長(zhǎng)鏈非編碼RNA與宮頸癌

符文慧，侯敢，黃迪南

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長(zhǎng)鏈非編碼RNA與宮頸癌

符文慧，侯敢，黃迪南

廣東醫(yī)科大學(xué) 生物化學(xué)與分子生物學(xué)研究所，廣東 湛江 524023

符文慧, 侯敢, 黃迪南. 長(zhǎng)鏈非編碼RNA與宮頸癌. 生物工程學(xué)報(bào), 2019, 35(4): 598–606.Fu WH, Hou G, Huang DN. Long non-coding RNA and cervical cancer. Chin J Biotech, 2019, 35(4): 598–606.

長(zhǎng)鏈非編碼RNA (Long non-coding RNA，lncRNAs) 是RNA的其中一員，其結(jié)構(gòu)類似于mRNA，但由于沒有保守的開放閱讀框，因此不能編碼蛋白質(zhì)。LncRNAs曾被認(rèn)為是基因轉(zhuǎn)錄后的異?，F(xiàn)象或噪音，沒有任何的生物學(xué)功能。隨著研究的進(jìn)一步深入，發(fā)現(xiàn)其可作為重要的調(diào)控分子參與人類正常或異常的生物學(xué)活動(dòng)過程。LncRNAs與神經(jīng)系統(tǒng)功能、機(jī)體代謝紊亂以及腫瘤等疾病的發(fā)生發(fā)展密切相關(guān)。異常表達(dá)于宮頸癌的lncRNAs通過發(fā)揮抑制腫瘤或促進(jìn)腫瘤的作用，參與調(diào)控宮頸癌的各個(gè)生物學(xué)過程。文中結(jié)合最新報(bào)道就lncRNAs在宮頸癌的異常調(diào)節(jié)、分子調(diào)節(jié)機(jī)制和潛在臨床應(yīng)用方面進(jìn)行綜述。

長(zhǎng)鏈非編碼RNA，宮頸癌，異常調(diào)節(jié)，分子調(diào)節(jié)機(jī)制，潛在臨床應(yīng)用

宮頸癌是嚴(yán)重威脅婦女健康的第2位惡性腫瘤，每年全球新增宮頸癌病例約49萬(wàn)多例。近年來我國(guó)宮頸癌的發(fā)生有明顯上升和年輕化趨勢(shì)[1]。宮頸癌是由多種因素、多個(gè)基因以及多個(gè)環(huán)節(jié)共同相互作用形成復(fù)雜分子調(diào)控機(jī)制的疾病。早期宮頸癌以手術(shù)切除為主，預(yù)后良好，而中晚期宮頸癌以手術(shù)聯(lián)合放化療為主，預(yù)后較差[2]。宮頸癌的診斷和治療缺乏監(jiān)測(cè)腫瘤轉(zhuǎn)移、判斷預(yù)后、復(fù)發(fā)以及指導(dǎo)個(gè)體化治療的特異性指標(biāo)，所以，尋找理想有效的腫瘤分子標(biāo)志物，對(duì)于提高宮頸癌的診斷和治療具有重要意義。目前生命科學(xué)領(lǐng)域研究熱門的腫瘤分子標(biāo)志物是lncRNAs。陳干濤等學(xué)者應(yīng)用高通量lncRNA芯片技術(shù)檢測(cè)宮頸癌組織和正常宮頸組織lncRNA表達(dá)譜的變化，共檢測(cè)出30 586條lncRNA，進(jìn)行聚類分析和比較后，發(fā)現(xiàn)差異性表達(dá)的lncRNA共22 043條，其中11 545條表達(dá)上調(diào)，10 498條表達(dá)下調(diào)[3]。表明lncRNA在宮頸癌中扮演著重要的角色，而其在宮頸癌中具有什么功能和如何發(fā)揮作用值得探討。

絕大多數(shù)人類基因組都能被轉(zhuǎn)錄，但僅有少于2%的基因組為蛋白質(zhì)編碼基因，其余基因組轉(zhuǎn)錄生成非編碼RNA (Non-coding RNA，ncRNAs)。ncRNAs根據(jù)分子長(zhǎng)度可分成兩大類，即長(zhǎng)度小于200 nt的短鏈非編碼RNA (Small non-coding RNA，sncRNAs)和長(zhǎng)度大于200 nt的長(zhǎng)鏈非編碼RNA (Long non-coding RNA，lncRNAs)。根據(jù)鄰近蛋白編碼轉(zhuǎn)錄本的相對(duì)位置，lncRNAs可分為正義lncRNAs、反義lncRNAs、雙向lncRNAs、基因內(nèi)lncRNAs、基因間lncRNAs[4]。隨著二代測(cè)序技術(shù)的發(fā)展，lncRNAs在真核生物的生物學(xué)功能和行為機(jī)制逐漸被闡明。研究表明，lncRNAs可與DNA、RNA以及蛋白質(zhì)相互作用，通過對(duì)DNA甲基化、組蛋白修飾和miRNA競(jìng)爭(zhēng)抑制作用的不同分子機(jī)制調(diào)控細(xì)胞的生物學(xué)過程[5-7]。lncRNAs不僅廣泛參與機(jī)體正常的生長(zhǎng)發(fā)育過程，而且與人類疾病的發(fā)生發(fā)展密切相關(guān)。研究表明多種lncRNAs在宮頸癌的發(fā)生發(fā)展及宮頸癌治療后表達(dá)變化顯著[3,8]。因此，深入研究lncRNAs與宮頸癌之間的關(guān)系，有望為宮頸癌的臨床診斷和有效治療提供新的依據(jù)。lncRNAs在宮頸癌的異常調(diào)節(jié)詳見圖1。

1 lncRNAs在宮頸癌的異常調(diào)節(jié)

LncRNAs在細(xì)胞的多個(gè)生物學(xué)進(jìn)程中發(fā)揮功能，研究表明多種lncRNAs在宮頸癌中存在差異性表達(dá)，并且可作為抑癌基因或促癌基因參與宮頸癌細(xì)胞的生長(zhǎng)、分化、遷移、侵襲以及凋亡等過程，從而影響宮頸癌的發(fā)生與發(fā)展進(jìn)程[3,9]。

1.1 lncRNAs影響宮頸癌的進(jìn)程和預(yù)后

宮頸癌是由多種因素、多個(gè)基因以及多個(gè)環(huán)節(jié)通過復(fù)雜的分子調(diào)節(jié)機(jī)制共同相互作用而引發(fā)的疾病。越來越多的研究表明lncRNAs可用于腫瘤的診斷和預(yù)后評(píng)估[10-11]。Jin等通過lncRNA微陣列芯片發(fā)現(xiàn)異常表達(dá)于宮頸癌。在宮頸癌組織表達(dá)顯著升高，且其可促進(jìn)細(xì)胞周期、增殖、遷移和侵襲的過程，以及抑制細(xì)胞凋亡。機(jī)制研究表明沉默后，表達(dá)顯著升高，而下游的靶基因表達(dá)顯著降低，進(jìn)而抑制宮頸癌的發(fā)展進(jìn)程[12](圖1a)。另外，從正常宮頸組織、宮頸上皮內(nèi)瘤變(Cervical intraepithelial neoplasia，CIN) 至宮頸癌組織，F(xiàn)an等[13]發(fā)現(xiàn)炎癥相關(guān)lncRNA白介素7受體(Interleukin 7 receptor，)表達(dá)呈遞增趨勢(shì)。高表達(dá)與腫瘤的大小、FIGO分期、淋巴結(jié)轉(zhuǎn)移呈正相關(guān)，且其高表達(dá)的患者整體生存率縮短，具有不良的預(yù)后。Cox回歸分析表明可作為宮頸癌獨(dú)立的預(yù)后因子。功能實(shí)驗(yàn)顯示干擾表達(dá)可抑制宮頸癌的生長(zhǎng)，體外實(shí)驗(yàn)顯示Bcl-2表達(dá)降低，caspase-3表達(dá)升高，通過促進(jìn)細(xì)胞凋亡進(jìn)而抑制宮頸癌的生長(zhǎng)；并且體內(nèi)實(shí)驗(yàn)也顯示腫瘤增殖標(biāo)志物Ki-67表達(dá)降低而抑制宮頸癌的生長(zhǎng)(圖1b)。

與此相反，長(zhǎng)鏈非編碼、在宮頸癌中低表達(dá)。母系表達(dá)基因3 (Materally expressed gene 3，) 是首個(gè)被發(fā)現(xiàn)的印記lncRNA，具有抑制腫瘤的作用，其定位于染色體14q32。低表達(dá)于宮頸癌且與FIGO分期、腫瘤大小和淋巴結(jié)轉(zhuǎn)移呈負(fù)相關(guān)[14]。Wang等[15]通過RT-PCR和Western blotting分析顯示過表達(dá)后，PI3K、AKT、MMP-2、MMP-9和Bcl-2基因和蛋白表達(dá)都降低，而Bax和P21基因和蛋白表達(dá)都升高。這表明在宮頸癌中通過調(diào)節(jié)PI3K/AKT/Bcl-2/Bax/P21和PI3K/AKT/MMP- 2/9信號(hào)通路抑制宮頸癌的進(jìn)程(圖1c)。另外，轉(zhuǎn)錄因子鋅指蛋白667 (Zinc finger protein 667,) 也被稱為。其在宮頸癌中顯著低表達(dá)，且表達(dá)量與整體生存率、腫瘤大小和FIGO分期呈負(fù)相關(guān)，而高表達(dá)可降低宮頸癌細(xì)胞增殖和克隆能力[16](圖1d)。

1.2 lncRNAs影響宮頸癌的侵襲和遷移

侵襲是腫瘤細(xì)胞轉(zhuǎn)移過程中最關(guān)鍵的步驟，其包括細(xì)胞基質(zhì)的降解、腫瘤細(xì)胞動(dòng)力分子通路的激活、細(xì)胞間鏈接的轉(zhuǎn)變等[17]。lncRNAs對(duì)促進(jìn)細(xì)胞的生長(zhǎng)必不可少，其異常表達(dá)有助于腫瘤細(xì)胞的生長(zhǎng)存活。長(zhǎng)鏈非編碼ZEB1反義1 (LncRNA ZEB1 Antisense 1，)在宮頸癌中表達(dá)上調(diào)，且其與宮頸癌侵襲和遷移的臨床特性相關(guān)。Gan等[18]在實(shí)驗(yàn)中發(fā)現(xiàn)通過干擾表達(dá)可顯著降低p-p38表達(dá)，表明沉默可有效抑制p38MAPK信號(hào)通路。進(jìn)一步實(shí)驗(yàn)發(fā)現(xiàn)相對(duì)于對(duì)照組，共轉(zhuǎn)染siRNA和p38MAPK通路的抑制劑SB203580可使抑制上皮-間質(zhì)轉(zhuǎn)化(Epithelial-to-mesenchymal transition，EMT) 相關(guān)的蛋白E-鈣粘蛋白(E-cadherin) 表達(dá)顯著上調(diào)，而促進(jìn)EMT轉(zhuǎn)化的波形蛋白(Vimentin) 和N-鈣粘蛋白(N-cadherin) 沒有明顯變化。此外，干擾后，抑制HeLa細(xì)胞EMT轉(zhuǎn)化過程可被p38MAPK激活劑茴香霉素逆轉(zhuǎn)，表明低表達(dá)可通過阻斷p38MAPK信號(hào)通路抑制HeLa細(xì)胞EMT轉(zhuǎn)化，進(jìn)而抑制HeLa細(xì)胞侵襲和遷移(圖1e)。另外，Huang等發(fā)現(xiàn)同源盒基因轉(zhuǎn)錄物反義RNA (Homeobox gene transcript antisense RNA，)，一種高表達(dá)于宮頸癌的lncRNA，其與宮頸癌的不良預(yù)后相關(guān)[19]。Kim等[20]發(fā)現(xiàn)沉默后，VEGF和 MMP-9表達(dá)顯著降低，E-cadherin表達(dá)升高，而β-catenin和Vimentin表達(dá)降低，促進(jìn)EMT轉(zhuǎn)化的轉(zhuǎn)錄因子Snail和Twist表達(dá)降低，從而抑制宮頸癌侵襲和遷移。這些標(biāo)志物和轉(zhuǎn)錄因子都是腫瘤侵襲和遷移的重要參與者(圖1f)。另外，在沉默后，表達(dá)上調(diào)，而下游靶蛋白巨核細(xì)胞白血病因子1 (Megakaryoblastic leukemia 1，MKL1) 表達(dá)下調(diào)，并且可增加MKL1在胞質(zhì)的分布，表明通過抑制表達(dá)進(jìn)而促進(jìn)MKL1表達(dá)和改變MKL1細(xì)胞內(nèi)的分布從而促進(jìn)宮頸癌侵襲和遷移。然而，MKL1可結(jié)合啟動(dòng)子盒活化轉(zhuǎn)錄，并與形成正反饋而促進(jìn)表達(dá)?？偠灾?，MKL1是在宮頸癌侵襲和遷移的重要促發(fā)者[21](圖1f)。

1.3 lncRNAs影響宮頸癌的凋亡和增殖

lncRNAs通過調(diào)控腫瘤細(xì)胞的增殖和凋亡，進(jìn)而影響腫瘤細(xì)胞的轉(zhuǎn)歸。?；撬嵘险{(diào)基因1 (Taurine upregulated gene 1，) 是在宮頸癌表達(dá)上調(diào)的lncRNA，其與宮頸癌細(xì)胞的生物學(xué)特性和不良預(yù)后密切相關(guān)[22]。Hu等研究發(fā)現(xiàn)，通過實(shí)驗(yàn)敲除，細(xì)胞凋亡的線粒體通路相關(guān)蛋白Bcl-2表達(dá)顯著降低，caspase-3表達(dá)顯著升高，從而促進(jìn)宮頸癌細(xì)胞凋亡[23](圖1g)。此外，宮頸癌高表達(dá)lncRNA 1 (Cervical carcinoma high- expressed lncRNA 1，) 其過表達(dá)可促進(jìn)宮頸癌細(xì)胞增殖，而敲除則抑制細(xì)胞增殖[24]。RNA pull-down分析顯示生理上與mRNA結(jié)合，兩者之間相互作用，導(dǎo)致腫瘤增殖標(biāo)志物增殖細(xì)胞核抗原(Proliferating cell nuclear antigen，PCNA) 表達(dá)量上調(diào)，從而促進(jìn)宮頸癌細(xì)胞增殖(圖1h)。另外，下調(diào)肌動(dòng)蛋白纖維相關(guān)蛋白1-反義RNA 1 (Actin filament-associated protein 1-antisense RNA1，) 和癌癥相關(guān)區(qū)域長(zhǎng)非編碼RNA (Cancer-associated region long non-coding RNA，)可使細(xì)胞發(fā)生S期阻滯，S期相關(guān)蛋白CDK2和Cyclin A2表達(dá)量出現(xiàn)不同程度的下調(diào)，進(jìn)而抑制HeLa細(xì)胞增殖能力。表明和通過調(diào)節(jié)細(xì)胞周期而影響宮頸癌增殖[25](圖1i和1j)。

1.4 lncRNAs影響宮頸癌的放化療抵抗作用

越來越多的研究表明，lncRNAs可通過調(diào)節(jié)細(xì)胞周期、凋亡以及DNA損傷修復(fù)等方面發(fā)揮放化療抵抗的功能[26-29]。Iden等發(fā)現(xiàn)人漿細(xì)胞瘤轉(zhuǎn)化遷移基因1 (Plasmacytoma variant translocation 1，)，一種顯著高表達(dá)于宮頸癌的lncRNA，其高表達(dá)與化療藥物順鉑抵抗相關(guān)[30]。同時(shí)，Shen等[31]也發(fā)現(xiàn)抑制表達(dá)可使CaSki細(xì)胞中E-cadherin表達(dá)顯著升高，而Fibronectin和Vimentin表達(dá)顯著降低，從而增加CaSki細(xì)胞對(duì)紫杉醇敏感性，而高表達(dá)可誘導(dǎo)EMT轉(zhuǎn)化而使宮頸癌細(xì)胞對(duì)紫杉醇產(chǎn)生抵抗。這表明PVT1通過促進(jìn)EMT轉(zhuǎn)化而促進(jìn)宮頸癌細(xì)胞對(duì)紫杉醇產(chǎn)生抵抗(圖1k)。此外，易感候選基因2 (Cancer susceptibility candidate 2，) 是低表達(dá)于宮頸癌的lncRNA。沉默表達(dá)可顯著減弱順鉑抑制宮頸癌細(xì)胞增殖和提高半數(shù)致死量(IC50)值，而過表達(dá)則可增加順鉑抑制宮頸癌細(xì)胞增殖和降低IC50值。這表明低表達(dá)促進(jìn)宮頸癌對(duì)順鉑抵抗。機(jī)制研究顯示可競(jìng)爭(zhēng)性抑制，從而使下游靶蛋白PTEN (腫瘤抑制子) 表達(dá)上調(diào)，PTEN通過調(diào)控AKT信號(hào)通路而促進(jìn)宮頸癌細(xì)胞對(duì)順鉑化學(xué)敏感性[32](圖1l)。另外，核富集豐富轉(zhuǎn)錄本1 (Nuclear enriched abundant transcript 1，)是高表達(dá)于放療抵抗宮頸癌細(xì)胞的lncRNA[33]。沉默表達(dá)可減弱放療抵抗細(xì)胞增殖和減少電離輻射劑量，而過表達(dá)則相反。這表明高表達(dá)與宮頸癌放療抵抗密切相關(guān)。機(jī)制研究發(fā)現(xiàn)沉默后，表達(dá)上調(diào)，cyclin D1表達(dá)下調(diào)而使細(xì)胞周期阻滯于G0/G1期，并且caspase-3和caspase-9表達(dá)上調(diào)而誘導(dǎo)細(xì)胞凋亡。這表明高表達(dá)NEAT1通過調(diào)節(jié)細(xì)胞周期和凋亡促進(jìn)宮頸癌細(xì)胞對(duì)放療抵抗(圖1m)。綜上所述，在宮頸癌放化療中，lncRNAs可通過一定的分子調(diào)節(jié)機(jī)制發(fā)揮放化療抵抗功能。因此，對(duì)宮頸癌患者的治療，尤其是放療或化療抵抗的患者，通過調(diào)節(jié)lncRNAs可能是一個(gè)良好的選擇。

2 lncRNAs在宮頸癌的分子調(diào)節(jié)機(jī)制

2.1 lncRNAs與蛋白質(zhì)/mRNAs的相互作用

lncRNAs可與蛋白質(zhì)、mRNA或miRNA相互作用，通過調(diào)節(jié)基因表達(dá)參與生命體基本的生物學(xué)功能，例如基因印記、組蛋白修飾、mRNA剪接等[34]。宮頸癌相關(guān)lncRNAs可直接結(jié)合蛋白質(zhì)或mRNA在轉(zhuǎn)錄后水平發(fā)揮調(diào)控作用。是高表達(dá)于宮頸癌的lncRNA，其高表達(dá)可促進(jìn)宮頸癌細(xì)胞增殖和抑制細(xì)胞凋亡[35]。機(jī)制研究顯示可直接與細(xì)胞增殖相關(guān)轉(zhuǎn)錄因子白介素結(jié)合因子2 (Interleukin enhancer binding factor 2，)結(jié)合，這對(duì)mRNA水平無影響，但I(xiàn)LF2蛋白質(zhì)水平發(fā)生了顯著變化：沉默后，ILF2蛋白半衰期縮短，而過表達(dá)后，ILF2蛋白半衰期延長(zhǎng)。這表明可抑制ILF2蛋白降解，從而促進(jìn)宮頸癌細(xì)胞增殖和抑制細(xì)胞凋亡。此外，宮頸癌高表達(dá)可結(jié)合的mRNA使表達(dá)上調(diào)，進(jìn)而促進(jìn)宮頸癌細(xì)胞增殖[24]。這些研究表明在宮頸癌發(fā)展的過程中，lncRNAs與蛋白質(zhì)或mRNA相互作用發(fā)揮著關(guān)鍵的作用。

圖1 lncRNAs在宮頸癌的異常調(diào)節(jié)

2.2 lncRNAs與miRNAs的相互作用

競(jìng)爭(zhēng)內(nèi)源RNA (Competing endogenous RNA, ceRNA)假說是ncRNA家族中的lncRNAs、mRNA、假基因和環(huán)狀RNA通過其miRNA反應(yīng)元件(MiRNA response elements，MRE) 競(jìng)爭(zhēng)性地結(jié)合miRNA，從而調(diào)控基因的表達(dá)。也就是說lncRNAs可充當(dāng)ceRNA在轉(zhuǎn)錄后水平上抑制miRNA表達(dá)和活性[36-38]。Gao等報(bào)道表達(dá)與呈負(fù)相關(guān)，表明可通過負(fù)性調(diào)節(jié)表達(dá)而促進(jìn)宮頸癌細(xì)胞增殖、遷移和侵襲，從而促進(jìn)宮頸癌的發(fā)展[39]。另外，可競(jìng)爭(zhēng)性結(jié)合，使下游靶蛋白PTEN表達(dá)上調(diào)，從而促進(jìn)宮頸癌細(xì)胞對(duì)順鉑化學(xué)敏感性而抑制宮頸癌的發(fā)展[32]。此外，也可作為ceRNA抑制表達(dá)，從而使下游靶標(biāo)cyclin D1表達(dá)上調(diào)，加速細(xì)胞周期而促進(jìn)宮頸癌的發(fā)展[33]。綜上所述，lncRNA可充當(dāng)“miRNA海綿”抑制miRNA的表達(dá)，使miRNA下游靶標(biāo)表達(dá)上調(diào)或下調(diào)，從而促進(jìn)腫瘤或者抑制腫瘤的發(fā)展。

2.3 lncRNAs的單核苷酸多態(tài)性(Single nucleotide polymorphisms, SNPs)

全基因組關(guān)聯(lián)研究(Genome-wide association studies，GWAS) 揭示大量與疾病和性狀相關(guān)的遺傳變異關(guān)系密切，其中至少有三分之一已識(shí)別的變異不在蛋白質(zhì)編碼基因內(nèi)，而是映射到非編碼區(qū)間[40]。Verhaegh等首次報(bào)道H19基因的單核苷酸多態(tài)性與膀胱癌形成風(fēng)險(xiǎn)密切相關(guān)，從此拉開了lncRNA的單核苷酸與腫瘤研究的序幕[41]。多項(xiàng)研究表明抑癌基因或促癌基因單核苷酸多態(tài)性等體細(xì)胞突變?cè)趯m頸癌遺傳易感性中起重要作用[42-44]。Guo等[45]通過對(duì)510名宮頸癌患者與713名正常人進(jìn)行病例對(duì)照分析發(fā)現(xiàn)內(nèi)3個(gè)單倍體標(biāo)簽SNPs (rs920778，rs1899663和rs4759314)與宮頸癌形成風(fēng)險(xiǎn)關(guān)系緊密。其中在增強(qiáng)子基因內(nèi)的SNP rs920778與宮頸癌有強(qiáng)關(guān)聯(lián)性。相對(duì)于野生型rs920778 CC基因型，攜帶rs920778 (CT+TT) 突變基因型的患者形成宮頸癌的風(fēng)險(xiǎn)增加2.17倍。rs920778 SNP T變異等位基因定位于內(nèi)含子2區(qū)，可增強(qiáng)位于內(nèi)含子2區(qū)增強(qiáng)子的活性。并且相對(duì)于rs920778 CC者，攜帶rs920778 CT或TT基因型的宮頸癌患者mRNA表達(dá)顯著升高。這表明風(fēng)險(xiǎn)相關(guān)等位基因T與HOTAIR表達(dá)息息相關(guān)，并且SNP rs920778可促進(jìn)表達(dá)，進(jìn)而促進(jìn)宮頸癌的遺傳易感性。同時(shí)，Jin等也報(bào)道rs7958904通過調(diào)節(jié)宮頸癌細(xì)胞增殖影響宮頸癌的遺傳易感性[46]。此外，有研究表明TNF和HNRNPL相關(guān)免疫調(diào)節(jié)lncRNA (TNF and HNRNPL related immunoregulatory lncRNA，) 基因的rs7133268可減少宮頸癌前病變的遺傳易感性[47]。這些研究表明lncRNA的單核苷酸多態(tài)性在宮頸癌的發(fā)生與發(fā)展中發(fā)揮重要作用。

3 lncRNAs在宮頸癌的潛在臨床應(yīng)用

轉(zhuǎn)移和復(fù)發(fā)是宮頸癌臨床治療的最大障礙。所以，尋找有效的腫瘤標(biāo)志物對(duì)提高宮頸癌的預(yù)后具有重要價(jià)值。lncRNAs可用于宮頸癌的診斷和預(yù)后評(píng)估。例如，受試者工作特征曲線(Receiver operating characteristic curve，ROC) 分析顯示SPRY4內(nèi)含子轉(zhuǎn)錄本1 (SPRY4 intronic transcript 1，) 的表達(dá)是區(qū)分宮頸癌組織和正常組織的良好候選物(靈敏度：78.3%，特異性：63.6%)，ROC曲線下的面積(Area under ROC curve，AUC)為0.741(95%CI：0.632–0.849,<0.001)，表明用于宮頸癌的診斷準(zhǔn)確性較高[48]。此外，也可用于區(qū)分宮頸癌組織與正常組織(敏感性：60.6%，特異性：87.2%)以及淋巴結(jié)是否發(fā)生轉(zhuǎn)移(敏感度：85.1%，特異性：64.9%)，并且多因素Cox回歸模型顯示FIGO分期(<0.000 1，HR=1.994，95%CI: 1.359–2.927)、淋巴結(jié)轉(zhuǎn)移(=0.005，HR=2.636，95% CI: 1.348– 5.156) 和表達(dá)水平(=0.012，HR=2.863，95% CI: 1.263–6.490)，表明HOTAIR對(duì)宮頸癌診斷準(zhǔn)確性高，可作為宮頸癌預(yù)后評(píng)估的獨(dú)立預(yù)測(cè)因子[19]。綜上所述，lncRNAs中的和是宮頸癌有前途的標(biāo)志物，可作為宮頸癌診斷指標(biāo)和預(yù)后判斷的良好標(biāo)志物。

4 結(jié)語(yǔ)與展望

lncRNAs貫穿于生物學(xué)過程的始終，其通過各種不同的分子調(diào)節(jié)機(jī)制參與調(diào)控宮頸癌細(xì)胞的增殖、抗凋亡、遷移、放化療抵抗等過程，并且在宮頸癌發(fā)生發(fā)展過程中發(fā)揮著關(guān)鍵的作用。因此，這些lncRNAs都是宮頸癌理想的分子標(biāo)志物，有望成為宮頸癌治療的有效靶點(diǎn)。雖然在宮頸癌病理發(fā)展的機(jī)制中，lncRNAs的研究已經(jīng)取得了一定成就，但宮頸癌的發(fā)生發(fā)展并非單因素決定，lncRNAs參與宮頸癌發(fā)病具體的調(diào)控機(jī)制及功能模式有待進(jìn)一步的深入研究，有待與影響宮頸癌發(fā)病的其他因素相結(jié)合。例如：lncRNAs與表觀遺傳學(xué)的研究，包括DNA甲基化、組蛋白修飾、基因印跡、染色體重塑等方面；lncRNAs與miRNA調(diào)控網(wǎng)絡(luò)的研究以及l(fā)ncRNAs與細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)通路的研究等。后續(xù)研究的工作重心應(yīng)以現(xiàn)有的研究成果為切入點(diǎn)，進(jìn)一步深化lncRNAs調(diào)控宮頸癌發(fā)生發(fā)展機(jī)制的研究，全面揭示其中的奧秘。lncRNAs作為臨床宮頸癌診治的有效標(biāo)志物必將具有廣闊的應(yīng)用前景。

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Long non-coding RNA and cervical cancer

Wenhui Fu, Gan Hou, and Dinan Huang

Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, Guangdong, China

Long non-coding RNAs (lncRNAs) are members of RNA that are structurally similar to mRNA. They cannot encode proteins because they do not have a conserved open reading frame. LncRNAs were once regarded as abnormalities or noises or without any biological function after gene transcription. With the further development of research, it has been found that it can participate in normal or abnormal biological processes as an important regulator. LncRNAs are closely related to the development of nervous system function, metabolic disorders and tumors. LncRNAs abnormally expressed in cervical cancer participate in the regulation of various biological processes of cervical cancer by inhibiting or promoting tumors. This article reviews the recent reports on the abnormal regulation, molecular regulation mechanism and potential clinical application of lncRNAs in cervical cancer.

long non-coding RNAs, cervical cancer, abnormal regulation, molecular regulation mechanism, potential clinical application

10.13345/j.cjb.180493

November 28, 2018;

January 29, 2019

the First Science and Technology Project in Guangdong Province (No. 2008B030301023), Science and Technology Plan of Dongguan University (Nos. 200910815264, 2012108102016).

Gan Hou. Tel: +86-769-22896350; E-mail: 414786517@qq.com

廣東省首個(gè)科技項(xiàng)目(No. 2008B030301023)，東莞高等院校科技計(jì)劃(Nos. 200910815264, 2012108102016) 資助。

(本文責(zé)編 陳宏宇)