Down-Regulation of Neogenin Accelerated Glioma Progression through Promoter Methylation and Its Overexpression in SHG-44 Induced Apoptosis 英文参考文献.docVIP

Down-RegulationofNeogeninAcceleratedGlioma ProgressionthroughPromoterMethylationandIts OverexpressioninSHG-44InducedApoptosis XinminWu1,2.,YunqianLi2.,XilinWan1,TabithaMlowokaKayira1,RangjuanCao1,XingdaJu1, XiaojuanZhu1*,GangZhao2* 1KeyLaboratoryofMolecularEpigeneticsofMinistryofEducation,InstituteofCytologyandGenetics,NortheastNormalUniversity,Changchun,China,2Departmentof Neurosurgery,theFirstHospitalofJilinUniversity,Changchun,China Abstract Background: Dependence receptors have been proved to act as tumor suppressors in tumorigenesis. Neogenin, a DCC homologue,wellknownforitsfundamentalroleinaxonguidanceandcellulardifferentiation,isalsoadependencereceptor functioningtocontrolapoptosis.However,lossofneogeninhasbeenreportedinseveralkindsofcancers,butitsrolein gliomaremainstobefurtherinvestigated. Methodology/Principal Findings: Westernblot analysisshowedthat neogeninlevelwas loweringlioma tissues thanin theirmatchingsurroundingnon-neoplastictissues(n=13,p,0.01).Byimmunohistochemicalanalysisof69primaryand16 paired initial and recurrent glioma sections, we found that the loss of neogenin did not only correlate negatively with gliomamalignancy(n=69,p,0.01),butalsogliomarecurrence(n=16,p,0.05).Kaplan-MeierplotandCoxproportional hazardsmodellingshowedthatover-expressiveneogenincouldprolongthetumorlatency(n=69,p,0.001,1187.66162.6 daysversus 687.46254.2 days) andrestrainhigh-grade gliomadevelopment(n=69, p,0.01,HR:0.264, 95%CI:0.102 to 0.687).ByMethylationspecificpolymerasechainreaction(MSP),wereportedthatneogeninpromoterwasmethylatedin 31.0%(9/29)gliomas,butabsentin3kindsofgliomacelllines.Interestingly,theprevalenceofmethylationinhigh-grade gliomaswashigherthanlow-gradegliomasandnon-neoplasticbraintissues(n=33,p,0.05)andoverallmethylationrate increasedasgliomamalignancyadvanced.Furthermore,whencellswereover-expressedbyneogenin,theapoptoticratein SHG-44 was increased to 39.7% compared with 8.1% in the blank control (p,0.01) and 9.3% in the negative control (p,0.0