wnt signaling

Mesenchymal stem cells of human umbilical cord origin (hucMSCs) appear to be an attractive candidate for cell-based therapies. However, their efficacy requires improvement as poor survival and specific homing to the site of injury are the major barriers to their effective implementation in cell therapy. As Wnt signaling pathway is involved in the development and repair of organs, we adopted a preconditioning strategy of stem cells by using CHIR99021 compound (a Wnt pathway agonist) to potentiate hucMSCs beneficial effects and circumvent their therapeutic limitations.

We treated hucMSCs with 5 µM of CHIR99021 and evaluated the expression levels of genes involved in different biological processes through qRT-PCR. Subsequently, we examined the effectiveness of preconditioned cells (CHIR99021-hucMSCs) in a cisplatin-induced rat acute kidney injury model. Amelioration in tissue injury was evaluated by histopathology, immunohistochemistry and renal functional assessment.

In treated groups, we observed preserved renal tissue architecture in terms of lesser epithelial cells necrosis (P ≤ 0.001) and cast formation ( ≤ 0.05). Accelerated proliferation of injured tubular cells (P ≤ 0.001) and low serum creatinine values (P ≤ 0.01) were observed in preconditioned hucMSCs group compared to untreated AKI rats. In addition, administration of preconditioned hucMSCs in kidney injury model offered better restoration of tubular cell membrane β-catenin molecules. Our findings showed that CHIR99021-modified hucMSCs may exhibit better capacity for cell migration and proliferation.

The results showed that preconditioning of stem cells with Wnt pathway activators could provide advanced benefits for organ repair, which may contribute to design a more effective therapeutic approach for renal regeneration.

Cisplatin resistance presents a considerable hurdle in the treatment of ovarian cancer, significantly impacting patient outcomes and limiting the effectiveness of chemotherapy. This study employs advanced bioinformatics techniques-including RNA sequencing (RNA-seq), DNA sequencing (DNA-seq), and chromatin immunoprecipitation sequencing (ChIP-seq)-to elucidate the molecular mechanisms underlying this resistance, with a particular focus on the long non-coding RNA (lncRNA) LINC02381. Our findings reveal that LINC02381 is significantly upregulated in ovarian cancer cells exhibiting resistance to cisplatin, suggesting its pivotal role in mediating this phenomenon. We further demonstrate that cytokines, particularly interleukin-12 (IL-12), secreted by immune cells within the tumor microenvironment, activate the Wnt signaling pathway. This activation leads to the binding of the transcription factor TCF7 to the promoter region of LINC02381, resulting in enhanced expression of this lncRNA. Notably, this interaction establishes a positive feedback loop in which LINC02381 not only promotes its own expression but also amplifies Wnt signaling activity. This cascade ultimately drives the upregulation of ATP-binding cassette (ABC) transporters, which are crucial for the efflux of cisplatin from cancer cells. Thus, the drug's intracellular concentration is reduced, and cell survival under chemotherapy pressure is facilitated. These insights uncover a novel mechanism of cisplatin resistance driven by the IL-12/Wnt/TCF7/LINC02381 axis, highlighting the complex interplay between immune signaling and drug resistance in ovarian cancer. Our findings suggest that targeting this regulatory pathway may offer promising therapeutic strategies to overcome chemotherapy resistance, paving the way for improved treatment outcomes in patients with ovarian cancer. Future research should focus on validating these mechanisms and exploring potential interventions that disrupt this feedback loop.

The process of wound healing is a dynamic event that starts with inflammation, proliferation, and migration of various types of fibroblast cells and aims to restore the integrity and functionality of damaged tissue. One crucial signaling pathway involved in wound healing is the Wnt signaling pathway. This study aimed to investigate the effects of a cocktail consisting of L-carnosine, zinc sulfate, and B-complex vitamins on the modulation of the Wnt signaling pathway during wound healing.

The optimal dosages of L-carnosine, zinc sulfate, and B-complex were used to prepare the cocktail. Then, the cocktail-mediated wound healing was measured through scratch assay on human dermal fibroblast (HDF) cells. Finally, the effects of the cocktail on the expression of SFRP1 , SFRP2 , SFRP4 , MMP7 , and RSPO2 genes involved in the Wnt signaling pathway were measured during the wound closure phenomenon by real-time quantitative polymerase chain reaction (RT-qPCR).

The scratch assay demonstrated the wound-healing effects of the prepared cocktail on HDF cells. Additionally, the RT-qPCR results showed that the cocktail can activate the Wnt signaling pathway by down-regulating the expression of SFRP1 , SFRP2 , SFRP4 , and MMP7 and up-regulating the expression of RSPO2 .

The data suggest that the L-carnosine, zinc sulfate, and B-complex vitamin cocktail exhibits wound healing properties by increasing fibroblast proliferation via the activation of the Wnt pathway.

The canonical Wnt signal transduction or the Wnt/β-catenin pathway plays a crucial role in both carcinogenesis and development of animals. Activation of the Gαq class of Gα proteins positively regulates Wnt/β-catenin pathway, and expression of Gαq in HEK293T cells or Xenopus oocytes leads to the inhibition of GSK-3β and cellular accumulation of β-catenin. This study investigated whether Gαq-mediated cellular accumulation of β-catenin could affect the transcriptional activity of this protein.

HEK-293T and HT-29 cells were used for cell culture and transfection. Protein localization and quantification were assessed by using immunofluorescence microscopy, cell fractionation assay, and Western blotting analysis. Gene expression at the transcription level was examined by quantitative reverse transcriptase/real-time PCR method.

Transcription of two cellular β-catenin target genes (c-MYC and CCND1) and the β-catenin/TCF reporter luciferase gene (TopFlash plasmid) significantly increased by Gαq activation. The Gαq-mediated increase in the expression level of the β-catenin-target genes was sensitive to the expression of a minigene encoding a specific Gαq blocking peptide. The results of cell fractionation and Western blotting experiments showed that activation of Gαq signaling increased the intracellular β-catenin protein level, but it blocked its membrane localization.

Our results reveal that the Gαq-dependent cellular
accumulation of β-catenin can enhance β-catenin transcriptional activity.

An increasing number of studies have suggested that unveiling the molecular network of miRNAs may provide novel therapeutic targets or biomarkers. In this study, we investigated the probable molecular functions that are related to microRNA-802 (miR-802) and evaluated its prognostic value in breast cancer utilizing bioinformatics tools.

PPI network, pathway enrichment and transcription factor analysis were applied to obtain hub genes among overlapping genes of four miRNA target prediction databases. Prognosis value assessments and expression analysis of hub genes using bioinformatics tools, as well as their literature validation were performed.

Our results showed a significant correlation of the miR-802 overexpression with poor patient survival rate (BC, p=2.7e-5). We determined 247 target genes significant for GO and KEGG terms. Analysis of TFs by TRUST showed that RUNX3, FOXO3, and E2F1 are possible TFs that regulate the miR-802 expression and target genes network. According to our analysis; 21 genes might have an important function in miR-802 molecular processes and regulatory networks. The result shows that among these 21 genes, 8 genes (CASC3, ITGA4, AGO3, TARDBP, MED13L, SF1, SNRPE and CRNKL1) are positively correlated with patient survival. Therefore these genes could be considered and experimentally evaluated as a prognostic biomarker for breast cancer.

The comprehensive bioinformatics study on miR-802 target genes provided insight into miR-802 mediated pathways and processes. Furthermore, representing candidate target genes by prognostic values indicates the potential clinical application of miR-802 in breast cancer.

Wnt signaling plays a critical role during embryogenesis and is responsible for regulating the homeostasis of the adult stem cells and cells fate via a multitude of signaling pathways and associated transcription factors, receptors, effectors, and inhibitors. For this review, published articles were searched from PubMed Central, Embase, Medline, and Google Scholar. The search terms were Wnt, canonical, noncanonical, signaling pathway, β-catenin, environment, and heavy metals. Published articles on Wnt signaling pathways and heavy metals as contributing factors for causing diseases via influencing Wnt signaling pathways were included. Wnt canonical or noncanonical signaling pathways are the key regulators of stem cell homeostasis that control many mechanisms. There is an adequate balance between β-catenin dependent and independent Wnt signaling pathways and remain highly conserved throughout different development stages. Environmental heavy metal exposure may cause either inhibition or overexpression of any component of Wnt signaling pathways such as Wnt protein, transcription factors, receptors, ligands, or transducers to impede normal cellular function via negatively affecting Wnt signaling pathways. Environmental exposure to heavy metals potentially contributes to diseases via deregulated Wnt signaling pathways.

Precise regulation of signal transduction pathways is crucial for normal animal development and for maintaining cellular and tissue homeostasis in adults. The Wnt/Frizzled-mediated signaling includes canonical and non-canonical signal transduction pathways. Upregulation or downregulation of the canonical Wnt-signaling (or the Wnt/β-Catenin signal transduction) leads to a variety of human diseases, including many human cancers, neurodegenerative, skin, bone and heart deficiencies. Therefore, Wnt/β-Catenin signal transduction is a potential clinical target for the treatment of not only human cancers but also some other human chronic diseases. Here, some recent results including the results from my laboratory highlighting the role of Wnt/β-Catenin signal transduction in human cancers will be reviewed. After a brief overview on canonical Wnt signaling and introducing some critical β-Catenin/TCF-target genes, the interaction of canonical Wnt signaling with some common human cancers will be discussed. Finally, the different segments of this signaling pathway, which have been considered as targets for clinical purposes, will be discussed.

It is estimated that up to 20% of all types of human cancers worldwide are attributed to viruses. The genome of oncogenic viruses carries genes that have protein products that act as oncoproteins in cell proliferation and transformation. The modulation of cell cycle control mechanisms, cellular regulatory and signaling pathways by oncogenic viruses, plays an important role in viral carcinogenesis. Different signaling pathways play a part in the carcinogenesis that occurs in a cell. Among these pathways, the Wnt signaling pathway plays a predominant role in carcinogenesis and is known as a central cellular pathway in the development of tumors. There are three Wnt signaling pathways that are well identified, including the canonical or Wnt/β-catenin dependent pathway, the noncanonical or β-catenin-independent planar cell polarity (PCP) pathway, and the noncanonical Wnt/Ca2 pathway. Most of the oncogenic viruses modulate the canonical Wnt signaling pathway. This review discusses the interaction between proteins of several human oncogenic viruses with the Wnt signaling pathway.

Colorectal cancer is one of the mostly diagnosed malignancies worldwide. The main risk factors for colorectal cancer include the mutation of tumor suppressor genes or proto-oncogenes and unhealthy lifestyle. Vegetable and fruit consumption with multiple anticancer agents can reduce the risk of colon cancer. Resveratrol, is a natural polyphenolic product that inhibits proliferation and induces apoptosis through several pathways. In this study, the effects of resveratrol on β-catenin (CTNNB1) and GSK-3β expression affecting the Wnt-signaling pathway, were examined and morphology changes were analyzed in colon cancer cells with high levels of β-catenin such as HCT-116.
HCT-116 cells were seeded into 6-well plates and the cells were treated with various concentrations of resveratrol (25, 50 and 100 μM) for 24, 48 and 72 hours. β-catenin and GSK-3β expression were examined by Quantitative Real-time PCR and morphology changes were analyzed.
Our result showed that resveratrol in 25 and 50 μM concentrations of resveratrol reduces β-catenin and GSK-3β expression in 24h (p-value; 0.001). Gene expressions were found to increase in 48h and 72h treatment with resveratrol in the concentration of 50 and 100 μM (p-value; 0.001).
considering our data, we suggest that low doses of resveratrol could reduce β-catenin expression, which can affect the Wnt-signaling pathway. While, high doses can increase the GSK-3β expression, playing a role in the destruction of β-catenin, inhibition of its accumulation in the cytoplasm and nuclear, apoptosis induction and cellular proliferation inhibition. On the other hand, low doses of resveratrol can decrease GSK-3β expression and suppress proliferation.

High-glucose (HG) stress, a mimic of diabetes mellitus (DM) in culture cells, alters expression of a large number of genes including Wnt and NF-κB signaling-related genes; however, the role of Wnt signaling during HG-mediated fibroblast damage and the relationship between Wnt and NF-κB signaling have not been understood. In this study, we aimed to investigate the ffects of Wnt signaling on HG-mediated damages.
Wnt3a was treated to HG-stressed human primary foreskin fibroblasts and the levels of Wnt signaling markers and cell proliferation were monitored. In addition, Wnt3a and NF-κB signaling inhibitor were assisted to analyze the relationship between two pathways.
The results indicated that HG treatment repressed β-catenin level, and Wnt3a treatment increased the levels of β-catenin and FZD8 as well as cell proliferation. RNA-seq based transcriptome analysis identified 207 up-regulated and 200 down-regulated genes upon Wnt3a supply. These altered genes are distributed into 20 different pathways. In addition, gene ontology (GO) analysis indicates that 20 GO terms are enriched. Wnt signaling genes were further verified by qRT-PCR and the results were similar with RNA-seq assay. Since NF-κB signaling negatively regulates Wnt marker gene expression, Bay117082, a typical NF-κB signaling inhibitor and Wnt3a were supplemented for testing β-catenin and phosphorylated IκBα (p-IκBα), respectively.
HG positively inhibits Wnt signaling, and signaling activation via supplementation of Wnt3a rescued the defect caused by HG. NF-κB signaling negatively regulates accumulation of β-catenin, but Wnt signaling has no effects on IκBα activation.

Coronary artery disease (CAD) is the major cause of mortality and morbidity worldwide. The aim of this study was to explore the effect of resveratrol (RES) on Canonical β catenin/Wnt and forkhead box O (FOXO) pathways in CAD patients. We performed this study on 10 metabolic syndrome patients with three-vessel CAD and 10 sex-aged matched healthy subjects. The effects of RES on β-Catenin, manganese superoxide dismutase (MnSOD), and peroxisome proliferator-activated receptor delta (PPAR-δ) expression were evaluated in peripheral blood mononuclear cells (PBMCs) of participants. RES could increase the MnSOD expression in CAD patients (38%, p