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·綜述·

作者單位：315211 寧波，寧波大學(xué)醫(yī)學(xué)院

微小RNA與腫瘤微環(huán)境

微小RNA是一組無(wú)編碼功能的RNA，約為22個(gè)核苷酸長(zhǎng)度，它通過(guò)逆向互補(bǔ)結(jié)合mRNA 的3’-非轉(zhuǎn)錄區(qū)調(diào)節(jié)基因的表達(dá)[1]。微小RNA在細(xì)胞增殖、細(xì)胞分化、細(xì)胞周期、細(xì)胞凋亡、細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)、器官的形成、造血細(xì)胞的分化和腫瘤的形成、轉(zhuǎn)移等過(guò)程中扮演著重要的角色[2]。據(jù)不完全統(tǒng)計(jì)，微小RNA調(diào)節(jié)人類三分之一的基因翻譯[3]。其可以作為原癌基因或抑癌基因存在于不同的腫瘤中，例如直腸癌、伯基特淋巴瘤、肺癌、大細(xì)胞淋巴瘤、膠質(zhì)母細(xì)胞瘤和B細(xì)胞淋巴瘤等[3]。最近的研究表明，微小RNA在腫瘤的微環(huán)境中表達(dá)異常。腫瘤微環(huán)境中的微小RNA可來(lái)源于循環(huán)中的微小RNA、腫瘤細(xì)胞分泌的微小RNA或趨化因子招募的微小RNA。細(xì)胞外的微小RNA作為聯(lián)系細(xì)胞與細(xì)胞之間的信使，在血管的形成、基質(zhì)的降解和重塑等腫瘤微環(huán)境相關(guān)的進(jìn)程中扮演不可或缺的重要角色[4]。研究微小RNA與腫瘤微環(huán)境的相互作用機(jī)制可以拓寬對(duì)腫瘤發(fā)病機(jī)制的認(rèn)識(shí)，從而為腫瘤的預(yù)防和治療提供新的方向。

腫瘤微環(huán)境是復(fù)雜多元的，其由細(xì)胞外基質(zhì)和基質(zhì)細(xì)胞構(gòu)成，其中基質(zhì)細(xì)胞包括免疫細(xì)胞、纖維母細(xì)胞、內(nèi)皮細(xì)胞、骨髓誘導(dǎo)細(xì)胞和干細(xì)胞。細(xì)胞外基質(zhì)主要通過(guò)細(xì)胞以旁分泌和自分泌方式釋放的細(xì)胞外分子影響腫瘤的發(fā)展。對(duì)于基質(zhì)細(xì)胞，其不具有維持細(xì)胞正常結(jié)構(gòu)和功能的能力，但是，通過(guò)細(xì)胞的聯(lián)系或腫瘤細(xì)胞分泌的細(xì)胞因子，正常的基質(zhì)細(xì)胞獲得變異的表型和支持腫瘤細(xì)胞生長(zhǎng)的特性[5-7]。在細(xì)胞外基質(zhì)和基質(zhì)細(xì)胞功能失調(diào)的狀態(tài)下，纖維母細(xì)胞和免疫細(xì)胞生產(chǎn)趨化因子和生長(zhǎng)因子促進(jìn)細(xì)胞的侵襲和生長(zhǎng)，并且招募其它細(xì)胞到腫瘤細(xì)胞中(如間充質(zhì)干細(xì)胞)[7]。腫瘤微環(huán)境在腫瘤發(fā)生和發(fā)展中的潛在作用引起了研究者們的持續(xù)關(guān)注。腫瘤微環(huán)境不但通過(guò)營(yíng)養(yǎng)支持有助于腫瘤細(xì)胞的生存，而且有助于腫瘤細(xì)胞的轉(zhuǎn)移和侵襲。

一、微小RNA對(duì)腫瘤微環(huán)境中腫瘤轉(zhuǎn)移的作用

1. 調(diào)節(jié)上皮間質(zhì)轉(zhuǎn)化(EMT)

腫瘤細(xì)胞要實(shí)現(xiàn)遠(yuǎn)處轉(zhuǎn)移，先要從原發(fā)灶脫落進(jìn)入周圍組織，然后進(jìn)入血管或淋巴管，通過(guò)循環(huán)系統(tǒng)到達(dá)其他器官。研究表明微小RNA通過(guò)改變轉(zhuǎn)錄信號(hào)表達(dá)參與EMT的過(guò)程。腫瘤細(xì)胞主要通過(guò)改變細(xì)胞黏附分子的表達(dá)，實(shí)現(xiàn)EMT，從而發(fā)生轉(zhuǎn)移。腫瘤細(xì)胞EMT活動(dòng)受3組核心轉(zhuǎn)錄因子的調(diào)節(jié)，這些轉(zhuǎn)錄因子均直接或間接抑制E-鈣黏素的表達(dá)[7]。調(diào)控啟動(dòng)EMT的轉(zhuǎn)錄因子包括Snail 鋅指家族轉(zhuǎn)錄因子(SNAI1和SNAI2)、鋅指E-box綁定的同源家族蛋白(ZEB1和ZEB2)和基本螺旋-環(huán)-螺旋家族轉(zhuǎn)錄因子(TWIST1、TWIST2和E12/E47)[8]。微小RNA-138通過(guò)和波形蛋白、ZEB2、EZH2等靶向結(jié)合來(lái)調(diào)節(jié)EMT活動(dòng)[9]。與此類似，在NCI60細(xì)胞中，微小RNA-200則通過(guò)和E-鈣黏素、ZEB1和ZEB2的靶向結(jié)合抑制細(xì)胞的轉(zhuǎn)錄活動(dòng)進(jìn)而抑制腫瘤細(xì)胞的EMT。微小RNA-30a和SNAI1靶向結(jié)合，進(jìn)而激活下游的轉(zhuǎn)錄生長(zhǎng)因子-β(TGF-β)促進(jìn)EMT的活動(dòng)，下調(diào)的微小RNA-30a能抑制EMT[10]。微小RNA還通過(guò)調(diào)控編碼黏附連接極性復(fù)合蛋白和信號(hào)調(diào)節(jié)蛋白等靶基因的表達(dá)，參與決定上皮細(xì)胞或間質(zhì)細(xì)胞的表型。微小RNA-661能抑制黏連蛋白1的表達(dá)，促進(jìn)EMT[11]。另外，腫瘤細(xì)胞受腫瘤微環(huán)境中的許多細(xì)胞外信號(hào)的刺激而發(fā)生EMT。TGF-β、Wnt信號(hào)和生長(zhǎng)因子受體在腫瘤細(xì)胞的EMT中扮演不可或缺的角色，與微小RNA的作用相關(guān)，可見(jiàn)，微小RNA的的激活呈現(xiàn)一個(gè)廣泛的調(diào)節(jié)網(wǎng)絡(luò)，其可通過(guò)控制基因的表達(dá)進(jìn)而影響細(xì)胞的EMT[12-14]。

2. 調(diào)節(jié)基質(zhì)金屬蛋白酶(MMPs)的表達(dá)

腫瘤的進(jìn)展不僅依靠癌細(xì)胞的內(nèi)部因素，而且與外部因素(細(xì)胞外基質(zhì)蛋白)密切相關(guān)。細(xì)胞外基質(zhì)蛋白是基底膜組成的特異成分，作為一道屏障其能防止細(xì)胞的侵襲。而基底膜的層黏連蛋白和Ⅳ型膠原蛋白具有抗轉(zhuǎn)移作用。另外，基底膜降解釋放的大量生長(zhǎng)因子能促進(jìn)腫瘤生長(zhǎng)、轉(zhuǎn)移、血管生成[15]。MMPs作為細(xì)胞外基質(zhì)降解的酶在基底膜降解的過(guò)程中扮演重要角色。MMPs的轉(zhuǎn)移機(jī)制可能與蛋白酶激活受體(PARs)有關(guān)，MMP1能激活PAR-1進(jìn)而促進(jìn)腫瘤的轉(zhuǎn)移[16]。MMPs還可以激活腫瘤干細(xì)胞中的TGF-β和Wnt信號(hào)從而調(diào)節(jié)腫瘤干細(xì)胞的增殖和轉(zhuǎn)移[17]。MMPs來(lái)源于基質(zhì)細(xì)胞中的巨噬細(xì)胞，肥大細(xì)胞和纖維母細(xì)胞，此外一些內(nèi)皮細(xì)胞在適當(dāng)條件的刺激下也能產(chǎn)生MMPs[18]。研究表明一些微小RNA可以抑制MMPs的表達(dá)。有研究者通過(guò)熒光素酶活性序列分析得出微小RNA-152能通過(guò)綁定MMP3的轉(zhuǎn)錄物而減少M(fèi)MP3的表達(dá)[19]。另外，微小RNA-200c的過(guò)表達(dá)會(huì)下調(diào)MMP14的表達(dá)；相反，敲除微小RNA-200c能增加MMP14的表達(dá)進(jìn)而增加腫瘤細(xì)胞的侵襲性[20]。此外，微小RNA可以同時(shí)與多種MMPs的亞群結(jié)合進(jìn)而抑制MMPs。在胰腺癌Panc-1細(xì)胞中，微小RNA-143明顯減少M(fèi)MP2和MMP9的表達(dá)，同時(shí)抑制Panc-1細(xì)胞的生長(zhǎng)、侵襲、肝轉(zhuǎn)移和體內(nèi)種植瘤的生長(zhǎng)[21]。由此可見(jiàn)，不同的微小RNA可以調(diào)節(jié)不同的MMPs進(jìn)而影響腫瘤細(xì)胞的轉(zhuǎn)移和侵襲。

3. 介導(dǎo)血管的形成

腫瘤的生長(zhǎng)需要新的血管以滿足其高代謝和營(yíng)養(yǎng)需求。當(dāng)細(xì)胞處于缺氧狀態(tài)時(shí)，缺氧誘導(dǎo)因子(HIF)會(huì)轉(zhuǎn)錄上調(diào)大量腫瘤微環(huán)境和腫瘤細(xì)胞中的血管生長(zhǎng)因子，包括內(nèi)皮生長(zhǎng)因子、血管生成素2、基質(zhì)誘導(dǎo)因子1和干細(xì)胞因子[22-23]。當(dāng)這些因子與特殊受體結(jié)合表達(dá)于血管內(nèi)皮細(xì)胞和平滑肌細(xì)胞表面，就會(huì)形成新的毛細(xì)血管作為血管形成的起始。抑制線粒體的功能和通過(guò)抑制泛素連接酶的功能進(jìn)而抑制HIF的降解可以促進(jìn)血管的形成。此外，血管的形成需要多種信號(hào)通路的參與，血管生成素與其受體Tie結(jié)合，激活磷脂酰3肌醇，進(jìn)而激活下游的蛋白激酶、活性氧和絲裂原蛋白激酶通路，促進(jìn)內(nèi)皮細(xì)胞和一氧化氮的合成，從而促進(jìn)血管的形成。另外Tie信號(hào)的激活還可以通過(guò)核因子κB參與血管的合成[24]。微小RNA能調(diào)節(jié)血管形成因子，微小RNA-210介導(dǎo)的內(nèi)皮細(xì)胞血管的形成與微小RNA-210誘導(dǎo)的線粒體新陳代謝有關(guān)，過(guò)度表達(dá)的微小RNA-210會(huì)增加葡萄糖轉(zhuǎn)運(yùn)蛋白(GLUT-1)，上調(diào)的GLUT-1能增加血管內(nèi)皮生長(zhǎng)因子和血小板衍化生長(zhǎng)因子水平，成為血管形成的起點(diǎn)[25]。另外，微小RNA-210通過(guò)靶向結(jié)合肝配蛋白A3和蛋白酪氨酸磷酸化酶1B減少細(xì)胞血管內(nèi)皮生長(zhǎng)因子的水平進(jìn)而抑制血管的生成[26]。微小RNA介導(dǎo)的血管形成為腫瘤轉(zhuǎn)移提供了通路。

二、微小RNA對(duì)腫瘤微環(huán)境中免疫細(xì)胞的作用

免疫細(xì)胞是一群異源的細(xì)胞，在不同的腫瘤中代表不同的特性。腫瘤起始細(xì)胞(M2巨噬細(xì)胞，骨髓誘導(dǎo)的抑制細(xì)胞)、腫瘤抑制細(xì)胞(M1巨噬細(xì)胞，CD8+和CD4+T細(xì)胞)和調(diào)節(jié)性T細(xì)胞等免疫細(xì)胞存在于腫瘤微環(huán)境中，這些免疫細(xì)胞的平衡將決定著腫瘤的免疫逃避或清除。這個(gè)平衡是一個(gè)復(fù)雜的過(guò)程，同時(shí)它又涉及來(lái)源于腫瘤微環(huán)境中細(xì)胞因子的整合調(diào)節(jié)。此外，這個(gè)平衡的調(diào)節(jié)也受一部分微小RNA的影響。微小RNA通過(guò)與免疫細(xì)胞的聯(lián)系參與腫瘤進(jìn)展的機(jī)制包括：①通過(guò)改變免疫細(xì)胞的免疫識(shí)別能力進(jìn)而參與腫瘤細(xì)胞的免疫逃避；②招募相關(guān)的細(xì)胞信號(hào)和細(xì)胞趨化因子參與免疫細(xì)胞的活動(dòng)；③轉(zhuǎn)化免疫細(xì)胞的形式進(jìn)而改變免疫細(xì)胞的功能[27]。微小RNA-9有下調(diào)主要組織相容性復(fù)合體Ⅰ的能力，從而阻止免疫系統(tǒng)對(duì)腫瘤細(xì)胞的辨認(rèn)[28]。另一方面，腫瘤中下調(diào)的微小RNA-9會(huì)導(dǎo)致轉(zhuǎn)錄基因B7-H3的上調(diào)，進(jìn)而使其表達(dá)于腫瘤細(xì)胞的表面[29]。隨后B7-H3傳遞抑制信號(hào)給T細(xì)胞和自然殺傷細(xì)胞，從而抑制這些免疫細(xì)胞的抗腫瘤作用。微小RNA-21和微小RNA-126/126*有助于調(diào)節(jié)腫瘤微環(huán)境，他們不僅調(diào)節(jié)基質(zhì)細(xì)胞，而且對(duì)可溶性因子和信號(hào)分子也有調(diào)節(jié)作用。調(diào)節(jié)性T細(xì)胞是重要的基質(zhì)組成成分和有免疫抑制效應(yīng)的免疫細(xì)胞[30]。在惡性胸膜滲出的非小細(xì)胞肺癌患者中，微小RNA-141減少趨化因子的表達(dá)，趨化性分析表明微小RNA-141-趨化因子1-趨化因子2信號(hào)通路能減少調(diào)節(jié)性T細(xì)胞轉(zhuǎn)移到惡性胸膜滲出液從而發(fā)揮其抗腫瘤作用。在動(dòng)物模型中微小RNA-141抑制腫瘤的生長(zhǎng)和轉(zhuǎn)移，這個(gè)抑制功能是通過(guò)微小RNA-141-趨化因子1-趨化因子2信號(hào)通路減少招募調(diào)節(jié)性T細(xì)胞實(shí)現(xiàn)的[31]。一些微小RNA還能調(diào)節(jié)巨噬細(xì)胞，綁定在Tnfa 3’UTR的微小RNA-125b抑制TNF-α的產(chǎn)生和通過(guò)靶向干擾素調(diào)節(jié)因子4維持M1巨噬細(xì)胞的表型[32]。巨噬細(xì)胞-146通過(guò)核轉(zhuǎn)錄因子-κB通路直接抑制TNF受體相關(guān)因子6和IL-1受體相關(guān)激酶1，減少促炎性細(xì)胞因子的釋放和促進(jìn)轉(zhuǎn)化了的M2巨噬細(xì)胞的激活。大量的研究已經(jīng)表明微小RNA與腫瘤微環(huán)境中免疫細(xì)胞的聯(lián)系與腫瘤的生長(zhǎng)和免疫逃避有關(guān)。

三、微小RNA在腫瘤微環(huán)境中的治療作用

過(guò)去，腫瘤藥物的研究主要集中在腫瘤細(xì)胞的生物學(xué)特性，但腫瘤細(xì)胞的生物學(xué)特性并不能完全解釋腫瘤的復(fù)雜性和特殊性。最近研究者們的研究重點(diǎn)已經(jīng)從腫瘤細(xì)胞的生物學(xué)特性轉(zhuǎn)到腫瘤的微環(huán)境。微小RNA作為基質(zhì)細(xì)胞的一部分，在腫瘤的發(fā)生和發(fā)展中具有重要的作用。腫瘤的靶向治療能減輕藥物的不良反應(yīng)和提高治療的效果，目前對(duì)靶向治療有效的癌基因有表皮生長(zhǎng)因子受體和人類表皮生長(zhǎng)因子受體2。微小RNA也在腫瘤的發(fā)生、轉(zhuǎn)移和侵襲中扮演著不可或缺的角色。對(duì)微小RNA的靶向治療可能會(huì)給腫瘤的治療帶來(lái)新的突破。Cheng等[33]克服了微小RNA難以跨膜的難點(diǎn)，利用酸性腫瘤微環(huán)境，綁定反義RNA于低pH誘導(dǎo)的跨膜結(jié)構(gòu)的肽(pHLIP)，從而使微小RNA順利進(jìn)入腫瘤細(xì)胞中。pHLIP-anti155和傳統(tǒng)的鹽酸強(qiáng)力霉素加抗炎類固醇具有相似的化學(xué)治療作用，但pHLIP-anti155的抗腫瘤治療劑量小，此外，pHLIP-anti155能抑制腫瘤細(xì)胞的遠(yuǎn)處轉(zhuǎn)移。

微小RNA模擬物和反義微小RNA(anti-miRs)可用于治療癌癥，但微小RNA很難跨膜進(jìn)入細(xì)胞內(nèi)，對(duì)其進(jìn)行化學(xué)修飾和納米粒載體傳遞能大大地增加寡核苷酸的治療效果和減少其毒性作用。微小RNA和小分子藥物的共納米粒傳遞可將兩者轉(zhuǎn)載到相同的腫瘤細(xì)胞從而發(fā)揮共同的抗腫瘤作用。在吉西他濱抵抗的胰腺癌細(xì)胞MIA PaCa-2R 和CAPAN-1R中，微小RNA-205/吉西他濱的模擬物能減少ZEB-1、Smad聯(lián)系蛋白1、脂蛋白受體相關(guān)蛋白1和人類大鼠肉瘤蛋白同源蛋白的表達(dá)，上調(diào)E-鈣黏素和微囊蛋白的表達(dá)，從而減少腫瘤細(xì)胞的轉(zhuǎn)移和侵襲，并能恢復(fù)吉西他濱的化學(xué)治療敏感性。另外在接種MIA PaCa-2R細(xì)胞的轉(zhuǎn)移瘤模型中，微小RNA-205/吉西他濱組腫瘤細(xì)胞的生長(zhǎng)處于停滯狀態(tài)，而無(wú)吉西他濱組和單獨(dú)吉西他濱組只能達(dá)到中等的治療效果[34]。在人乳腺癌細(xì)胞MDA-MB-231中，相比于單獨(dú)用微小RNA-34a或阿霉素，采用含有微小RNA-34a及阿霉素的納米粒更能減少BCL-2的表達(dá)，抑制細(xì)胞的轉(zhuǎn)移，并能引起大量細(xì)胞凋亡。微小RNA-34a及阿霉素結(jié)合治療的優(yōu)越性同樣能體現(xiàn)在皮下接種MDA-MB-231細(xì)胞的小鼠身上[35]。但是納米粒的共傳遞也并非只有優(yōu)點(diǎn)，藥物的累積作用會(huì)增加肝臟的負(fù)擔(dān)，另外循環(huán)中的微小RNA作為配體可以和toll樣受體結(jié)合引起炎性反應(yīng)促進(jìn)腫瘤的生長(zhǎng)和轉(zhuǎn)移[36]。

四、展望

微小RNA在腫瘤微環(huán)境中通過(guò)EMT、MMPs和血管生成影響腫瘤的轉(zhuǎn)移，其也通過(guò)免疫細(xì)胞調(diào)節(jié)腫瘤的進(jìn)展。盡管我們對(duì)腫瘤微環(huán)境的認(rèn)識(shí)還處于基礎(chǔ)階段，但是針對(duì)腫瘤微環(huán)境中微小RNA的治療已經(jīng)初見(jiàn)成效。對(duì)微小RNA和腫瘤微環(huán)境的深入研究，有助于我們提高腫瘤的治療效果和改善預(yù)后。但是，微小RNA和腫瘤微環(huán)境的聯(lián)系是一個(gè)復(fù)雜的過(guò)程，需要我們進(jìn)一步探索微小RNA的上游和下游信號(hào)，它們相互作用需要的背景環(huán)境，以及相關(guān)治療的不良反應(yīng)。

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(本文編輯：洪悅民)

葛曙雄王涌

【摘要】微小RNA是小的非編碼RNA，能調(diào)節(jié)腫瘤的發(fā)生、轉(zhuǎn)移和侵襲。微小RNA不僅表達(dá)于不同的腫瘤細(xì)胞，而且也表達(dá)于腫瘤的微環(huán)境中。隨著人們對(duì)腫瘤微環(huán)境的不斷探究，微小RNA在腫瘤微環(huán)境中的作用也逐漸明確。腫瘤微環(huán)境由細(xì)胞外基質(zhì)和基質(zhì)細(xì)胞構(gòu)成，其參與腫瘤的生長(zhǎng)、轉(zhuǎn)移和血管生成，這些過(guò)程均有微小RNA的參與。對(duì)微小RNA和腫瘤微環(huán)境關(guān)系的剖析有助于進(jìn)一步了解腫瘤發(fā)生的病理和生理機(jī)制。該文就微小RNA在腫瘤微環(huán)境中的作用的相關(guān)研究作一綜述。

【關(guān)鍵詞】微小RNA；腫瘤微環(huán)境；免疫細(xì)胞

MicroRNAs and tumor microenvironmentGeShuxiong,WangYong.MedicalSchoolofNingboUniversity,Ningbo315211,China

Correspondingauthor,WangYong,E-mail:robinwang9401@sina.com

【Abstract】MicroRNAs (miRNAs) are a class of small non-coding RNAs which regulate the incidence, metastasis and invasion of malignant tumors. MiRNAs are not only expressed in different tumor cells, but also in tumor microenvironment. Along with deeper exploration of tumor microenvironment, the role of miRNAs in tumor microenvironment has been gradually identified. Tumor microenvironment consists of extracellular matrix and stromal cells, which is involved in tumor growth, metastasis and angiogenesis. MiRNAs participate in all these events. Understanding the miRNAs and tumor microenvironment contributes to identifying the pathological and physiological mechanisms of tumor occurrence. In this review, relevant studies about the role of miRNAs in tumor microenvironment were summarized.

【Key words】MicroRNAs; Tumor microenvironment; Immunocyte

收稿日期：(2015-07-31)

通訊作者，王涌，E-mail：robinwang9401@sina.com

基金項(xiàng)目：寧波市社會(huì)發(fā)展重大擇優(yōu)委托科技攻關(guān)項(xiàng)目(2012C5013)

DOI:10.3969/j.issn.0253-9802.2016.01.002