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)。

[ 1 ] BERTUCCIO P, TURATI F, CARIOLI G, et al. Global trends and predictions in hepatocellular carcinoma mortality[J]. J Hepatol, 2017,67(2): 302-309.

[ 2 ] TORRE L A, BRAY F, SIEGEL R L, et al. Global cancer statistics, 2012[J]. CACancer J Clin, 2015,65(2):87-108.

[ 3 ] ESTELLER M. Non-coding RNAs in human disease[J]. Nat Rev Genet, 2011,12(12):861-874.

[ 4 ] MA L, BAJIC V B, ZHANG Z. On the classification of long non-coding RNAs[J]. RNA Biol, 2014,10(6):924-933.

[ 5 ] GUTTMAN M, RINN J L. Modular regulatory principles of large non-coding RNAs[J]. Nature, 2012,482(7385):339-346.

[ 6 ] ZHANG X D, WANG Y, YE L H. Hepatitis B virus X protein accelerates the development of hepatoma[J]. Cancer Biol Med, 2014,11(3):182-190.

[ 7 ] ZHAO J, FAN Y, WANG K, et al. LncRNA HULC affects the differentiation of Treg in HBV-related liver cirrhosis[J]. Int Immunopharmacol, 2015,28(2):901-905.

[ 8 ] Du Y, KONG G, YOU X, et al. Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18[J]. J Biol Chem, 2012,287(31):26302-26311.

[ 9 ] LI D, LIU X, ZHOU J, et al. Long noncoding RNA HULC modulates the phosphorylation of YB-1 through serving as a scaffold of extracellular signal-regulated kinase and YB-1 to enhance hepatocarcinogenesis[J]. Hepatology, 2017,65(5):1612-1627.

[10] CUI M, ZHENG M, SUN B, et al. A long noncoding RNA perturbs the circadian rhythm of hepatoma cells to facilitate hepatocarcinogenesis[J]. Neoplasia, 2015,17(1):79-88.

[11] SU D N, WU S P, CHEN H T, et al. HOTAIR, a long non-coding RNA driver of malignancy whose expression is activated by FOXC1, negatively regulates miRNA-1 in hepatocellular carcinoma[J]. Oncol Lett, 2016,12(5):4061-4067.

[12] JIANG L, LI J, SONG L. Bmi-1, stem cells and cancer[J]. Acta Biochim Biophys Sin (Shanghai), 2009,41(7):527-534.

[13] XU C R, LEE S, HO C, et al. Bmi1 functions as an oncogene independent of Ink4A/Arf repression in hepatic carcinogenesis[J]. Mol Cancer Res, 2009,7(12):1937-1945.

[14] CHIBA T, MIYAGI S, SARAYA A, et al. The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma[J]. Cancer Res, 2008,68(19):7742-7749.

[15] FU W M, ZHU X, WANG W M, et al. Hotair mediates hepatocarcinogenesis through suppressing miRNA-218 expression and activating P14 and P16 signaling[J]. J Hepatol, 2015,63(4):886-895.

[16] LI H, AN J, WU M, et al. LncRNA HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2[J]. Oncotarget, 2015,6(29):27847-27864.

[17] LI H, TANG X M, LIU Y, et al. Association of functional genetic variants of HOTAIR with hepatocellular carcinoma (HCC) susceptibility in a Chinese population[J]. Cell Physiol Biochem, 2017,44(2):447-454.

[18] TAO R, HU S, WANG S, et al. Association between indel polymorphism in the promoter region of lncRNA GAS5 and the risk of hepatocellular carcinoma[J]. Carcinogenesis, 2015,36(10):1136-1143.

[19] LU Z, XIAO Z, LIU F, et al. Long non-coding RNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1)[J]. Oncotarget, 2016,7(1):241-254.

[20] PASCUAL G, AVGUSTINOVA A, MEJETTA S, et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36[J]. Nature, 2017,541(7635):41-45.

[21] CUI M, XIAO Z, WANG Y, et al. Long noncoding RNA HULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway[J]. Cancer Res, 2015,75(5):846-857.

[22] YANG F, HUO X S, YUAN S X, et al. Repression of the long noncoding RNA-LET by histone deacetylase 3 contributes to hypoxia-mediated metastasis[J]. Mol Cell, 2013,49(6):1083-1096.

[23] WANG Y, HE L, Du Y, et al. The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling[J]. Cell Stem Cell, 2015,16(4):413-425.

[24] ZHU P, WANG Y, WU J, et al. LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cells[J]. Nat Commun, 2016,7:13608.

[25] YUAN S X, WANG J, YANG F, et al. Long noncoding RNA DANCR increases stemness features of hepatocellular carcinoma by derepression of CTNNB1[J]. Hepatology, 2016,63(2):499-511.

[26] LUO F, SUN B, LI H, et al. A MALAT1/HIF-2alpha feedback loop contributes to arsenite carcinogenesis[J]. Oncotarget, 2016,7(5):5769-5787.

[27] SUI C J, ZHOU Y M, SHEN W F, et al. Long noncoding RNA GIHCG promotes hepatocellular carcinoma progression through epigenetically regulating miR-200b/a/429[J]. J Mol Med (Berl), 2016,94(11):1281-1296.

[28] WANG Y, HU Y, WU G, et al. Long noncoding RNA PCAT-14 induces proliferation and invasion by hepatocellular carcinoma cells by inducing methylation of miR-372[J]. Oncotarget, 2017,8(21):34429-34441.

[29] ZHOU C C, YANG F, YUAN S X, et al. Systemic genome screening identifies the outcome associated focal loss of long noncoding RNA PRAL in hepatocellular carcinoma[J]. Hepatology, 2016,63(3):850-863.

[30] ZHANG J, LI Z, LIU L, et al. Long noncoding RNA TSLNC8 is a tumor suppressor that inactivates the interleukin-6/STAT3 signaling pathway[J]. Hepatology, 2018,67(1):171-187.

[31] HUANG M S, ZHU T, LI L, et al. LncRNAs and circRNAs from the same gene: masterpieces of RNA splicing[J]. Cancer Lett, 2017,415:49-57.

[32] HERNANDEZ J M, ELAHI A, CLARK C W, et al. MiR-675 mediates downregulation of Twist1 and Rb in AFP-secreting hepatocellular carcinoma[J]. Ann Surg Oncol, 2013,20Suppl 3:S625-S635.

[33] RAMANI K, MAVILA N, KO K S, et al. Prohibitin 1 regulates the H19-Igf2 axis and proliferation in hepatocytes[J]. J Biol Chem, 2016,291(46):24148-24159.

[34] HUSEMANN Y, GEIGL J B, SCHUBERT F, et al. Systemic spread is an early step in breast cancer[J]. Cancer Cell, 2008,13(1):58-68.

[35] LI S P, XU H X, YU Y, et al. LncRNA HULC enhances epithelial-mesenchymal transition to promote tumorigenesis and metastasis of hepatocellular carcinomaviathe miR-200a-3p/ZEB1 signaling pathway[J]. Oncotarget, 2016,7(27):42431-42446.

[36] XU Y, WANG B, ZHANG F, et al. Long non-coding RNA CCAT2 is associated with poor prognosis in hepatocellular carcinoma and promotes tumor metastasis by regulating snail2-mediated epithelial-mesenchymal transition[J]. Onco Targets Ther, 2017,10:1191-1198.

[37] QI H L, LI C S, QIAN C W, et al. The long noncoding RNA, EGFR-AS1, a target of GHR, increases the expression of EGFR in hepatocellular carcinoma[J]. Tumour Biol, 2016,37(1):1079-1089.

[38] YUAN J H, YANG F, WANG F, et al. A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma[J]. Cancer Cell, 2014,25(5):666-681.

[39] PAN Y, QIN T, YIN S, et al. Long non-coding RNA UC001kfo promotes hepatocellular carcinoma proliferation and metastasis by targeting alpha-SMA[J]. Biomed Pharmacother, 2017,87:669-677.

[40] DONG L, NI J, HU W, et al. Upregulation of long non-coding RNA plncRNA-1 promotes metastasis and induces epithelial-mesenchymal transition in hepatocellular carcinoma[J]. Cell Physiol Biochem, 2016,38(2):836-846.

[41] LI T, XIE J, SHEN C, et al. Upregulation of long noncoding RNA ZEB1-AS1 promotes tumor metastasis and predicts poor prognosis in hepatocellular carcinoma[J]. Oncogene, 2016,35(12):1575-1584.

[42] HUANG J F, GUO Y J, ZHAO C X, et al. Hepatitis B virus X protein (HBx)-related long noncoding RNA (lncRNA) down-regulated expression by HBx (Dreh) inhibits hepatocellular carcinoma metastasis by targeting the intermediate filament protein vimentin[J]. Hepatology, 2013,57(5):1882-1892.

[43] WANG T H, LIN Y S, CHEN Y, et al. Long non-coding RNA AOC4P suppresses hepatocellular carcinoma metastasis by enhancing vimentin degradation and inhibiting epithelial-mesenchymal transition[J]. Oncotarget, 2015,6(27):23342-23357.

[44] ZHANG L, YANG F, YUAN J H, et al. Epigenetic activation of the miR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma[J]. Carcinogenesis, 2013,34(3):577-586.

[45] WANG T H, YU C C, LIN Y S, et al. Long noncoding RNA CPS1-IT1 suppresses the metastasis of hepatocellular carcinoma by regulating HIF-1alpha activity and inhibiting epithelial-mesenchymal transition[J]. Oncotarget, 2016,7(28):43588-43603.

[46] LIU F, YUAN J H, HUANG J F, et al. Long noncoding RNA FTX inhibits hepatocellular carcinoma proliferation and metastasis by binding MCM2 and miR-374a[J]. Oncogene, 2016,35(41):5422-5434.

[47] YUAN S X, YANG F, YANG Y, et al. Long noncoding RNA associated with microvascular invasion in hepatocellular carcinoma promotes angiogenesis and serves as a predictor for hepatocellular carcinoma patients’ poor recurrence-free survival after hepatectomy[J]. Hepatology, 2012,56(6):2231-2241.

[48] YANG Z, ZHOU L, WU L M, et al. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation[J]. Ann Surg Oncol, 2011,18(5):1243-1250.

[49] YANG Z, LU Y, XU Q, et al. HULC and H19 played different roles in overall and disease-free survival from hepatocellular carcinoma after curative hepatectomy: a preliminary analysis from gene expression omnibus[J]. Dis Markers, 2015,2015:191029.

[50] ZHUO H, TANG J, LIN Z, et al. The aberrant expression of MEG3 regulated by UHRF1 predicts the prognosis of hepatocellular carcinoma[J]. Mol Carcinog, 2016,55(2):209-219.

[51] AMARAVADI R K, LIPPINCOTT-SCHWARTZ J, YIN X M, et al. Principles and current strategies for targeting autophagy for cancer treatment[J]. Clin Cancer Res, 2011,17(4):654-666.

[52] XIONG H, NI Z, HE J, et al. LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells[J]. Oncogene, 2017,36(25):3528-3540.

[53] GANDHY S U, IMANIRAD P, JIN U H, et al. Specificity protein (Sp) transcription factors and metformin regulate expression of the long non-coding RNA HULC[J]. Oncotarget, 2015,6(28):26359-26372.

[54] YANG L, ZHANG X, LI H, et al. The long noncoding RNA HOTAIR activates autophagy by upregulating ATG3 and ATG7 in hepatocellular carcinoma[J]. Mol Biosyst, 2016,12(8):2605-2612.

[55] TAKAHASHI K, YAN I K, KOGURE T, et al. Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer[J]. FEBS Open Bio, 2014,4:458-467.

[56] QU L, DING J, CHEN C, et al. Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA[J]. Cancer Cell, 2016,29(5):653-668.

[57] KOGURE T, YAN I K, LIN W L, et al. Extracellular vesicle-mediated transfer of a novel long noncoding RNA TUC339: a mechanism of intercellular signaling in human hepatocellular cancer[J]. Genes Cancer, 2013,4(7-8):261-272.

[58] CHANG L, WANG G, JIA T, et al. Armored long non-coding RNA MEG3 targeting EGFR based on recombinant MS2 bacteriophage virus-like particles against hepatocellular carcinoma[J]. Oncotarget, 2016,7(17):23988-24004.

[59] ATIANAND M K, CAFFREY D R, FITZGERALD K A. Immunobiology of long noncoding RNAs[J]. Annu Rev Immunol, 2017,35:177-198.

[60] JIANG R, TANG J, CHEN Y, et al. The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion[J]. Nat Commun, 2017,8:15129.

[61] RIPPE K, LUKE B. TERRA and the state of the telomere[J]. Nat Struct Mol Biol, 2015,22(11):853-858.

[62] ROAKE C M, ARTANDI S E. Approaching TERRA firma: genomic functions of telomeric noncoding RNA[J]. Cell, 2017,170(1):8-9.