呂鑫 許碧純 沈薇
[摘要] microRNA(miRNA)是一類長(zhǎng)18~22個(gè)核苷酸的內(nèi)源性非編碼小RNA,在轉(zhuǎn)錄后水平調(diào)節(jié)靶基因的表達(dá),參與細(xì)胞生長(zhǎng)、分化和凋亡等生物學(xué)過(guò)程,其異常表達(dá)與胃癌的發(fā)生、發(fā)展密切相關(guān)。近年研究發(fā)現(xiàn),DNA甲基化可能是miRNA表達(dá)異常的調(diào)控機(jī)制。miRNA基因啟動(dòng)子區(qū)DNA高甲基化或低甲基化改變可使miRNA表達(dá)失調(diào),進(jìn)而導(dǎo)致miRNA的靶基因表達(dá)異常,參與胃癌的發(fā)生、發(fā)展。本文就DNA甲基化調(diào)控miRNA在胃癌中的研究進(jìn)展作一綜述。
[關(guān)鍵詞] microRNA;DNA甲基化;胃癌
[中圖分類號(hào)] R735.2 [文獻(xiàn)標(biāo)識(shí)碼] A [文章編號(hào)] 1673-7210(2016)11(c)-0048-04
Research progress of microRNA DNA methylation in gastric cancer
LU Xin XU Bichun SHEN Wei
College of Basic Medicine, Shenyang Medical College, Liaoning Province, Shenyang 110034, China
[Abstract] microRNA (miRNA) is a kind of 18-22 nucleotides of endogenous non-coding small RNA, which regulates the expression of target genes at the posttranscriptional level, involves in many biological processes including cell growth, differentiation and apoptosis. The relationship between the abnormal expression of miRNA and gastric cancer has been verified. Recent researches have shown that DNA hypermethylation or hypomethylation may be the regulatory mechanisms of abnormal expression of miRNA which results in the abnormal expression of target genes and involves in the carcinogenesis of gastric cancer. Therefore, this article mainly reviewed on miRNA DNA methylation in gastric cancer.
[Key words] microRNA; DNA methylation; Gastric cancer
胃癌是世界范圍內(nèi)常見(jiàn)的消化道腫瘤之一。2011年統(tǒng)計(jì)報(bào)道,過(guò)去10年胃癌的發(fā)病率在男性和女性惡性腫瘤中分別居第4位和第5位[1]。表觀遺傳學(xué)改變?cè)谖赴┑陌l(fā)生、發(fā)展中發(fā)揮重要的作用,miRNA和DNA甲基化是表觀遺傳學(xué)的重要內(nèi)容。許多腫瘤中存在miRNA異常表達(dá),進(jìn)而發(fā)揮著癌基因或抑癌基因樣的作用,而miRNA異常表達(dá)的機(jī)制尚不清楚。由于部分miRNA基因啟動(dòng)子區(qū)CpG島的存在,DNA甲基化可能是其調(diào)控機(jī)制之一。有研究報(bào)道,在淋巴癌、肺癌、胃癌等多種腫瘤中,miRNA基因上游啟動(dòng)子區(qū)域甲基化狀態(tài)改變可使miRNA表達(dá)失調(diào)[2-3]。研究其調(diào)控關(guān)系有助于深入探討胃癌發(fā)生的表觀遺傳學(xué)機(jī)制,尋找胃癌靶向治療的新靶點(diǎn)。本文就近年來(lái)受DNA甲基化調(diào)控的miRNA與胃癌的關(guān)系研究作一綜述。
1 miRNA的功能
miRNA是一種單鏈的內(nèi)源性非編碼小RNA,長(zhǎng)度一般為18~22個(gè)核苷酸,在RNA聚合酶Ⅱ或RNA聚合酶Ⅲ轉(zhuǎn)錄下,由莖環(huán)結(jié)構(gòu)的轉(zhuǎn)錄前體加工而合成。它們廣泛存在于真核生物的細(xì)胞內(nèi),參與多種生物學(xué)過(guò)程并高度保守。1993第一次被報(bào)道,在21世紀(jì)被真正的識(shí)別。研究發(fā)現(xiàn),miRNA通過(guò)與靶基因3′非翻譯區(qū)(3′-UTR)不完全互補(bǔ)結(jié)合引起靶mRNA的降解或抑制其翻譯,調(diào)控基因的表達(dá),進(jìn)而在細(xì)胞的增殖、凋亡、代謝過(guò)程中發(fā)揮作用[4]。每個(gè)miRNA可以有多個(gè)靶基因,同一基因也可能被眾多miRNA靶識(shí)別,由此形成復(fù)雜的調(diào)控網(wǎng)絡(luò),精細(xì)調(diào)控功能基因的表達(dá)。
2 DNA甲基化異常與胃癌
DNA甲基化最常見(jiàn)的就是CpG二核苷酸中胞嘧啶的甲基化修飾,在DNA甲基轉(zhuǎn)移酶(DNA methyltransferases,DNMTs)催化下,胞嘧啶5位碳原子上發(fā)生甲基轉(zhuǎn)移,生成5-甲基胞嘧啶(5-mC)。在基因組的某些區(qū)域中,通常是基因的啟動(dòng)子區(qū)域,5′端非翻譯區(qū)和第一外顯子區(qū)CpG序列密度非常高,超過(guò)均值5倍以上,成為鳥(niǎo)嘌呤和胞嘧啶的富集區(qū),稱之為CpG島[5]。在正常細(xì)胞中,位于抑癌基因啟動(dòng)子區(qū)域的CpG島處于低水平或未甲基化狀態(tài)。在腫瘤中該區(qū)域的CpG島呈高甲基化狀態(tài),染色質(zhì)構(gòu)象發(fā)生改變,抑癌基因的表達(dá)被關(guān)閉,參與腫瘤的發(fā)生。研究報(bào)道p16基因啟動(dòng)子區(qū)高甲基化在胃癌發(fā)生中起重要作用[6]。胃癌中胰島素樣生長(zhǎng)因子結(jié)合蛋白-3(IGFBP-3),Ras相關(guān)結(jié)構(gòu)域家族1A基因(RASSF1A)沉默與其啟動(dòng)子DNA甲基化有關(guān)[7-8]。最近的研究檢測(cè)發(fā)現(xiàn),102例胃癌標(biāo)本中有絲分裂前期檢查點(diǎn)基因(CHFR)的甲基化率為34.3%,并提示CHFR甲基化是增加抗癌藥物多西紫杉醇治療敏感性的重要因素[9]。轉(zhuǎn)錄因子21(TCF21)低表達(dá)與胃癌侵襲、轉(zhuǎn)移及預(yù)后密切相關(guān),異常DNA甲基化是導(dǎo)致TCF21低表達(dá)的重要原因[10]。DNA甲基化在胃癌的發(fā)病過(guò)程中起著重要作用,其相互關(guān)系的研究進(jìn)展,將為胃癌的早期診斷、治療、預(yù)后判斷等提供新的理論基礎(chǔ)。
3 胃癌中miRNA的異常表達(dá)
在胃癌中存在多種miRNA的異常表達(dá),并通過(guò)不同途徑調(diào)控各自靶基因的表達(dá),發(fā)揮癌基因或抑癌基因樣作用。
3.1 促癌作用的miRNA高表達(dá)
部分miRNA在胃癌組織和細(xì)胞系中的表達(dá)往往高于非胃癌組織和細(xì)胞系,通過(guò)促進(jìn)腫瘤細(xì)胞的增殖、轉(zhuǎn)移、侵襲等多種機(jī)制發(fā)揮其致腫瘤作用。miRNA-221及miRNA-222在胃癌組織中異常高表達(dá),調(diào)控其靶基因p21家族成員p27、p57表達(dá)下降,促進(jìn)細(xì)胞增殖[11]。而敲除胃癌細(xì)胞系SGC7901中miRNA-211、miRNA-222表達(dá)后可抑制細(xì)胞的增殖,并增加了胃癌細(xì)胞對(duì)放療的敏感性[12]。miRNA-21在胃癌中的過(guò)度表達(dá)增加了對(duì)抑癌基因——磷酸酶張力蛋白同源物(PTEN)的抑制作用,下調(diào)程序性細(xì)胞死亡因子4(PDCD4)的表達(dá),從而促進(jìn)胃癌的淋巴結(jié)轉(zhuǎn)移和血管侵襲[13-14]。有報(bào)道m(xù)iR-17-5p/20a在胃癌組織中表達(dá)增高。在胃癌細(xì)胞中沉默miR-17-5p/20a表達(dá)后,誘導(dǎo)細(xì)胞周期的阻滯及細(xì)胞調(diào)亡,并揭示miR-17-5p/20a通過(guò)轉(zhuǎn)錄后調(diào)控其靶基因p21和p53誘導(dǎo)的核蛋白1(TP53INP1)的表達(dá)[15]。對(duì)miR-421在胃癌中表達(dá)的研究發(fā)現(xiàn),進(jìn)展期胃癌標(biāo)本中miR-421表達(dá)明顯高于正常對(duì)照組和癌前病變組,miR-421通過(guò)調(diào)節(jié)其靶基因——上皮型鈣黏蛋白(E-cadherin)和半胱天冬酶-3(Caspase-3)的表達(dá)抑制胃癌細(xì)胞凋亡,促進(jìn)細(xì)胞轉(zhuǎn)移。miR-421的表達(dá)程度與患者預(yù)后密切相關(guān)[16]。miRNA-199a-3p在早期胃癌患者中的表達(dá)水平明顯增高,而患者術(shù)后miRNA-199a-3p表達(dá)明顯降低。其診斷早期胃癌的敏感度和特異度以及準(zhǔn)確性分別為76%、74%、75%,表明其可能是比較理想的胃癌診斷標(biāo)志物[17]。miR-544在胃癌中發(fā)揮癌基因樣作用,在胃癌細(xì)胞中過(guò)表達(dá)miR-544能抑制其靶基因——易洛魁家族同源盒基因1(IRX1)的抑癌作用,并促進(jìn)細(xì)胞增殖,參與細(xì)胞周期調(diào)控[18]。
3.2 抑癌作用的miRNA低表達(dá)
如miR-339在原發(fā)性胃癌組織中表達(dá)明顯降低。在胃癌細(xì)胞中過(guò)表達(dá)miR-339可明顯抑制細(xì)胞增殖、遷移、侵襲和致瘤性[19]。miR-129-5p過(guò)表達(dá)減少胃癌SGC7901/VCR和SGC7901/ADR細(xì)胞的耐藥性,而下調(diào)miR-129-5p有相反的效果[20]。研究表明,miR-200b和miR-200c在胃癌標(biāo)本和細(xì)胞株中表達(dá)下調(diào),miR-200b和miR-200c水平與臨床分期顯著相關(guān)[21]。人胃癌組織中miR-146a/b與泛素樣含PHD和環(huán)指域1基因(UHRF1)的表達(dá)呈負(fù)相關(guān)。miR-146a和miR-146b作為UHRF1的直接調(diào)控上游因子,通過(guò)靶向3′-UTR降低UHRF1的表達(dá)[22]。miR-433和miR-127在胃癌組織中的表達(dá)顯著下調(diào)。而且,較低水平的miR-433和miR-127與臨床胃癌患者pM或pTNM分期相關(guān)。在胃癌細(xì)胞系HGC-27中,miR-433和miR-127過(guò)表達(dá)可通過(guò)與致癌相關(guān)基因——鼠類肉瘤病毒癌基因(KRAS)和促分裂素原活化蛋白激酶4(MAPK4)相互作用抑制細(xì)胞增殖、遷移和侵襲[23]。
4 胃癌中DNA甲基化調(diào)控miRNA異常表達(dá)
miRNA的表達(dá)失調(diào)與轉(zhuǎn)錄失調(diào)、染色體異常和表觀遺傳改變有關(guān)。DNA甲基化是一種重要的基因表達(dá)調(diào)節(jié)方式,是表觀遺傳修飾的重要內(nèi)容。近年來(lái)研究報(bào)道,啟動(dòng)子區(qū)CpG島的DNA甲基化狀態(tài)參與調(diào)控胃癌中miRNA的異常表達(dá)[24-34]。
4.1 DNA高甲基化與miRNA表達(dá)
DNA甲基化包括基因組總體甲基化水平降低和某些基因啟動(dòng)子區(qū)域發(fā)生高甲基化。CpG島高甲基化可導(dǎo)致基因表達(dá)缺失。Ando等[24]于2009年首次證實(shí)DNA甲基化參與調(diào)控胃癌細(xì)胞中miRNA的異常表達(dá),發(fā)現(xiàn)在多種胃癌細(xì)胞株中miR-124a-1,miR-124a-2和miR-124a-3啟動(dòng)子區(qū)高甲基化導(dǎo)致其表達(dá)下調(diào)。應(yīng)用去甲基化藥物5-氮雜-2′-脫氧胞苷(5-Aza-CdR)使細(xì)胞恢復(fù)了miRNAs的表達(dá)。同時(shí)作者發(fā)現(xiàn),幽門(mén)螺旋桿菌感染誘導(dǎo)miRNA啟動(dòng)子甲基化,增加胃癌的發(fā)病風(fēng)險(xiǎn)。最近的報(bào)道發(fā)現(xiàn),胃腺癌中啟動(dòng)子區(qū)高甲基化誘導(dǎo)miR-124a表達(dá)沉默,并證實(shí)了其新的靶基因——多胺代謝酶精胺氧化酶(SMOX)[25]。Hashimoto等[26]觀察到胃癌標(biāo)本及細(xì)胞中miR-181c的表達(dá)降低,5-Aza-CdR處理胃癌細(xì)胞后,miR-181c表達(dá)恢復(fù)。應(yīng)用甲基化特異性PCR(MSP)和亞硫酸氫鈉測(cè)序PCR(BSP)檢測(cè)到miR-181c啟動(dòng)子區(qū)CpG島的高甲基化狀態(tài),提示胃癌中存在miRNA-181c基因甲基化沉默,并通過(guò)靶點(diǎn)癌基因NOTCH4及KRAS發(fā)揮致癌作用。有報(bào)道在乳腺癌、食道癌等多種腫瘤中miR-10b發(fā)揮癌樣作用,但Kim等[27]發(fā)現(xiàn),胃癌中miR-10b啟動(dòng)子區(qū)域發(fā)生高甲基化,誘導(dǎo)miR-10b表達(dá)沉默,導(dǎo)致其靶基因——微管關(guān)聯(lián)蛋白R(shí)P/EB家族成員1(MAPRE1)過(guò)表達(dá),進(jìn)而促進(jìn)胃癌細(xì)胞增殖。在胃癌組織和5種胃癌細(xì)胞中檢測(cè)到miR-335的低表達(dá),應(yīng)用MSP和BSP檢測(cè)miR-335啟動(dòng)子上游CpG島的DNA甲基化狀態(tài),結(jié)果顯示miR-335表達(dá)與DNA甲基化狀態(tài)呈負(fù)相關(guān)[28]。最近的研究報(bào)道發(fā)現(xiàn),胃癌細(xì)胞中miR-219.2、miR-663b、miR-1237、miR-495、miR-200c和miR-141的轉(zhuǎn)錄受DNA甲基化調(diào)控。由于啟動(dòng)子區(qū)DNA高甲基化導(dǎo)致其表達(dá)下降。且miR-495通過(guò)調(diào)節(jié)其靶基因——肝再生磷酸酶(PRL-3)表達(dá),參與胃癌腹膜轉(zhuǎn)移的發(fā)生。在胃癌細(xì)胞中應(yīng)用DNA甲基化轉(zhuǎn)移酶抑制劑——地西他濱可恢復(fù)miR-200c和miR-141的表達(dá),為地西他濱在胃癌治療中的應(yīng)用提供了有力的證據(jù)[29-31]。
4.2 DNA低甲基化與miRNA表達(dá)
腫瘤基因組廣泛低甲基化的程度與腫瘤惡性程度密切相關(guān),其作為生物學(xué)指標(biāo)具有一定的診斷價(jià)值。部分miRNA基因啟動(dòng)子區(qū)的異常低甲基化誘導(dǎo)其表達(dá)增加,發(fā)揮對(duì)靶基因的抑制作用,促進(jìn)腫瘤的發(fā)展轉(zhuǎn)移。Tsai等[32]報(bào)道,胃癌組織中miRNA-196b基因啟動(dòng)子區(qū)CpG島呈低甲基化狀態(tài),提示其為miRNA-196b表達(dá)異常增加的機(jī)制之一。體外實(shí)驗(yàn)證實(shí),胃癌細(xì)胞中miRNA-196b基因啟動(dòng)子區(qū)高甲基化處理,抑制miRNA-196b轉(zhuǎn)錄激活。研究發(fā)現(xiàn)胃癌組織中miRNA-210表達(dá)升高,檢測(cè)其啟動(dòng)子區(qū)CpG島呈低甲基化狀態(tài)。miRNA-210通過(guò)抑制其靶基因——與sprouty相關(guān)的細(xì)胞膜蛋白(SPRED2)表達(dá),促進(jìn)胃癌細(xì)胞遷移[33]。新的研究報(bào)道證實(shí)胃癌組織及患者血漿中miR-106a表達(dá)明顯升高,并與胃癌的淋巴轉(zhuǎn)移和分期相關(guān)。MSP檢測(cè)表明與癌旁組織比較,胃癌組織中miR-106a的基因啟動(dòng)子區(qū)CpG島甲基化率顯著降低[34]。
5 展望
綜上所述,DNA甲基化可能是胃癌中miRNA表達(dá)異常的調(diào)控機(jī)制。miRNA基因啟動(dòng)子區(qū)異常高甲基化或低甲基化狀態(tài),可使miRNA表達(dá)失調(diào),進(jìn)而發(fā)揮癌基因或抑癌基因樣的作用,參與胃癌的發(fā)生、發(fā)展。隨著對(duì)甲基化的miRNA及其作用靶點(diǎn)研究的進(jìn)一步深入,其為胃癌的表觀遺傳修飾提供了新的研究方向。DNA甲基化是一種可逆的表觀遺傳學(xué)修飾方式,甲基化miRNA也有望為胃癌的靶向治療開(kāi)辟嶄新的領(lǐng)域。
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(收稿日期:2016-08-20 本文編輯:王紅雙)