Wnt-/-β-catenin pathway signaling in human hepatocellular carcinoma

The molecular basis of the carcinogenesis of hepatocellular carcinoma(HCC) has not been adequately clarified, which negatively impacts the development of targeted therapy protocols for this overwhelming neoplasia. The aberrant activation of signaling in the HCC is primarily due to the deregulated expression of the components of the Wnt-/-β-catenin. This leads to the activation of β-catenin/T-cell factor-dependent target genes that control cell proliferation, cell cycle, apoptosis, and cell motility. The deregulation of the Wnt pathway is an early event in hepatocarcinogenesis. An aggressive phenotype was associated with HCC, since this pathway is implicated in the proliferation, migration, and invasiveness of cancer cells, regarding the cell's own survival. The disruption of the signaling cascade Wnt-/-β-catenin has shown anticancer properties in HCC's clinical evaluations of therapeutic molecules targeted for blocking the Wnt signaling pathway for the treatment of HCC, and it represents a promising perspective. The key to bringing this strategy in to clinical practice is to identify new molecules that would be effective only in tumor cells with aberrant signaling β-catenin.

Efficacy of Yisui granule(益髓颗粒)on myelodysplastic syndromes in SKM-1 mouse xenograft model through suppressing Wnt/β-catenin signaling pathway

OBJECTIVE:To unmask the underlying mechanisms of Yisui granule(益髓颗粒,YSG)for the treatment of Myelodysplastic syndromes(MDS).METHODS:Our study used an SKM-1 mouse xenograft model of MDS to explore the anti-tumor potential of YSG and its safety,assess its effect on overall survival(OS),and evaluate whether its mechanism is associated with the demethylation of the secreted frizzled related protein 5(s FRP5)gene and suppressing Wnt/β-catenin pathway.Bisulfite amplicon sequencing was applied to detect the level of methylation of the s FRP5 gene;western blotting,immunofluorescence staining,and real-time Polymerase Chain Reaction were performed to detect DNA methyltransferase 1(DNMT1),s FRP5,and other Wnt/β-catenin pathway-related m RNA and protein expression.RESULTS:The results showed that high-dosage YSG exerted an anti-tumor effect similar to that of decitabine,improved OS,and reduced long-term adverse effects in the long term.Mechanically,YSG reduced the expression of DNMT1 methyltransferase,decreased the methylation,and increased the expression of the Wnt/β-catenin pathway antagonist-s FRP5.Furthermore,components of the Wnt/β-catenin pathway,including Wnt3a,β-catenin,c-Myc,and cyclin D1,were down-regulated in response to YSG,suggesting that YSG could treat MDS by demethylating the s FRP5 gene and suppressing the Wnt/β-catenin pathway.CONCLUSIONS:Our findings demonstrated that YSG could be used alone or in combination with decitabine to improve outcomes in the MDS animal model,providing an alternative solution for treating MDS.

Role of Wnt signaling pathway hypofunction mediated by dephosphorylation of β-catenin in impaired wound healing of type 1 diabetic rats

Objective To investigate the role of Wnt signaling pathway hypofunction mediated by dephosphorylation ofβ-catenin in the impaired wound healing of type 1 diabetic rats.Methods The back skin defect wounds were produced in rats with type 1 diabetes.These rats were divided into control,diabetes,lithium chloride treatment,and epidermal growth factor(EGF)

Danzhi Jiangtang capsule(丹蛭降糖胶囊) alleviate hyperglycemiaand periodontitis via Wnt/β-catenin signaling in diabetic rats

OBJECTIVE:To elucidate whether Danzhi Jiangtang capsule(丹蛭降糖胶囊,DJC)has treatment effects on diabetic periodontitis and the potential mechanism.METHODS:One week after the induction of diabetes by streptozotocin(STZ),60 male Wistar rats were ligated by orthodontic ligation thread in cervical portion of bilateral maxillary first molar to induce diabetic periodontitis.Periodontitis was exanimated by tooth tissue morphology after 4 weeks.And then all rats were divided into 5 groups:diabetic periodontitis group(DP,n=20),periodontal basic treatment group(DP+BT,n=20),periodontal basic treatment+DJC treatment group(DP+BT+DJC,n=20)and additional Wnt/β-catenin inhibitor group(DP+BT+DJC+WIKI4/21 H7,n=20).Eight weeks after different interventions,fasting plasma glucose(FPG),C-peptide and glycosylated hemoglobin(Hb Alc)of rats were measured and then all rats were sacrificed.The paraffin sections of periodontal tissue were executed hematoxylin-eosin(HE)staining and immunohistochemical examination.The m RNA and protein levels of inflammatory cytokines were evaluated by quantitative polymerase chain reaction(Q-PCR)and Western blotting(WB).The protein levels of Wnt/β-catenin signaling molecules were measured by WB.RESULTS:The blood glucose and C-peptide concentrations in DP,DP+BT and DP+BT+DJC groups were gradually reduced,with gradually decreased distance of CEJ-A and the percentage of periodontal ligament(PDL),as well as gradually increased Hb Alc.The number of monocytes and leukocytes in the junctional epithelium and periodontal connective tissue was markedly decreased in DP+BT+DJC group(P<0.05),which was slightly reduced in DP+BT group comparing to DP group.The protein levels of Wnt1 andβ-catenin were obviously up-regulated with DJC treatment,while the SOST and DDK1 were markedly down-regulated with DJC treatment.The expression levels of BGP were lowest in DP group and highest in DP+BT+DJC group,while the tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ)and metalloproteinase-3(MMP-3)were highest in DP group and lowest in DP+BT+DJC group.All these changes could be reversed by Wnt/β-catenin inhibitor.CONCLUSION:DJC can improve the hyperglycemia and both distal alveolar bone loss and alveolar bone loss in furcation area of diabetic periodontitis rats by reducing the inflammation of gingival tissue and regulating the expressions of BGP,TNF-α,IFN-γand MMP-3 potentially through Wnt/β-catenin signaling.

Liuwei Dihuang pill suppresses metastasis by regulating the wnt pathway and disrupting β-catenin/T cell factor interactions in a murine model of triple-negative breast cancer

OBJECTIVE:To investigate if the Liuwei Dihuang pill(LWDHP)can inhibit metastasis to the liver and lungs in mice bearing triple-negative breast cancer(TNBC),and the molecular mechanism underpinning this action.METHODS:Ninety-nine TNBC bearing-mice were distributed randomly to five groups:control(Con),paclitaxel(PTX),low-dose LWDHP(LLP,2.3 g·kg^-1·d^-1),middle-dose LWDHP(MLP,4.6 g·kg^-1·d^-1)and high-dose LWDHP(HLP,9.2 g·kg^-1·d^-1).The LWDHP were administered(p.o.)to the agonal stage.The morphology of BC cells was observed by hematoxylin&eosin staining.Expression of axin-2,β-catenin,T cell factor(TCF),cyclin-D1 and vascular endothelial growth factor(VEGF)was detected by western blotting or immunofluorescence.β-catenin/TCF-1 interaction was measured using a co-immunoprecipitation assay.RESULTS:After LWDHP treatment,metastasis of BC cells to the lungs and liver was inhibited,expression of axin-2 was increased,expression of TCF-1,β-catenin,cyclin-D1 and VEGF was decreased,andβ-catenin/TCF-1 interaction was disrupted.CONCLUSION:The LWDHP could inhibit metastasis of BC cells to the liver and lungs.The molecular mechanism underlying this action may be regulation of protein expression andβ-catenin/TCF-1 interactions in the Wnt pathway.