Catenin Beta Research Articles

Pan-cancer analysis of CTNNB1 with potential as a therapeutic target for human tumorigenesis

BackgroundDespite the different studies on the oncogenic role of Catenin Beta 1 (CTNNB1) and its association with cancer pathogenesis, there is no pan-cancer study to clarify its oncogenic role in tumorigenesis and cancer development. MethodsBy using Cancer Genome Atlas (TCGA), and The Genotype Tissue Expression (GTEx), and cbioportal databases we evaluated the expression of CTNNB1 in all 33 cancer types. Furthermore, CTNNB1 phosphorylation and methylation pattern were assessed using the UALCAN portal. In addition, survival analysis, tumor-immune infiltration, CTNNB1 molecular mechanisms, and gene enrichment analysis were carried out using different bioinformatic tools and databases. ResultsOur findings indicate the overall increase of CTNNB1 levels in most cancers, associated with the worst patient outcome and prognosis. CTNNB1 seems to affect tumor immune infiltration by mediating tumor-infiltrating lymphocytes and cancer-associated fibroblast. Also, enrichment analysis indicated that CTNNB1 is related to different cellular signaling process such as Wnt and Hippo signaling pathways. ConclusionCollectively, CTNNB1 is a pivotal oncogene with the capability to be considered as an ideal biomarker and therapeutic target in different cancers.

Gene enrichment analysis and protein–protein interaction network topology delineates S-Phase kinase-associated protein 1 and catenin beta-1 as potential signature genes linked to glioblastoma prognosis

Background: Glioblastoma (GBM) is the most malignant and accounts for 60% of brain tumors in adults. Current therapy for GBM involves surgical removal of the tumor followed by radiotherapy with concomitant adjuvant therapy temozolomide. Despite improvements in therapy, patient survival remains low. The exact etiology of a brain tumor is uncertain, and numerous unknown genes are involved in the progression of GBM. The aim of the present study was to evaluate various genes involved in GBM through bioinformatic approach. Methods: In the present study, gene expression profile of GSE68424 was retrieved from the GEO database to explore the genes in GBM. Results: Analysis of expression profile data revealed that 33 genes were upregulated and 1189 genes were downregulated based on the log2 fold change cut-off criteria. The genes S-Phase kinase-associated protein 1 (SKP1) and Catenin beta-1 (CTNNB1) have been linked to GBM prognosis. Conclusion: SKP1 and CTNNB1 were identified as a candidate gene for GBM study as a result of these findings. Catenin beta-1 was the protein with the highest closeness centrality value and is the key component of canonical Wnt signaling downstream pathway. More study is needed to establish the molecular function of SKP1 and CTNNB1 in GBM development, as well as the biomarker's specificity and sensitivity.

Circ_0008784 activates Wnt/β-catenin pathway to affect the proliferation and apoptosis of triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC), as a subtype of breast tumors with aggressive nature, threatens the health of females across the globe. It's urgent to explore novel therapeutic targets for the improvement of TNBC treatments. Bioinformatics was used to identify circular RNA (circRNA) differentially expressed in TNBC tissues. The circular structure and expression in TNBC cells was subjected to analysis of quantitative polymerase chain reaction (qPCR) and PCR-agarose gel electrophoresis. Functional experiments and qPCR assays were carried out to probe the biological functions of circ_0008784 and microRNA-506-3p (miR-506-3p). It was verified by the assays that circ_0008784 propels proliferation and inhibit apoptosis of TNBC cells; and miR-506-3p was found to suppress proliferation and facilitate apoptosis of TNBC cells. TOP/FOP-Flash reporter, luciferase reporter, RNA-binding protein immunoprecipitation (RIP), RNA pulldown and rescue assays were implemented for exploring the underlying mechanisms of circ_0008784. It was found that circ_0008784 regulates Wnt/β-catenin signaling pathway, and augments TNBC cell progression via sponging miR-506-3p to modulate catenin beta 1 (CTNNB1). Circ_0008784 activates Wnt/β-catenin pathway to affect the proliferation and apoptosis of TNBC cells. Elucidating the mechanism of circ_0008784 underlying TNBC is of great significance to TNBC treatment.

Quercetin up-regulates the expression of tumor-suppressive microRNAs in human cervical cancer.

Quercetin, a flavonol present in many vegetables and fruits, has been identified as a chemoprevention agent in several cancer models. However, the molecular mechanism of quercetin's anticancer activity is not entirely understood. MicroRNAs (miRNAs), small noncoding RNAs, have been reported to play key roles in various biological processes by regulating their target genes. We hypothesized that quercetin can exert an anticancer effect through the regulation of miRNAs. To test this hypothesis, we investigated the effects of quercetin on the expression of tumor-suppressive miRNAs in cervical cancer. Quercetin up-regulated the in vivo and in vitro expression of tumor-suppressive miRNAs miR-26b, miR-126, and miR-320a. Quercetin suppressed the level of β-catenin, encoded by catenin beta 1 (CTNNB1), by up-regulating miR-320a in HeLa cells. Moreover, quercetin increased the expression of mir-26b, mir-126, and mir-320a precursors in HeLa cells. The results from this study show that quercetin has the potential to prevent cervical cancer by regulating the expression of tumor-suppressive miRNAs.

M6A demethylase FTO regulate CTNNB1 to promote adipogenesis of chicken preadipocyte

BackgroundN6-methyladenosine (m6A) is an abundant post-transcriptional RNA modification that affects various biological processes. The fat mass and obesity-associated (FTO) protein, a demethylase encoded by the FTO gene, has been found to regulate adipocyte development in an m6A-dependent manner in multiple species. However, the effects of the m6A methylation and FTO demethylation functions on chicken adipogenesis remain unclear. This study aims to explore the association between m6A modification and chicken adipogenesis and the underlying mechanism by which FTO affects chicken preadipocyte development.ResultsThe association between m6A modification and chicken lipogenesis was assessed by treating chicken preadipocytes with different doses of methyl donor betaine and methylation inhibitor cycloleucine. The results showed that betaine significantly increased methylation levels and inhibited lipogenesis, and the inverse effect was found in preadipocytes after cycloleucine treatment. Overexpression of FTO significantly inhibited m6A levels and promoted proliferation and differentiation of chicken preadipocytes. Silencing FTO showed opposite results. Mechanistically, FTO overexpression increased the expression of catenin beta 1 (CTNNB1) by improving RNA stability in an m6A-dependent manner, and we proved that FTO could directly target CTNNB1. Furthermore, CTNNB1 may be a positive regulator of adipogenesis in chicken preadipocytes.Conclusionsm6A methylation of RNA was negatively associated with adipogenesis of chicken preadipocytes. FTO could regulate CTNNB1 expression in a demethylation manner to promote lipogenesis.

Notoginsenoside R1 Promotes Proliferation and Osteogenic Differentiation of hPDLSCs via Wnt/β-Catenin Signaling Pathway.

To investigate the roles of Notoginsenoside R1 (NG-R1) on the proliferation and osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) and explore its possible mechanism. hPDLSCs were isolated and, then characterized by flow cytometry. Cell-counting kit-8 (CCK-8) and colony assays were used to validate the effect of different NG-R1 concentrations on hPDLSCs proliferation and the optimal concentration was determined. Quantitative detection of alkaline phosphatase (ALP) activity at optimal concentration and the mineralization of the cells was investigated by Alizarin Red S staining. qRT-PCR and Western blot were utilized to examine the factors expression levels of ALP, Runx Family Transcription Factor 2 (RUNX2), Collagen I (Col-1) and catenin beta 1 (CTNNB1; β-catenin). In addition, the tankyrase inhibitor XAV-939 was used to explore NG-R1's role in canonical Wnt signaling. hPDLSCs were positive for surface antigens CD90 while negative for CD34 and CD45, which indicated that we have successfully isolated the hPDLSCs. Furthermore, a concentration of 20μmol NG-R1 dramatically enhanced hPDLSCs proliferation, ALP activity, and mineral deposition. ALP, RUNX2, COL-1, and β-catenin expression were all rised in comparison to control group. After XAV-939 was added to disrupt the canonical Wnt signaling, the impact of NG-R1 appeared to be reversed. These findings suggest that NG-R1 can stimulate osteogenic differentiation of hPDLSCs, which is probably attributable to canonical Wnt signaling activation.

Systems biology and OMIC data integration to understand gastrointestinal cancers.

Gastrointestinal (GI) cancers are a set of diverse diseases affecting many parts/ organs. The five most frequent GI cancer types are esophageal, gastric cancer (GC), liver cancer, pancreatic cancer, and colorectal cancer (CRC); together, they give rise to 5 million new cases and cause the death of 3.5 million people annually. We provide information about molecular changes crucial to tumorigenesis and the behavior and prognosis. During the formation of cancer cells, the genomic changes are microsatellite instability with multiple chromosomal arrangements in GC and CRC. The genomically stable subtype is observed in GC and pancreatic cancer. Besides these genomic subtypes, CRC has epigenetic modification (hypermethylation) associated with a poor prognosis. The pathway information highlights the functions shared by GI cancers such as apoptosis; focal adhesion; and the p21-activated kinase, phosphoinositide 3-kinase/Akt, transforming growth factor beta, and Toll-like receptor signaling pathways. These pathways show survival, cell proliferation, and cell motility. In addition, the immune response and inflammation are also essential elements in the shared functions. We also retrieved information on protein-protein interaction from the STRING database, and found that proteins Akt1, catenin beta 1 (CTNNB1), E1A binding protein P300, tumor protein p53 (TP53), and TP53 binding protein 1 (TP53BP1) are central nodes in the network. The protein expression of these genes is associated with overall survival in some GI cancers. The low TP53BP1 expression in CRC, high EP300 expression in esophageal cancer, and increased expression of Akt1/TP53 or low CTNNB1 expression in GC are associated with a poor prognosis. The Kaplan Meier plotter database also confirmed the association between expression of the five central genes and GC survival rates. In conclusion, GI cancers are very diverse at the molecular level. However, the shared mutations and protein pathways might be used to understand better and reveal diagnostic/prognostic or drug targets.

Genomic characterization reveals distinct mutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract.

Neuroendocrine carcinomas of the gastrointestinal tract (GI-NECs) remain a disease of grim prognosis with limited therapeutic options. Their molecular characteristics are still undefined. This study aimed to explore the underlying genetic basis and heterogeneity of GI-NECs. Comprehensive genomic analysis using whole-exome sequencing was performed on 143 formalin-fixed, paraffin-embedded samples of surgically resected GI-NEC with a thorough histological evaluation. Mutational signatures, somatic mutations, and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes. Survival analysis was conducted to identify the independent factors. In total, 143 GI-NECs were examined: the stomach, 87 cases (60.8%); the esophagus, 29 cases (20.3%); the colorectum, 20 cases (14.0%); and the small intestine, 7 cases (4.9%). Eighty-three (58.0%) and 60 (42.0%) cases were subclassified into small cell and large cell subtypes, respectively. GI-NECs showed distinct genetic alterations from their lung counterparts and non-neuroendocrine carcinomas in the same locations. Obvious heterogeneity of mutational signatures, somatic mutations, and copy number variations was revealed across anatomic locations rather than histological subtypes. Except for tumor protein p53 (TP53) and retinoblastoma 1 (RB1), the most frequently mutated genes in the stomach, esophagus, colorectum, and small intestine were low-density lipoprotein receptor-related protein 1B (LRP1B), notch receptor 1 (NOTCH1), adenomatosis polyposis coli (APC), catenin beta 1 (CTNNB1), respectively. Mutations in the WNT-β-catenin, NOTCH and erythroblastic leukemia viral oncogene B (ERBB) pathways were prevalently identified in gastric, esophageal, and colorectal NECs, respectively. Importantly, 104 (72.7%) GI-NECs harbored putative clinically relevant alterations, and non-gastric location and RB1 bi-allelic inactivation with copy number alterations were identified as two independent poor prognostic factors. Furthermore, we found that tumor cells in GI-NECs first gain clonal mutations in TP53, RB1, NOTCH1 and APC, followed by subsequent whole-genome doubling (WGD) and post-WGD clonal mutations in LRP1B, CUB and Sushi multiple domains 3 (CSMD3), FAT tumor suppressor homolog 4 (FAT4) and erb-b2 receptor tyrosine kinase 4 (ERBB4), and finally develop subclonal mutations. GI-NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations. Moreover, potentially actionable alterations and prognostic factors were revealed for GI-NECs.

Aging-related features predict prognosis and immunotherapy efficacy in hepatocellular carcinoma.

The aging microenvironment serves important roles in cancers. However, most studies focus on circumscribed hot spots such as immunity and metabolism. Thus, it is well ignored that the aging microenvironment contributes to the proliferation of tumor. Herein, we established three prognosis-distinctive aging microenvironment subtypes, including AME1, AME2, and AME3, based on aging-related genes and characterized them with “Immune Exclusion,” “Immune Infiltration,” and “Immune Intermediate” features separately. AME2-subtype tumors were characterized by specific activation of immune cells and were most likely to be sensitive to immunotherapy. AME1-subtype tumors were characterized by inhibition of immune cells with high proportion of Catenin Beta 1 (CTNNB1) mutation, which was more likely to be insensitive to immunotherapy. Furthermore, we found that CTNNB1 may inhibit the expression of C-C Motif Chemokine Ligand 19 (CCL19), thus restraining immune cells and attenuating the sensitivity to immunotherapy. Finally, we also established a robust aging prognostic model to predict the prognosis of patients with hepatocellular carcinoma. Overall, this research promotes a comprehensive understanding about the aging microenvironment and immunity in hepatocellular carcinoma and may provide potential therapeutic targets for immunotherapy.

Pharmacological effects of the Cassia Seed on atherosclerosis: A meta-analysis based on network pharmacology.

The aim of this study was to shed light on the active ingredients and potential targets of Cassia Seed about anti-atherosclerosis based on network pharmacology. The active ingredients and potential targets of Cassia Seed were obtained from traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) and SwissTargetPrediction database. Then, atherosclerosis-related targets were screened via GeneCards, online mendelian inheritance in man, therapeutic target database and DrugBank database. The common targets and protein-protein interaction (PPI) network was later identified and built. Furthermore, we used the database for annotation, visualization and integrated discovery (DAVID) database server to accomplish the enrichment analysis. The compounds-targets-pathways network was ultimately constructed by Cytoscape. A total of 14 active ingredients and 475 related targets were sifted from Cassia Seed. Among 574 potential atherosclerotic targets, there were 99 targets overlapped with those of Cassia Seed. Topological analysis with Cytoscape revealed that proto-oncogene tyrosine-protein kinase proto-oncogene tyrosine-protein kinase Src, transcription factor AP-1 (JUN), mitogen-activated protein kinase 8 (MAPK8), mitogen-activated protein kinase 14 (MAPK14) and catenin beta-1 were considered as the hub gene. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis suggested that the Cassia Seed had the potential to influence varieties of biological processes and pathways, including positive regulation of smooth muscle cell proliferation, inflammatory response, tumor necrosis factor (TNF) signaling pathway, vascular endothelial growth factor (VEGF) signaling pathway and arachidonic acid (ARA) metabolism. Taken together, our findings support that anti-atherosclerosis effects of Cassia Seed are characterized by multi-component, multi-target and multi-path mechanism of action.

Osteoprogenitor SFRP1 prevents exhaustion of hematopoietic stem cells via PP2A-PR72/130-mediated regulation of p300.

Remodeling of the bone marrow microenvironment in chronic inflammation and in aging reduces hematopoietic stem cell (HSC) function. To assess the mechanisms of this functional decline of HSC and find strategies to counteract it, we established a model in which the Sfrp1 gene was deleted in Osterix+ osteolineage cells (OS1Δ/Δ mice). HSC from these mice showed severely diminished repopulating activity with associated DNA damage, enriched expression of the reactive oxygen species pathway and reduced single-cell proliferation. Interestingly, not only was the protein level of Catenin beta-1 (bcatenin) elevated, but so was its association with the phosphorylated co-activator p300 in the nucleus. Since these two proteins play a key role in promotion of differentiation and senescence, we inhibited in vivo phosphorylation of p300 through PP2A-PR72/130 by administration of IQ-1 in OS1Δ/Δ mice. This treatment not only reduced the b-catenin/phosphop300 association, but also decreased nuclear p300. More importantly, in vivo IQ-1 treatment fully restored HSC repopulating activity of the OS1Δ/Δ mice. Our findings show that the osteoprogenitor Sfrp1 is essential for maintaining HSC function. Furthermore, pharmacological downregulation of the nuclear b-catenin/phospho-p300 association is a new strategy to restore poor HSC function.

Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy.

Simple SummaryAtezolizumab/bevacizumab (Atezo/Bev) combination immunotherapy has become a front-line therapy for unresectable hepatocellular carcinoma (u-HCC), but some patients are initially nonresponders. We investigated the potential of cell-free DNA (cfDNA)/circulating tumor DNA (ctDNA) as biomarkers for predicting the therapeutic outcome of u-HCC patients treated with anti-programmed cell death1-ligand1 (PD-L1)/vascular endothelial growth factor (VEGF) therapy. Patients with high levels of cfDNA showed a significantly lower overall response rate and shorter progression-free survival and overall survival (OS) than those with low levels of cfDNA. Ultradeep sequencing of cfDNA showed that the telomerase reverse transcriptase (TERT) promoter, tumor protein 53 (TP53) and catenin beta 1 (CTNNB1) were the most frequently mutated genes in ctDNA. Lastly, a TERT ctDNA mutation and a high alpha-fetoprotein (AFP) level were independent predictors of shorter OS in u-HCC patients treated with Atezo/Bev therapy and could stratify their prognoses. Collectively, cfDNA/ctDNA profiling may be useful to predict therapeutic outcome in u-HCC patients treated with Atezo/Bev therapy.Combination immunotherapy with anti-programmed cell death1-ligand1 (PD-L1) and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for patients with unresectable HCC (u-HCC). However, limited patients obtain clinical benefits. Cell-free DNA (cfDNA) in peripheral blood contains circulating tumor DNA (ctDNA) that reflects molecular abnormalities in tumor tissue. We investigated the potential of cfDNA/ctDNA as biomarkers for predicting the therapeutic outcome in u-HCC patients treated with anti-PD-L1/VEGF therapy. We enrolled a multicenter cohort of 85 HCC patients treated with atezolizumab and bevacizumab (Atezo/Bev) between 2020 and 2021. Pretreatment plasma was collected, and cfDNA levels were quantified. Ultradeep sequencing of cfDNA was performed with a custom-made panel for detecting mutations in 25 HCC-related cancer genes. We evaluated the association of cfDNA/ctDNA profiles and clinical outcomes. Patients with high plasma cfDNA levels showed a significantly lower response rate and shorter progression-free survival and overall survival (OS) than those with low cfDNA levels. ctDNA detected in 55% of HCC patients included the telomerase reverse transcriptase (TERT) promoter in 31% of these patients, tumor protein 53 (TP53) in 21%, catenin beta 1 (CTNNB1) in 13% and phosphatase and tensin homolog (PTEN) in 7%. The presence or absence of ctDNA did not predict the efficacy of Atezo/Bev therapy. Twenty-six patients with a TERT mutation had significantly shorter OS than those without. The presence of a TERT mutation and alpha-fetoprotein (AFP) ≥ 400 ng/mL were independent predictors of poor OS according to multivariate Cox proportional hazard analysis and could be used to stratify patients treated with Atezo/Bev therapy based on prognosis. In conclusion, pretreatment cfDNA/ctDNA profiling may be useful for predicting the therapeutic outcome in u-HCC patients treated with anti-PD-L1/VEGF therapy.

Cuproptosis-Related Risk Score Predicts Prognosis and Characterizes the Tumor Microenvironment in Hepatocellular Carcinoma.

AimsCuproptosis is a recently identified form of programmed cell death; however, its role in hepatocellular carcinoma (HCC) remains unclear.MethodsA set of bioinformatic tools was integrated to analyze the expression and prognostic significance of ferredoxin 1 (FDX1), the key regulator of cuproptosis. A cuproptosis-related risk score (CRRS) was developed via correlation analyses, least absolute shrinkage and selection operator (LASSO) Cox regression, and multivariate Cox regression. The metabolic features, mutation signatures, and immune profile of CRRS-classified HCC patients were investigated, and the role of CRRS in therapy guidance was analyzed.Results FDX1 was significantly downregulated in HCC, and its high expression was associated with longer survival time. HCC patients in the high-CRRS group showed a significantly lower overall survival (OS) and enriched in cancer-related pathways. Mutation analyses revealed that the high-CRRS HCC patients had a high mutational frequency of some tumor suppressors such as tumor protein P53 (TP53) and Breast-cancer susceptibility gene 1 (BRCA1)-associated protein 1 (BAP1) and a low frequency of catenin beta 1 (CTNNB1). Besides, HCC patients with high CRRS showed an increase of protumor immune infiltrates and a high expression of immune checkpoints. Moreover, the area under the curve (AUC) values of CRRS in predicting the efficiency of sorafenib and the non-responsiveness to transcatheter arterial chemoembolization (TACE) in HCC patients reached 0.877 and 0.764, respectively.SignificanceThe cuproptosis-related signature is helpful in prognostic prediction and in guiding treatment for HCC patients.

The m6A methyltransferase WTAP plays a key role in the development of diffuse large B-cell lymphoma via regulating the m6A modification of catenin beta 1

BackgroundDiffuse large B-cell lymphoma (DLBCL) is the most frequently occurring subtype of lymphoma. Unfortunately, the fundamental processes underlying the pathogenesis of DLBCL remain little understood. N6-methyladenosine (m6A) methylation has been shown to be the most common internal alteration of mRNAs found in eukaryotes, and it is thought to play a key role in cancer pathogenesis. However, the precise relationship between m6A mRNA methylation and DLBCL pathogenesis remains to be fully elucidated.MethodsThe mRNA and protein expression of Wilms tumor 1-associating protein (WTAP) were determined using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis in lymphoma cells lines. The effects of WTAP expression on human lymphoma cells lines were assessed using cell proliferation assays, colony formation assays, and CCK8 assays. The Gene Expression Profiling Interactive Analysis (GEPIA) database was used to screen candidate gene targets of WTAP. Finally, the regulatory mechanisms of WTAP in DLBCL were investigated using methylated RNA immunoprecipitation (MeRIP) assays.ResultsThis study investigated the precise function of WTAP in DLBCL formation. The results demonstrated that the levels of m6A RNA methylation and WTAP expression were both elevated in DLBCL cell lines and tissues. Downregulation of WTAP expression in DLBCL cells caused a reduction in cell growth in a functional sense. WTAP knockdown reduced catenin beta 1 (CTNNB1) m6A methylation and CTNNB1 total mRNA levels. Furthermore, CTNNB1 overexpression eliminated the WTAP-induced reduction of cell growth in DLBCL cells.ConclusionsIn conclusion, these findings demonstrated that WTAP promotes DLBCL development via modulation of m6A methylation in CTNNB1.

MiR-2682-3p antagonizes its host lncRNA-MIR137HG by interacting with the same target FUS to regulate the progression of gastric cancer

BackgroundThe mechanism of long non-coding RNA MIR137HG in human gastric cancer (GC) is currently unknown. In the present study, we aimed to explore the function and mechanism of MIR137HG in gastric cancer.MethodsThe expression of lncRNA-MIR137HG in 69 gastric cancer samples and their paired surgical margin (SM) tissue samples were tested by QRT-PCR. UCSC was used to find the gene location relationship among MIR137HG and its embedded miRNAs. TargetScan was used to predict the targets of miR-2682-3p. Starbase was used to predict the candidate proteins that interacted with MIR137HG. Western blot, co-focus, and RIP assay were used to verify the direct interaction between MIR137HG and FUS (fused in sarcoma/translocated in liposarcoma, FUS/TLS), while dual-luciferase reporter assay was used to confirm the interaction between miR-2682-3p and FUS. Cell migration assays, colony formation, and xenografts assay were used to investigate the function of MIR137HG and miR-2682-3p to tumor growth and metastasis. Western blot assay was used to explore the downstream candidate protein of FUS.ResultsData showed that MIR137HG expressed significantly higher in GC than in SM. MIR137HG promoted colony formation and migration in vitro and promoted tumor formation and metastasis in vivo. MIR137HG is distributed in both the nucleus and cytoplasm. It was co-located with FUS and could directly interact with FUS, which might interact with other proteins, such as MET(MET-proto-oncogene, receptor tyrosine kinase), RHOC(ras homolog family member), and CTNNB1(catenin beta1). These proteins may involve different signaling pathways to regulate gastric cancer progression. By contrast, the embedded miR-2682-3p could antagonize the series functions of its host lncRNA-MIR137HG by targeting FUS.ConclusionslncRNA-MIR137HG promoted growth and metastasis in gastric cancer by interacting with FUS, while miR-2682-3p could inhibit the function of MIR137HG via the same target FUS.

Emerging Therapies for Hepatocellular Carcinoma (HCC).

Simple SummaryPrimary liver cancer, also known as Hepatocellular carcinoma (HCC), is considered to be a major global health challenge. Due to delays in diagnosis at early asymptomatic stages, HCC reaches a severe aggressive stage, thereby having a significant negative impact on patient survival. In addition, HCC shows marked resistance to conventional cancer treatments such as chemo- and radiotherapy. A variety of new and advanced therapies are continuously being evaluated to acquire a breakthrough in HCC treatment to enhance overall and recurrence-free survival. Appropriate identification and selection of target genes and utilization of safe and effective therapeutic approaches, such as gene therapy or immunotherapy, are key strategies for the effective treatment for HCC. This review paper intends to provide a perspective on emerging approaches as avenues towards more effective and safer therapies for HCC.Hepatocellular carcinoma (HCC) arises from hepatocytes and accounts for 90% of primary liver cancer. According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, globally HCC is the sixth most common cancer and the third most common cause of cancer-related deaths. Reasons for HCC prognosis remaining dismal are that HCC is asymptomatic in its early stages, leading to late diagnosis, and it is markedly resistant to conventional chemo- and radiotherapy. Liver transplantation is the treatment of choice in early stages, while surgical resection, radiofrequency ablation (RFA) and trans arterial chemoembolization (TACE) are Food and Drug Administration (FDA)-approved treatments for advanced HCC. Additional first line therapy for advanced HCC includes broad-spectrum tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, as well as a combination of immunotherapy and anti-angiogenesis therapy, namely atezolizumab and bevacizumab. However, these strategies provide nominal extension in the survival curve, cause broad spectrum toxic side effects, and patients eventually develop therapy resistance. Some common mutations in HCC, such as in telomerase reverse transcriptase (TERT), catenin beta 1 (CTNNB1) and tumor protein p53 (TP53) genes, are still considered to be undruggable. In this context, identification of appropriate gene targets and specific gene delivery approaches create the potential of gene- and immune-based therapies for the safe and effective treatment of HCC. This review elaborates on the current status of HCC treatment by focusing on potential gene targets and advanced techniques, such as oncolytic viral vectors, nanoparticles, chimeric antigen receptor (CAR)-T cells, immunotherapy, and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), and describes future prospects in HCC treatment.

Deubiquitinating enzyme JOSD2 promotes hepatocellular carcinoma progression through interacting with and inhibiting CTNNB1 degradation.

Although a variety of molecular targets have been identified, hepatocellular carcinoma (HCC) remains among the leading causes of death. As functions of they deubiquitinating enzyme Josephin domain containing 2 (JOSD2) in cancers are still poorly understood, we investigated its function and molecular mechanism in the regulation of HCC progression. Here, we indicated that JOSD2 expression is elevated in patient samples with HCC and positively associated with poor prognosis. Moreover, the promoting roles of JOSD2 in HCC cell survival, migration, and invasion were determined using in vitro models. Importantly, a mechanistic study revealed that JOSD2 binds to and decreases the ubiquitination level of catenin beta 1 (CTNNB1), a key component of Wnt signaling, thereby augmenting Wnt pathway transduction. Furthermore, a series of rescue experiments confirmed the significance of CTNNB1 in the modulation of HCC progression by JOSD2. Our study uncovered JOSD2 as a novel prognostic marker for patients with HCC and identified CTNNB1 as a pivotal partner and downstream target protein of JOSD2, which may aid in the development of JOSD2 as a promising molecular target for HCC treatment.

Molecular Stratification of Medulloblastoma: Clinical Outcomes and Therapeutic Interventions

Medulloblastoma (MB) is the most common malignant pediatric posterior fossa tumor. Recent genetic, epigenetic, and transcriptomic analyses have classified MB into three subgroups, Wingless Type (WNT), Sonic Hedgehog (SHH), and non-WNT/non-SHH (originally termed Group 3 and Group 4), with discrete patient profiles and prognoses. WNT is the least common subgroup with the best prognosis, characterized by nuclear β-catenin expression, mutations in Catenin beta-1 (CTNNB1), and chromosome 6 monosomy. SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway. Originally, the presence of TP53 gene alterations and/or MYC amplifications was considered the most reliable prognostic factor. However, recent molecular analyses have subdivided SHH MB into several subtypes with distinct characteristics such as age, TP53 mutation, MYC amplification, presence of metastases, TERT promoter alterations, PTEN loss, and other chromosomal alterations as well as SHH pathway-related gene mutations. The third non-WNT/non-SHH MB (Group3/4) subgroup is genetically highly heterogeneous and displays several molecular patterns, including MYC and OTX2 amplification, GFI1B activation, KBTBD4 mutation, GFI1 rearrangement, PRDM6 enhancer hijacking, KDM6A mutation, LCA histology, chromosome 10 loss, isochromosome 17q, SNCAIP duplication, and CDK6 amplification. However, based on molecular profiling and methylation patterns, additional non-WNT/non-SHH MB subtypes have been described. Recent WHO (2021) guidelines stratified MB into four molecular subgroups with four and eight further subgroups for SHH and non-WNT/non-SHH MB, respectively. In this review, we discuss advancements in genetics, epigenetics, and transcriptomics for better characterization, prognostication, and treatment of MB using precision medicine.

Dysregulation of Wnt signaling in bone of type 2 diabetes mellitus and diabetic Charcot arthropathy

BackgroundType 2 diabetes mellitus (T2DM) patients show a markedly higher fracture risk and impaired fracture healing when compared to non-diabetic patients. However in contrast to type 1 diabetes mellitus, bone mineral density in T2DM is known to be normal or even regionally elevated, also known as diabetic bone disease. Charcot arthropathy is a severe and challenging complication leading to bone destruction and mutilating bone deformities. Wnt signaling is involved in increasing bone mineral density, bone homeostasis and apoptotic processes. It has been shown that type 2 diabetes mellitus is strongly associated with gene variants of the Wnt signaling pathway, specifically polymorphisms of TCF7L2 (transcription factor 7 like 2), which is an effector transcription factor of this pathway.MethodsBone samples of 19 T2DM patients and 7 T2DM patients with additional Charcot arthropathy were compared to 19 non-diabetic controls. qPCR analysis for selected members of the Wnt-signaling pathway (WNT3A, WNT5A, catenin beta, TCF7L2) and bone gamma-carboxyglutamate (BGLAP, Osteocalcin) was performed and analyzed using the 2-ΔΔCt- Method. Statistical analysis comprised one-way analysis of variance (ANOVA).ResultsIn T2DM patients who had developed Charcot arthropathy WNT3A and WNT5A gene expression was down-regulated by 89 and 58% compared to healthy controls (p < 0.0001). TCF7L2 gene expression showed a significant reduction by 63% (p < 0.0001) and 18% (p = 0.0136) in diabetic Charcot arthropathy. In all diabetic patients BGLAP (Osteocalcin) was significantly decreased by at least 59% (p = 0.0019).ConclusionsFor the first time with this study downregulation of members of the Wnt-signaling pathway has been shown in the bone of diabetic patients with and without Charcot arthropathy. This may serve as future therapeutic target for this severe disease.

CircRNA CTNNB1 (circCTNNB1) ameliorates cerebral ischemia/reperfusion injury by sponging miR-96-5p to up-regulate scavenger receptor class B type 1 (SRB1) expression

ABSTRACT Emerging studies show that circRNA catenin beta 1 (circCTNNB1) plays a critical role in cancer. However, the expression and function of circCTNNB1 in cerebral ischemia/reperfusion injury (IRI) have not been reported. The present study discovered that circCTNNB1 and scavenger receptor class B type 1 (SRB1) expression levels were significantly down-regulated in mouse astrocytes (mAS) treated with oxygen glucose deprivation and reperfusion (OGD/R), and similar results were observed in a mouse middle cerebral artery occlusion model. Overexpression of circCTNNB1 alleviated cell apoptosis, oxidative stress and the inflammatory response induced by OGD/R in vitro. Up-regulation of circCTNNB1 increased SRB1 expression levels to protect mAS cells from OGD/R-induced damage. CircCTNNB1 and SRB1 interacted with miR-96-5p, and the overexpression of miR-96-5p efficiently reversed the function of circCTNNB1 in OGD/R-treated mAS cells. CircCTNNB1 protected against cerebral ischemia-reperfusion injury by up-regulating SRB1 in vivo. In conclusion, our findings suggest that circCTNNB1 acts as a competitive endogenous RNA for miR-96-5p to alleviate cerebral IRI, which provides novel evidence that circCTNNB1 and SRB1 may be biomarkers and therapeutic targets for cerebral IRI.