王一茹,唐 杰
解放軍總醫(yī)院 超聲科,北京 100853
前列腺癌上皮-間質(zhì)轉(zhuǎn)化研究進展
王一茹,唐 杰
解放軍總醫(yī)院 超聲科,北京 100853
上皮-間質(zhì)轉(zhuǎn)化是上皮細(xì)胞向間質(zhì)細(xì)胞轉(zhuǎn)變的過程,其與腫瘤侵襲、轉(zhuǎn)移等惡性行為密切相關(guān),近年受到廣泛關(guān)注。前列腺癌是老年男性發(fā)病率較高的腫瘤,上皮-間質(zhì)轉(zhuǎn)化在前列腺癌轉(zhuǎn)移過程中具有重要作用。本文對前列腺癌上皮-間質(zhì)轉(zhuǎn)化研究進展作一綜述,為深入了解前列腺癌轉(zhuǎn)移機制及防治提供思路。
前列腺;腫瘤;轉(zhuǎn)移;上皮間質(zhì)轉(zhuǎn)化
前列腺癌(prostate cancer,PCa)是危及中老年男性生命的惡性腫瘤。由于環(huán)境污染、飲食結(jié)構(gòu)西方化、人口老齡化、前列腺抗原(prostate specific antigen,PSA)篩查和前列腺穿刺活檢的推廣普及等因素,我國前列腺癌的發(fā)病率明顯上升。據(jù)2012中國腫瘤登記年報統(tǒng)計數(shù)據(jù),前列腺癌是我國男性發(fā)病排名第6位的惡性腫瘤,其發(fā)病率為9.92/100 000,死亡率為4.34/100 000。前列腺癌患者死亡往往是由于腫瘤轉(zhuǎn)移導(dǎo)致的[1]。腫瘤轉(zhuǎn)移是惡性腫瘤的行為特征,其發(fā)生進展機制極為復(fù)雜。上皮-間質(zhì)轉(zhuǎn)化(epithelial-mesenchymal transitions,EMT)使上皮源性的腫瘤細(xì)胞獲得遷移、侵襲能力,在腫瘤轉(zhuǎn)移中具有重要作用[2]。本文將對近幾年的前列腺癌EMT相關(guān)研究,尤其在臨床樣本中的研究進展作一綜述。
上皮-間質(zhì)轉(zhuǎn)化的概念提出于20世紀(jì)80年代[3],是指上皮細(xì)胞在一定條件下轉(zhuǎn)化成間質(zhì)細(xì)胞的過程,使之具有更強的遷移、侵襲及抗凋亡能力[4],并以上皮表型的缺失和間質(zhì)表型的獲得為主要特征。根據(jù)不同的生物學(xué)環(huán)境,EMT分為3個類型:Ⅰ型是指在移植、胚胎發(fā)生和器官發(fā)育過程中的EMT;Ⅱ型是與組織再生和器官纖維化相關(guān)的EMT;Ⅲ型是與腫瘤進展和轉(zhuǎn)移相關(guān)的EMT[5]。無論是何種類型的EMT,其關(guān)鍵事件主要包括[2]:上皮細(xì)胞間連接的分解;頂端-基底極性的消失;細(xì)胞形態(tài)中細(xì)胞骨架結(jié)構(gòu)的重組和改變;上皮相關(guān)基因表達水平的下調(diào)和間質(zhì)表型相關(guān)基因的激活;細(xì)胞偽足和運動能力的增加;降解細(xì)胞外基質(zhì)蛋白促使侵襲。此外,經(jīng)歷了EMT的細(xì)胞還能夠抵抗衰老和凋亡。
腫瘤轉(zhuǎn)移是惡性腫瘤的重要生物學(xué)特征,癌細(xì)胞的侵襲性和轉(zhuǎn)移能力是導(dǎo)致腫瘤患者復(fù)發(fā)、惡化的病理基礎(chǔ)。腫瘤的侵襲、轉(zhuǎn)移過程是多因素參與、動態(tài)變化的復(fù)雜過程[6]。上皮源性的惡性腫瘤發(fā)生EMT能夠使腫瘤細(xì)胞擺脫細(xì)胞-細(xì)胞間連接而更具侵襲性,因此在腫瘤的侵襲和轉(zhuǎn)移過程中起著重要作用。對于前列腺癌臨床樣本中EMT發(fā)生、發(fā)展相關(guān)機制及其與腫瘤預(yù)后相關(guān)的研究,目前已取得了一定進展。
有些學(xué)者通過檢測臨床樣本中EMT標(biāo)記物即EMT相關(guān)基因的表達,分析其與前列腺癌分級、分期、轉(zhuǎn)移及術(shù)后復(fù)發(fā)等惡性行為的相關(guān)性。Tomita等[7]對83例原位前列腺癌樣本進行檢測,發(fā)現(xiàn)上皮細(xì)胞標(biāo)記物E-cadherin表達與間質(zhì)細(xì)胞標(biāo)記物N-黏鈣蛋白(N-cadheirn)表達呈負(fù)相關(guān);Zhang等[8]在267例前列腺癌組織中發(fā)現(xiàn),波形蛋白(vimentin)的高表達與短期內(nèi)的生化復(fù)發(fā)具有相關(guān)性,但與Gleason評分無相關(guān)性;Lang等[9]在54例前列腺癌樣本及8例發(fā)生骨轉(zhuǎn)移的樣本中發(fā)現(xiàn),Vimentin的陽性表達與骨轉(zhuǎn)移及腫瘤低分化相關(guān);Jaggi等[10]在44例根治術(shù)的前列腺癌組織中發(fā)現(xiàn),N-cadherin表達增加與Gleason評分密切相關(guān)。上述研究在前列腺癌原發(fā)灶、轉(zhuǎn)移灶等多種臨床樣本中檢測到EMT相關(guān)基因的表達,并認(rèn)為上皮細(xì)胞標(biāo)記物E-cadherin等表達與前列腺癌預(yù)后呈正相關(guān),間質(zhì)細(xì)胞標(biāo)記物N-cadheirn、Vimentin等表達則與前列腺癌預(yù)后呈負(fù)相關(guān)。
近年文獻報道了一些新的參與EMT的基因表達、信號通路及相關(guān)蛋白,在臨床樣本中得到了證實。Ju等[11]研究發(fā)現(xiàn),細(xì)胞周期蛋白Cyclin D1能夠通過抑制轉(zhuǎn)化生長因子-β(transforming growth factor beta,TGF-β)、Snail和Twist而對前列腺癌患者的預(yù)后具有一定提示作用;Zhang等[8]通過對287例行前列腺癌根治術(shù)患者的癌組織進行分析并經(jīng)過7年的隨訪認(rèn)為,NF-κB調(diào)節(jié)的EMT能夠預(yù)測前列腺癌的生物復(fù)發(fā)。這些參與EMT的基因在前列腺癌組織中的表達得到證實,使EMT發(fā)生機制的研究更加深入,也提供了治療的新靶點。
然而,也有一部分文獻研究并未得出臨床樣本中EMT相關(guān)基因表達與前列腺癌轉(zhuǎn)移具有相關(guān)性的結(jié)論。Sethi等[12]報道在10例前列腺癌根治術(shù)的樣本中,E-cadherin的下降與骨轉(zhuǎn)移的發(fā)生沒有顯著的相關(guān)性;Vimentin在原發(fā)腫瘤和轉(zhuǎn)移癌的表達沒有顯著統(tǒng)計學(xué)差異。這些研究結(jié)論的不一致,可能是以下幾個原因?qū)е耓13]:研究尚缺乏明確的標(biāo)記物,缺乏縱向評估的病例,病理組織較難全面反應(yīng)標(biāo)記物表達的情況。
研究表明,一些轉(zhuǎn)錄因子能夠抑制上皮細(xì)胞E-cadherin的表達,直接參與EMT過程。這些轉(zhuǎn)錄因子中較為經(jīng)典的有Snail、ZEB和Twist家族:Beach等[14]在前列腺癌細(xì)胞系中證實,Snail能夠直接結(jié)合于E-cadherin的E-boxes區(qū)抑制轉(zhuǎn)錄;Drake等[15]發(fā)現(xiàn),在前列腺癌細(xì)胞中沉默ZEB1能夠上調(diào)E-cadherin的表達而抑制EMT的發(fā)生;Wallerand等[16]在轉(zhuǎn)移的膀胱癌和前列腺癌中發(fā)現(xiàn),Twist識別并結(jié)合于E-cadherin的E-box區(qū)使其沉默;Cho等[17]認(rèn)為,TGF-β1誘導(dǎo)的STAT3磷酸化和HIF-1的表達通過與Twist1的啟動子相結(jié)合,使Twist1表達上調(diào),從而促進前列腺癌的浸潤。除了在前列腺癌細(xì)胞系上進行的機制研究外,這些經(jīng)典的轉(zhuǎn)錄因子在前列腺癌組織中的表達也得到了驗證。Graham等[18]對前列腺癌和良性前列腺組織進行了組織芯片的研究,發(fā)現(xiàn)ZEB1表達與Gleason評分相關(guān),并在正常前列腺組織中表達缺失;Kwok等[19]對46例前列腺癌和45例良性前列腺增生組織的研究發(fā)現(xiàn),Twist在癌組織中較良性前列腺增生組織高表達,在Gleason評分≥7的組織中高表達,尤其在骨和淋巴結(jié)轉(zhuǎn)移灶高表達;Bethnsawy等[20]對197例行前列腺癌根治術(shù)患者的局部前列腺癌組織中13個EMT相關(guān)基因進行了免疫組化染色分析,其中E-cadherin、Snail、Twist和Vimentin的表達與前列腺癌患者的預(yù)后密切相關(guān)。
近期研究發(fā)現(xiàn)了一些新的參與EMT的轉(zhuǎn)錄因子,Wang等[21]SOX(sry-related high mobility group box)家族成員SOX4 (sex-determining region Y-box 4)在前列腺癌細(xì)胞中與ERG共同參與EMT的過程;并對241例前列腺癌組織芯片進行分析,認(rèn)為SOX4在前列腺癌進展中具有重要作用并能夠作為預(yù)測前列腺癌患者預(yù)后的標(biāo)記物[22];Katoh等[23]關(guān)于FOX(Forkhead box)家族的綜述中指出FoxC2、FoxM1、FoxF1和FoxO1等通過直接參與TGF-β通路或間接調(diào)節(jié)ZEB轉(zhuǎn)錄因子而參與了EMT的過程;我們的前期研究也發(fā)現(xiàn),F(xiàn)oxM1能夠作用于Snail2而參與前列腺癌EMT的過程[24]。
大小為20 ~ 25個核苷酸并具有調(diào)控功能的非編碼RNA-微小RNA(microRNA,miRNA)能夠選擇性地結(jié)合于mRNA,抑制其轉(zhuǎn)錄或促進其降解而抑制基因表達。研究表明,miRNA能調(diào)節(jié)EMT的多個信號通路及EMT相關(guān)轉(zhuǎn)錄因子。目前對于EMT相關(guān)miRNA研究最多的是miR-200家族(miR-200a、miR-200b、miR-200c、miR-141和miR-429),它們通過作用于ZEB1和ZEB2參與調(diào)節(jié)EMT[25]。
近年在前列腺癌組織中的研究發(fā)現(xiàn)了一些與EMT相關(guān)的miRNA,在前列腺癌的轉(zhuǎn)移和預(yù)后中發(fā)揮了重要作用。Josson等[26]發(fā)現(xiàn)miR-409-3p/-5p在發(fā)生骨轉(zhuǎn)移和高Gleason評分的前列腺癌組織中表達增加;Wang等[27]研究認(rèn)為,miR-100在前列腺癌組織中較正常組織下調(diào),在骨轉(zhuǎn)移灶中表達較原發(fā)灶明顯降低,其與腫瘤EMT呈負(fù)相關(guān),而miR-100的缺失能夠通過AGO2蛋白(argonaute 2,AGO2)表達上調(diào)而促進前列腺癌的轉(zhuǎn)移,證實miR-100/AGO2在調(diào)節(jié)前列腺癌轉(zhuǎn)移中具有重要作用;Kim等[28]證實miR-200c靶基因的表達模式能夠預(yù)測臨床前列腺癌樣本中成紅細(xì)胞病毒E26致癌物(erythroblastosis virus E26 oncogen,ERG)的狀態(tài),并認(rèn)為miR-200c在調(diào)控由ERG上調(diào)的ZEB1中有重要作用,miR-200c重構(gòu)能夠逆轉(zhuǎn)ERG誘導(dǎo)的EMT;Tucci等[29]在218例人前列腺癌轉(zhuǎn)移組織或轉(zhuǎn)移淋巴結(jié)中發(fā)現(xiàn),p63/miR-205軸缺失,證實其能夠成為前列腺癌轉(zhuǎn)移行為的提示指標(biāo);Peng等[30]對比分析原位前列腺癌組織和骨轉(zhuǎn)移灶組織的miRNA,證實miR-143和miR-145在骨轉(zhuǎn)移灶中下調(diào);Majid等[31]研究認(rèn)為,表達miR-23b能夠抑制EMT引起的Vimentin和Snail的下調(diào),增加上皮標(biāo)記物E-cadherin的表達,與前列腺癌患者無復(fù)發(fā)存活率(recurrence-free survival,RFS)呈正相關(guān)。
近年對于另一種具有調(diào)控功能的長鏈非編碼RNA—lncRNA的研究不斷升溫。lncRNA是指>200個核苷酸的非編碼RNA,與其他非編碼RNA比較具有類型多、作用模式多和數(shù)量多的特點。近期研究發(fā)現(xiàn),lncRNA參與了許多腫瘤的發(fā)生及發(fā)展,對EMT的過程也有重要的調(diào)控作用:Gupta等[32]研究發(fā)現(xiàn),lncRNA HOTAIR(HOX antisense intergenic RNA)能夠重建乳腺癌上皮細(xì)胞基因表達的模式,以增加腫瘤的侵襲性和轉(zhuǎn)移性;Hu等[33]通過建立人乳腺上皮細(xì)胞MCF10A/Twist細(xì)胞模型,采用芯片的方式篩選Twist誘導(dǎo)的EMT過程中調(diào)節(jié)或激活WNT信號通路的lncRNA;Zhao等[34]發(fā)現(xiàn),胃癌中HULC的高表達與淋巴結(jié)轉(zhuǎn)移、遠(yuǎn)處轉(zhuǎn)移及腫瘤進展、分級相關(guān),使HULC沉默能夠有效逆轉(zhuǎn)EMT;Xu等[35]研究認(rèn)為,HOTAIR的表達水平在胃癌組織與淋巴結(jié)轉(zhuǎn)移、TNM分期顯著相關(guān),活體研究結(jié)果表明,HOTAIR能夠通過調(diào)節(jié)Snail促進EMT。前列腺癌EMT相關(guān)lncRNA的研究尚未見報道,考慮到lncRNA將成為繼miRNA之后又一具有重要功能的非編碼RNA,可能極具研究價值。
越來越多的研究證實,在發(fā)生轉(zhuǎn)移的腫瘤患者中常常存在循環(huán)腫瘤細(xì)胞(circulating tumor cells,CTCs),這成為腫瘤轉(zhuǎn)移EMT發(fā)生后續(xù)過程中新的研究方向,并將成為研究腫瘤轉(zhuǎn)移過程及提示臨床預(yù)后的新方法[36]。Aceto等[37]研究發(fā)現(xiàn),乳腺癌患者血液中如果有在腫瘤原位形成的循環(huán)腫瘤細(xì)胞群(CTC clusters),與單個的CTCs相比具有23 ~50倍轉(zhuǎn)移風(fēng)險;Chen等[38]分離出前列腺癌患者外周血的CTCs并對其進行研究,發(fā)現(xiàn)與非腫瘤細(xì)胞相比,CTCs細(xì)胞彈性和膜的平滑度增加,其侵襲性和活動能力也增強,除表達促進間質(zhì)轉(zhuǎn)化的基因IGF1、IGF2、EGFR、FOXP3和TGFB3外,在去勢抵抗的腫瘤樣本中還檢測到一些EMT相關(guān)基因(PTPRN2,ALDH1,ESR2和WNT5A)的表達;Armstrong等[39]證實,在已發(fā)生轉(zhuǎn)移的去勢抵抗前列腺癌患者中,>80%的CTCs共表達上皮細(xì)胞蛋白(EpCAM、CK和E-cadherin)和間質(zhì)細(xì)胞蛋白(Vimentin、N-cadherin和O-cadherin)。研究CTCs的首要任務(wù)是將其從血液中準(zhǔn)確捕捉并快速分離出來。目前分離CTCs的方法依賴于CTCs的物理特性、表面標(biāo)記物或者某些功能特征,報道較多的是微流體CTC分離技術(shù)。而分離技術(shù)的改進將為檢測血液中少量的CTCs提供極大幫助。對血液中CTCs的檢測、追蹤及干預(yù),有望成為控制和治療前列腺癌轉(zhuǎn)移的有效方法。
EMT在前列腺癌轉(zhuǎn)移中具有重要的作用,在此過程中給予干預(yù)是治療侵襲性前列腺癌的理想方法。Reka等[40]和Chua等[41]研究認(rèn)為,雷帕霉素和17-AGG能夠抑制TGF-β通路而成為EMT的抑制劑,ALK5、MEK和SRC能夠通過EGF、HGF及IGF-1等誘導(dǎo)因素抑制EMT。另有一些化合物經(jīng)研究證實能夠參與抑制或逆轉(zhuǎn)前列腺癌的EMT:Bhat等[42]研究發(fā)現(xiàn)槲皮黃酮可以通過EGFR/PI3K/Akt通路逆轉(zhuǎn)前列腺癌細(xì)胞EMT過程;Ha等[43]研究發(fā)現(xiàn),MMP-9能夠調(diào)節(jié)茴香腦的抗轉(zhuǎn)移活性抑制前列腺癌細(xì)胞EMT過程;Wu等[44]研究認(rèn)為,水飛薊賓能夠上調(diào)Cytokeratin-18、下調(diào)Vimentin并抑制ZEB1和SLUG等轉(zhuǎn)錄因子而逆轉(zhuǎn)前列腺癌細(xì)胞系EMT。目前以EMT作為治療靶點的研究多處于臨床前的基礎(chǔ)研究。針對腫瘤EMT的治療方法,目前除了靶向發(fā)生EMT的細(xì)胞進行治療外,抑制EMT誘發(fā)因素、抑制參與EMT的轉(zhuǎn)錄因子和miRNA也有一定的治療作用。
上皮-間質(zhì)轉(zhuǎn)化是腫瘤轉(zhuǎn)移機制中不可或缺的重要組成部分,其發(fā)生、發(fā)展是一個多因素參與的復(fù)雜生物學(xué)過程。只有充分認(rèn)識EMT發(fā)生的分子機制,對EMT誘發(fā)因素、信號通路進行阻斷,調(diào)控EMT關(guān)鍵分子和核心轉(zhuǎn)錄因子,并在RNA水平予以調(diào)節(jié),才能阻滯或逆轉(zhuǎn)EMT的發(fā)生,并有望成為前列腺癌轉(zhuǎn)移早期診斷和防治的有效方法。
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Advances in epithelial-mesenchymal transition in prostate cancer
WANG Yiru, TANG Jie
Department of Ultrasonography, Chinese PLA General Hospital, Beijing 100853, China
TANG Jie. Email: txiner@vip.sina.com
Epithelial-mesenchymal transition (EMT) is a process in which the epithelial cells transform into mesenchymal cells. As it closely associates with the malignant behavior of tumor such as invasion and metastasis, it attracts widespread attention in recent years. Prostate cancer is a threat for elder men, and EMT plays an important role in prostate cancer metastasis. In this paper, the research progress of EMT in prostate cancer will be reviewed to expand thoughts of the mechanism, prevention and treatment of prostate cancer metastasis.
prostate; neoplasms; metastasis; epithelial-mesenchymal transition
R 445.1
A
2095-5227(2015)01-0097-04
10.3969/j.issn.2095-5227.2015.01.030
時間:2014-11-05 09:58
http://www.cnki.net/kcms/detail/11.3275.R.20141105.0958.001.html
2014-09-10
國家自然科學(xué)基金項目(81471682)
Supported by the National Natural Science Foundation of China(81471682)
王一茹,女,在讀博士,醫(yī)師。研究方向:超聲醫(yī)學(xué)。Email: wyr389006865@163.com
唐杰,男,主任醫(yī)師,教授,博士生導(dǎo)師。Email: txin er@vip.sina.com