489 receptorα,erα) ^;% : #!"#$%&(epthelialgrowthfactor, EGF) ;+, ; [3]!"#$%&>? X` < < M N O < _ < = >? (estrogenreceptor, ER) [4], ();+, O,EGFX` C

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1 : (2017) Basic& ClinicalMedicine April2017 Vol.37 No.4 研究论文 1, 1, 2, 1, 2 (1 -./01, ;2 / , ) :! 89!"#$%&(EGF):& ()* Ishikawa+,;, <=>? α(erα)@ Ack1ABCDE ; "# <= FG,EGF H Ishikawa(),CCK 8IJK& ()+,;WesternblotJK() ERαL Ack1MNO; N< PQRST()U,JK Ishikawa()+,@ ERαL Ack1MNOVW $% EGFX+Y Ishikawa()+,(P<0 05), ' ERαTyr 537 MNO@ Ack1MNO; PQRU,()+, GZ(P<0 05),ERαTyr 537 MNO@ Ack1MNO[\GC $& EGF' Ishikawa()+,,BE X ]^ ERαTyr 537 MNO@<_ Ack1< `abc ' :& ;!"#$%&; <=>?;Ack1; PQR;MNO :R ()*+:A Epidermalgrowthfactorpromotes proliferationofendometrialadenocarcinomacellineishikawa ZHANGJing 1,TIANTian 1,LIUJing 2,CUIZhu mei 1,LIUYuan bo 2 (1 Dept.ofGynecology,theafiliatedHospitalofQingdaoUniversity,Qingdao266003; 2 Dept.ofHematology,BeijingTiantanHospital,CapitalMedicalUniversity,Beijing100050,China) Abstract:Objective Toinvestigatetheefectofepidermalgrowthfactor(EGF)ontheproliferationofendometrial adenocarcinomacels,phosphorylationofestrogenreceptorα(erα)andack1intheabsenceofestrogen.methods IshikawacellinewasstimulatedbyEGFwithoutestrogensetings,CelCountingKit 8(CCK 8)wasusedtoeval uatecelproliferation,westernblotwasusedtodetecterαphosphorylationandack1phosphorylation.giving tyrosineinhibitordasatinibtoasestheefectofegfoncelproliferation,phosphorylationoferαandack1inish ikawacels.results EGFenhancedtheproliferationofendometrialadenocarcinomacels(P<0 05).EGFin ducederαphosphorylationattyr 537andphosphorylationofAck1.Comparedwithuntreatedcontrol,Dasatinib inhibitedtheproliferationofendometrialadenocarcinomacels(p<0 05),phosphorylationofERαTyr 537and Ack1.Conclusions EGFpromotesIshikawacelsproliferationintheposiblewayofactivatingERαsite specific phosphorylationattyr 537andphosphorylationAck1,whichcouldbeblockedbydasatinib. Keywords:endometrialneoplasms;epidermalgrowthfactor;estrogenreceptor;Ack1;dasatinib;phosphorylation & ; #,*, H&?;, #, *,B H & A ; O [1 2], E 89 & # <=bc,b <=>? α(estrogen : : : ( ) (correspondingauthor):cuizhumei1966@126.com;yuanbol@ccmu.edu.cn

2 489 receptorα,erα) ^;% : #!"#$%&(epthelialgrowthfactor, EGF) ;+, O@6 ; [3]!"#$%&>? X` < < M N O < _ < = >? (estrogenreceptor, ER) [4], ();+, O,EGFX` CD Ack1]^ < =>?(androgenreceptor,ar) MNO,' ()+, [5] EGFA& :()+,; L ce c 89 & ()* Ishikawa 89 :, A <= G,EGF:& ()+,;, 89B Ack1@ ERαMNO;c*, EGF:& ( )+,; L ccde 1,-."# 1 1, (): <= & ()* ) 1 1 );Ack1? p Ack1?L ER? (Abcam Biotechnology );ERTyr 537 MNO?(SantaCruz ); P Q R (CelSignaling Technology ); L O ; (2 3 b ); CCK 8 (CelCountingKit 8,23 O 89) 1 2 "# ( ) L S T: 10% 6 100U/mL- = 100U/mL =; DMEM F/ 12 7 (),H 37 CO 2?! 5%; ( ) " # ( ) $ % & 90% ~ 100%U,0 25%' O 1 3; +, b () SH:! +,;() EGF(100μg/L)ST, E2(β estradiol,10μg/l)st, PQR(dasat CCK 8JK()+,:+:!+,; Ishikawa(),, 0 25%' OU-. ()/7, / ; Ishikawa() H 96, 2 EGF@ PQR 24hU, 3* CCK JK()+, WesternblotJK ERTyr 537 MNOL Ack1MNO:A 6 Ishikawa(),#( )+,9:;, PQR ST Ishikawa() 2hU, 2 EGFST 1hU, ; PBS ( ) 3, <=> 200μLRIPA()?@7,HA B 20min,CDE (), ()?@,4 G 12000r/min 15min, +B 7, BCAI F G,+ 40μg H I,` 10%J KLNM NO P,300mA Q G 2h,RSTU VWX 2hU,= > Ack1 p Ack1 ERp Y537L ER? 4 Y 3,15min/,?RSY 1h, 3,15min/,O I Image J Z,` MNO[; \MNO [; ]; &^ ^ [; ; : G 1 3 /01 _ SPSS19 0 `Z!a,`G bc% W,_ (! ± (x±s)!, _ H tj 2 $% ,EGF56789:; EGF(10μg/L)@ E2(10μg/L)ST; Ishikawa () &^( H:* (P<0 05)( 1) P<0 05comparedwithcontrol 1 234,EGF78 Ishikawa Fig1 EGFpromotestheproliferationofIshikawacels intheabsenceofestrogen(x±s,n=9)

490 Basic&ClinicalMedicine 2017 37(4) P<0 05comparedwithcontrol; # P<0 05comparedwithdasatinib:0&EGF:100 2 <=>?@ABCDE EGF!

$Ishikawa PQR(10nmol/L~800nmol/L) EGF]^; Ishikawa()+,, PQR & +=,() &^ Z (P<0 05)( 2) 2 3 EGF Ack1 FGH ERIJKL FG EGF]^,Ishikawa()MNO(<_O VW); Ack1@ Tyr 537ER[\( 2 100μg/LEGFST Ishikawa(), :*, Ack1@$

3 490 Basic&ClinicalMedicine (4) P<0 05comparedwithcontrol; # P<0 05comparedwithdasatinib:0&EGF:100 2 <=>?@ABCDE EGF! Ishikawa Fig2 DasatinibinhibitedtheproliferationofIshikawacelsinducedbyEGF(x±s,n=9) 2 2 < = >? EGF! Ishikawa PQR(10nmol/L~800nmol/L) EGF]^; Ishikawa()+,, PQR & +=,() &^ Z (P<0 05)( 2) 2 3 EGF Ack1 FGH ERIJKL FG EGF]^,Ishikawa()MNO(<_O VW); Ack1@ Tyr 537ER[\( 2 100μg/LEGFST Ishikawa(), :*, Ack1@ ERTyr 537 ;MNO[\ ( 3,! 1) 2 4 <=>? EGF! ERTyr 537IJ KL FG PQRX EGF]^; ERTyr 537 MNO, G+=,ER Ack1 M N 1 EGFO Ishikawa Ack1 p Ack1 ER H ERTyr 537 N<! Table1 EfectsofEGFonexpresionsofAck1,p Ack1, ERandERTyr 537proteininIshikawacels (x±s,n=9) group p Ack1/Ack1 p ER/ER control ± ± EGF ± ± P<0 05comparedwithcontrolgroup. NO[\ Z, PQR &/H 400nmol/L,Ack1L ERTyr 537 MNO ( 4,! 2) N 2 DasatinibO Ishikawa Ack1 p Ack1 ERH ERTyr 537 N<! Table2 EfectsofDasatinibonexpresionsofAck1, p Ack1,ERandERTyr 537proteinin Ishikawacels(x±s,n=9) group p Ack1/Ack1 p ER/ER control ± ± nmol/L ± ± nmol/L ± ± nmol/L ± ± # 100nmol/L ± ± # 200nmol/L ± # ± # 3 EGF Ishikawa M Ack1H ER Tyr 537IJKL FG Fig3 EGFinducedAck1andTyr 537ER phosphorylationofishikawacellines 400nmol/L ± # ± # 800nmol/L ± # ± # P<0 05comparedwithcontrolgroup; # P<0 05comparedwithDasat inib:0&egf:100group.

4 491 4 <=>? Ishikawa M EGF! Ack1H ER FG Fig4 DasatinibinhibitedEGFinducedphosphorylationofAck1andER 3 & <= >? %<_& () C %;!, # EGFLB>? ' ()+, [6] EGF <=;, ` ;, B>? %U ();+, OL _ O [7] `? EGF:& () Ishikawa;+,', X ; c &E EGF!"#$%&>? %UX` ]^ NMNO, < N< `a,' () [8] 89,A? < = FG,() Src< ^; AR NMNO AR_O;c,X]^ [5] < = G EGF:& ce!,egfa <= GX' & Ishikawa;+,,E X EGF]^ ERαTyr 537 MNO@ N< Ack1 MNObc N< PQR G ; EGF]^; ERαTyr 537 MNO@ Ack1MNO[\,^ Ishikawa ()+, GZ, C :H Ack1 B & CD ERα Tyr 537 ;_O, 89 N< ;() ^` a,a();+,@ O b, O MN B;MN ; N B, B #MNO [9] N< ();, ()+,, ()+,@ #6 [10] PQR N<,` CD Bcr Abl@ Src<? ;#$ [11], 89; b89!, PQRX [12], X ( );+,@ [13] 89, PQRGC ARTyr 267@ ARTyr 534 MNO [\, PQRA ; a [14] 89 PQRA& () X ERαTyr Ack1 < MNO, PQRA& ; ; a P (: [1]WongYF,CheungTH,LoKW,etal.Identificationofmo lecularmarkersandsignalingpathwayinendometrialcancer inhongkongchinesewomenbygenome widegeneexpres sionprofiling[j].oncogene,2007,26: [2]ZhangY,LiuZ,YuX,etal.Theasociationbetweenmet abolicabnormalityandendometrialcancer:alargecase controlstudyinchina[j].gynecoloncol,2010,117: [3]EjskjaerK,SorensenBS,PoulsenSS,etal.Expresionof theepidermalgrowthfactorsysteminendometrioidendome trialcancer[j].gynecoloncol,2007,104: [4]BritonDJ,HutchesonIR,KnowldenJM,etal.Bidirec

5 492 Basic&ClinicalMedicine (4) tionalcrostalkbetweenerαandegfr signalingpath waysregulatestamoxifen resistantgrowth[j].breastcanc errestreat,2006,96: [5],,,. <= G!"#$% &]^ *)*+,L <=>?MNO[J].,2014,34: [6],,. PTEN: EGF]^ ;& () ERK_O; [J].() &,2002,18: [J].,2006,18: [8]SeshacharyuluP,PonnusamyMP,HaridasD,etal.Targe tingtheegfr signalingpathwayincancertherapy[j]. ExpertOpinTherTargets,2012,16: [9]TraxlerP.Tyrosinekinasesastargetsincancertherapy succesesand failures[j]. ExpertOpin TherTargets, 2003,7: [10] NormannoN,DeLucaA,BiancoC,etal.Epidermal growthfactorreceptor(egfr)signalingincancer[j]. Gene,2006,366:2 17. [11]LeXF,MaoW,LuZ,etal.Dasatinibinducesautophag icceldeathinhumanovariancancer[j].cancer,2010, 116: [12]PichotCS,HartiqSM,XiaL,etal.Dasatinibsynergizes withdoxorubicintoblockgrowth,migration,andinvasion ofbreastcancercels[j].brjcancer,2009,101: [13],. PQR%: ; [J].,2011,26: [14],,,. PQR () <=>? M N O E 8 9 [J]. 8 9, 2016,28: 新闻点击 QRS TUVWX 据英国 BBC 新闻 (BBCNEWS) 报道, 有研究指出, 孤单会抑制免疫系统, 让人更容易罹患疾病, 危害程度是肥胖的 2 倍美国芝加哥大学 (UniversityofChicago) 研究人员发现, 在晚年觉得最为孤单的群体中, 早死风险比那些觉得最被需要的群体高出近 15% 研究称, 孤单危害健康的程度是肥胖的 2 倍研究团队说, 远离人群会弱化人体抗病毒的能力, 并让血压升高到心脏病发作或脑卒中的危险值, 并增加忧郁症风险研究团队发现, 免疫系统基因 CTRA 在 50 岁以上感到非常寂寞的群体身上特别活跃, 这会抑制对抗病毒的免疫反应, 并且增加炎性反应, 这与心脏疾病和虚弱等许多健康问题有关研究人员 JohnCacioppo 认为, 觉得寂寞的人可以通过公益活动来交友, 如念书给盲友听, 或是指导儿童的运动队等另外, 养宠物作伴也会有帮助, 他发现养狗会降低寂寞感, 但养猫蜥蜴或仓鼠就没有这种效果该项研究发表在美国国家科学院院报 (PNAS) Y T ZWX 据美国 WebMD 医学新闻网 ( ) 报道, 研究人员认为, 长期住在嘈杂路边的人可能会增加罹患忧郁症的风险相较于住家附近较少交通噪声的人来说, 住在交通繁忙区域的人罹患忧郁症的风险提高 25% 然而, 德国的研究人员发现, 这种风险大部分局限在穷人失业者教育程度低吸烟或是失眠的人 Esen 大学的研究人员 EsterOrban 认为, 虽然他们不能确认, 但认为噪声会造成压力与烦恼如果噪声持续很长一段时间, 且很大声的话, 可能会造成忧郁症如果觉得马路上的噪声很大, 可以使用耳塞, 如果噪声会干扰睡眠, 卧室最好远离繁忙交通的路段这篇报告刊登在环境健康展望 (EnvironmentalHealthPerspectives)

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