降鈣素基因相關(guān)肽基因啟動子區(qū)CpG島甲基化與胰腺癌發(fā)生發(fā)展的關(guān)系研究

降鈣素基因相關(guān)肽基因啟動子區(qū)CpG島甲基化與胰腺癌發(fā)生發(fā)展的關(guān)系研究降鈣素基因相關(guān)肽基因啟動子區(qū)CpG島甲基化與胰腺癌發(fā)生發(fā)展的關(guān)系研究

摘要：

降鈣素基因相關(guān)肽（CGRP）在胰腺癌的發(fā)生發(fā)展中起著重要的作用。CpG島甲基化是一種可逆的表觀遺傳學(xué)修飾，與腫瘤的發(fā)生發(fā)展有關(guān)。本研究旨在探討CGRP基因啟動子區(qū)CpG島甲基化與胰腺癌的關(guān)系，以及其對胰腺癌患者生存期的影響。通過利用MethPrimer軟件篩選出CGRP基因啟動子區(qū)的CpG島，采用甲基化特異性PCR（MSP）技術(shù)檢測CGRP基因啟動子區(qū)CpG島的甲基化狀態(tài)，結(jié)合臨床病理資料分析CGRP基因啟動子區(qū)CpG島甲基化與胰腺癌發(fā)生發(fā)展的關(guān)系。結(jié)果顯示，CGRP基因啟動子區(qū)存在一個CpG島，該CpG島甲基化程度與胰腺癌組織中CGRPmRNA的表達(dá)呈負(fù)相關(guān)。此外，CGRP基因啟動子區(qū)CpG島甲基化程度較高的胰腺癌患者生存期明顯短于甲基化程度較低的患者。本研究表明，CGRP基因啟動子區(qū)CpG島甲基化與胰腺癌的發(fā)生發(fā)展密切相關(guān)，可能成為胰腺癌的潛在治療靶點。

關(guān)鍵詞：降鈣素基因相關(guān)肽基因、CpG島甲基化、胰腺癌、生存期、甲基化特異性PCR

Abstract：

Calcitoningene-relatedpeptide(CGRP)playsanimportantroleinthedevelopmentofpancreaticcancer.CpGislandmethylationisareversibleepigeneticmodificationthatisrelatedtotheoccurrenceanddevelopmentoftumors.TheaimofthisstudywastoinvestigatetherelationshipbetweenCpGislandmethylationinthepromoterregionoftheCGRPgeneandpancreaticcancer,aswellasitsimpactonthesurvivalofpancreaticcancerpatients.UsingMethPrimersoftware,wescreenedouttheCpGislandinthepromoterregionoftheCGRPgene,anddetectedthemethylationstatusoftheCpGislandusingmethylation-specificPCR(MSP)technology.WealsoanalyzedtherelationshipbetweenCpGislandmethylationinthepromoterregionoftheCGRPgeneandtheoccurrenceanddevelopmentofpancreaticcancer,combinedwithclinicalandpathologicaldata.TheresultsshowedthattherewasaCpGislandinthepromoterregionoftheCGRPgene,andthedegreeofCpGislandmethylationwasnegativelycorrelatedwiththeexpressionofCGRPmRNAinpancreaticcancertissues.Inaddition,thesurvivaltimeofpancreaticcancerpatientswithhigherCpGislandmethylationlevelsinthepromoterregionoftheCGRPgenewassignificantlyshorterthanthatofpatientswithlowermethylationlevels.ThisstudysuggeststhatCpGislandmethylationinthepromoterregionoftheCGRPgeneiscloselyassociatedwiththeoccurrenceanddevelopmentofpancreaticcancer,andmaybeapotentialtherapeutictargetforpancreaticcancer.

Keywords:calcitoningene-relatedpeptidegene,CpGislandmethylation,pancreaticcancer,survivaltime,methylation-specificPCPancreaticcancerisadevastatingdiseasewithahighmortalityrate,andnewtherapeutictargetsareurgentlyneeded.Inrecentyears,increasingevidencehasrevealedthatepigeneticmodifications,suchasDNAmethylation,playacriticalroleintheinitiationandprogressionofvariouscancers,includingpancreaticcancer.

Inthisstudy,theresearchersfocusedontheCGRPgene,whichencodescalcitoningene-relatedpeptide,aneuropeptidethathasbeenimplicatedinthedevelopmentofpancreaticcancer.TheyanalyzedDNAmethylationlevelsinthepromoterregionoftheCGRPgeneinacohortofpancreaticcancerpatientsandfoundasignificantassociationbetweenhighlevelsofCpGislandmethylationandshortersurvivaltime.

ThesefindingssuggestthatepigeneticsilencingoftheCGRPgenethroughCpGislandmethylationmaycontributetothedevelopmentandprogressionofpancreaticcancer.Therefore,targetingCpGislandmethylationintheCGRPgenemayrepresentapromisingnewapproachforthetreatmentofpancreaticcancer.

However,furtherstudieswillbeneededtoconfirmthesefindingsandexploretheunderlyingmechanismsbywhichCGRPgenemethylationcontributestopancreaticcancerdevelopment.TheresultsofthisstudyprovideastartingpointforsuchinvestigationsandmayleadtothedevelopmentofnewtherapeuticstrategiesforthisdevastatingdiseasePancreaticcancerisadevastatingdiseasewithhighmortalityrates.AccordingtotheAmericanCancerSociety,pancreaticcanceristhefourthleadingcauseofcancer-relateddeathsinbothmenandwomenwitha5-yearsurvivalrateoflessthan10%.Despiteadvancesinmedicaltreatments,theoverallsurvivalrateforpancreaticcancerpatientsremainspoorduetothelackofearlydetectionmethodsandeffectivetherapies.

RecentstudieshaveuncoveredapotentialrelationshipbetweentheCGRPgeneandpancreaticcancer.CGRPisaneuropeptideinvolvedinpainperceptionandinflammation,andhasalsobeenshowntoplayaroleinthedevelopmentandprogressionofvariouscancers,includingpancreaticcancer.Inpancreaticcancer,CGRPpromotestumorgrowthandinvasionbyactivatingcellularsignalingpathwaysthatstimulatecellproliferationandinhibitcelldeath.

AnotherimportantaspectofCGRP’sinvolvementinpancreaticcancerisitsregulationbyCpGislandmethylation.CpGislandsareregionsofDNAlocatedneargenepromotersthatarerichincytosine-guaninedinucleotides.CpGislandhypermethylationisacommonepigeneticalterationthatoccursincancercellsandcanresultinthedownregulationoftumorsuppressorgenes,includingCGRP.

StudieshaveshownthatCpGislandhypermethylationoftheCGRPgeneisassociatedwithdecreasedCGRPexpressionandincreasedpancreaticcancerrisk.ThedownregulationofCGRPexpressionpromotestumorgrowthandprogressionbyreducingtheanti-tumorimmuneresponseandincreasinginflammation.Therefore,targetingCpGislandmethylationintheCGRPgenemayrepresentapromisingnewapproachforthetreatmentofpancreaticcancer.

OnepotentialstrategyfortargetingCGRPgenemethylationinpancreaticcanceristheuseofepigeneticdrugsknownasDNAmethyltransferaseinhibitors(DNMTinhibitors).DNMTinhibitorscanpreventDNAmethylationbyinhibitingtheactivityofDNAmethyltransferaseenzymes,therebyleadingtothere-expressionofsilencedgenessuchasCGRP.SeveralstudieshaveshownpromisingresultsfortheuseofDNMTinhibitorsinthetreatmentofvariouscancers,includingpancreaticcancer.

AnotherpotentialstrategyfortargetingCGRPgenemethylationistheuseofCRISPR/Cas9geneeditingtechnology.CRISPR/Cas9hasemergedasapowerfultoolformodifyinggeneexpressionbytargetinganddisruptingspecificDNAsequences.BytargetingtheCGRPgenepromoterregion,CRISPR/Cas9couldpotentiallydisruptCpGislandmethylationandrestoreCGRPexpressioninpancreaticcancercells.

Inconclusion,therelationshipbetweenCGRPgenemethylationandpancreaticcancerprovidesanexcitingnewavenueforthedevelopmentofnoveltherapiesforthisdevastatingdisease.TheuseofepigeneticdrugsorgeneeditingtechnologiesfortargetingCGRPgenemethylationinpancreaticcancerpatientsmayoffersignificantbenefitsintermsofimprovingprognosisandoutcomes.However,furtherresearchisneededtofullyelucidatetheunderlyingmechanismsanddeterminetheoptimalapproachfortargetingCGRPgenemethylationinpancreaticcancerPancreaticcancerisahighlyaggressiveandlethaldiseasethatisdifficulttodiagnoseandtreat.Despiterecentadvancesinchemotherapyandmoleculartargetedtherapies,theprognosisforpatientsremainspoor,withafive-yearsurvivalrateoflessthan10%.Therefore,thedevelopmentofnewapproachesforthepreventionandtreatmentofpancreaticcancerisurgentlyneeded.

Inrecentyears,epigeneticmodificationshaveemergedasapromisingtargetforcancertherapy.Epigeneticalterations,suchasDNAmethylation,histonemodification,andnon-codingRNAregulation,playcriticalrolesincancerdevelopmentandprogression.AbnormalDNAmethylation,inparticular,hasbeenobservedinmanytypesofcancer,includingpancreaticcancer.ThisinvolvestheadditionofmethylgroupstocytosineresidueswithinCpGdinucleotides,resultingintherepressionofgenetranscription.Theseepigeneticchangesarereversibleandcanbetargetedbydifferentdrugs,makingthemattractiveoptionsforcancertherapy.

Onegenethatisimplicatedinpancreaticcanceristhecalcitoningene-relatedpeptide(CGRP)gene.CGRPisaneuropeptidethathasbeenshowntopromotecancercellproliferation,migration,andinvasioninpancreaticcancer.IncreasedexpressionofCGRPhasbeenobservedinhumanpancreaticcancertissues,andhasbeenassociatedwithapoorprognosisforpatients.Therefore,targetingCGRPexpressionmayrepresentanoveltherapeuticstrategyforpancreaticcancer.

RecentstudieshaveshownthatthemethylationstatusoftheCGRPgeneissignificantlyassociatedwithpancreaticcancerprogressionandpatientsurvival.Specifically,hypermethylationoftheCGRPgenehasbeenfoundtobeapredictorofshorteroverallsurvivalinpancreaticcancerpatients.ThissuggeststhattargetingtheCGRPmethylationmaybeaneffectivewaytoinhibitpancreaticcancergrowthandimproveoutcomes.

VariousepigeneticdrugshavebeendevelopedthattargetDNAmethylation,including5-azacytidineand5-aza-2’-deoxycytidine.ThesedrugsarethoughttoworkbyinhibitingDNAmethyltransferaseenzymes,whichareresponsibleforaddingmethylgroupstocytosineresidues.ByreducingCGRPgenemethylation,thesedrugsmaybeabletore-activateCGRPexpressionincancercells,leadingtodecreasedcancercellgrowth,migration,andinvasion.

Inadditiontoepigeneticdrugs,geneeditingtechnologiesprovideapromisingapproachtotargetingCGRPgenemethylationinpancreaticcancer.TheCRISPR-Cas9system,forexample,canbeusedtospecificallytargetandmodifyDNAmethylationpatternsincancercells.BytargetingtheCGRPgene,CRISPR-Cas9maybeabletodeleteormodifykeymethylatedCpGdinucleotides,resultinginthere-activationofCGRPexpressionandtheinhibitionofcancergrowth.

Despitethepromisingpotentialoftheseapproaches,furtherresearchisneededtofullyu