Search Results (57)

The Wntβ-catenin signaling pathway is a key regulator of gastrointestinal (GI) tumorigenesis, modulating cellular processes such as proliferation, differentiation, and epithelial-to-mesenchymal transition (EMT). In this review, we evaluate the expression and mutation profiles of core Wntpathway components in the most common GI malignancies. Our findings outline notable alterations in ligands, receptors, co-receptors, and intracellular effectors across different GI cancers. In gastric cancer tissue, elevated levels of Wnt proteins, FZD7 receptor, and LRP5/6, along with β-catenin accumulation and reduced APC expression, are associated with poor prognosis. In colorectal cancer samples, common APC mutations and Wnt ligand overexpression contribute to β-catenin nuclear localization and EMT. Esophageal cancer specimens exhibit co-overexpression of Wnt2 and Wnt5A, as well as receptors such as FZD2 and FZD6, which are linked to worse prognosis and reduced survival. Liver cancer tissue commonly harbors CTNNB1 mutations, which encode β-catenin and are associated with poor differentiation. In pancreatic cancer samples, overexpression of Wnt ligands, FZD receptors, and β-catenin is associated with the presence of distant metastasis and poor clinical outcomes. In conclusion, this pathway represents a promising avenue for identifying novel diagnostic, prognostic, and therapeutic biomarkers in GI cancers, warranting further clinical investigation. Full article

Pancreatic cancer (PC) is a highly aggressive malignancy with increasing incidence and poor survival. Hispanic/Latino (H/L) patients, despite having a lower overall incidence than Non-Hispanic White (NHW) patients, are often diagnosed younger and at more advanced stages, leading to worse outcomes. The molecular mechanisms underlying these disparities remain unclear. This study characterizes mutations in key oncogenic pathways—TP53, WNT, PI3K, TGF-Beta, and RTK/RAS—among H/L and NHW patients using publicly available datasets. We analyzed genomic data from 4248 PC patients (407 H/L; 3841 NHW), comparing mutation frequencies across pathways. Chi-squared tests assessed group differences, and Kaplan–Meier analysis evaluated survival outcomes by pathway alterations. TGF-Beta pathway mutations were less common in H/L patients (18.4% vs. 24.4%, p = 8.6 × 10⁻³), with notable differences in SMAD2 (1.5% vs. 0.4%, p = 6.3 × 10⁻³) and SMAD4 (15% vs. 19.9%, p = 0.02). While overall differences in other pathways were not statistically significant, several genes showed borderline significance, including ERBB4, ALK, HRAS, RIT1 (RTK/RAS), and CTNNB1 (WNT). No significant survival differences were observed in H/L patients, but NHW patients with TP53 alterations showed borderline survival associations. This study reveals ethnicity-specific pathway alterations in PC, with SMAD2, ERBB4, ALK, and CTNNB1 mutations being more frequent in H/L patients, while SMAD4 and PI3K alterations had prognostic value in NHW patients. These findings indicate the importance of incorporating ethnicity-specific molecular profiling into precision oncology for PC. Full article

Mesenchymal stromal cells of the tumor microenvironment (TME) play a significant role in the progression of multiple myeloma (MM). The cells of the TME demonstrate resistance to treatment, thereby creating a favorable environment for disease relapse. The status of the TME during remission is poorly understood. An association between treatment response and TME status (including signaling pathways) has been suggested. One of the key players in the establishment of the MM TME is WNT signaling. In this study, we evaluated the expression of WNT family proteins in the TME and MM cells to assess their potential as TME markers and predictors of treatment response. A bioinformatic analysis of normal and malignant plasma cells, combined with an analysis of published data, revealed the following differentially expressed WNT genes: WNT5A, WNT10B, CTNNB1, and WNT3A. Immunohistochemical staining with the antibodies against the proteins encoded by the genes was conducted on trephine biopsy samples of bone marrow from healthy donors and patients with different responses to therapy. A quantitative analysis of the immunohistochemical data revealed differences in the amounts of WNT3A, WNT5A, WNT10B, and β-catenin proteins in the bone marrow before treatment depending on the subsequent responses of the patients to therapy. Multiplex fluorescent immunohistochemical staining with tyramide signal amplification revealed that WNT3A was predominantly present in mesenchymal stromal cells, whereas WNT5A and WNT10B were primarily observed in plasma cells. β-catenin was detected in both cell types. We analyzed the mRNA levels of the WNT gene family and CTNNB1 in MSC cultures from healthy donors and patients using qPCR. These genes were differentially expressed in MSC cultures derived from patients and healthy donors, as well as between patients grouped according to their response to therapy. Therefore, WNT proteins and β-catenin can be considered potential markers to assess the state of the tumor niche. Full article

Hair follicles, unique skin appendages, undergo cyclic phases (anagen, catagen, telogen) governed by melatonin and associated molecular pathways. Melatonin, synthesized in the pineal gland, skin, and gut, orchestrates these cycles through antioxidant activity and signaling cascades (e.g., Wnt, BMP). This review examines melatonin’s biosynthesis across tissues, its regulation of cashmere growth patterns, and its interplay with non-coding RNAs and the gut–skin axis. Recent advances highlight melatonin’s dual role in enhancing antioxidant capacity (via Keap1-Nrf2) and modulating gene expression (e.g., Wnt10b, CTNNB1) to promote hair follicle proliferation. By integrating multi-omics insights, we construct a molecular network of melatonin’s regulatory mechanisms, offering strategies to improve cashmere yield and quality while advancing therapies for human alopecia. Full article

Hepatoblastoma (HB) is the most common malignant liver tumor in children under five years of age. Although globally rare, it accounts for a large proportion of liver cancer in children and has poor survival rates in high-risk and metastatic cases. This review discusses the molecular mechanisms, diagnostic methods, and therapeutic strategies of HB. Mutations in the CTNNB1 gene and the activation of the Wnt/β-catenin pathway are essential genetic factors. Furthermore, genetic syndromes like Beckwith–Wiedemann syndrome (BWS) and Familial Adenomatous Polyposis (FAP) considerably heighten the risk of associated conditions. Additionally, epigenetic mechanisms, such as DNA methylation and the influence of non-coding RNAs (ncRNAs), are pivotal drivers of tumor development. Diagnostics include serum biomarkers, immunohistochemistry (IHC), and imaging techniques. Standard treatments are chemotherapy, surgical resection, and liver transplantation (LT). Emerging therapies like immunotherapy and targeted treatments offer hope against chemotherapy resistance. Future research will prioritize personalized medicine, novel biomarkers, and molecular-targeted therapies to improve survival outcomes. Full article

Background: Ovarian cancer (OC) is the third most common and second most lethal onco-gynecological disease in the world, with high-grade serous ovarian cancer (HGSOC) making up the majority of OC cases worldwide. The current serological biomarkers used for OC diagnosis are lacking sensitivity and specificity, thus new biomarkers are greatly needed. Recently, the chromatin remodeling complex gene ARID1A, Notch and Wnt pathway gene expression, as well as HOX-related gene promoter methylation have been linked with promoting OC. Methods: In this pilot study, 10 gene expression biomarkers and 4 promoter methylation biomarkers were examined as potential diagnostic and prognostic indicators of OC in 65 fresh-frozen gynecologic tumor tissues. Results: Out of 10 genes analyzed, the expression of eight biomarkers was significantly reduced in OC cases compared to benign, and HOX-related gene promoter methylation significantly increased in OC tumors. Out of 14 biomarkers, CTNNB1 showed the best single biomarker separation of HGSOC from benign cases (AUC = 0.97), while a combination of the seven Notch pathway-related gene expressions (NOTCH1, NOTCH2, NOTCH3, NOTCH4, DLL1, JAG2, and HES1) demonstrated the best separation of HGSOC from the benign cases (AUC = 1). Conclusions: The combination of multiple gene expression or gene promoter methylation biomarkers shows great promise for the development of an effective biomarker-based diagnostic approach for OC. Full article

Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy with poor prognosis, mainly due to the presence of cancer stem cells (CSCs), a small subpopulation of cells that contribute to therapy resistance and tumor progression. The principal objective of this study was to investigate the role of miRNA-21 in the maintenance of cancer cell stemness and the possibility of altering it. The CD44 antigen was used as a marker for CSC isolation from oral cancer cell cultures. CD44+ and CD44− populations were sorted via magnetic separation. miRNA-21 inhibition was performed in CD44+ cells via transfection. CD44+ cells possessed a significantly higher migration and invasion potential compared to CD44− cells, higher levels of miRNA-21 (p = 0.004) and β-catenin (p = 0.005), and lower levels of BAX (p = 0.015). miRNA-21 inhibition in CD44+ cells reduced migration, invasion, and colony formation while increasing apoptosis. Stemness markers were significantly downregulated following miRNA-21 inhibition: OCT4 (p = 0.013), SOX2 (p = 0.008), and NANOG (p = 0.0001), as well as β-catenin gene (CTNNB1) (p < 0.05), an important member of WNT signaling pathway. Apoptotic activity was enhanced, with a significant downregulation of the antiapoptotic Bcl-2 (p = 0.008) gene. In conclusion, miRNA-21 plays a critical role in the regulation of oral cancer CD44+ cells properties. Targeting and inhibiting miRNA-21 in CD44+ cells could represent a promising novel strategy in OSCC treatment. Full article

Metastasis is a well-known factor worsening colorectal cancer (CRC) prognosis, but mortality mechanisms in non-metastatic patients with poor outcomes are less understood. TCF12 is a transcription factor that can be physically associated with the long non-coding RNA MALAT1, creating an alliance with correlated expression levels in CRC patients. This TCF12–MALAT1 alliance is linked to poorer prognosis independently of age and metastasis. To identify the downstream effects responsible for this outcome, we analyzed 2312 common target genes of TCF12 and MALAT1, finding involvement in pathways like Aurora B, ATM, PLK1, and non-canonical WNT. We investigated the impact of WNT downstream genes CTNNB1 and CCND1, encoding β-catenin and cyclin D1, respectively, on survival in CRC patients with this alliance. Tumors with higher TCF12 and MALAT1 gene expressions alongside increased β-catenin gene expressions were classified as having a “Pan-CMS-2 pattern”, showing relatively better prognoses. Conversely, tumors with high TCF12, MALAT1, and cyclin D1 gene expressions but low β-catenin expression were categorized as “TMBC pattern”, associated with poor survival, with survival rates dropping sharply from 60% at one year to 30% at three years. This suggests that targeting cyclin D1-associated CDK4/6 could potentially reduce early mortality risks in TMBC patients, supporting personalized medicine approaches. Full article

The bioactive compounds in herbal extracts may provide effective hair loss treatments with fewer side effects compared to synthetic medicines. This study evaluated the effects of Buebang 3 CMU and Sanpatong rice bran extracts, macerated with dichloromethane or 95% ethanol, on hair growth promotion and hair loss prevention. Overall, Buebang 3 CMU extracts contained significantly higher levels of bioactive compounds, including γ-oryzanol, tocopherols, and various polyphenols such as phytic acid, ferulic acid, and chlorogenic acid, compared to Sanpatong extracts. Additionally, ethanolic extracts demonstrated greater bioactive content and antioxidant activities than those extracted with dichloromethane. These compounds enhanced the proliferation of human hair follicle dermal papilla cells (HFDPCs) by 124.28 ± 1.08% (p < 0.05) and modulated anti-inflammatory pathways by reducing nitrite production to 3.20 ± 0.36 µM (p < 0.05). Key hair growth signaling pathways, including Wnt/β-catenin (CTNNB1), Sonic Hedgehog (SHH, SMO, GLI1), and vascular endothelial growth factor (VEGF), were activated by approximately 1.5-fold to 2.5-fold compared to minoxidil. Also, in both human prostate cancer (DU-145) and HFDPC cells, the ethanolic Buebang 3 CMU extract (Et-BB3-CMU) suppressed SRD5A1, SRD5A2, and SRD5A3 expression—key pathways in hair loss—by 2-fold and 1.5-fold more than minoxidil and finasteride, respectively. These findings suggest that Et-BB3-CMU holds promise for promoting hair growth and preventing hair loss. Full article

Androgenetic alopecia (AGA) is a genetic condition characterized by an excessive response to androgens, leading to hairline regression in men and hair thinning at the vertex in women, which can negatively impact self-esteem. Conventional synthetic treatments for AGA are often limited by their side effects. In contrast, Thai medicinal plants offer a promising alternative with fewer adverse effects. This study investigates the synergistic phytochemical and pharmacological effects of a novel Hair Rise^TM microemulsion, formulated with bioactive extracts from rice bran (Oryza sativa), shallot bulb (Allium ascalonicum), licorice root (Glycyrrhiza glabra), and corn kernels (Zea mays), for the treatment of hair loss. The microemulsion, in concentrations of 50%, 75%, and 100% (v/v), significantly enhanced the proliferation of human hair follicle dermal papilla cells (HFDPCs) compared to minoxidil. Additionally, it upregulated critical hair growth signaling pathways, including Wnt/β-catenin (CTNNB1), Sonic Hedgehog (SHH, SMO, GLI1), and vascular endothelial growth factor (VEGF), surpassing standard controls such as minoxidil and purmorphamine. The microemulsion also demonstrated potent anti-inflammatory and antioxidant properties by reducing nitric oxide production and oxidative stress, factors that contribute to inflammation and follicular damage in AGA. Furthermore, Hair Rise^TM inhibited 5α-reductase (types 1–3), a key enzyme involved in androgen metabolism, in both human prostate cancer cells (DU-145) and HFDPCs. These findings suggest that Hair Rise^TM microemulsion presents a promising natural therapy for promoting hair growth and reducing hair loss via multiple synergistic mechanisms, offering a potent, plant-based alternative to synthetic treatments. Full article

Background: The homologous proteins identified as cellular retinoic acid-binding proteins I and II (CRABP-I and CRABP-II) belong to a subset of intracellular proteins characterized by their robust affinity for retinoic acid, which plays an indispensable role in the development of hair follicle, including differentiation, proliferation, and apoptosis in keratinocytes. Previous research on Hu sheep hair follicles revealed the specific expression CRABP1 in dermal papilla cells (DPCs), suggesting that CRABP1 has a potential role in regulating the DPC population. Therefore, the main purpose of this study is to expose the performance of the CRABP1 genes in the development and proliferation of DPCs. Methods: Initially, overexpression and inhibition of CRABP1 in the DPCs were conducted through overexpression vector and siRNA. CCK-8, EDU, and RT-PCR cell cycle assays and immunostaining were performed to evaluate the proliferation and cell cycle of dermal papilla cells (DPCs). Although, the influence of CRABP1 upon β-catenin in dermal papilla cells (DPCs) was found using immunofluorescence labeling. Finally, RT-PCR was conducted to assess the impact of CRABP1 on the expression levels of CTNNB1, TCF4, and LEF1 in DPCs involved in the Wnt/β-catenin signaling pathway. Results: The results showed that CRABP1 overexpression promotes the growth rates of DPCs and significantly enhances the proportion of S-phase cells compared with the control group (p < 0.05). The results were the opposite when CRABP1 was a knockdown. In contrast, there was a significant decline in the mRNA expression levels of CTNNβ1, LEF1 (p < 0.05), and TCF4 (p < 0.01) by CRABP1 knockdown. Conclusions: This study found that CRABP1 influences the expression of important genes within the Wnt/β-catenin signaling pathway and promotes DPC proliferation. This investigation provides a theoretical framework to explain the mechanisms that control hair follicle morphogenesis and development. Full article

Background: Desmoid-type fibromatosis (DTF) is a locally aggressive myofibroblastic/fibroblastic neoplasm with a high risk of local recurrence. It has a variety of histologic features that might confuse diagnosis, especially when detected during core needle biopsy. The Wnt/β-catenin pathway is strongly linked to the pathogenesis of DT fibromatosis. Method: This study examined 33 desmoid-type fibromatoses (DTFs) from 32 patients, analyzing its clinical characteristics, histologic patterns, occurrence rates, relationship with clinical outcomes, immunohistochemical and molecular findings. Results: The DTFs exhibit a range of 1 to 7 histologic patterns per tumor, including conventional, hypercellular, myxoid, hyalinized/hypocellular, staghorn/hemangiopericytomatous blood vessels pattern, nodular fasciitis-like, and keloid-like morphology. No substantial association was found between the existence of different histologic patterns and the clinical outcome. All thirty-three (100%) samples of DTF had a variable percentage of cells that were nuclear positive for β-catenin. An NGS analysis detected novel non-CTNNB1 mutations in two DTFs, including BCL10, MPL, and RBM10 gene mutations. Conclusions: This study reveals a diverse morphology of DTFs that could result in misdiagnosis. Therefore, surgical pathologists must comprehend this thoroughly. Also, the importance of the newly identified non-CTNNB1 gene mutations is still unclear. More research and analyses are needed to completely grasp the clinical implications of these mutations. Full article

CTNNB1 pathogenic variants are related to the improper functioning of the WNT/β-catenin pathway, promoting the development of different types of cancer of somatic origin. Bioinformatics analyses of genetic variation are a great tool to understand the possible consequences of these variants on protein structure and function and their probable implication in pathologies. The objective of this study is to describe the impact of the missense variants of uncertain significance (VUS) of the CTNNB1 gene on structure and function of the β-catenin protein. The CTNNB1 variants were obtained from the GnomAD v2.1.1 database; subsequently, a bioinformatic analysis was performed using the VarSome, UCSC Genome Browser, UniProt, the Kinase Library database, and DynaMut2 platforms to evaluate clinical significance, gene conservation, consensus sites for post-translational modifications, and the dynamics and stability of proteins. The GnomAD v2.1.1 database included 826 variants of the CTNNB1 gene, of which 385 were in exons and exon/intron boundaries. Among these variants, 214 were identified as missense, of which 146 were classified as VUS. Notably, 12 variants were in proximity to consensus sites for post-translational modifications (PTMs). The in silico analysis showed a slight tendency towards probably pathogenic for c.59C>T (p.Ala20Val) and c.983T>C (p.Met328Thr) missense VUS. These findings provide possible functional implications of these variants in some types of cancer. Full article

4-O-Methyl-ascochlorin (MAC), a derivative of the prenyl–phenol antibiotic ascochlorin extracted from the fungus Ascochyta viciae, shows anticarcinogenic effects on various cancer cells. 5-Fluorouracil (5-FU) is used to treat colorectal cancer (CRC); however, its efficacy must be enhanced. In this study, we investigated the molecular mechanisms by which MAC acts synergistically with 5-FU to inhibit cell proliferation and induce apoptosis in CRC cells. MAC enhanced the cytotoxic effects of 5-FU by suppressing the Akt/mTOR/p70S6K and Wnt/β-catenin signaling pathways. It also reduced the viability of 5-FU-resistant (5-FU-R) cells. Furthermore, expression of anti-apoptosis-related proteins and cancer stem-like cell (CSC) markers by 5-FU-R cells decreased in response to MAC. Similar to MAC, the knockdown of CTNNB1 induced apoptosis and reduced expression of mRNA encoding CRC markers in 5-FU-R cells. In summary, these results suggest that MAC and other β-catenin modulators may be useful in overcoming the 5-FU resistance of CRC cells. Full article

Ovarian follicular GCs are strongly implicated in the growth, development, and atresia of ovarian follicles. The Wnt/β-catenin and Notch signaling pathways participate in GC proliferation, differentiation, apoptosis, and steroid hormone production during follicular development. However, the crosstalk between Wnt and Notch signaling in GCs remains unclear. This study investigated this crosstalk and the roles of these pathways in apoptosis, cell cycle progression, cell proliferation, and steroid hormone secretion in bovine follicular GCs. The interaction between β-catenin and Notch2 in GCs was assessed by overexpressing CTNNB1, which encodes β-catenin. The results showed that inhibiting the Notch pathway by Notch2 silencing in GCs arrested the cell cycle, promoted apoptosis, reduced progesterone (P4) production, and inhibited the Wnt2-mediated Wnt/β-catenin pathway in GCs. IWR-1 inhibited Wnt2/β-catenin and Notch signaling, reduced GC proliferation, stimulated apoptosis, induced G1 cell cycle arrest, and reduced P4 production. CTNNB1 overexpression had the opposite effect and increased 17β-estradiol (E2) production and Notch2 protein expression. Co-immunoprecipitation assays revealed that Notch2 interacted with β-catenin. These results elucidate the crosstalk between the Wnt/β-catenin and Notch pathways and the role of these pathways in bovine follicular GC development. Full article