惡性間葉腫瘤的間葉-上皮表型轉(zhuǎn)化研究進(jìn)展*

楊吉龍 杜曉玲 王國文 楊 蘊(yùn)

惡性間葉腫瘤的間葉-上皮表型轉(zhuǎn)化研究進(jìn)展*

楊吉龍①杜曉玲②王國文①楊 蘊(yùn)①

相對(duì)于上皮性腫瘤的上皮-間葉表型轉(zhuǎn)化（epithelial to mesenchymal transition，EMT）及間葉-上皮表型轉(zhuǎn)化（mesenchymal to epithelial transition，MET）的研究，惡性間葉性腫瘤中MET相關(guān)研究較少。MET在分子水平上反映為上皮性標(biāo)志物如E-鈣粘素E-cadherin的上調(diào)和間葉性標(biāo)志物如波形蛋白Vimentin的下調(diào)，其過程涉及始動(dòng)信號(hào)、轉(zhuǎn)錄因子調(diào)節(jié)、表面標(biāo)志物的改變、信號(hào)通路改變等多個(gè)環(huán)節(jié)。本文概述了惡性間葉腫瘤中與MET緊密相關(guān)的TGF-β等始動(dòng)因素、SNAI等關(guān)鍵轉(zhuǎn)錄因子、miRNA調(diào)節(jié)因素對(duì)重要細(xì)胞信號(hào)通路等影響及MET對(duì)腫瘤的演進(jìn)及轉(zhuǎn)歸的影響等方面的研究，為針對(duì)MET的臨床應(yīng)用奠定基礎(chǔ)。

肉瘤 間葉-上皮表型轉(zhuǎn)化 E-鈣粘素 靶向治療

細(xì)胞的上皮-間葉表型轉(zhuǎn)化（epithelial to mesenchymal transition，EMT）和間葉-上皮表型轉(zhuǎn)化（mesenchymal to epithelial transition，MET）在胚胎發(fā)育和器官形成方面發(fā)揮重要作用［1］。越來越多的證據(jù)表明MET在惡性腫瘤的演進(jìn)中具有關(guān)鍵作用［2-4］。在上皮性腫瘤中EMT的上皮細(xì)胞喪失細(xì)胞之間的粘附分子，細(xì)胞表型發(fā)生了轉(zhuǎn)換、極性改變、細(xì)胞骨架重塑，在乳腺癌等惡性腫瘤的侵襲轉(zhuǎn)移中起關(guān)鍵作用且與腫瘤的預(yù)后不良相關(guān)［5-7］。肉瘤中MET研究較少，MET的臨床意義及其相關(guān)分子機(jī)制如始動(dòng)因素、轉(zhuǎn)錄因子、調(diào)節(jié)因素、對(duì)細(xì)胞形態(tài)及功能的影響、對(duì)重要細(xì)胞信號(hào)通路的影響等問題尚需系統(tǒng)且深入的探討。同時(shí)，MET的啟動(dòng)、發(fā)生、后續(xù)反應(yīng)是一個(gè)復(fù)雜的通路，其中有多個(gè)位點(diǎn)、步驟、分子可能是潛在的治療靶點(diǎn)或有用的生物標(biāo)記物。因此，對(duì)MET的深入了解有助于明確肉瘤的發(fā)病及演進(jìn)機(jī)制，并有助于發(fā)現(xiàn)或篩選新的預(yù)防方法及特異性治療靶點(diǎn)。

1 MET

越來越多的證據(jù)表明與EMT相反的MET過程在惡性腫瘤的演進(jìn)中起關(guān)鍵作用［2-4］。在惡性腫瘤中，可能存在兩種類型的MET且與腫瘤的演進(jìn)相關(guān)：一種MET是癌細(xì)胞轉(zhuǎn)移過程中在遠(yuǎn)隔部位形成轉(zhuǎn)移病灶時(shí)發(fā)生的表型轉(zhuǎn)變，另一種是肉瘤中間葉源性細(xì)胞向上皮性細(xì)胞的分化或者獲得上皮樣表型［8］。在第一種類型的MET中，MET促進(jìn)了癌細(xì)胞在遠(yuǎn)處轉(zhuǎn)移部位形成與原發(fā)病相似腫瘤的過程。在這個(gè)過程中，具有間葉表型特征的轉(zhuǎn)移性癌細(xì)胞克服了局部組織的多重障礙而重新獲得上皮樣表型［1，9］。有研究顯示在乳腺癌及膀胱癌等病變中，對(duì)比原發(fā)灶和轉(zhuǎn)移灶發(fā)現(xiàn)上皮標(biāo)志物鈣黏著蛋白E-cadherin表達(dá)先缺失繼而上調(diào)，即EMT和MET過程的轉(zhuǎn)換［10-12］。

相對(duì)于上皮性腫瘤中MET的研究，第二種類型的MET即間葉腫瘤細(xì)胞出現(xiàn)上皮樣表型的報(bào)道較少。Yang等［13］在體外實(shí)驗(yàn)發(fā)現(xiàn)軟骨肉瘤細(xì)胞系SW1353呈現(xiàn)出類似上皮組織的極性改變，表達(dá)E-cadherin、上皮橋粒斑蛋白和胞質(zhì)緊密粘連蛋白ZO-1，這種改變與SW細(xì)胞系的c-Met原癌基因有關(guān)。在滑膜肉瘤中SYT-SSX1融合蛋白通過SNAI1和Slug（SNAI2）的調(diào)節(jié)可誘導(dǎo)MET［14］。平滑肌肉瘤中抑制Slug表達(dá)也可引起E-cadherin表達(dá)的顯著增加，同時(shí)細(xì)胞形態(tài)向圓形變化，細(xì)胞增殖、侵襲及遷移能力減弱，即發(fā)生MET［15］。Saulnier等［16］用體外實(shí)驗(yàn)也證實(shí)脂肪間葉細(xì)胞經(jīng)MET可分化為肝細(xì)胞樣細(xì)胞，形態(tài)和功能上類似肝細(xì)胞及間葉細(xì)胞表型，N-cadherin和Vimentin降低，E-cadherin表達(dá)升高，并認(rèn)為和SNAI1和TWIST下調(diào)密切相關(guān)。

2 MET的分子標(biāo)記

MET時(shí)細(xì)胞喪失運(yùn)動(dòng)性并重獲細(xì)胞之間的密切聯(lián)系，在分子水平上反映為上皮標(biāo)志物的上調(diào)和間葉標(biāo)志物的下調(diào)。典型的上皮細(xì)胞標(biāo)志物如E-鈣粘蛋白、廣譜角蛋白Pan-CK、EMA、β-鈣粘蛋白、CD44和CD34等，間葉標(biāo)志物包括波形蛋白Vimentin和神經(jīng)鈣黏著蛋白N-cadherin、α-平滑肌肌動(dòng)蛋白（α-SMA），結(jié)蛋白Desmin，MSA和其他特殊標(biāo)記物如NSE，F(xiàn)N和SYN等。MET中最重要的標(biāo)志物是E-cadherin，它是界定上皮細(xì)胞的標(biāo)志之一，其編碼基因CDH1被公認(rèn)為癌浸潤轉(zhuǎn)移抑制基因［17］。EMT時(shí)，E-cadherin表達(dá)下調(diào)，細(xì)胞連接及骨架改變引發(fā)細(xì)胞極性改變，進(jìn)而促進(jìn)癌細(xì)胞的浸潤和轉(zhuǎn)移［18］。E-cadherin表達(dá)下調(diào)可以視為EMT的原因和結(jié)果，也是EMT的分子標(biāo)志。同樣的，在轉(zhuǎn)移灶中癌細(xì)胞再次表達(dá)E-cadherin是癌MET的重要標(biāo)志［2］。N-鈣粘蛋白是一種跨膜糖蛋白，其表達(dá)導(dǎo)致E-鈣粘蛋白的表達(dá)下調(diào)從而增加癌細(xì)胞的運(yùn)動(dòng)以及遷移。波形蛋白Vimentin是一種通常表達(dá)在間充質(zhì)來源的細(xì)胞Ⅲ型中間纖維，有報(bào)道顯示其表達(dá)涉及胚胎發(fā)育及傷口愈合及腫瘤的侵襲。因此，N-鈣粘蛋白和波形蛋白被認(rèn)為是典型的間葉表型標(biāo)志物［4］。需要強(qiáng)調(diào)的是，盡管肉瘤中有MET過程發(fā)生，間葉性腫瘤細(xì)胞獲得E-鈣粘蛋白和β-鈣粘蛋白等上皮樣表型標(biāo)記的增加，但在多數(shù)肉瘤細(xì)胞中典型的間葉標(biāo)志物如Vimentin等仍然占主導(dǎo)地位。

3 肉瘤中MET發(fā)生過程及其機(jī)制

作為EMT和MET的關(guān)鍵指標(biāo)之一，E-cadherin的在腫瘤的進(jìn)展中起關(guān)鍵作用，其功能喪失會(huì)增加腫瘤的侵襲性［2，4，14，19-21］。有文獻(xiàn)顯示TGF-β、AKT等信號(hào)通路異常、融合基因表達(dá)產(chǎn)物如SYT-SXX、小RNA如miR-30的調(diào)節(jié)等因素對(duì)MET有調(diào)節(jié)或者啟動(dòng)作用［14，22-24］。在MET中，與E-cadherin轉(zhuǎn)錄有關(guān)的因素如若干鋅指同系物家族（SNAI1和Slug）、堿性螺旋-環(huán)-螺旋家族（E47和TWIST）、ZEB家族（ZEB1、ZEB2）等被認(rèn)為是調(diào)節(jié)MET的關(guān)鍵分子［15］。轉(zhuǎn)錄因子SNAI、ZEB、E47及KLF8直接抑制E-Cadherin的轉(zhuǎn)錄，如SNAI1和Slug可與E-cad啟動(dòng)子的E-box基序結(jié)合直接抑制E-cadherin的轉(zhuǎn)錄［25］，而TWIST、Goosecoid、E2.2及FOXC2則間接抑制E-cadherin的轉(zhuǎn)錄［1］?；と饬鲋腥诤系鞍譙YT-SSX1和SYT-SSX2可以克服SNAI1/Slug介導(dǎo)的E-cadherin轉(zhuǎn)錄抑制，從而促進(jìn)E-cadherin的表達(dá)而出現(xiàn)上皮樣分化［14，20］。因此，MET的機(jī)制可能是上行信號(hào)如TGF-β、SYT-SSX等因素誘導(dǎo)或者調(diào)節(jié)與E-鈣粘蛋白轉(zhuǎn)錄緊密相關(guān)的轉(zhuǎn)錄因子，增加E-鈣粘蛋白的表達(dá)，從而誘導(dǎo)細(xì)胞出現(xiàn)上皮樣表型。

4 肉瘤中MET的始動(dòng)信號(hào)

肉瘤中MET發(fā)生的始動(dòng)信號(hào)包括由生長因子受體如血小板衍生生長因子受體（PDGFR）、成纖維細(xì)胞生長因子受體（FGFR）、c-Met、轉(zhuǎn)化生長因子β-1（TGF-β1）、胰島素相關(guān)的生長因子1受體（IGF1R）等介導(dǎo)的生長信號(hào)等［3，6，26-28］。除了這些，MET的過程中其他幾個(gè)啟動(dòng)信號(hào)已被證明如SYT-SSX融合蛋白、腎母細(xì)胞瘤蛋白WT1、骨形態(tài)發(fā)生蛋白7（BMP7）、WNT4、細(xì)胞骨架蛋白formin IV154-157、自分泌運(yùn)動(dòng)因子/磷酸葡萄糖異構(gòu)酶（autocrine motility factor/ phosphoglucose isomerase，AMF/PGI）和Wnt受體低密度脂蛋白受體相關(guān)蛋白5（LRP5）等。

在滑膜肉瘤中融合蛋白SYT-SSX1和SYT-SSX2克服了SNAI1/Slug介導(dǎo)的E-cadherin轉(zhuǎn)錄抑制，從而誘導(dǎo)間葉細(xì)胞的上皮表型分化［14］。腎個(gè)體的發(fā)育是個(gè)很好描述MET的過程，這個(gè)過程中腎母細(xì)胞瘤蛋白WT1、骨形態(tài)發(fā)生蛋白7（BMP7）、WNT4和細(xì)胞骨架蛋白formin IV154-157等幾個(gè)基因是誘導(dǎo)MET的重要因素［1，29］。作為參與葡萄糖代謝一種多功能酶，AMF/PGI的沉默可導(dǎo)致人肺纖維肉瘤細(xì)胞出現(xiàn)MET且惡性度降低，抑制了AMF/PG的人骨肉瘤細(xì)胞系MG-63和小鼠骨肉瘤細(xì)胞系LM8出現(xiàn)上皮樣表型且有生長、運(yùn)動(dòng)和侵襲能力的下降［30］。LRP5在骨肉瘤中高表達(dá)且與相對(duì)較低的轉(zhuǎn)移率和無病生存率相關(guān)［27］?？扇苄訪RP5（sLRP5）的轉(zhuǎn)染導(dǎo)致Saos-2骨肉瘤細(xì)胞中E-鈣粘蛋白顯著上調(diào)和N-鈣粘蛋白下調(diào)，且與SNAI1/Slug下調(diào)有關(guān)，增加的E-cadherin主要出現(xiàn)在細(xì)胞間接觸的邊界，與E-cadherin介導(dǎo)的抑制腫瘤侵襲和轉(zhuǎn)移相關(guān)聯(lián)［27］。

5 MET相關(guān)的轉(zhuǎn)錄因子

在EMT及MET過程中的關(guān)鍵分子包括生長因子如（TGF-β，Wnts）、轉(zhuǎn)錄因子（SNAIs，LEF，nuclear β-catenin）、細(xì)胞-細(xì)胞間的分子粘合分子（鈣黏著蛋白cadherins，連環(huán)蛋白catenins）和細(xì)胞-細(xì)胞外粘附基質(zhì)（ECM）的粘附分子（整合素integrins，焦接觸蛋白focal contact proteins，細(xì)胞外基質(zhì)蛋白）、細(xì)胞骨架調(diào)節(jié)劑（Rho家族）和胞外蛋白酶（基質(zhì)金屬蛋白酶MMPs，纖維蛋白溶酶原活化劑PIAs）等［1-4，6，9，21，26-28］。這些分子里，轉(zhuǎn)錄因子的作用最強(qiáng)烈和直接［3，7，9，14，19，23，31-32］。MET主要涉及的轉(zhuǎn)錄因子包括SNAI1、Slug、E47、TWIST、ZEB1及ZEB2等。在上皮性惡性腫瘤的進(jìn)展中，E-Cadherin不同于其他的抑癌基因，其缺失與再表達(dá)不是取決于不可逆轉(zhuǎn)的基因缺失或者突變，調(diào)節(jié)其表達(dá)的機(jī)制是可逆的［33］。轉(zhuǎn)錄因子SNAIs、ZEB、E47及KLF8直接抑制E-Cadherin的轉(zhuǎn)錄，而Twist、Goosecoid、E2.2及Foxc2間接抑制E-Cadherin轉(zhuǎn)錄［1］。其中SNAI1和Slug可與E-cad啟動(dòng)子E-box基序結(jié)合直接抑制E-cad轉(zhuǎn)錄，活化的Akt通過GSK-3β磷酸化穩(wěn)定核β-catenin，后者作為中介也可激活Slug，從而抑制E-cad表達(dá)。反之，則誘導(dǎo)MET發(fā)生［25］。SIP1也是針對(duì)E2盒上的E-Cadherin的啟動(dòng)子的一種鋅指轉(zhuǎn)錄因子，這些轉(zhuǎn)錄因子參與上皮或間充質(zhì)細(xì)胞分化過程［4，21，31］。

6 MET相關(guān)miRNA

雖然已經(jīng)明確miR-200家族可以調(diào)節(jié)EMT，其他miRNA也參與了ETM及MET的調(diào)節(jié)［34］。如miR-138通過直接作用于波形蛋白mRNA、直接作用于ZEB和作為EZH2的表觀遺傳調(diào)節(jié)因子這三種不同的途徑調(diào)節(jié)EMT［35］。一些miRNA能夠直接調(diào)節(jié)E-cadherin的表達(dá)而調(diào)節(jié)MET，一些miRNA可以通過調(diào)節(jié)轉(zhuǎn)錄因子及MET相關(guān)信號(hào)通路進(jìn)而調(diào)節(jié)E-cadherin的表達(dá)［36］。miRNA的些調(diào)節(jié)過程中有的需要初始或上游信號(hào)，而有的是獨(dú)立于上游信號(hào)。最重要的是miRNA的這些調(diào)節(jié)功能在腫瘤的進(jìn)展過程中非常重要，因而可以作為潛在的治療靶點(diǎn)。

與MET相關(guān)的miRNA包括miR-302-367、miR-30、miR-9、miR-23b、miR-29c、miR-194及miR-101［8］。miRNA簇302-367作用于TGF-β受體2，促進(jìn)E-Cadherin的表達(dá)，誘導(dǎo)多能干細(xì)胞的產(chǎn)生效率并促進(jìn)間充質(zhì)細(xì)胞到上皮細(xì)胞變化必要的集落形成［37］。miR-30通過直接靶向作用于SNAI1 mRNA的3'-UTR進(jìn)而負(fù)性調(diào)節(jié)SNAI1的表達(dá)［38］。在黑色素瘤中miRNA-9通過抑制NF-κB1-SNAI1途徑上調(diào)E-Cadherin蛋白并誘導(dǎo)MET。miR-23bmiR-29cmiR-194通過恢復(fù)E-Cadherin和減少波形蛋白Vimentin表達(dá)而誘導(dǎo)MET［39］。miR-101導(dǎo)致內(nèi)源性EZH2的降解和并恢復(fù)E-鈣粘蛋白的細(xì)胞膜定位［40］。

7 具有上皮樣表型改變的肉瘤

目前已經(jīng)在滑膜肉瘤、平滑肌肉瘤等多個(gè)軟組織肉瘤中有報(bào)道顯示上皮細(xì)胞樣分化或者上皮樣表型的出現(xiàn)，且在這些腫瘤的進(jìn)展和預(yù)后中有重要作用［4］。如在滑膜肉瘤中E-cadherin和β-catenin的表達(dá)降低和核β-連環(huán)蛋白的異常表達(dá)是滑膜肉瘤不良預(yù)后因素，同樣在中國滑膜肉瘤樣本中E-cadherin和β-catenin的表達(dá)與其上皮分化相關(guān)，E-鈣粘蛋白和β-catenin的表達(dá)減少提示其有潛在的高復(fù)發(fā)或轉(zhuǎn)移風(fēng)險(xiǎn)且預(yù)后較差。在人平滑肌肉瘤細(xì)胞系SK-LMS-1中抑制Slug表達(dá)可引起E-cadherin表達(dá)顯著增加，同時(shí)細(xì)胞形態(tài)向圓形變化，細(xì)胞增殖、侵襲及遷移能力減弱，即發(fā)生MET［15］。在人平滑肌肉瘤組織中，檢測(cè)到E-鈣粘蛋白、EMA及CK等上皮樣標(biāo)記的表達(dá)，且與平滑肌肉瘤患者較長的生存期顯著相關(guān)［4］。上皮樣肉瘤為來源組織不明的罕見間葉腫瘤，腫瘤細(xì)胞顯示主要是上皮分化的多向分化，表型為上皮和間葉標(biāo)記物的表達(dá)如細(xì)胞角蛋白，EMA，波形蛋白和CD34［41］。大多數(shù)上皮樣肉瘤強(qiáng)烈表達(dá)鈣粘素，這可能有助于形成他們的上皮樣外觀，但是由于缺乏E-鈣粘蛋白表達(dá)，這些腫瘤僅顯示了不完整的上皮細(xì)胞分化［42］。透明細(xì)胞肉瘤有時(shí)可能因顯示上皮樣外觀而被誤診為其他軟組織腫瘤如上皮樣平滑肌肉瘤及上皮樣肉瘤等［60］，但其細(xì)胞角蛋白、EMA、結(jié)蛋白、肌特異性肌動(dòng)蛋白（MSA）等標(biāo)記是缺失的。透明細(xì)胞肉瘤和惡性黑色素瘤依靠免疫組化染色是很難區(qū)分的，這在一定程度上提示他們可能共享了上皮細(xì)胞的分化模式［43］。

在常見原發(fā)性骨惡性腫瘤如Ewing肉瘤/原始神經(jīng)外胚層腫瘤（ES/PNET）、骨肉瘤、脊索瘤等病變中有報(bào)道顯示上皮樣表型改變。ES/PNET因經(jīng)常表達(dá)細(xì)胞角蛋白CK而提示其有上皮細(xì)胞分化［44］。Schuetz等［44］研究了30例ES/PNETs結(jié)果發(fā)現(xiàn)，盡管E-鈣粘蛋白為陰性，但緊密連接的標(biāo)記物如claudin-1、ZO-1和occludin等高表達(dá)，提示在ES/PNET中形成緊密連接，從而提示ES/PNET局部發(fā)生了上皮細(xì)胞分化。在骨肉瘤中上皮鈣粘蛋白標(biāo)記物-11（CDH11）的表達(dá)及AMF/PGI干擾實(shí)驗(yàn)的結(jié)果提示MET的存在，且與患者的存活顯著相關(guān)［45］。Niinaka等［30］報(bào)道了人類和小鼠的骨肉瘤細(xì)胞系中AMF/PGI的沉默誘導(dǎo)MET的發(fā)生，主要體現(xiàn)在E-鈣粘蛋白和細(xì)胞角蛋白表達(dá)上調(diào)和Vimentin的下調(diào)。脊索瘤是一種比較少見的骨腫瘤，據(jù)報(bào)道脊索瘤頻繁表達(dá)多種粘附分子和上皮細(xì)胞標(biāo)記物如角蛋白、EMA、血管細(xì)胞粘附分子VCAM、CD44、N-鈣粘蛋白和E-鈣粘蛋白等，提示腫瘤細(xì)胞可能通過上皮分化特征性的細(xì)胞-細(xì)胞相互作用機(jī)制而生長［46-48］。此外，Saad和Collins表明脊索瘤的E-cadherin的表達(dá)與腫瘤復(fù)發(fā)、無病生存期和生存率顯著相關(guān)，可以預(yù)測(cè)兒童的脊索瘤的預(yù)后［49］。Triana等［50］報(bào)道在脊索瘤中降低E-Cadherin表達(dá)及提高N-Cadherin的表達(dá)可能會(huì)將其從侵襲性較低的腫瘤轉(zhuǎn)變?yōu)榍忠u性更強(qiáng)的腫瘤表型。

8 肉瘤MET的臨床應(yīng)用

在上皮性腫瘤中，MET多發(fā)在轉(zhuǎn)移灶的形成過程中且有重要的生物學(xué)意義，誘導(dǎo)MET即逆轉(zhuǎn)EMT對(duì)治療有顯著的影響。如臨床試驗(yàn)中高表達(dá)E-Cadherin的非小細(xì)胞肺癌患者接受埃羅替尼靶向藥物治療效果比較好［1］；組蛋白脫乙?；敢种苿﹙orinostat通過誘導(dǎo)頭頸癌細(xì)胞系KB和Hep-2發(fā)生MET，可增加靶向藥物吉非替尼的治療作用等［51］。乳腺癌MDA-MB-231細(xì)胞系、前列腺DU-145細(xì)胞系和肝細(xì)胞共同培養(yǎng)時(shí)細(xì)胞形態(tài)發(fā)生上皮樣改變及表達(dá)E-cadherin和E-cadherin蛋白陰性表達(dá)的細(xì)胞相比化療抗性明顯增高且有預(yù)后價(jià)值［52］。盡管Kase等［25］檢測(cè)331例Ⅰ～Ⅲ期肺癌患者的E-Cadherin和β-catenin表達(dá)發(fā)現(xiàn)E-Cadherin無獨(dú)立預(yù)后價(jià)值，但是β-catenin表達(dá)減少且和預(yù)后有顯著關(guān)系。Soltermann等［53］利用免疫組織化學(xué)觀察533例非小細(xì)胞肺癌MET改變，單變量分析顯示間葉標(biāo)記骨膜蛋白periostin的表達(dá)和PFS下降顯著相關(guān)。

在間葉源性腫瘤中，MET臨床意義尚探討不多但已經(jīng)顯示出其在靶向治療中的重要作用。Saulnier等［16］體外實(shí)驗(yàn)證實(shí)脂肪間葉細(xì)胞經(jīng)MET可分化為肝細(xì)胞樣細(xì)胞，而且具有成熟肝細(xì)胞一些特征，如富含環(huán)氧化物酶EPHX1和前列腺素受體PGER4，可以發(fā)揮藥物代謝功能，對(duì)于臨床有潛在意義。某些臨床證明發(fā)生MET的肉瘤患者，高表達(dá)E-cadherin較表達(dá)缺失者對(duì)于化療藥物更加敏感［1］。Slug等［4］發(fā)現(xiàn)轉(zhuǎn)錄因子是肉瘤MET過程中的重要調(diào)節(jié)因子，也是潛在的治療靶標(biāo)，如神經(jīng)母細(xì)胞瘤中下調(diào)Slug可增加伊馬替尼、依托泊苷、阿霉素等藥物誘導(dǎo)凋亡的靈敏度。此外，在放療治療中Slug缺失的細(xì)胞對(duì)放射所致的DNA損傷很敏感。所以，抑制Slug和其他轉(zhuǎn)錄因子，誘導(dǎo)MET可能會(huì)提高腫瘤對(duì)放化療的敏感性。

9 結(jié)論

間葉惡性腫瘤中MET在分子水平上反映為上皮性標(biāo)志物如E-鈣粘素（E-cadherin）的上調(diào)和間葉性標(biāo)志物如波形蛋白（Vimentin）的下調(diào)，其過程涉及始動(dòng)信號(hào)、轉(zhuǎn)錄因子調(diào)節(jié)、表面標(biāo)記的改變、miRNA的調(diào)節(jié)、信號(hào)通路改變等多個(gè)環(huán)節(jié)，并對(duì)腫瘤的演進(jìn)及轉(zhuǎn)歸有非常重要的作用。明確MET相關(guān)機(jī)制并針對(duì)這一復(fù)雜過程中的特定環(huán)節(jié)進(jìn)行干預(yù)，可能有一定的臨床應(yīng)用前景。

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（2014-09-10收稿）

（2014-12-04修回）

（本文編輯：鄭莉）

Mesenchymal to epithelial transition in malignant mesenchymal tumors

Jilong YANG1,Xiaoling DU2,Guowen WANG1,Yun YANG1

1Department of Bone and Soft Tissue Tumors,Tianjin Medical University Cancer Hospital and Institute,National Clinical Research Center of Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin,Tianjin 300060,China;3Department of Diagnostics,Tianjin Medical University,Tianjin 300061,China

Jilong YANG;E-mail:yangjilong@tjmuch.com

Mesenchymal to epithelial transition(MET),whereby mesenchymal cells become more epithelial like in phenotype, was observed to occur during normal development and in cancers.Numerous investigations have been conducted on MET in carcinomas.In addition,accumulating evidence also suggests the critical function of MET in sarcomas.Integrated analyses reveal that MET may be an important biological and clinical process in sarcomas,and transcription factors such as Slug may also perform central functions in epithelial differentiation in several sarcomas such as leiomyo-sarcoma and synovial sarcoma.Given the scarcity of investigations and evidence,several important issues about MET,such as its molecular markers,signaling mechanisms,micro RNA regulations, and clinical significance,need to be clarified.In this article,we review several important questions about MET in sarcomas,including molecular markers,signaling mechanisms,regulation by miRNAs,and therapeutic implications.

sarcoma,mesenchymal to epithelial transition,E-cadherin,targeted therapy

10.3969/j.issn.1000-8179.20141559

①天津醫(yī)科大學(xué)腫瘤醫(yī)院骨與軟組織腫瘤科，國家腫瘤臨床研究中心，天津市腫瘤防治重點(diǎn)實(shí)驗(yàn)室（天津市300060）；②天津醫(yī)科大學(xué)診斷學(xué)教研室

*本文課題受國家自然科學(xué)基金項(xiàng)目（編號(hào)：81372872，81402215）資助

楊吉龍 yangjilong@tjmuch.com

楊吉龍 專業(yè)方向?yàn)楣桥c軟組織腫瘤。

E-mail：yanglilong@tjmuch.com