MDM2 is upregulated in PDAC tissues and correlates with clinicopathological characteristics

 D. Zhu, et al. Cancer Letters 477 (2020) 107–121 Fig. 3. MDM2 is upregulated in PDAC tissues and correlates with clinicopathological characteristics, and dysbindin expression is positively correlated withMDM2expressioninPDACtissues.(A)WesternblotanalysisshowingMDM2proteinlevelsinPDACtissues(n=8)andpairedadjacentnoncanceroustissues. Thedataarepresentedasthemean ± SEM.(B)qRT-PCRanalysisshowingMDM2mRNAlevelsinPDACtissues(n=8)andpairedadjacentnoncanceroustissues. Thedataarepresentedasthemean ± SEM.(C)MDM2expressionwasdetectedonatissuemicroarraycontaining63PDACspecimensand57adjacentnoncancerous tissues.RepresentativeIHCstainingprofilesofMDM2indifferentgroupsareshown.ANT,adjacentnoncanceroustissue;T,tumourtissue.Scalebars:top,200μm; bottom,50μm.(D)MDM2expressionlevelsin63PDACtissuesand57adjacentnoncanceroustissueswereanalysedbyPearson\'schi-squaretest.(E)Analysisofthe IHC scores for MDM2 in PDAC tissues and adjacent noncancerous tissues. 

 

ANT, adjacent noncancerous tissue; T, tumour tissue. The data are presented as the mean ± SEM.(F)Kaplan-MeiersurvivalanalysisshowingtheoverallsurvivalofPDACpatientswithhighorlowMDM2expression(n=63).(G)Theassociation betweendysbindinandMDM2IHCscoresin20PDACtissueswasanalysedbyPearson\'scorrelationanalysis(r=0.639,p < 0.01).(H)RepresentativeIHCstaining profiles of dysbindin and MDM2 in PDAC tissues (n = 20) and adjacent noncancerous tissues. Scale bars: top, 100 μm; bottom, 50 μm ***P < 0.001. Table 1 Table 2 Correlations between MDM2 expression and clinical characteristics in patients Univariate and multivariate analyses of prognostic parameters for survival in with PDAC Cell Counting Kit-8 (CCK-8). PDAC patients. Variable Patient number MDM2 expression P-value (χ2 Variable Univariate analysis (n = 63) test) high low (n = 29) HR 95% CI P-value (n = 34) MDM2 expression (high vs. low) 2.085 1.175–3.699 0 Suramin hexasodium salt.012* Age (years) Age (≤60 years vs. >60 years) 1.278 0.721–2.268 0.401 ≤60 24 15 9 Gender (male vs. female) 0.878 0.5–1.541 0.651 >60 39 19 20 0.191 Tumour location (head vs. body/tail) 1.229 0.7–2.157 0.473 Gender Tumour size (≤4 cm vs. >4 cm) 1.589 0.873–2.895 0.13 Male 36 24 12 Nodal status(N0 vs. N1) 1.479 0.841–2.6 0.174 Female 27 10 17 0.06 Perineural invasion(absent vs. present) 0.434 0.242–0.78 0.005* Tumour location Histological Grade (differentiation) 1.425 0.816–2.489 0.21###http://www.glpbio.com/simage/GA11233-L-NAME-hydrochloride-4.png####3 Head 37 20 17 Body/tail 26 14 12 0.506 Variable Multivariate analysis Tumour size (cm) HR 95% CI P-value ≤4 42 21 21 >4 21 13 8 0.000* MDM2 expression (high vs. low) 2.523 1.276–4.987 0.008* Perineural invasion(absent vs. present) 0.337 0.167–0.681 0.002* Nodal status N0 35 16 19 N1 25 15 10 0.423 Univariate analysis and multivariate analyses were analysed by Cox propor- Unknown 3 tional hazards model. 

 

HR, hazard ratio; 95% CI, 95% confidence interval. Perineural invasion *Statistically significant. P-value<0.05 are in bold. Absent 36 20 16 Present 27 14 13 0.609 Histological Grade (differentiation) Ⅰ,Ⅱ 34 15 19 Ⅲ 29 19 10 0.000* assays showed that upregulating dysbindin promoted the metastasis *Statistically significant. P-value<0.05 are in bold. andinvasionofAspc-1andBxpc-3cells(Fig.1D).Conversely,knocking down dysbindin expression decreased the migration and invasion of Panc-1 and Capan-2 (Fig. 1E). Transduced cells were injected into the tail vein of nude mice to 3. Results observetheinvivoeffectsofdysbindinonPDACmetastasis.Stablecell lineswithdysbindinoverexpressionorknockdownwereestablished.As 3.1. Dysbindin promotes PDAC metastasis and invasion in vitro and in vivo showninFig AR-13324.1GandH,thenumberofmetastaticlungnodulesandthe incidence of lung metastasis were increased when dysbindin was up- First, we detected dysbindin expression in PDAC cells and human regulated,whiletheseeffectswerecompletelyreversedwhendysbindin pancreatic ductal epithelial cells. 

 

The data showed that dysbindin ex- was downregulated. These studies indicate that dysbindin promotes pression was higher in PDAC cells than in human pancreatic ductal PDAC metastasis and invasion in vitro and in vivo. epithelial cells (Fig. 1A). Among the PDAC cells, dysbindin expression wasrelativelyhigherinPanc-1andCapan-2cells(Fig.1A).Toevaluate 3.2. Dysbindin overexpression increases MDM2 expression in PDAC, and whetherdysbindinpromotesPDACmetastasisandinvasioninvitroand MDM2 knockdown decreases PDAC metastasis and attenuates dysbindin- invivo,weusedalentivirustooverexpressorsilencedysbindin.Then, enhanced metastasis and invasion we used a transwell assay to evaluate cell motility. Dysbindin protein and mRNA expression levels are shown in Fig. 1B and C. Transwell To further elucidate the mechanism by which dysbindin promotes 113

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