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        E-鈣黏蛋白和波形蛋白的表達(dá)情況與結(jié)腸癌相關(guān)臨床病理因素的關(guān)聯(lián)性及其對(duì)患者預(yù)后的影響

        2017-09-14 06:48:38曾祥岳孫振強(qiáng)王琦三王海江
        中國(guó)全科醫(yī)學(xué) 2017年27期
        關(guān)鍵詞:脈管關(guān)聯(lián)性結(jié)腸癌

        曾祥岳,孫振強(qiáng),王琦三,葛 磊,王海江*

        ·論著·

        ·專題研究·

        E-鈣黏蛋白和波形蛋白的表達(dá)情況與結(jié)腸癌相關(guān)臨床病理因素的關(guān)聯(lián)性及其對(duì)患者預(yù)后的影響

        曾祥岳1,孫振強(qiáng)2,王琦三1,葛 磊1,王海江1*

        目的腫瘤的進(jìn)展是一個(gè)多因素參與、相互影響的復(fù)雜病理生理過程,本研究意在探討上皮-間質(zhì)轉(zhuǎn)化(EMT)標(biāo)志物E-鈣黏蛋白(E-cadherin)和波形蛋白(Vimentin)的表達(dá)情況與結(jié)腸癌相關(guān)臨床病理因素的關(guān)聯(lián)性,并分析其對(duì)患者預(yù)后的影響。方法收集2009-01-01—2014-01-01于新疆醫(yī)科大學(xué)附屬腫瘤醫(yī)院胃腸外科行結(jié)腸癌根治術(shù)且術(shù)后病理檢查明確診斷的116例TNM分期Ⅲ期患者結(jié)腸癌組織及其癌旁組織標(biāo)本。應(yīng)用免疫組織化學(xué)SP法檢測(cè)結(jié)腸癌組織中E-cadherin、Vimentin的表達(dá)情況,采取門診或病房復(fù)查、電話等相結(jié)合的方式進(jìn)行隨訪,隨訪截止時(shí)間為2015-01-01。116例結(jié)腸癌術(shù)后患者中107例獲得隨訪,隨訪時(shí)間為4.1~63.0個(gè)月,隨訪率為92.2%(107/116),中位隨訪時(shí)間為46.0個(gè)月;記錄患者累積生存率(OS)及無病生存率(DFS)。采用多因素Logistic回歸分析分析E-cadherin、Vimentin表達(dá)情況與臨床病理因素的關(guān)聯(lián)性;采用Kaplan-Meier法繪制生存曲線,生存分析采用Log-rank檢驗(yàn)。結(jié)果116例患者結(jié)腸癌組織中E-cadherin和Vimentin的陽性表達(dá)率分別為79.3%(92/116)、15.5%(18/116)。癌胚抗原(CEA)、腫瘤直徑、脈管侵犯情況、分化程度、淋巴結(jié)轉(zhuǎn)移情況的E-cadherin陽性表達(dá)率比較,差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。腫瘤直徑、脈管侵犯情況、神經(jīng)侵犯情況、分化程度、淋巴結(jié)轉(zhuǎn)移情況的Vimentin陽性表達(dá)率比較,差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。多因素Logistic回歸分析結(jié)果顯示,CEA、脈管侵犯情況、分化程度與E-cadherin的表達(dá)情況存在關(guān)聯(lián)性(P<0.05);脈管侵犯情況、神經(jīng)侵犯情況、分化程度與Vimentin的表達(dá)情況存在關(guān)聯(lián)性(P<0.05)。E-cadherin陽性表達(dá)患者OS及DFS高于E-cadherin陰性表達(dá)患者(P<0.05);Vimentin陽性表達(dá)患者的OS及DFS低于Vimentin陰性表達(dá)患者(P<0.05)。結(jié)論CEA、脈管侵犯情況、分化程度與E-cadherin表達(dá)情況存在關(guān)聯(lián)性,脈管侵犯情況、神經(jīng)侵犯情況、分化程度與Vimentin表達(dá)情況存在關(guān)聯(lián)性;E-cadherin、 Vimentin是判斷結(jié)腸癌患者預(yù)后的重要指標(biāo)。

        結(jié)腸腫瘤;上皮-間質(zhì)轉(zhuǎn)化;鈣黏著糖蛋白類;波形蛋白;預(yù)后

        曾祥岳,孫振強(qiáng),王琦三,等.E-鈣黏蛋白和波形蛋白的表達(dá)情況與結(jié)腸癌相關(guān)臨床病理因素的關(guān)聯(lián)性及其對(duì)患者預(yù)后的影響[J].中國(guó)全科醫(yī)學(xué),2017,20(27):3360-3367.[www.chinagp.net]

        ZENG X Y,SUN Z Q,WANG Q S,et al.Correlation of the expressions of E-cadherin and Vimentin with the clinicopathological factors and prognosis of colon cancer[J].Chinese General Practice,2017,20(27):3360-3367.

        近年來隨著我國(guó)人口老齡化加劇、人民生活水平的不斷提高、飲食習(xí)慣和飲食結(jié)構(gòu)的改變,結(jié)腸癌發(fā)病率呈逐年上升趨勢(shì)[1]。新疆是一個(gè)多民族聚居地,其獨(dú)特的飲食結(jié)構(gòu)使之成為我國(guó)結(jié)腸癌的高發(fā)區(qū),嚴(yán)重威脅人們的身體健康,雖然術(shù)后的進(jìn)一步治療已經(jīng)取得了很大的進(jìn)展,但仍面臨著嚴(yán)峻挑戰(zhàn)[2-3]。以手術(shù)為主的綜合治療是目前治療結(jié)腸癌的主要手段[4],但結(jié)腸癌術(shù)后的復(fù)發(fā)、轉(zhuǎn)移及預(yù)后不容樂觀,尤以肝、肺轉(zhuǎn)移居多,其發(fā)生率可高達(dá)40%~50%[5]。而復(fù)發(fā)和轉(zhuǎn)移是導(dǎo)致結(jié)腸癌患者治療失敗的主要原因,故正確評(píng)估及發(fā)掘潛在影響結(jié)腸癌患者預(yù)后的相關(guān)因素,篩選出術(shù)后復(fù)發(fā)、轉(zhuǎn)移的高?;颊卟⒓皶r(shí)進(jìn)行有效干預(yù)和治療,抑制結(jié)腸癌術(shù)后的局部復(fù)發(fā)和遠(yuǎn)處轉(zhuǎn)移將顯著提高手術(shù)療效以及患者的生存率、生存質(zhì)量。上皮-間質(zhì)轉(zhuǎn)化(EMT)與腫瘤的侵襲轉(zhuǎn)移密切相關(guān)[6],其在胃癌、肝癌、乳腺癌、肺癌等多種惡性腫瘤的侵襲轉(zhuǎn)移中的作用已得到公認(rèn)[7-8],在結(jié)直腸癌的復(fù)發(fā)、轉(zhuǎn)移中也起著關(guān)鍵性作用。本研究通過檢測(cè)接受手術(shù)治療并經(jīng)病理檢查確診的結(jié)腸癌患者術(shù)后標(biāo)本中E-鈣黏蛋白(E-cadherin)和波形蛋白(Vimentin)的表達(dá)情況,探討其與結(jié)腸癌相關(guān)臨床病理因素的關(guān)聯(lián)性及其對(duì)預(yù)后的影響,為結(jié)腸癌的綜合治療開辟一個(gè)新的突破口,提供新的治療思路。

        1 資料與方法

        1.1 一般資料 收集2009-01-01至2014-01-01于新疆醫(yī)科大學(xué)附屬腫瘤醫(yī)院胃腸外科行結(jié)腸癌根治術(shù)且術(shù)后病理檢查診斷明確的116例患者的結(jié)腸癌組織及其癌旁組織標(biāo)本。116例患者中男68例,女48例;漢族69例,維吾爾族47例;高分化腺癌32例,中分化腺癌57例,低分化腺癌27例。納入標(biāo)準(zhǔn):(1)均行結(jié)腸癌根治術(shù)的TNM分期Ⅲ期結(jié)腸癌患者;(2)術(shù)前未行任何放化療及其他藥物治療;(3)術(shù)前無其他的多原發(fā)腫瘤及遠(yuǎn)處轉(zhuǎn)移;(4)有確切的術(shù)后病理診斷;(5)病歷資料完整,有術(shù)后隨訪資料。排除標(biāo)準(zhǔn):(1)TNM分期Ⅰ、Ⅱ、Ⅳ期結(jié)腸癌患者;(2)術(shù)前經(jīng)新輔助放化療;(3)因結(jié)腸癌復(fù)發(fā)行第2次手術(shù)或行姑息性手術(shù);(4)非腫瘤因素死亡。TNM分期參照國(guó)際抗癌聯(lián)盟(UICC)和美國(guó)癌癥聯(lián)合會(huì)(AJCC)合作制訂的第7版腫瘤分期指南[9],依據(jù)2007年WHO結(jié)直腸癌病理分型標(biāo)準(zhǔn)評(píng)價(jià)組織學(xué)分類和分化程度[10]。

        本研究?jī)r(jià)值:

        上皮-間質(zhì)轉(zhuǎn)化(EMT)與腫瘤的侵襲轉(zhuǎn)移密切相關(guān),在結(jié)直腸癌、肝癌、肺癌等多種惡性腫瘤的原位浸潤(rùn)和侵襲轉(zhuǎn)移中發(fā)揮了重要作用,其在侵襲能力越強(qiáng)的組織中表達(dá)越明顯,所以本研究只納入了行結(jié)腸癌根治術(shù)且術(shù)后病理診斷明確的TNM分期Ⅲ期結(jié)腸癌患者,而未納入行相同治療的Ⅰ、Ⅱ期患者,所得結(jié)論真實(shí)可靠性強(qiáng)。且目前E-鈣黏蛋白(E-cadherin)和波形蛋白(Vimentin)的表達(dá)情況與結(jié)腸癌相關(guān)臨床病理因素的關(guān)聯(lián)性的報(bào)道很少,本研究進(jìn)一步完善了該方面的研究。

        1.2 試劑 DAB顯色試劑盒、免疫組織化學(xué)二抗均購(gòu)自北京中杉金橋生物技術(shù)有限公司。E-cadherin抗體和Vimentin抗體購(gòu)自福州邁新生物技術(shù)開發(fā)有限公司。

        1.3 免疫組織化學(xué)SP法檢測(cè)E-cadherin、Vimentin表達(dá)情況 取本院標(biāo)本庫(kù)中保存的新鮮結(jié)腸癌組織冷凍標(biāo)本,采用SP法按照免疫試劑盒(北京中杉金橋生物技術(shù)有限公司)說明書檢測(cè)結(jié)腸癌組織中E-cadherin、Vimentin表達(dá)情況。E-cadherin和Vimentin的陽性染色判定標(biāo)準(zhǔn)是細(xì)胞內(nèi)出現(xiàn)棕褐色顆粒。每張切片低倍顯微鏡下(×100)隨機(jī)選擇10個(gè)視野,高倍鏡下(×400)計(jì)數(shù)每個(gè)視野100個(gè)癌細(xì)胞中陽性細(xì)胞的百分比,取10個(gè)視野的平均百分比作為判定結(jié)果。對(duì)陽性細(xì)胞所占百分比進(jìn)行評(píng)分,陰性:0分,≤10%:1分,>10%~74%:2分,>74%:3分。染色強(qiáng)度評(píng)分:0分為無色,1分為淡黃色,2分為棕黃色,3分為棕褐色(對(duì)照背景著色判斷染色深淺)。兩者積分相乘,陰性(-):0分,陽性(+):0~5分,強(qiáng)陽性(++):6~9分。

        1.4 隨訪 術(shù)后第1年內(nèi)每3個(gè)月隨訪1次,1年以后每6個(gè)月隨訪1次,復(fù)查出現(xiàn)復(fù)發(fā)、轉(zhuǎn)移后仍然每3個(gè)月隨訪1次,采取門診或病房復(fù)查、電話等相結(jié)合的方式進(jìn)行隨訪,隨訪截止時(shí)間為2015-01-01。隨訪時(shí)間為4.1~64.0個(gè)月,中位隨訪時(shí)間為46.0個(gè)月。門診隨訪辦根據(jù)隨訪情況建立完整的住院患者隨訪個(gè)人檔案,其中8例患者因電話號(hào)碼更換失訪,還有1例因不配合拒絕隨訪,最終共107例患者獲得隨訪,隨訪率為92.2%(107/116)。記錄患者累積生存率(OS)及無病生存率(DFS)。

        1.5 統(tǒng)計(jì)學(xué)方法 采用SPSS 17.0統(tǒng)計(jì)軟件進(jìn)行數(shù)據(jù)處理。計(jì)數(shù)資料組間比較采用χ2檢驗(yàn);E-cadherin、Vimentin表達(dá)情況與臨床病理因素的關(guān)聯(lián)性應(yīng)用多因素Logistic回歸分析;采用Kaplan-Meier法繪制生存曲線,生存分析采用Log-rank檢驗(yàn)。以P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

        2 結(jié)果

        2.1 E-cadherin、Vimentin表達(dá)情況 116例患者結(jié)腸癌組織中E-cadherin的陽性表達(dá)率為79.3%(92/116)(見圖1-A、B,本文圖1彩圖見本刊官網(wǎng)www.chinagp.net電子期刊相應(yīng)文章),其中男55例,女37例;漢族55例,維吾爾族37例;高分化腺癌28例,中分化腺癌48例,低分化腺癌16例。 Vimentin的陽性表達(dá)率為15.5%(18/116)(見圖1-C、D),其中男10例,女8例;漢族12例,維吾爾族6例;高分化腺癌2例,中分化腺癌7例,低分化腺癌9例。

        2.2 E-cadherin、Vimentin表達(dá)情況與臨床病理因素的關(guān)聯(lián)性 癌胚抗原(CEA)、腫瘤直徑、脈管侵犯情況、分化程度、淋巴結(jié)轉(zhuǎn)移情況的E-cadherin陽性表達(dá)率比較,差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。腫瘤直徑、脈管侵犯情況、神經(jīng)侵犯情況、分化程度、淋巴結(jié)轉(zhuǎn)移情況的Vimentin陽性表達(dá)率比較,差異有統(tǒng)計(jì)學(xué)意義(P<0.05,見表1)。

        表1 E-cadherin、Vimentin表達(dá)情況與臨床病理因素的關(guān)聯(lián)性分析(n=116)

        Table1 Correlation of the expressions of E-cadherin and Vimentin with the clinicopathological factors of colon cancer

        臨床病理因素E-cadherin陽性 陰性 χ2值 P值 Vimentin陽性 陰性 χ2值 P值 年齡(歲)3.0010.0832.2840.131 <604571141 ≥604717757性別0.2470.6190.0830.774 男55131058 女3711840民族0.0170.8980.4560.499 漢族55141257 維吾爾族3710641CEA(μg/L)6.0970.0143.2950.069 ≤5496550 >543181348腫瘤直徑(cm)4.8660.0274.4700.035 ≤56110764 >531141134腫瘤位置0.3060.5800.1150.734 左半結(jié)腸4811851 右半結(jié)腸4413948脈管侵犯12.1020.0015.3460.021 有1512819 無77121079神經(jīng)侵犯0.4380.5084.4710.034 有145613 無78191285分化程度8.7570.0139.0890.011 高分化腺癌284230 中分化腺癌489750 低分化腺癌1611918淋巴結(jié)轉(zhuǎn)移4.4250.0355.7920.016 N1497452 N243171446

        注:CEA=癌胚抗原,E-cadherin=E-鈣黏蛋白,Vimentin=波形蛋白

        以E-cadherin、Vimentin表達(dá)情況為因變量,年齡、性別、民族、CEA、腫瘤直徑、腫瘤位置、脈管侵犯情況、神經(jīng)侵犯情況、分化程度、淋巴結(jié)轉(zhuǎn)移為自變量(賦值見表2),進(jìn)行多因素Logistic回歸分析結(jié)果顯示,CEA、脈管侵犯情況、分化程度與E-cadherin表達(dá)情況存在關(guān)聯(lián)性(P<0.05,見表3),脈管侵犯情況、神經(jīng)侵犯情況、分化程度與Vimentin表達(dá)情況存在關(guān)聯(lián)性(P<0.05,見表4)。

        2.3 E-cadherin、Vimentin表達(dá)情況與患者預(yù)后的關(guān)系 E-cadherin陽性表達(dá)、E-cadherin陰性表達(dá)患者的累積生存率(OS)及無病生存率(DFS)比較,差異有統(tǒng)計(jì)學(xué)意義(χ2值分別為5.080、10.837,P值分別為0.024、0.001,見圖2、3);Vimentin陽性表達(dá)、Vimentin陰性表達(dá)患者的OS及DFS比較,差異有統(tǒng)計(jì)學(xué)意義(χ2值分別為6.593、7.998,P值分別為0.010、0.005,見圖4、5)。

        表2 E-cadherin、Vimentin的表達(dá)情況與臨床病理因素關(guān)聯(lián)性的多因素Logistic回歸分析賦值表

        Table2 Assignment for multivariate Logistic regression analysis of the correlation between the expressions of E-cadherin and Vimentin with the clinicopathological factors of colon cancer

        變量賦值E-cadherin陽性=1,陰性=2Vimentin陽性=1,陰性=2年齡(歲)<60=1,≥60=2性別男性=1,女性=2民族漢族=1,維族=2CEA≤5=1,>5=2腫瘤直徑(cm)≤5=1,>5=2腫瘤位置左半結(jié)腸=1,右半結(jié)腸=2脈管侵犯是=1,否=2神經(jīng)侵犯是=1,否=2分化程度低分化腺癌=1,中分化腺癌=2,高分化腺癌=3淋巴結(jié)轉(zhuǎn)移N1=1,N2=2

        表3 E-cadherin表達(dá)情況與臨床病理因素關(guān)聯(lián)性的多因素Logistic回歸分析

        Table3 Multivariate Logistic regression analysis of the correlation between the expression of E-cadherin and the clinicopathological factors of colon cancer

        變量BSEWaldχ2值P值OR值(95%CI)CEA1.4450.5846.1360.0130.236(0.075,0.740)腫瘤直徑0.9760.5453.2060.0740.377(1.129,1.097)脈管侵犯1.2800.5814.8530.0283.596(1.152,11.230)分化程度0.9100.3815.7080.0172.485(1.178,5.243)淋巴結(jié)轉(zhuǎn)移0.4150.5810.5110.4750.660(0.211,2.061)

        表4 Vimentin表達(dá)情況與臨床病理因素關(guān)聯(lián)性的多因素Logistic回歸分析

        Table4 Multivariate Logistic regression analysis of the correlation between the expression of Vimentin and the clinicopathological factors of colon cancer

        變量BSEWaldχ2值P值OR值(95%CI)腫瘤直徑0.7150.6261.3060.2532.044(0.600,6.968)脈管侵犯1.4100.6434.8150.0280.244(0.069,0.860)神經(jīng)侵犯1.4870.6804.8780.0290.226(0.060,0.857)分化程度1.0590.4465.640.0180.347(0.145,0.831)淋巴結(jié)轉(zhuǎn)移0.5240.6880.5790.4471.688(0.438,6.503)

        圖2 E-cadherin陽性表達(dá)、E-cadherin陰性表達(dá)患者OS比較

        Figure2 Comparison of OS between E-cadherin positive and negative patients

        圖3 E-cadherin陽性表達(dá)、E-cadherin陰性表達(dá)患者DFS比較

        Figure3 Comparison of DFS between E-cadherin positive and negative patients

        注:A為E-鈣黏蛋白(E- cadherin) 陰性表達(dá),B為E- cadherin陽性表達(dá),C為波形蛋白(Vimentin)陰性表達(dá),D為Vimentin陽性表達(dá)

        圖1 E-cadherin與Vimentin在結(jié)腸癌組織中的表達(dá)情況(免疫組織化學(xué)SP法,×100)

        Figure1 Expression of E-cadherin and Vimentin in colon cancer tissues detected by immunohistochemistry with SP method

        圖4 Vimentin陽性表達(dá)、Vimentin陰性表達(dá)患者OS比較

        Figure4 Comparison of OS between Vimentin positive and negative patients

        圖5 Vimentin陽性表達(dá)、Vimentin陰性表達(dá)患者DFS比較

        Figure5 Comparison of DFS between Vimentin positive and negative patients

        3 討論

        結(jié)腸癌作為臨床消化道的常見、多發(fā)腫瘤,其發(fā)病率和病死率在我國(guó)呈現(xiàn)新的發(fā)展趨勢(shì),而新疆獨(dú)特的氣候因素及飲食結(jié)構(gòu)使之尤為突出[3]。趙化榮等[3]研究結(jié)果顯示,結(jié)直腸癌已成為新疆第3大惡性腫瘤。如若能夠提高早期檢出率,則將極大提高手術(shù)切除率,延長(zhǎng)患者生存時(shí)間,但早期結(jié)直腸癌患者缺乏特異性的臨床特征,待臨床癥狀出現(xiàn)后就診已處于中晚期,常用的腫瘤標(biāo)志物CEA、CA199等也均缺乏較好的特異性,因此,完善影響患者預(yù)后的危險(xiǎn)因素,有效干預(yù)、預(yù)防復(fù)發(fā)和轉(zhuǎn)移顯得尤為重要[11]。而腫瘤的侵襲轉(zhuǎn)移是一個(gè)多基因參與、多步驟、復(fù)雜、連續(xù)的過程,腫瘤增殖細(xì)胞之間黏附分子減少導(dǎo)致黏附力減弱和運(yùn)動(dòng)增強(qiáng)是腫瘤細(xì)胞發(fā)生侵襲轉(zhuǎn)移的基礎(chǔ),其中EMT在這個(gè)過程中發(fā)揮重要作用,是腫瘤侵襲轉(zhuǎn)移的關(guān)鍵步驟[12]。作為EMT過程的標(biāo)志性蛋白,E-cadherin表達(dá)水平的異常降低、Vimentin表達(dá)水平的升高被認(rèn)為是啟動(dòng)EMT的主要分子標(biāo)識(shí)[13]。E-cadherin是一種鈣離子依賴的跨膜糖蛋白,廣泛存在于上皮細(xì)胞表面,參與形成細(xì)胞間的連接、維持細(xì)胞的完整性、介導(dǎo)細(xì)胞間的信號(hào)傳導(dǎo),其功能的發(fā)揮有賴于與連接素共同構(gòu)成復(fù)合體[14]。在E-cadherin功能正常的情況下腫瘤細(xì)胞相互黏附,若黏附分子E-cadherin表達(dá)水平降低,則會(huì)導(dǎo)致腫瘤細(xì)胞間連接解體[15],使腫瘤細(xì)胞失去極性,同時(shí)還參與細(xì)胞基底膜、胞外基質(zhì)的降解和破壞,從而破壞組織學(xué)屏障,為腫瘤細(xì)胞侵襲做好準(zhǔn)備[16]。本研究發(fā)現(xiàn)116例結(jié)腸癌組織中E-cadherin陰性表達(dá)24例,陰性表達(dá)率為 20.7%,且多出現(xiàn)在腫瘤分化程度低、無神經(jīng)侵犯、CEA表達(dá)水平高的腫瘤細(xì)胞中。本研究結(jié)果顯示,CEA、脈管侵犯情況、分化程度與E-cadherin表達(dá)情況存在關(guān)聯(lián)性,E-cadherin的低表達(dá)增加了腫瘤細(xì)胞侵襲性,使其浸潤(rùn)深度加深,TNM分期增高,侵及血管及淋巴管的機(jī)會(huì)增加,故術(shù)后結(jié)腸癌組織中脈管侵犯率相應(yīng)增加,腫瘤細(xì)胞表面的標(biāo)志物或者腫瘤細(xì)胞直接進(jìn)入血液系統(tǒng)和淋巴系統(tǒng),導(dǎo)致血液中CEA水平明顯增高,這與相關(guān)研究結(jié)果相一致[17-19]。KARAMITOPOULOU等[20]的研究結(jié)果顯示,隨著腫瘤分化程度下降(尤其黏液腺癌和印戒細(xì)胞癌)、遠(yuǎn)處轉(zhuǎn)移,E-cadherin表達(dá)水平逐漸降低,可見在結(jié)腸癌的進(jìn)展過程中,E-cadherin 的低表達(dá)使腫瘤細(xì)胞間的黏附作用降低,細(xì)胞活動(dòng)性增強(qiáng),所以腫瘤細(xì)胞易于脫落形成單個(gè)轉(zhuǎn)移細(xì)胞并在局部浸潤(rùn)或侵入脈管內(nèi)而發(fā)生遠(yuǎn)處轉(zhuǎn)移,E-cadherin 表達(dá)水平降低是腫瘤細(xì)胞惡性度高,侵襲擴(kuò)散能力增強(qiáng)的一個(gè)重要危險(xiǎn)因素。

        Vimentin作為間葉組織表達(dá)的一種中間絲蛋白,生物學(xué)功能是維持細(xì)胞器極性,形成細(xì)胞骨架,促進(jìn)細(xì)胞黏附及移行[21]。病理情況下,細(xì)胞骨架的角蛋白轉(zhuǎn)變成Vimentin,細(xì)胞骨架蛋白重排,形成細(xì)胞-基質(zhì)黏附結(jié)構(gòu),細(xì)胞表型發(fā)生改變,變異細(xì)胞運(yùn)動(dòng)能力增強(qiáng)[22]。大量研究證明Vimentin在多種惡性腫瘤(如肺癌、胃癌、前列腺癌等)中表達(dá),且與腫瘤細(xì)胞的分化、侵襲和轉(zhuǎn)移密切相關(guān)[7-8]。Vimentin表達(dá)水平升高使腫瘤細(xì)胞浸潤(rùn)和轉(zhuǎn)移能力上升,導(dǎo)致腫瘤的侵襲性生長(zhǎng)與轉(zhuǎn)移,促進(jìn)了腫瘤惡性進(jìn)展[23-24]。本研究結(jié)果顯示116例結(jié)腸癌組織中Vimentin陽性表達(dá)18例,陽性表達(dá)率為15.5%,Vimentin陽性表達(dá)多出現(xiàn)在合并有分化程度低、腫瘤直徑大于5 cm、淋巴結(jié)轉(zhuǎn)移、神經(jīng)侵犯、脈管侵犯的患者術(shù)后標(biāo)本組織中,多因素Logistic回歸分析提示神經(jīng)侵犯情況、脈管侵犯情況、分化程度與Vimentin表達(dá)情況存在關(guān)聯(lián)性。SUN等[25]認(rèn)為E-cadherin 的陰性表達(dá)和Vimentin的陽性表達(dá)也多見于侵襲性腫瘤且伴有淋巴結(jié)轉(zhuǎn)移的患者,而本研究尚未發(fā)現(xiàn)E-cadherin及Vimentin的異常表達(dá)與淋巴結(jié)轉(zhuǎn)移有關(guān),究其原因,考慮與本研究標(biāo)本例數(shù)較少,患者年齡、癌組織分化程度、病理分期的例數(shù)差異較大有關(guān),有待擴(kuò)大樣本量進(jìn)一步研究[26]。

        目前公認(rèn)的影響結(jié)腸癌預(yù)后的危險(xiǎn)因素主要包括TNM分期、分化程度、脈管侵犯情況、放化療等,復(fù)發(fā)、轉(zhuǎn)移則是術(shù)后治療成功與否的關(guān)鍵,而關(guān)于E-cadherin和Vimentin對(duì)結(jié)腸癌患者預(yù)后的影響,目前學(xué)術(shù)界尚無統(tǒng)一意見[27-28]。易呈浩等[29]對(duì)1 368例結(jié)直腸癌患者的研究結(jié)果顯示,隨著結(jié)腸癌腫瘤原發(fā)灶的浸潤(rùn)深度增加,尤其是原發(fā)腫瘤浸出漿膜后,患者DFS和OS顯著下降,且低分化腺癌常顯示出較高的惡性程度,特別是黏液腺癌和印戒細(xì)胞癌,預(yù)后比一般腺癌差得多。CHENG等[30]對(duì)2 042例結(jié)直腸癌患者的研究結(jié)果提示,分化程度越低,腫瘤細(xì)胞侵襲性越強(qiáng),侵犯范圍越深,TNM分期越高,更容易復(fù)發(fā)、轉(zhuǎn)移,是影響患者預(yù)后的獨(dú)立危險(xiǎn)因素。相關(guān)研究結(jié)果表明,結(jié)腸癌組織中E-cadherin低表達(dá)和Vimentin表達(dá)水平的異常升高,與惡性腫瘤的分化程度、局部侵襲及脈管、神經(jīng)的侵犯密切相關(guān),進(jìn)而影響結(jié)腸癌患者的預(yù)后[31]。本研究結(jié)果顯示,E-cadherin、Vimentin為影響結(jié)腸癌患者預(yù)后的危險(xiǎn)因素,E-cadherin和Vimentin的表達(dá)情況在OS及DFS上存在明顯差異,與上述研究結(jié)果一致。故檢測(cè)E-cadherin、Vimentin表達(dá)情況能評(píng)估腫瘤細(xì)胞發(fā)生轉(zhuǎn)移的潛在危險(xiǎn)性,有助于對(duì)結(jié)直腸癌腫瘤細(xì)胞增殖能力、分化程度、惡性擴(kuò)散潛能及患者預(yù)后進(jìn)行判斷。

        總之,CEA、脈管侵犯情況、分化程度與E-cadherin表達(dá)情況存在關(guān)聯(lián)性,脈管侵犯情況、神經(jīng)侵犯情況、分化程度與Vimentin表達(dá)情況存在關(guān)聯(lián)性;E-cadherin、Vimentin為結(jié)腸癌患者預(yù)后的重要影響因素,其提示E-cadherin和Vimentin可以作為判斷結(jié)腸癌患者預(yù)后及評(píng)估有無遠(yuǎn)處轉(zhuǎn)移的重要指標(biāo),為靶向結(jié)腸癌EMT的生物治療打下理論基礎(chǔ)[32],為結(jié)腸癌的綜合治療開辟一個(gè)新的突破口,提供新的治療思路。

        作者貢獻(xiàn):曾祥岳進(jìn)行研究設(shè)計(jì)與實(shí)施、資料收集整理、撰寫論文并對(duì)文章負(fù)責(zé);孫振強(qiáng)、王琦三、葛磊進(jìn)行研究實(shí)施與評(píng)估、資料收集;王海江進(jìn)行質(zhì)量控制及審校。

        本文無利益沖突。

        本研究不足:

        本研究是回顧性的小樣本研究,沒有預(yù)期的設(shè)計(jì)和匹配,可能存在潛在的偏倚和限制,本研究結(jié)論有待通過一項(xiàng)前瞻性、大樣本、多中心的隨機(jī)臨床試驗(yàn)來驗(yàn)證。

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        (本文編輯:崔莎)

        CorrelationoftheExpressionsofE-cadherinandVimentinwiththeClinicopathologicalFactorsandPrognosisofColonCancer

        ZENGXiang-yue1,SUNZhen-qiang2,WANGQi-san1,GELei1,WANGHai-jiang1*

        1.DepartmentofGastrointestinalSurgery,AffiliatedTumorHospitalofXinjiangMedicalUniversity,Urumqi830011,China2.DepartmentofAnorectalSurgery,theFirstAffiliatedHospitalofZhengzhouUniversity,Zhengzhou450000,China

        *Correspondingauthor:WANGHai-jiang,Professor,Chiefphysician;E-mail:wanghaijiang@medmail.com.cn

        ObjectiveThe development of tumor is a complex pathophysiological process involving many interrelated factors.The purpose of this study was to investigate the correlation of the expressions of epithelial mesenchymal transition(EMT) markers(E-cadherin and Vimentin) with the clinicopathological factors and prognosis of colon cancer.MethodsImmunohistochemistry with SP method was performed to detect the expressions of E-cadherin and Vimentin in the colon cancer and adjacent tissue specimens taken from 116 stage Ⅲ colon cancer patients who underwent radical resection of colon cancer in Department of Gastrointestinal Surgery of Affiliated Tumor Hospital of Xinjiang Medical University from January 1,2009 to January 1,2014 and pathologically diagnosed as colon cancer postoperatively.The patients were followed up by outpatient or ward review,telephone and so on with a deadline of January 1st 2015.Totaled 92.2% of the participants(107/116) were followed up for 4.1-63.0 months with a median follow-up of 46.0 months.Overall survival(OS) and disease-free survival(DFS) of patients were recored.Multivariate Logistic regression analysis was performed to investigate the correlation of the expressions of E-cadherin and Vimentin with the clinicopathological factors of colon cancer.Kaplan-Meier survival analysis was conducted to estimate the survival function.Survival rate was compared with the Log-rank test.ResultsThe positive rate of E-cadherin and Vimentin expressions in all the participants was 79.3%(92/116),15.5%(18/116),respectively.The positive rates of E-cadherin of carcinoembryonic antigen(CEA),tumor diameter,vascular invasion,differentiation degree of colon cancer cells,lymphatic metastasis showed significant differences(P<0.05).The positive rates of Vimentin of tumor diameter,vascular invasion,perineural invasion,differentiation degree of colon cancer cells,lymphatic metastasis showed significant differences(P<0.05).Multivariate Logistic regression analysis found that CEA,vascular invasion and differentiation degree of colon cancer cells were significantly associated with the expression of E-cadherin(P<0.05).Vascular invasion,nerve invasion and differentiation degree of colon cancer cells were significantly associated with the expression of vimentin(P<0.05).Notable differences were found in the cumulative OS and DFS between E-cadherin positive group and negative group(P<0.05).The cumulative OS and DFS differed significantly between Vimentin positive group and negative group(P<0.05).ConclusionCEA,vascular invasion and the differentiation degree of colon cancer cells are the associated factors for the expression of E-cadherin.Vascular invasion,nerve invasion and the differentiation degree of colon cancer cells are the associated factors for the expression of Vimentin.E-cadherin and Vimentin are important adverse prognostic factors in colon cancer.

        Colonic neoplasms;Epithelial-mesenchymal transition;Cadherins;Vimentin;Prognosis

        新疆維吾爾自治區(qū)自然科學(xué)基金(201233146-13)

        R 735.35

        A

        10.3969/j.issn.1007-9572.2017.27.008

        2017-02-18;

        2017-07-28)

        1.830011 新疆烏魯木齊市,新疆醫(yī)科大學(xué)附屬腫瘤醫(yī)院胃腸外科

        2.450000 河南省鄭州市,鄭州大學(xué)第一附屬醫(yī)院肛腸外科

        *通信作者:王海江,教授,主任醫(yī)師;E-mail:wanghaijiang@medmail.com.cn

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