lncRNA-在腫瘤中的作用

1、lncRNA 在腫瘤中的作用長鏈非編碼RNA(long non-coding RNA, lncRNA)是一類轉(zhuǎn)錄本長度超過200nt、不編碼蛋白的RNA，這類RNA起初被認(rèn)為是基因組轉(zhuǎn)錄的“噪音”，隨著2007年Hotair功能的被發(fā)掘，lncRNA的功能漸漸明晰。據(jù)計算，約有93%的轉(zhuǎn)錄本為lncRNA1，lncRNA通常位于細(xì)胞核和細(xì)胞質(zhì)。但是lncRNA的基因轉(zhuǎn)錄水平一般低于蛋白質(zhì)編碼基因，序列保守性差，承受的進(jìn)化壓力小，但promoter序列通常比較保守。lncRNA與小分子RNA相比，序列更長、空間結(jié)構(gòu)也較為復(fù)雜，參與表達(dá)調(diào)控的機(jī)制也更具有多樣性和復(fù)雜性。盡管目前只有一小部分lncR

2、NA的功能有相關(guān)報道，但可以明確的是lncRNA參與發(fā)育、分化、代謝等多方面的調(diào)控。lncRNA在癌癥中顯示出多種生物學(xué)功能：包括表觀遺傳調(diào)控、DNA損傷和細(xì)胞周期調(diào)控、對microRNA的調(diào)控、參與信號轉(zhuǎn)導(dǎo)通路和介導(dǎo)激素導(dǎo)致的癌癥2。在癌癥中，lncRNA可以作為癌基因和抑癌基因的轉(zhuǎn)錄調(diào)控分子3。比如過表達(dá)的HOTAIR lncRNA與惡性乳腺癌4、結(jié)腸癌5、肝癌6和胃腸道間質(zhì)瘤7有關(guān)。而lncRNA TARID可以預(yù)防癌癥形成，通過甲基化抑癌基因的表達(dá)8。表觀遺傳調(diào)控表觀遺傳是指遺傳表型和基因表達(dá)發(fā)生了可遺傳的改變，而不涉及DNA 序列的變化，主要包括DNA 甲基化、組蛋白修飾和染色質(zhì)重塑

3、等修飾形式。近年來研究表明，lncRNAs 通過表觀遺傳調(diào)控介導(dǎo)癌癥發(fā)生中起到至關(guān)重要的作用。lncRNAs 能夠通過表觀遺傳調(diào)控、轉(zhuǎn)錄調(diào)控以及轉(zhuǎn)錄后調(diào)控等多個層面調(diào)節(jié)基因的表達(dá)，從而參與癌癥中細(xì)胞增殖、分化和凋亡等多種生物學(xué)過程9。在癌癥發(fā)展過程中，lncRNAs 參與了多種表觀遺傳復(fù)合物的調(diào)節(jié)過程，從而抑制或激活基因的表達(dá)。例如，lncRNAs可以與多梳蛋白復(fù)合體結(jié)合來調(diào)控癌癥發(fā)生4。PRC1和2是已知的致癌基因，能夠?qū)е略S多惡性腫瘤的發(fā)生。FAL1 lncRNA 與PRC1的亞基BMI1結(jié)合。在卵巢癌,FAL1被證明可以加快癌癥的進(jìn)展和縮短病人的生存時間。FAL1與BMI1結(jié)合可阻止BM

4、I1降解以穩(wěn)定PRC1復(fù)合物，這可使PRC1占據(jù)和抑制p21等目標(biāo)基因的啟動子,導(dǎo)致細(xì)胞周期失調(diào)和增加腫瘤發(fā)生的機(jī)會10。除了PRC復(fù)合物,lncRNAs還與SWI/SNF染色質(zhì)重塑復(fù)合物有關(guān)，SWI/SNF是一類重要的依賴ATP的染色質(zhì)重塑復(fù)合物,能夠改變核小體的高級折疊結(jié)構(gòu)，干擾組蛋白與DNA結(jié)合，暴露啟動子序列的結(jié)合位點，使轉(zhuǎn)錄因子能與特異性啟動子序列結(jié)合，從而激活基因轉(zhuǎn)錄11-14。在癌癥中, SWI/SNF染色質(zhì)重塑復(fù)合物被廣泛認(rèn)為是一種腫瘤抑制分子，因為有害突變出現(xiàn)在大約20%的癌癥中15。Lnc TCF7在肝癌細(xì)胞(HCC)高表達(dá)，在肝癌干細(xì)胞的自我更新能力的維護(hù)中起重要作用12

5、。Lnc TCF7可以激活Wnt信號通路，通過結(jié)合和募集SWI/SNF復(fù)合物來與TCF7基因的啟動子結(jié)合激活基因的表達(dá)，這導(dǎo)致了肝癌腫瘤的發(fā)生。除此以外，lncRNAs還可以參與由DNA 甲基化、乙?；冉閷?dǎo)的基因轉(zhuǎn)錄過程來調(diào)控腫瘤發(fā)生過程。DNA損傷和細(xì)胞周期調(diào)控lncRNAs 廣泛參與DNA 損傷修復(fù)、細(xì)胞周期調(diào)控等生理或病理過程調(diào)控腫瘤的發(fā)生發(fā)展。對DNA損傷進(jìn)行修復(fù)和細(xì)胞周期檢查點的適當(dāng)調(diào)節(jié)對于維持細(xì)胞的完整性很重要12。p53 基因是研究最廣泛的抑癌基因之一, 也是細(xì)胞內(nèi)的一個強(qiáng)大的轉(zhuǎn)錄因子, 在正常狀態(tài)下呈低水平表達(dá)。在各種應(yīng)激包括DNA 損傷時, p53 可以被不同的信號通路激活

6、, 通過增強(qiáng)其下游多種基因的轉(zhuǎn)錄而引起細(xì)胞周期阻滯、凋亡或衰老, 保持細(xì)胞基因組的完整性并清除損傷細(xì)胞16, 17。在癌癥中，lncRNAs作為調(diào)控分子調(diào)控P53基因和細(xì)胞周期17。例如，lincRNA-p21召集核糖核蛋白hnRNP-k來促進(jìn)P21的轉(zhuǎn)錄，P21是一種調(diào)控p53信號通路的關(guān)鍵分子。lincRNA-p21的缺失使得G1/S檢查點失控導(dǎo)致細(xì)胞的增殖增加18。還有，lncRNA gadd7可抑制細(xì)胞周期G1/S 期轉(zhuǎn)換，在DNA受到紫外線、鉑順化合物和生長抑制等損傷時會誘導(dǎo)lncRNA gadd7的表達(dá)19?？偟膩碚f，這些機(jī)制表明lncRNAs在DNA損傷修復(fù)、細(xì)胞周期過程、細(xì)胞凋

7、亡調(diào)控中是至關(guān)重要的把關(guān)分子，在這些過程中，lncRNA的失調(diào)會讓癌細(xì)胞獲得永生性。與miRNA的作用microRNA與很多疾病的發(fā)生發(fā)展有關(guān)，包括癌癥20。miRNA可與靶RNA互補(bǔ)配對，導(dǎo)致基因的表達(dá)受制和蛋白合成受阻21。LncRNAs可與microRNA直接或間接作用，導(dǎo)致其失去調(diào)節(jié)功能。競爭性內(nèi)源RNA(ceRNA)假說是一種全新的基因表達(dá)調(diào)控模式，長鏈非編碼RNA轉(zhuǎn)錄物通過microRNA應(yīng)答元件競爭結(jié)合相同的microRNA來調(diào)控各自的表達(dá)水平，從而影響細(xì)胞的功能22。例如，H19lncRNA，是一個被研究了數(shù)十年的重要的癌癥發(fā)生遺傳因素23。H19 lncRNA編碼和產(chǎn)生mir

8、-675促進(jìn)胃癌24、結(jié)直腸癌25、神經(jīng)膠質(zhì)瘤26的發(fā)生。PCAT-1 lncRNA在前列腺癌組織中高表達(dá)27,PCAT-1 lncRNA可通過干擾miR-34調(diào)控MYC的表達(dá)28。研究表明,PCAT-1lncRNA結(jié)合MYC 3非翻譯區(qū)，防止miR-34a作用于目標(biāo)序列。研究表明，LncRNAs是作為一種競爭性內(nèi)源性 RNA 與miRNA相互作用，參與靶基因的表達(dá)調(diào)控，來調(diào)節(jié)癌癥惡化和轉(zhuǎn)移。信號通路和激素調(diào)節(jié)已有確鑿的證據(jù)證明信號通路的異常激活與癌癥的發(fā)生發(fā)展有關(guān)。lncRNAs在這些信號通路中的作用已經(jīng)成為癌癥發(fā)生機(jī)制的重要組成部分。所以對lncRNAs的研究也有望找到有潛力的治療癌癥的藥

9、物。已有研究證實轉(zhuǎn)化生長因子(TGF-)29，Hedgehog信號通路30、Wnt信號通路31在腫瘤發(fā)展中的作用。例如,TGF-可通過lncRNA-ATB促進(jìn)肝癌癌細(xì)胞轉(zhuǎn)移。異常的Hedgehog信號導(dǎo)致H19 lncRNA 表達(dá)升高，促進(jìn)小鼠骨肉瘤發(fā)生。一些癌癥是由激素調(diào)節(jié)紊亂所致32。尤其是,雌激素和雄激素能刺激乳腺癌和前列腺癌的發(fā)生33, 34。鑒于這些激素受體通路在推動癌癥惡化的關(guān)鍵作用,lncRNAs也參與其中也就不足為奇了。雄激素受體(AR)在前列腺癌進(jìn)展中起著重要的作用35。事實上,治療前列腺癌的方法主要包括雄激素剝奪療法(ADT)36。 雄激素刺激后,AR結(jié)合兩個抑制雄性激素的

10、lncRNAs PCAT2937和DRAIC38，抑制促癌基因的轉(zhuǎn)錄。低PCAT29和DRAIC表達(dá)與前列腺癌患者的不良預(yù)后狀況相關(guān)。結(jié)語lncRNAs可以調(diào)節(jié)癌癥發(fā)生的方方面面。雖然目前我們對于lncRNAs的認(rèn)識有明顯的增長，但這只是冰山一角，lncRNAs在癌癥中行使的復(fù)雜生物學(xué)功能，其詳細(xì)的調(diào)控機(jī)制仍有待深入研究。參考文獻(xiàn)1.Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009; 136(4): 629-41.2.Sahu A, Singhal U, Chinn

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