長(zhǎng)鏈非編碼RNA在肝細(xì)胞肝癌中的研究進(jìn)展

馬 杰， 張 莉， 向作林

1. 復(fù)旦大學(xué)附屬中山醫(yī)院放療科，上海 200032 2. 同濟(jì)大學(xué)附屬東方醫(yī)院放療科，上海 200120

肝細(xì)胞肝癌(HCC)是肝癌中最常見的病理類型。在世界范圍內(nèi)，肝癌患者死亡率在所有癌癥總死亡率中排第2位。特別是在東亞、東南亞、非洲及歐洲南部，肝癌的發(fā)病率、死亡率仍呈上升趨勢(shì)[1]。中國(guó)每年肝癌發(fā)病和死亡患者約占全球的一半[2]。傳統(tǒng)手術(shù)治療對(duì)于部分HCC患者的病情改善有明顯療效，但相當(dāng)數(shù)量的患者對(duì)治療不耐受，遠(yuǎn)期復(fù)發(fā)進(jìn)展。因此，作為未來(lái)精準(zhǔn)治療的關(guān)鍵，HCC相關(guān)調(diào)控因子成為目前研究的重點(diǎn)。

現(xiàn)代基因?qū)W研究[3]發(fā)現(xiàn)，人類基因組中只有不到2%的基因序列編譯蛋白質(zhì)，超過(guò)90%的序列可轉(zhuǎn)錄為非編碼RNA。早期觀點(diǎn)認(rèn)為非編碼RNA是翻譯的“噪聲”，不行使功能。近年來(lái)，隨著高分辨率芯片及高通量測(cè)序技術(shù)的發(fā)展，人們發(fā)現(xiàn)長(zhǎng)鏈非編碼RNA(long noncoding RNA, lncRNA)不僅起轉(zhuǎn)錄干擾作用，而且是基因調(diào)控中不可或缺的部分。越來(lái)越多的研究表明，非編碼RNA在疾病發(fā)展過(guò)程中起著重要作用。在HCC中，lncRNA的調(diào)控作用越發(fā)引起關(guān)注。

LncRNA是一類長(zhǎng)度超過(guò)200nt的內(nèi)源性RNA，在表觀遺傳水平、轉(zhuǎn)錄過(guò)程中發(fā)揮了重要的調(diào)控作用。根據(jù)與鄰近編碼RNA的位置關(guān)系，lncRNA可分為5類：正義lncRNA、反義lncRNA、雙向lncRNA、內(nèi)含子源性lncRNA、基因間lncRNA。LncRNA空間和組織形式上的多樣性使其有多種功能[4]。在細(xì)胞核內(nèi)，lncRNA可以參與染色質(zhì)的相互作用、轉(zhuǎn)錄調(diào)控與RNA加工過(guò)程；在細(xì)胞質(zhì)內(nèi)，lncRNA在轉(zhuǎn)錄產(chǎn)物的修飾、翻譯過(guò)程的調(diào)節(jié)與信號(hào)通路的調(diào)控中扮演重要角色。由于lncRNA長(zhǎng)度大于200 nt，可以折疊為復(fù)雜的高級(jí)結(jié)構(gòu)，其作用模式在多種情況下脫離了作為核苷酸序列的一級(jí)結(jié)構(gòu)基礎(chǔ)(與同源RNA序列直接結(jié)合)，而偏向了二級(jí)或更高級(jí)結(jié)構(gòu)[5]。目前，已有多篇文獻(xiàn)報(bào)道，HCC相關(guān)的lncRNA以多種形式參與HCC進(jìn)展調(diào)控，但由于lncRNA高級(jí)結(jié)構(gòu)和作用形式的復(fù)雜性和未知性，其在HCC中的調(diào)控作用尚需深入探討。本文就lncRNA在HCC中的研究進(jìn)展進(jìn)行綜述。

1 LncRNA在HCC發(fā)生中的作用

HCC的發(fā)生涉及病毒感染、基因調(diào)控失調(diào)、遺傳變異等多種因素。乙型肝炎病毒x蛋白(HBx)是乙型肝炎病毒(HBV)致癌效應(yīng)的重要載體[6]。有研究[7-8]證實(shí)，lncRNA HULC在HBX誘導(dǎo)下表達(dá)上升；作為HBV的下游靶點(diǎn)，其在肝硬化、HCC發(fā)生過(guò)程中發(fā)揮了調(diào)控作用。但也有研究[9]顯示，在HBV陰性患者的癌組織中，HULC依然高表達(dá)。該研究還發(fā)現(xiàn)，HULC可通過(guò)細(xì)胞外調(diào)節(jié)蛋白激酶(ERK)提高YB-1蛋白的磷酸化水平，使YB-1從YB-1/mRNAs復(fù)合物中釋放，進(jìn)而激活Cyclin D1、Cyclin E1、MMP3等致癌相關(guān)mRNA的表達(dá)，誘導(dǎo)HCC的發(fā)生。正常細(xì)胞的晝夜節(jié)律異常是腫瘤發(fā)生的重要誘因，CLOCK復(fù)合體參與管控細(xì)胞晝夜節(jié)律。研究[10]顯示，HULC可以改變HCC細(xì)胞內(nèi)CLOCK的表達(dá)模式、延長(zhǎng)其表達(dá)周期，干擾細(xì)胞節(jié)律，促進(jìn)HCC發(fā)生。以上研究說(shuō)明，HULC在HCC發(fā)生過(guò)程中調(diào)控有多樣性。

LncRNA HOTAIR與多個(gè)類型腫瘤的發(fā)生發(fā)展及臨床預(yù)后密切相關(guān)。在HCC細(xì)胞中，F(xiàn)OXC1可通過(guò)結(jié)合HOTAIR上游區(qū)域而激活其表達(dá)，激活的HOTAIR繼而通過(guò)占據(jù)miR-1結(jié)合位點(diǎn)來(lái)負(fù)性調(diào)節(jié)miR-1對(duì)下游的調(diào)控，發(fā)揮其促癌效應(yīng)；miR-1還能通過(guò)直接結(jié)合HOTAIR序列來(lái)負(fù)性調(diào)控HOTAIR，構(gòu)成一個(gè)負(fù)性反饋環(huán)路[11]。Bmi-1是miR-218的下游靶點(diǎn)，作為原癌基因在腫瘤形成與腫瘤干細(xì)胞特性的維持中發(fā)揮重要作用[12-14]。Fu等[15]研究發(fā)現(xiàn)，HOTAIR通過(guò)招募EZH2于miR-218啟動(dòng)子位點(diǎn)來(lái)沉默其表達(dá)，增強(qiáng)下游Bmi-1編譯，從而抑制P14ARF和P16Ink4a 信號(hào)通路，促進(jìn)HCC形成。HOTAIR還可抑制CREB、P300、RNA polⅡ募集于SETD2的啟動(dòng)子位點(diǎn)，降低SETD2的表達(dá)和磷酸化水平，誘導(dǎo)HCC干細(xì)胞的分化[16]。HOTAIR在肝腫瘤干細(xì)胞特性的維持和分化方面具有重要意義。

單核苷酸多態(tài)性(SNP)是人類可遺傳變異中最常見的一種，lncRNA相關(guān)SNP參與HCC的發(fā)生。在中國(guó)人群中，rs920778C > T多態(tài)性與HOTAIR的高表達(dá)相關(guān)，影響HCC的易感性和增殖能力[17]；在中國(guó)漢族人群中，rs145204276多態(tài)性與HCC易感性相關(guān)，rs145204276多態(tài)性可能通過(guò)干預(yù)lncRNA GAS5啟動(dòng)子區(qū)甲基化水平而影響其對(duì)HCC細(xì)胞凋亡的抑制作用，進(jìn)而促進(jìn)HCC的發(fā)生[18]。

2 LncRNA在HCC發(fā)展中的調(diào)節(jié)

HCC的發(fā)展主要包括腫瘤細(xì)胞的增殖和轉(zhuǎn)移。在HCC發(fā)展過(guò)程中，腫瘤血管生成是維持其高代謝水平的基礎(chǔ)，鞘氨醇激酶1(Sphk1)參與這一過(guò)程。HULC通過(guò)競(jìng)爭(zhēng)性隔離miRNA-107的作用，上調(diào)E2F1表達(dá)水平，促進(jìn)SPHK1的表達(dá)，進(jìn)而調(diào)控腫瘤血管形成[19]。脂質(zhì)代謝相關(guān)因子已被證實(shí)與腫瘤的轉(zhuǎn)移起始有很強(qiáng)的相關(guān)性[20]，而HULC可以通過(guò)HULC/miR-9/PPARA/ACSL1/cholesterol/RXRA正反饋環(huán)路擾亂HCC細(xì)胞的正常脂質(zhì)代謝[21]。因此，HULC可能通過(guò)脂質(zhì)代謝相關(guān)途徑參與HCC的轉(zhuǎn)移。在缺氧狀態(tài)下，HCC細(xì)胞中組蛋白H3、H4的乙酰化水平會(huì)下降，lncRNA LET的表達(dá)也隨之受到抑制；同時(shí)，下調(diào)的lncRNA LET會(huì)通過(guò)干擾低氧誘導(dǎo)因子-1α(HIF-1α)mRNA的翻譯來(lái)影響HIF-1α的表達(dá)量和穩(wěn)定性，從而誘發(fā)缺氧相關(guān)的癌細(xì)胞轉(zhuǎn)移[22]。

腫瘤干細(xì)胞自我更新行為在腫瘤的轉(zhuǎn)移、復(fù)發(fā)以及異質(zhì)性形成過(guò)程中具有重要意義。LncTCF7是一種在HCC和肝腫瘤干細(xì)胞中高表達(dá)的lncRNA，目前發(fā)現(xiàn)其在肝腫瘤干細(xì)胞的自我更新和腫瘤擴(kuò)散過(guò)程中有調(diào)控作用。LncTCF7通過(guò)募集SWI-SNF復(fù)合體于TCF7的啟動(dòng)子上，激活Wnt通路來(lái)促進(jìn)HCC的發(fā)展[23]。LncBRM同樣在HCC細(xì)胞及腫瘤干細(xì)胞中高表達(dá)，可以與BRM蛋白交聯(lián)以啟動(dòng)BRG1/BRM交換，從而通過(guò)BRG1嵌入式BAF復(fù)合體來(lái)激活YAP1通路，使HCC干細(xì)胞維持自我更新和HCC發(fā)生[24]。除此之外，lncRNA DANCR與miRNA競(jìng)爭(zhēng)性結(jié)合CTNNB1 的mRNA序列，通過(guò)調(diào)控CTNNB1表達(dá)來(lái)調(diào)控影響HCC干細(xì)胞特性[25]。

表觀遺傳學(xué)改變?cè)贖CC發(fā)展中同樣具有重要作用。據(jù)報(bào)道，在亞砷酸鹽誘導(dǎo)形成的HCC細(xì)胞內(nèi)，lncRNA MALAT1與HIF-2α顯著高表達(dá)并能增強(qiáng)腫瘤細(xì)胞的轉(zhuǎn)移侵襲能力。其中，MALAT1可以通過(guò)泛素-蛋白酶體途徑增強(qiáng)HIF-2α的表達(dá)；反之，HIF-2α對(duì)MALAT1具有轉(zhuǎn)錄調(diào)節(jié)作用，兩者構(gòu)成一個(gè)反饋環(huán)路在HCC發(fā)展中發(fā)揮作用[26]。LncRNA GIHCG通過(guò)募集EZH2及DNMT1來(lái)上調(diào)miR-200b/a/429啟動(dòng)子區(qū)域組蛋白H3K27的三甲基化和DNA甲基化水平，進(jìn)而沉默miR-200b/a/429表達(dá)，促進(jìn)HCC細(xì)胞的增殖和轉(zhuǎn)移[27]。LncRNA PCAT-14通過(guò)誘導(dǎo)miR-372啟動(dòng)子甲基化而沉默miR-372的表達(dá)，從而調(diào)控ATAD2和Hedgehog通路表達(dá)水平，促進(jìn)HCC細(xì)胞的增殖和侵襲[28]。

大多數(shù)基因組拷貝數(shù)變異(CNVs)是基因組不穩(wěn)定造成的，因此一部分CNVs具有致癌效應(yīng)。癌細(xì)胞中多種CNVs位于非編碼區(qū)域，與lncRNA異常表達(dá)相關(guān)。在HCC中，lncRNA PRAL存在高頻的拷貝數(shù)缺失，而其通過(guò)結(jié)合HSP90蛋白促進(jìn)HSP90與p53的結(jié)合，從而提高p53核內(nèi)表達(dá)，促進(jìn)腫瘤細(xì)胞的凋亡，發(fā)揮抑癌作用[29]。同樣，lncRNA TSLNC8在HCC中存在拷貝數(shù)缺失，而TSLNC8可通過(guò)與TKT和STAT3競(jìng)爭(zhēng)，并誘導(dǎo)IL-6/STAT3通路失活，發(fā)揮抑癌作用[30]。LncRNA PRAL和TSLNC8拷貝數(shù)變異參與HCC的發(fā)生與發(fā)展。

研究[31]發(fā)現(xiàn)，一部分lncRNA是其他類型非編碼RNA的來(lái)源，與miRNA關(guān)系密切。LncRNA H19是miR-675的前體，而miR-675在HCC細(xì)胞的多種生物行為中扮演重要角色，比如通過(guò)Rb蛋白影響HCC細(xì)胞增殖，通過(guò)Twist1調(diào)節(jié)間充質(zhì)-上皮細(xì)胞轉(zhuǎn)化(MET)過(guò)程等，干預(yù)HCC發(fā)展[32]。除此之外，H19在HCC細(xì)胞中的促增殖作用還可以通過(guò)抑制PHB1表達(dá)來(lái)實(shí)現(xiàn)，PHB1通過(guò)與CTCF的作用可以反向調(diào)控H19的表達(dá)。H19與PHB1構(gòu)成的作用環(huán)路在HCC中發(fā)揮作用[33]。

以往認(rèn)為惡性腫瘤轉(zhuǎn)移是腫瘤發(fā)展的晚期階段，但越來(lái)越多的證據(jù)表明，在腫瘤發(fā)展的早期，甚至原發(fā)灶腫瘤未形成時(shí)，腫瘤細(xì)胞可能已經(jīng)發(fā)生了轉(zhuǎn)移[34]。上皮細(xì)胞-間充質(zhì)轉(zhuǎn)化(EMT)是上皮細(xì)胞通過(guò)特定程序轉(zhuǎn)化為具有間質(zhì)表型細(xì)胞的過(guò)程，與腫瘤的轉(zhuǎn)移侵襲行為密切相關(guān)。目前發(fā)現(xiàn)部分lncRNAs參與這一過(guò)程，詳見表1。

表1 通過(guò)EMT增強(qiáng)HCC細(xì)胞侵襲轉(zhuǎn)移能力的lncRNA

3 LncRNA在HCC預(yù)后中的價(jià)值

HCC的預(yù)后相關(guān)指標(biāo)與lncRNA的表達(dá)關(guān)系密切。Yuan等[47]在215例HCC患者中發(fā)現(xiàn)，癌組織中的MVIH高表達(dá)與無(wú)復(fù)發(fā)生存率(RFS，P<0.001) 和總存活率(OS，P=0.007)較低明顯相關(guān)，而且組織中MVIH高表達(dá)是患者低RFS的獨(dú)立危險(xiǎn)因素。研究[48]通過(guò)分析110例接受肝移植術(shù)后HCC患者的臨床數(shù)據(jù)發(fā)現(xiàn)，HCC組織中HOTAIR高表達(dá)可作為HCC復(fù)發(fā)的獨(dú)立預(yù)后因素[風(fēng)險(xiǎn)比(HR)=3.564，P=0.001]；尤其是在米蘭標(biāo)準(zhǔn)所定義的適合行肝移植術(shù)指標(biāo)范圍以外的患者中，HOTAIR高表達(dá)組RFS患者更低。Yang等[49]在240例HCC患者中發(fā)現(xiàn)，HULC異常高表達(dá)與OS(HR=0.885，P=0.023)和無(wú)病生存率[DFS, HR=0.913，P=0.045)]相關(guān)；H19過(guò)表達(dá)是HCC患者DFS的危險(xiǎn)因素(HR=1.071，P=0.022)，在HBV陽(yáng)性的HCC患者中，H19呈現(xiàn)高表達(dá)趨勢(shì)(OR=1.14，P=0.037)。MEG3高表達(dá)同樣與HCC的預(yù)后相關(guān)。研究[50]入組的72例HCC病例中，MEG3高表達(dá)組DFS、OS優(yōu)于低表達(dá)組(P<0.05)，其表達(dá)量可以作為HCC患者的獨(dú)立預(yù)后因素(P=0.038)。研究[41]通過(guò)比較102例HCC組織和21例正常肝組織，發(fā)現(xiàn)ZEB1-AS1高表達(dá)者OS(P=0.017)和DFS(P=0.013)降低，說(shuō)明ZEB1-AS1異常表達(dá)是患者生存率的獨(dú)立預(yù)測(cè)因素。

4 LncRNA在HCC治療中的前景

腫瘤細(xì)胞的自噬現(xiàn)象與腫瘤耐藥性的關(guān)系是目前研究的熱點(diǎn)。前期已有學(xué)者發(fā)現(xiàn)腫瘤細(xì)胞的自噬與化療敏感性形成有關(guān)[51]。轉(zhuǎn)錄因子SP對(duì)HULC具有調(diào)控作用，HULC可通過(guò)穩(wěn)定Sirt1來(lái)誘導(dǎo)自噬行為，削弱HCC的化療敏感性[52]。因此，二甲雙胍這類可降低SP及其管控基因表達(dá)的藥物具有增強(qiáng)化療效果的潛力[53]。HOTAIR在HCC中可以通過(guò)上調(diào)ATG3和ATG7的水平誘導(dǎo)自噬的發(fā)生[54]。另外，研究[55]還發(fā)現(xiàn)，部分基于胞外囊泡進(jìn)行轉(zhuǎn)運(yùn)的lncRNA與HCC化療敏感性的改變關(guān)系密切，如lincRNA-ROR。lncARSR通過(guò)胞外囊泡向周圍組織傳遞腎癌耐藥性改變的信號(hào)[56]。LncRNA對(duì)HCC細(xì)胞化療敏感性的影響也可能通過(guò)胞外囊泡形式傳遞給周圍癌細(xì)胞，HCC細(xì)胞中經(jīng)胞外囊泡轉(zhuǎn)運(yùn)的lncRNA如TUC339，同樣可以改變腫瘤表型[57]。

以外源lncRNA對(duì)相關(guān)調(diào)控通路進(jìn)行干擾也是有潛力的治療手段。研究[58]利用MS2病毒樣顆粒(VLPs)與GE11多肽交聯(lián)，成功構(gòu)建了MEG3運(yùn)載體，其經(jīng)網(wǎng)格蛋白介導(dǎo)的內(nèi)吞作用，靶向作用于EGFR陽(yáng)性的HCC細(xì)胞。外源導(dǎo)入的MEG3在胞內(nèi)通過(guò)增強(qiáng)p53及下游GDF15的表達(dá)，降低MDM2表達(dá)，進(jìn)而抑制HCC細(xì)胞的增殖。研究結(jié)果顯示了lncRNA與生物工程結(jié)合應(yīng)用于HCC治療的潛在價(jià)值。

近年來(lái)，免疫治療成為腫瘤學(xué)治療領(lǐng)域的熱點(diǎn)，是癌癥治療探索過(guò)程中的里程碑。LncRNA在免疫調(diào)控方面的重要作用顯示其在免疫治療中的應(yīng)用價(jià)值[59]，如lncEGFR特異性結(jié)合EGFR，通過(guò)阻斷其與c-CBL的相互作用及隨后的泛素化來(lái)穩(wěn)定EGFR的表達(dá)，引起調(diào)節(jié)性T細(xì)胞的分化、細(xì)胞毒性T細(xì)胞的抑制以及HCC的發(fā)展[60]。通過(guò)靶向調(diào)節(jié)lncRNA來(lái)協(xié)助免疫治療具有較高的潛力。

5 總結(jié)和展望

在中國(guó)，HCC的發(fā)病率和死亡率非常高，故針對(duì)HCC相關(guān)的研究顯得尤為迫切。前期的研究成果和臨床新技術(shù)已在提高HCC療效方面取得了較為滿意的效果，但不同生理狀況和病理類型等個(gè)體化因素對(duì)療效和預(yù)后影響很大，故目前對(duì)于HCC的治療正向個(gè)體化、精準(zhǔn)化的方向發(fā)展。LncRNA作為在腫瘤發(fā)展過(guò)程中起廣泛調(diào)控作用的因子，是個(gè)體化精準(zhǔn)治療的重要一環(huán)。雖然目前對(duì)lncRNA在HCC中的作用還未充分了解，但最新發(fā)現(xiàn)的lncRNA TERRA與端粒酶之間的密切聯(lián)系和對(duì)端粒長(zhǎng)度的監(jiān)控作用顯示出lncRNA在腫瘤領(lǐng)域作用的深度[61- 62]。因此，lncRNA在HCC組織中的調(diào)控作用是今后研究的重點(diǎn)，也是臨床檢測(cè)、診斷和治療的潛在靶點(diǎn)。

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