Dickkopf-related protein 1/cytoskeleton-associated protein 4 signaling activation by Helicobacter pylori-induced activator protein-1 promotes gastric tumorigenesis via the PI3K/AKT/mTOR pathway

BACKGROUND Gastric cancer(GC)is a common malignant tumor with high incidence and mortality rates globally,especially in East Asian countries.Helicobacter pylori(H.pylori)infection is a significant and independent risk factor for GC.However,its underlying mechanism of action is not fully understood.Dickkopf-related protein(DKK)1 is a Wnt signaling antagonist,and cytoskeleton-associated protein(CKAP)4 is a newly identified DKK1 receptor.Recent studies found that the binding of DKK1 to CAKP4 mediated the procancer signaling of DKK1 independent of Wnt signaling.We hypothesize that H.pylori-induced activation of DKK1/CKAP4 signaling contributes to the initiation and progression of GC.AIM To investigate the interaction of H.pylori infection,DKK1 and CAKP4 in GC,as well as the underlying molecular mechanisms.METHODS RNA sequencing was used to identify differentially expressed genes(DEGs)between H.pylori-infected and uninfected primary GC cells.Gain-and loss-offunction experiments were performed to verify the H.pylori-induced upregulation of activator protein-1(AP-1)in GC cells.A dual-luciferase reporter assay and co-immunoprecipitation were used to determine the binding of AP-1 to the DKK1 promoter and DKK1 to CKAP4.Western blotting and immunohistochemistry detected the expression of DKK1,CKAP4,and phosphatidylinositol 3-kinase(PI3K)pathway-related proteins in GC cells and tissues.Functional experiments and tumorigenicity in nude mice detected malignant behavior of GC cells in vitro and in vivo.RESULTS We identified 32 DEGs between primary GC cells with and without H.pylori infection,including JUN,fos-like antigen-1(FOSL1),and DKK1,and confirmed that the three proteins and CKAP4 were highly expressed in H.pylori-infected GC cells,H.pylori-infected gerbil gastric tissues,and human GC tissues.JUN and FOSL1 form AP-1 to transcriptionally activate DKK1 expression by binding to the DKK1 promoter.Activated DKK1 bound to CKAP4,but not the most common Wnt coreceptor low-density lipoprotein receptor-related protein 5/6,to promote GC cell growth,colony formation,migration,invasion,and xenograft tumor growth in nude mice.All these effects were driven by activation of the PI3K/AKT/mammalian target of rapamycin(mTOR)pathway.Targeting the PI3K signaling pathway by LY294002 inhibited DKK1-mediated CKAP4/PI3K signaling activity and the malignant behavior of GC cells.CONCLUSION H.pylori induces JUN and FOSL1 expression to form AP-1,which transcriptionally activates DKK1.Binding of DKK1 to KAKP4 contributes to gastric tumorigenesis via the PI3K/AKT/mTOR pathway.

Expression of Dickkopf-related Protein 1 in Patients with Temporomandibular Osteoarthritis after Treatment with Hyaluronic Acid

We previously reported that the increased expression of Dickkopf-related protein 1(DKK1)is positively related to vascular endothelial growth factor in the synovial fluid from patients with temporomandibular joint disorders(TMDs).DKK1 is involved in angiogenic activities in the TMD synovium in vitro,but the expression of DKK1 after treatment of TMD-osteoarthritis(TMD-OA)with hyaluronic acid(HA)remains unknown.In this study,we assessed the expression of DKK1 in the synovial fluid of TMD-OA patients before and after treatment with HA via enzyme-linked immunosorbent assay.We also investigated the role of DKK1 in TMD-OA via immunohistochemical staining.The relationship between the expression of DKK1 and the clinicopathological characteristics was determined by Pearson analysis.The results showed that the expression of DKK1 was significantly decreased after treatment with HA.Correlation analyses indicated that the expression of DKK1 in the TMD-OA samples was closely correlated with mouth opening and pain.These findings suggest that DKK1 could play an important role in the pathogenesis and treatment of TMD.Reduction of the pain by HA treatment may be correlated with the decreased expression of DKK1.

Clinical significance and prognostic value of tumor necrosis factor-α and dickkopf related protein-1 in ankylosing spondylitis

BACKGROUND Ankylosing spondylitis(AS)frequently occurs in people aged 30-45 years,and its prevalence is generally believed to be between 0.1%and 1.4%globally.At present,the“gold standard”for diagnosis of AS requires the provision of pelvic X-rays,which makes it more difficult to perform in population-based epidemiological studies.Therefore,the identification of serological indicators related to the diagnosis,treatment,and prognosis of AS patients is of great significance.AIM To analyze the therapeutic,diagnostic significance and prognostic value of dickkopf-related protein-1(DKK-1)and tumor necrosis factor-α(TNF-α)in AS.METHODS A total of 113 patients with active AS were selected as the research group,and 100 healthy subjects who underwent physical examination were selected as the control group.The levels of DKK-1 and TNF-α in peripheral blood in the two groups were compared.The diagnostic and predictive values of DKK-1 and TNF-α for AS were analyzed with ROC curves,and the factors influencing AS recurrence were analyzed with COX regression.RESULTS Before treatment,the research group showed lower DKK-1 levels but higher TNF-αlevels than the control group(both aP<0.05).In the research group,DKK-1 was up-regulated and TNF-αwas down-regulated after 12 wk of treatment(aP<0.05).The area under the curve,sensitivity and specificity of DKK-1 combined with TNF-αfor diagnosing AS were 0.934,82.30%and 97.00%,respectively.Before treatment,the area under the curve,cutoff value,sensitivity and specificity of DKK-1 for predicting the curative effect were 0.825,68.42 pg/mL,73.68%and 80.00%,respectively,and those of TNF-αwere 0.863,32.79 ng/L,92.11%and 77.33%,respectively.DKK-1 and TNF-αlevels after treatment were closely related to the curative effect(aP<0.05).C-reactive protein,the Bath Ankylosing Spondylitis Disease Activity Index,DKK-1,and TNF-αwere risk factors for AS recurrence(aP<0.05).CONCLUSION DKK-1 and TNF-αare effective in the diagnosis and treatment of AS and are risk factors for its recurrence.In addition,DKK-1 may be a potential target for the diagnosis of AS.