of Spemann organizer effector genes and inducing head and axial defects.
We identify a ‘4Y’ endocytic signal in ZNRF3, which Ptprk maintains unphosphorylated to promote Wnt receptor depletion. Our discovery of PTPRK as a negative regulator of Wnt receptor turnover provides a rationale for its tumor suppressive function and reveals that in PTPRK-RSPO3 recurrent cancer fusions both fusion partners, in fact, encode ZNRF3 regulators.

Effects of miR‑106b‑3p on cell proliferation and epithelial‑mesenchymal transition, and targeting of ZNRF3 in esophageal squamous cell carcinoma.

Previous studies have demonstrated that the dysregulation of microRNAs (miRs) is frequently associated with cancer progression.
Deregulation of miR‑106b‑3p has been observed in various types of human cancer. However, the biological function of miR‑106b‑3p in esophageal squamous cell carcinoma (ESCC) remains unclear. Thus, the aim of this study was to investigate the role of miR‑106b‑3p in ESCC.
In the current study, the results indicated that miR‑106b‑3p was upregulated in ESCC cell lines and tissues. An increase in miR‑106b‑3p using miR mimics significantly promoted the proliferation of ESCC cells in vitro.
Furthermore, the results demonstrated that miR‑106b‑3p overexpression promoted migration, invasion and epithelial‑mesenchymal transition (EMT) of ESCC cells. In addition, zinc and ring finger 3 (ZNRF3) was identified as a target of miR‑106b‑3p in ESCC cells, and the ZNRF3 expression level was inversely associated with miR‑106b‑3p. It was also demonstrated that miR‑106b‑3p has a role in EMT by regulating Wnt/β‑catenin signaling pathway in ESCC.
In conclusion, these data suggested that miR‑106b‑3p promotes cell proliferation and invasion, partially by downregulating ZNRF3 and inducing EMT via Wnt/β‑catenin signaling in ESCC cells.
Thus, miR‑106b‑3p and ZNRF3 may be novel molecular targets for the future treatment of ESCC.

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