LINE-1在腫瘤早期診斷和治療中的研究與應(yīng)用

寇艷妮，岑山，李曉宇

LINE-1在腫瘤早期診斷和治療中的研究與應(yīng)用

寇艷妮，岑山，李曉宇

中國醫(yī)學(xué)科學(xué)院&北京協(xié)和醫(yī)學(xué)院，醫(yī)藥生物技術(shù)研究所免疫生物學(xué)室，北京 100050

長散布元件-1 (long interspersed elements-1, LINE-1)約占人類基因組的17%，是人類基因組中唯一具有自主轉(zhuǎn)座能力的轉(zhuǎn)座子。LINE-1可通過逆轉(zhuǎn)錄轉(zhuǎn)座過程插入到新的基因位點(diǎn)上，從而會導(dǎo)致基因組的不穩(wěn)定。因而機(jī)體對LINE-1的復(fù)制和轉(zhuǎn)座有著嚴(yán)格的限制，在正常體細(xì)胞中幾乎檢測不到LINE-1的表達(dá)。然而，在絕大多數(shù)的腫瘤組織或癌組織中LINE-1的表達(dá)卻普遍存在，提示LINE-1的表達(dá)和轉(zhuǎn)座與腫瘤的發(fā)生發(fā)展密切相關(guān)。LINE-1在腫瘤細(xì)胞中的差異表達(dá)可以作為腫瘤早期診斷的標(biāo)志物，同時也可作為腫瘤治療預(yù)后評價的重要指標(biāo)。與此同時，LINE-1作為腫瘤治療潛在靶點(diǎn)的可行性也在評估和驗證中。本文介紹了在臨床方面LINE-1作為腫瘤診斷、預(yù)后方面的應(yīng)用，以及作為腫瘤治療潛在靶點(diǎn)的研究進(jìn)展，以期為臨床上腫瘤的診斷和治療提供一些參考。

長散布元件-1；腫瘤；診斷；治療；預(yù)后

轉(zhuǎn)座子是一類可以在同一染色體內(nèi)或在不同染色體間自由移動的基因序列，其中“轉(zhuǎn)座”即是指其位置的轉(zhuǎn)移。根據(jù)轉(zhuǎn)座方式的不同，轉(zhuǎn)座子可分為DNA轉(zhuǎn)座子和RNA轉(zhuǎn)座子兩類：DNA轉(zhuǎn)座子的轉(zhuǎn)座是利用轉(zhuǎn)座酶將自身的DNA片段從原有的基因位點(diǎn)上切下后，再整合到基因組的其他位點(diǎn)上；而RNA轉(zhuǎn)座子又被稱為逆轉(zhuǎn)錄轉(zhuǎn)座子(retrotrans-posons)，它首先通過轉(zhuǎn)錄生成RNA中間體，然后以該RNA為模板逆轉(zhuǎn)錄生成cDNA并插入到新的基因位點(diǎn)上。逆轉(zhuǎn)錄轉(zhuǎn)座子通過這樣“復(fù)制–粘貼”的轉(zhuǎn)座機(jī)制在人類基因組中得以擴(kuò)增和蔓延，從而在真核基因組中積累了大量重復(fù)序列。長散布元件-1 (long interspersed elements-1, LINE-1)是逆轉(zhuǎn)錄轉(zhuǎn)座子的一種，也是人類基因組中現(xiàn)今唯一具有自主轉(zhuǎn)座活性的轉(zhuǎn)座子，約占人類基因組的17%[1]。LINE-1曾在物種形成和生物進(jìn)化中發(fā)揮了至關(guān)重要的作用，但其逆轉(zhuǎn)錄轉(zhuǎn)座活性對于基因組維持穩(wěn)定性來說也是巨大的威脅。LINE-1的逆轉(zhuǎn)錄轉(zhuǎn)座能夠引起基因組DNA的異常轉(zhuǎn)錄、選擇性剪接、插入突變、DNA損傷從而導(dǎo)致基因組不穩(wěn)定[2,3]。大量的證據(jù)表明，LINE-1通過逆轉(zhuǎn)錄轉(zhuǎn)座直接或間接地參與了腫瘤的發(fā)生和發(fā)展，在正常組織和癌旁組織中LINE-1的表達(dá)與癌組織中的也有不同，評估LINE-1作為腫瘤早期診斷標(biāo)志物、預(yù)后評價指標(biāo)和抗癌藥物靶點(diǎn)的潛力，能夠為更新腫瘤診斷和預(yù)后手段以及腫瘤的治療提供理論依據(jù)，也能為腫瘤的早期發(fā)現(xiàn)和個性化治療提供借鑒和參考[1,4～6]。本文就近年來LINE-1在腫瘤中的表達(dá)以及作為生物標(biāo)志物在腫瘤的早期診斷、治療和預(yù)后判定中的應(yīng)用進(jìn)展作一綜述。

1 LINE-1的結(jié)構(gòu)與功能

LINE-1全長6 kb，包括含有內(nèi)部啟動子的5′端非翻譯區(qū)(untranslated region, UTR)、兩個不重疊的開放式讀碼框架(open reading frame, ORF)ORF1和ORF2以及以poly(A)尾結(jié)尾的3′端UTR，靈長類動物的LINE-1 5?UTR還含有一個物種特異性的ORF0編碼區(qū)。ORF1和ORF2編碼的蛋白對LINE-1的逆轉(zhuǎn)錄轉(zhuǎn)座是不可缺少的。ORF1p由338個氨基酸組成，大小約40 kDa，其C端相當(dāng)保守，參與RNA結(jié)合；N端具有亮氨酸拉鏈的結(jié)構(gòu)特征，能夠介導(dǎo)蛋白質(zhì)之間的相互作用；ORF2p約150 kDa，包括三個保守的結(jié)構(gòu)域，分別是N端的核酸內(nèi)切酶結(jié)構(gòu)域，具有識別AA|TTTT序列并行使切割雙鏈DNA的功能；中間的逆轉(zhuǎn)錄酶結(jié)構(gòu)域，具有逆轉(zhuǎn)錄酶活性；C端的鋅指狀結(jié)構(gòu)域，參與DNA、蛋白質(zhì)和RNA的識別和結(jié)合[7]。

LINE-1轉(zhuǎn)錄生成LINE-1 mRNA，LINE-1 mRNA既作為基因組DNA模板，又行使mRNA的功能。LINE-1 mRNA在細(xì)胞質(zhì)中翻譯表達(dá)出ORF1p和ORF2p兩種蛋白。ORF1p和ORF2p與LINE-1 mRNA順式結(jié)合，組裝成核糖核蛋白復(fù)合物(ribo-nucleoprotein complexes, RNPs)轉(zhuǎn)運(yùn)入核，隨后通過靶位點(diǎn)引導(dǎo)逆轉(zhuǎn)錄過程(target-site primed reverse transcription, TPRT)插入到新的基因位點(diǎn)上(圖1)[8]。除自身可以自主轉(zhuǎn)座以外，LINE-1還能協(xié)助不具有自主轉(zhuǎn)座能力的轉(zhuǎn)座子或重復(fù)序列進(jìn)行轉(zhuǎn)座[9]。與其他類型的逆轉(zhuǎn)錄轉(zhuǎn)座子一樣，LINE-1通過逆轉(zhuǎn)錄轉(zhuǎn)座向基因組提供可進(jìn)行非等位基因重組的序列，它的擴(kuò)增極大地塑造了多細(xì)胞生物的基因組多樣性。

之前的證據(jù)顯示，LINE-1的逆轉(zhuǎn)錄轉(zhuǎn)座頻繁地發(fā)生在生殖細(xì)胞、神經(jīng)細(xì)胞以及成年人的大腦中[10,11]，除此之外，由于LINE-1會通過逆轉(zhuǎn)錄轉(zhuǎn)座機(jī)制向基因組插入LINE-1或其他轉(zhuǎn)座子，從而改變或破壞基因的結(jié)構(gòu)和功能，為了維持基因組的穩(wěn)定性，宿主通過表觀遺傳修飾和非編碼小RNA調(diào)控網(wǎng)絡(luò)等管控機(jī)制嚴(yán)格控制著LINE-1的轉(zhuǎn)座活性，所以，LINE-1在分化程度高的正常體細(xì)胞組織中表達(dá)水平很低，甚至不表達(dá)[12]。LINE-1仍有可能被遺傳毒性刺激、氧化刺激、運(yùn)動刺激和生理刺激所激活[11]。研究表明，LINE-1在大多數(shù)腫瘤組織中都出現(xiàn)了啟動子低甲基化，LINE-1 mRNA、ORF1p和ORF2p過表達(dá)的情況，是多種類型腫瘤的共同的特征(表1)[13～32]。

圖1 LINE-1的轉(zhuǎn)座過程

A：LINE-1轉(zhuǎn)錄生成LINE-1 mRNA。B：LINE-1 mRNA翻譯表達(dá)出ORF1p和ORF2p兩種蛋白質(zhì)，ORF1p和ORF2p與LINE-1 mRNA相結(jié)合生成LINE-1 RNP。C: ORF2p具有核酸內(nèi)切酶活性和逆轉(zhuǎn)錄酶活性，通過靶位點(diǎn)引導(dǎo)逆轉(zhuǎn)錄過程將LINE-1整合到新的基因位點(diǎn)上。

表1 LINE-1的轉(zhuǎn)座與相關(guān)腫瘤/癌癥

2 LINE-1作為腫瘤診斷的生物標(biāo)志物

2.1 LINE-1在腫瘤中的低甲基化現(xiàn)象

DNA甲基化是真核生物表觀遺傳調(diào)控機(jī)制之一，其中，脊椎動物基因組的DNA甲基化修飾主要發(fā)生在DNA的胞嘧啶–鳥嘌呤二核苷酸(cytosine phosphate-guanosine, CpG)島[33]。一般認(rèn)為，CpG島的甲基化可以通過影響轉(zhuǎn)錄因子結(jié)合或改變?nèi)旧|(zhì)結(jié)構(gòu)抑制相應(yīng)RNA轉(zhuǎn)錄。全基因組DNA低甲基化是惡性腫瘤中常見的表觀遺傳現(xiàn)象，并且這種現(xiàn)象可能在腫瘤的發(fā)生發(fā)展過程中發(fā)揮關(guān)鍵作用。LINE-1作為基因組中廣泛散在的高度重復(fù)序列，其啟動子區(qū)富含CpG島，CpG島的甲基化大多發(fā)生在與LINE-1相關(guān)的啟動子序列中，因此，LINE-1啟動子甲基化狀態(tài)已成為全基因組甲基化狀態(tài)的替代指標(biāo)[34]。

LINE-1啟動子的高度甲基化是抑制LINE-1轉(zhuǎn)錄的重要手段[35]，而啟動子的去甲基化意味著機(jī)體為LINE-1 mRNA的轉(zhuǎn)錄松綁。Chalitchagorn等[36]的研究顯示，包括乳腺癌、結(jié)直腸癌、肺癌、頭頸部癌、膀胱癌、食道癌、肝癌、前列腺和胃癌在內(nèi)的大多數(shù)腫瘤組織樣本中LINE-1啟動子的甲基化程度都顯著低于正常組織。與此同時，只有在某些惡性腫瘤細(xì)胞中才能檢測到完整的LINE-1 mRNA[21,22]，正常體細(xì)胞基因組中幾乎不含完整的LINE-1 mRNA[37]。Rodi?等[38]對LINE-1啟動子的甲基化程度與卵巢癌癌變階段之間的關(guān)系進(jìn)行了深入的研究，他們利用聯(lián)合亞硫酸氫鈉限制性內(nèi)切酶分析法(combined bisu-lfite restriction analysis PCR, COBRA PCR)對不同癌變階段的上皮性卵巢癌組織進(jìn)行檢測，結(jié)果表明，隨著腫瘤的惡化，LINE-1甲基化水平顯著降低，且LINE-1的甲基化水平與上皮卵巢癌的FIGO分期和腫瘤分級密切相關(guān)。

癌前病變是具備癌變可能性的良性病變，及早發(fā)現(xiàn)癌前病變并及時干預(yù)對于惡性腫瘤的防治具有重要意義。有研究表明，結(jié)直腸癌和乳腺癌的癌前病變與惡化的癌組織中的LINE-1甲基化水平都顯著低于正常組織，這表明LINE-1的低甲基化現(xiàn)象預(yù)示著腫瘤的發(fā)生，提示LINE-1低甲基化有成為腫瘤診斷生物標(biāo)志物的潛力[36,39]。

2.2 ORF1p的過表達(dá)是惡性腫瘤的標(biāo)志之一

ORF1p是RNA結(jié)合蛋白，盡管其發(fā)揮的確切作用尚不清楚，但ORF1p是LINE-1逆轉(zhuǎn)錄轉(zhuǎn)座所必須的[2]。Rodi?等[40]首次檢測了1027個腫瘤組織樣本中ORF1p的表達(dá)，結(jié)果顯示，約47%的腫瘤組織樣本表達(dá)ORF1p，而在非腫瘤性體細(xì)胞組織中則檢測不到ORF1p的表達(dá)。不同種類的腫瘤中ORF1p表達(dá)水平不同，有研究表明，ORF1p在90%以上的乳腺癌和卵巢癌、近90%的胰腺癌、50%～60%食管癌和結(jié)腸癌、50%的肺癌和40%前列腺癌中均可以檢測到過表達(dá)，而腎癌、肝癌、宮頸癌、原發(fā)性膠質(zhì)母細(xì)胞瘤和低級別B細(xì)胞淋巴瘤則幾乎不表達(dá)ORF1p[1,41]。ORF1p的表達(dá)水平與腫瘤的惡化程度相關(guān)，Rodi?等[25,26]還在89%的胰腺導(dǎo)管腺癌組織中都檢測到了ORF1p的表達(dá)，僅在27%的胰腺上皮內(nèi)瘤組織可以檢測到ORF1p，且胰腺導(dǎo)管腺癌原發(fā)部位組織和轉(zhuǎn)移癌組織中ORF1p表達(dá)無顯著性差異，這表明ORF1p的表達(dá)可能是一種獲得性特征，常見于腫瘤晚期的高級病變。目前，有研究團(tuán)隊為了推進(jìn)了ORF1p作為生物標(biāo)志物在腫瘤診斷上的臨床應(yīng)用，正在開發(fā)一種檢測和測量血液中的ORF1p含量的方法，用于更好地診斷前列腺癌[42]。

2.3 ORF2p在腫瘤組織中的表達(dá)

ORF2p具有逆轉(zhuǎn)錄酶和核酸內(nèi)切酶活性，用逆轉(zhuǎn)錄酶抑制劑處理癌細(xì)胞能引起細(xì)胞增殖下降，其核酸內(nèi)切酶結(jié)構(gòu)域能夠識別并切斷特定基因組DNA序列，造成DNA損傷[43]。ORF2p通過非常規(guī)機(jī)制進(jìn)行少量的翻譯表達(dá)[44]，這使研究ORF2p變得十分困難，所以相對于ORF1p，ORF2p之于癌癥的數(shù)據(jù)是有限的。多項研究表明[45,46]，正常乳腺組織中檢測不到ORF2p的表達(dá)，但在腫瘤發(fā)生早期，在乳腺組織還沒有出現(xiàn)明顯的組織學(xué)改變且檢測不到癌癥標(biāo)志物和表皮生長因子受體的時候，ORF2p的表達(dá)就出現(xiàn)了增加；與此同時，隨著腫瘤發(fā)展進(jìn)階，ORF2p的表達(dá)還會進(jìn)一步的上調(diào)。有研究小組在探究ORF2p在前列腺癌和結(jié)直腸癌中的表達(dá)時發(fā)現(xiàn)，內(nèi)源性O(shè)RF2p的過表達(dá)最早發(fā)生在前列腺上皮內(nèi)瘤和腸腺瘤這兩種癌前病變中，從癌前病變到癌組織的過渡中也檢測到了ORF2p表達(dá)的增加[1,30]。盡管還需要驗證其臨床相關(guān)性，但這些數(shù)據(jù)提示ORF2p的表達(dá)可能發(fā)生在腫瘤形成的早期，ORF2p的過表達(dá)有潛力成為一些特定腫瘤的早期診斷標(biāo)志物。

3 LINE-1作為腫瘤治療靶點(diǎn)

盡管還不清楚LINE-1在腫瘤發(fā)生發(fā)展過程發(fā)揮的具體作用，但大量的研究表明LINE-1的表達(dá)和逆轉(zhuǎn)錄轉(zhuǎn)座與腫瘤細(xì)胞的增殖[47]、形成[48]、分化[49]、上皮細(xì)胞間質(zhì)轉(zhuǎn)型[50]以及腫瘤侵襲[51]密切相關(guān)。LINE-1 ORF2編碼的逆轉(zhuǎn)錄酶在分化的體細(xì)胞組織中低表達(dá)或不表達(dá)且在生殖細(xì)胞、胚胎組織中高表達(dá)，這說明LINE-1逆轉(zhuǎn)錄酶的表達(dá)水平與細(xì)胞的增殖潛力相關(guān)[47]，提示可以利用LINE-1在腫瘤細(xì)胞和正常細(xì)胞中表達(dá)的差異來開發(fā)新的腫瘤治療方法。

WhaKuo等[52]用靶向ORF2編碼的逆轉(zhuǎn)錄酶的反義寡核苷酸處理人肝癌細(xì)胞Hep3B能夠間接抑制癌細(xì)胞的增殖。奈韋拉平、依非韋倫等非核苷類逆轉(zhuǎn)錄酶抑制劑(nonnucleoside RT inhibitors, NNRTIs)在抑制LINE-1逆轉(zhuǎn)錄酶活性的同時，也能強(qiáng)烈抑制結(jié)直腸癌、胰腺癌和前列腺癌細(xì)胞的增殖并促進(jìn)細(xì)胞死亡[53,54]。其中，依非韋倫是已獲美國FDA批準(zhǔn)，用于臨床艾滋病治療的抗逆轉(zhuǎn)錄病毒的藥物之一，具有抗病毒效果較強(qiáng)、耐受性良好、口服吸收好和單劑量給藥的終點(diǎn)半衰期相對較長等優(yōu)點(diǎn)。最新的研究結(jié)果顯示依非韋倫作用于癌細(xì)胞后可以通過損傷基因組和破壞核纖層誘導(dǎo)染色體結(jié)構(gòu)重塑，改變細(xì)胞核功能，觸發(fā)細(xì)胞自噬途徑并促進(jìn)細(xì)胞凋亡。同時，依非韋倫幾乎不能抑制非致瘤性細(xì)胞PNT2和WI-38增殖能力，依非韋倫作用后的PNT2和WI-38的核纖層結(jié)構(gòu)不發(fā)生改變，且不能觸發(fā)細(xì)胞的自噬機(jī)制[54]。依非韋倫還被證明能夠通過影響脂肪酸代謝途徑抑制三陰性乳腺癌細(xì)胞系的細(xì)胞增殖活性[32]。目前，依非韋倫已在轉(zhuǎn)移性去勢抵抗性前列腺癌患者中進(jìn)行了二期臨床試驗，與血藥濃度低的受試者相比，血藥濃度高的受試者出現(xiàn)癌癥轉(zhuǎn)移的概率相對更低[55]。除此之外，一些以LINE-1 ORF2p為靶點(diǎn)的核苷類逆轉(zhuǎn)錄酶抑制劑(nucleoside RT inhibitors, NRTIs)具有與NNRTIs相似的抗癌作用[56,57]。有研究表明，NRTIs阿巴卡韋能夠通過誘導(dǎo)前列腺癌細(xì)胞的抗增殖活性觸發(fā)細(xì)胞的衰老機(jī)制[56]。

4 LINE-1作為腫瘤預(yù)后的生物標(biāo)志物

LINE-1啟動子的甲基化狀態(tài)是支持LINE-1有潛力作為預(yù)后的分子標(biāo)志物的主要證據(jù),目前已經(jīng)在多種癌癥中證明了LINE-1啟動子的低甲基化與不良預(yù)后顯著相關(guān)。一項研究收集了643例結(jié)直腸癌患者的臨床病理資料，對患者進(jìn)行了為期4年的隨訪調(diào)查。結(jié)果顯示，LINE-1低甲基化與結(jié)直腸癌特異性死亡顯著相關(guān)；結(jié)直腸癌患者甲基化水平降低30%，死亡風(fēng)險增高2.37倍(HR：1.37；95%CI= 1.42～3.94)；將患者按甲基化程度分為四組(≥75%，60%～75%，45%～60%和<45%)，LINE-1甲基化程度低于45%的患者的死亡風(fēng)險比LINE-1甲基化程度高于75%的患者高5倍(HR：5；95%CI=1.92～13.1)[58]。還有研究在檢測了40名晚期結(jié)直腸癌患者的原發(fā)腫瘤組織中LINE-1啟動子的甲基化水平后發(fā)現(xiàn)，在都進(jìn)行過化療的背景下，LINE-1啟動子甲基化水平高的患者，無進(jìn)展生存期和總生存期要顯著高于LINE-1甲基化水平低的患者。一項針對食管鱗狀細(xì)胞癌的研究表明：LINE-1甲基化指數(shù)<0.78的患者的平均生存期為34個月，而LINE-1甲基化指數(shù)> 0.78的患者的平均生存期則為43個月[59]。之后，研究人員在肝細(xì)胞癌、食管癌、膀胱癌和肺癌的研究中也得到了相似的結(jié)果[41,60]。LINE-1啟動子的甲基化狀態(tài)可能深刻影響著腫瘤細(xì)胞的增殖、分化和侵襲，有望成為獨(dú)立的腫瘤預(yù)后指標(biāo)。

ORF1p在多類癌癥中過表達(dá)已成為癌癥的生物標(biāo)志物之一，ORF2p被證明能夠影響癌癥的發(fā)生發(fā)展，這兩條重要的證據(jù)支持ORF1p和ORF2p具有成為腫瘤預(yù)后評價生物標(biāo)志物的潛力。一項研究表明，腦膠質(zhì)瘤組織中ORF1p高表達(dá)的患者生存率要顯著低于ORF1p低表達(dá)的患者[61]。ORF1p大多定位在細(xì)胞質(zhì)中，但也有少量的ORF1p定位在細(xì)胞核中。一項LINE-1與乳腺癌預(yù)后關(guān)系的研究結(jié)果顯示，ORF1p在核內(nèi)的表達(dá)量與乳腺癌預(yù)后相關(guān)，與ORF1p大多定位在細(xì)胞質(zhì)的乳腺腫瘤患者相比，ORF1p定位在細(xì)胞核內(nèi)的患者的局部復(fù)發(fā)率和遠(yuǎn)端轉(zhuǎn)移率更高，其無病生存率和總體生存率相對較低[62]。同樣地，ORF2p的核定位情況也具有預(yù)后價值，有研究發(fā)現(xiàn)在乳腺導(dǎo)管內(nèi)原位癌中，ORF1p和ORF2p都定位在細(xì)胞質(zhì)，且定位在細(xì)胞質(zhì)中的ORF1p和ORF2p的表達(dá)量與患者的生存率無關(guān)，而在惡化程度更高的浸潤性導(dǎo)管癌的細(xì)胞核和細(xì)胞質(zhì)中均檢測到了ORF1p和ORF2p，且細(xì)胞核中ORF1p和ORF2p表達(dá)量高的患者的淋巴結(jié)轉(zhuǎn)移率要顯著高于細(xì)胞質(zhì)中ORF1p和ORF2p表達(dá)量高的患者，細(xì)胞核中ORF1p和ORF2p表達(dá)量高的患者的生存期也更短[63]，這可能是由于大量表達(dá)且定位在細(xì)胞核內(nèi)的ORF1p和ORF2p增加了LINE-1的逆轉(zhuǎn)錄轉(zhuǎn)座進(jìn)而增加了基因組的不穩(wěn)定。

5 結(jié)語與展望

越來越多的證據(jù)表明LINE-1的表達(dá)與腫瘤的發(fā)生發(fā)展存在密切的關(guān)聯(lián)，從LINE-1的角度出發(fā)尋找診斷、預(yù)后和治療癌癥的方法已成為新的方向。比如ORF1p和ORF2p可以作為癌癥診斷的生物標(biāo)志物，癌組織中LINE-1啟動子的甲基化狀態(tài)有望成為獨(dú)立的癌癥預(yù)后指標(biāo)，ORF2p也逐漸表現(xiàn)出成為治療靶點(diǎn)的潛力，一些逆轉(zhuǎn)錄酶抑制劑已在臨床試驗中表現(xiàn)出治療癌癥的希望。盡管已有相當(dāng)多的證據(jù)，但LINE-1的表達(dá)與腫瘤發(fā)生發(fā)展之間具體的影響機(jī)制仍未闡明，支持LINE-1作為癌癥治療靶點(diǎn)的實驗主要集中在細(xì)胞水平上，臨床試驗信息仍十分有限。與此同時，還需要開發(fā)更多能夠適應(yīng)臨床的、有效、靈敏和微創(chuàng)的檢測手段，比如ORF2p雖然有潛力成為一些特定腫瘤的早期診斷標(biāo)志物，但由于其表達(dá)較少，所以很難檢測，可以嘗試開發(fā)特定的逆轉(zhuǎn)錄酶活性測定法用于腫瘤的早期診斷。同時，LINE-1對于癌癥治療的潛在用途還未發(fā)掘，如LINE-1的表達(dá)與癌癥的化療、放療和免疫治療過程中出現(xiàn)的腫瘤耐藥性是否具有相關(guān)性，如果能夠證明化療、放療或免疫治療促進(jìn)了腫瘤中LINE-1的異常激活從而引起基因突變最終導(dǎo)致腫瘤耐藥性的形成，那么LINE-1就可以幫助臨床醫(yī)生提供更多、更有效的治療方案。

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Research and application on LINE-1 in diagnosis and treatment of tumorigenesis

Yanni Kou, Shan Cen, Xiaoyu Li

Long interspersed element-1 (LINE-1), which is the only autonomous retrotransposon in human genome, makes up about 17% of the human genome. For LINE-1 retrotransposition may result in genome instability, it was strictly restricted by organisms, and its expression was therefore barely detected in normal somatic cells. However, the expression of LINE-1 is a common phenomenon in most tumor or cancer tissues, suggesting a close relationship between LINE-1 expression and cancer development. Differentially expressed LINE-1 in cancer tissues can be used as a biomarker for tumor diagnosis and an important indicator of prognosis after cancer therapeutics. Meanwhile, the feasibility of LINE-1 as a potential drug target for tumor treatment has also been evaluating and verifying in clinicals. In this review, we introduce the application of LINE-1 as a biomarker in tumor diagnosis and prognostic, as well as the research progress in LINE-1 as potential drug target for tumor treatment, in order to provide some references for clinical application in cancer treatment.

long interspersed element-1; tumor; diagnosis; treatment; prognosis

2021-02-10;

2021-05-07

國家科技重大專項(編號：2018ZX10301408-004)和國家自然科學(xué)基金(編號：31870164)資助[Supported by the National Science and Technology Major Project of the Ministry of Science and Technology of China (No. 2018ZX10301408-004) and the National Natural Science Foundation of China (No. 31870164)]

寇艷妮，在讀碩士研究生，專業(yè)方向：LINE-1與腫瘤維持的內(nèi)在機(jī)制研究。E-mail: yanni_1995@126.com

李曉宇，博士，研究員，研究方向：病毒學(xué)。E-mail: xiaoyulik@hotmail.com

岑山，博士，研究員，研究方向：病毒學(xué)。E-mail: shancen@imb.pumc.edu.cn

10.16288/j.yczz.21-062

2021-05-31 15:52:03

URI: https://kns.cnki.net/kcms/detail/11.1913.R.20210531.0836.002.html

(責(zé)任編委: 宋旭)