H19基因在腫瘤研究領(lǐng)域的研究進(jìn)展

王曉東(綜述) 王曉娟 趙鵬飛 陳文捷 吳慧哲 魏敏杰△(審校)

(1中國醫(yī)科大學(xué)藥藥學(xué)院理學(xué)教研室 沈陽 110122; 2甘肅省衛(wèi)生學(xué)校2012級護(hù)理雙證書29班 蘭州 730000)

H19基因在腫瘤研究領(lǐng)域的研究進(jìn)展

王曉東(綜述) 王曉娟2趙鵬飛1陳文捷1吳慧哲1魏敏杰1△(審校)

(1中國醫(yī)科大學(xué)藥藥學(xué)院理學(xué)教研室 沈陽 110122;2甘肅省衛(wèi)生學(xué)校2012級護(hù)理雙證書29班 蘭州 730000)

自人的印跡基因群11P15.5被發(fā)現(xiàn)以來,已被證明其與人體各種生理異常密切相關(guān)。而作為最早被鑒定的印記基因之一的非編碼RNA分子H19 (lncRNA H19),不僅由于其與Beckwith-Wiedemann綜合征(BWS)、羅素因綜合征(SRS)相關(guān),而且H19能夠派生miRNA675的印記基因,與多種腫瘤相關(guān),可產(chǎn)生反義編碼的lncRNA 91H (功能尚不清楚)而引起學(xué)者關(guān)注。本文將首次從H19基因的印記屬性、SNP變異、lncRNA屬性及其可能的作用機(jī)制信號軸等方面就H19基因在腫瘤發(fā)生進(jìn)程中的研究現(xiàn)狀作一綜述。

基因印記; 腫瘤; lncRNAH19; miR675

H19印跡基因位于人染色體11P15.5及鼠的7號染色體上,屬于單拷貝基因,母系等位基因表達(dá),父系印跡,受位于H19基因上游4 kb處的差異甲基化區(qū)域(differentially methylated region,DMR)調(diào)控[1],基因印跡的分子基礎(chǔ)可能是DNA在胚胎發(fā)育的早期階段的甲基化[2]和染色質(zhì)結(jié)構(gòu)的變化。在某些病理條件下,基因印跡異常會導(dǎo)致一系列病理生理學(xué)改變[3],Uribe-Lewis[4]等于2011發(fā)現(xiàn)其甚至?xí)?dǎo)致腫瘤的發(fā)生。哺乳動物一個等位基因突變(遺傳或表觀遺傳)會導(dǎo)致一個或多個基因產(chǎn)物的缺乏,從而導(dǎo)致更多的印記紊亂[5],在腫瘤相關(guān)研究方面,印跡丟失已被廣泛關(guān)注,其中H19/IGF2為最重要的研究內(nèi)容之一[6]。長鏈非編碼RNA(long non-coding RNA,lncRNA)是指長度超過200個核苷酸的在眾多功能上,如可變剪接,染色質(zhì)重構(gòu)以及RNA代謝等[7]方面具有相關(guān)性的RNA,H19基因產(chǎn)物加工后生成的成熟H19全長為2.3 kb,是目前發(fā)現(xiàn)的唯一可以編碼產(chǎn)生lncRNA的印跡基因,在mRNA水平發(fā)揮作用。本文從H19基因的各層屬性出發(fā)總結(jié)H19基因在腫瘤研究領(lǐng)域的研究現(xiàn)狀。

H19基因的印記基因?qū)傩耘c腫瘤的關(guān)系H19印跡基因簇的各個基因可作為原癌基因或者抑癌基因[2]發(fā)揮作用,H19基因的印跡異常參與了許多遺傳病及腫瘤的發(fā)生。H19的印記基因?qū)傩栽谀[瘤研究中主要有以下模式:一是長期研究表明[8],IGF2/H19差異甲基化區(qū)域在腫瘤發(fā)展過程中具有促進(jìn)作用,在橫紋肌肉瘤細(xì)胞中,IGF2/H19基因上游(5’UTR區(qū))的差異甲基化區(qū)域通過DNA高甲基化造成印跡丟失,從而增加促進(jìn)其擴(kuò)散的IGF2表達(dá),降低miR675表達(dá),導(dǎo)致miR675的靶基因IGF1R,INSR等表達(dá)增加而使橫紋肌肉瘤細(xì)胞增殖;Gao等[9]發(fā)現(xiàn)腎上腺皮質(zhì)惡性腫瘤組織CIMP[10](CpG island methylator phenotype)現(xiàn)象,據(jù)惡性腫瘤組織甲基化程度的不同,分為CIMP-high和CIMP-low,CIMP致使包括H19基因(此文認(rèn)為H19基因是抑癌基因)在內(nèi)的多種腫瘤抑制基因低表達(dá),IGF2基因高表達(dá)[9],促進(jìn)腎上腺皮質(zhì)腺瘤的發(fā)生,且高甲基化與不良預(yù)后相關(guān),其原因可能是高甲基化使一些腫瘤抑制基因沉默[10]而促進(jìn)了腫瘤的發(fā)生。也有學(xué)者認(rèn)為IGF2和H19基因的交互印跡導(dǎo)致甲基化狀態(tài)差異,提出IGF2與H19基因共同競爭H19下游增強(qiáng)子的增強(qiáng)子學(xué)說[11],即在父源染色體上,H19啟動子發(fā)生甲基化,致使IGF2的啟動子被H19下游的增強(qiáng)子激活,IGF2得以表達(dá);在母源染色體上,H19啟動子未甲基化,則H19下游的增強(qiáng)子激活H19啟動子,H19得以表達(dá)。以上研究偏向于認(rèn)為,H19基因上游的甲基化差異導(dǎo)致H19低表達(dá),影響某些腫瘤的發(fā)展進(jìn)程。二是有學(xué)者對H19上游2 kb差異甲基化區(qū)域(DMR)的研究表明,區(qū)域的印記特性(甲基化狀態(tài))可以決定其是否與CTCF結(jié)合,通過這種結(jié)合可以調(diào)控下游基因是否表達(dá)而發(fā)揮作用[12-13]。三是Adriaenssens等[14]對乳腺癌和正常組織進(jìn)行分析比較,觀察H19基因的表達(dá)水平,發(fā)現(xiàn)乳腺癌組織中其檢測陽性率遠(yuǎn)遠(yuǎn)高于正常乳腺組織,而在表達(dá)上調(diào)的乳腺癌組織中基質(zhì)細(xì)胞占絕大多數(shù)。有研究[15]發(fā)現(xiàn),雌激素在乳腺癌發(fā)展中起著至關(guān)重要的作用,lncRNAH19可誘導(dǎo)雌激素的產(chǎn)生,Berteaux等[16]進(jìn)一步發(fā)現(xiàn),乳腺癌組織中H19過表達(dá)并促進(jìn)乳腺癌細(xì)胞由G1期向S期轉(zhuǎn)變,H19作為活躍的參與者促進(jìn)細(xì)胞增殖,增加腫瘤細(xì)胞的侵襲性,提示H19在乳腺癌細(xì)胞中促進(jìn)致瘤。因此lncRNA H19在一些腫瘤如腎上腺皮質(zhì)腫瘤中表達(dá)減少,卻在另一些腫瘤(如乳腺癌)中表達(dá)增加,我們認(rèn)為H19基因上游甲基化區(qū)的基因印記和在某些腫瘤環(huán)境下印記丟失與某些特定腫瘤的發(fā)展進(jìn)程相關(guān)。

H19基因SNP位點變異與腫瘤的關(guān)系

H19基因上游甲基化區(qū)的SNP位點變異與腫瘤的關(guān)系 許多相關(guān)研究表明,H19基因有很高的缺失率和突變率[17],目前H19基因5’UTR區(qū)的SNP位點變異的研究目前主要集中在rs2107425、rs10732516、rs2251375、rs2071094等位點。rs2107425位點與腫瘤關(guān)系的研究主要集中在胰腺癌、乳腺癌、膀胱癌、卵巢癌等腫瘤,與乳腺癌相關(guān)研究的代表的觀點主要有:O′Brien等[18]在白人和非洲美國人中發(fā)現(xiàn)rs2107425與乳腺癌(白人)發(fā)病風(fēng)險呈負(fù)相關(guān);而Odefrey[19]、Butt等[20]學(xué)者認(rèn)為rs2107425位點變異與乳腺癌風(fēng)險正相關(guān);Riaz等[21]全基因組關(guān)聯(lián)研究荷蘭乳腺癌患者發(fā)現(xiàn)純合性rs2107425(AA)與乳腺癌的不良預(yù)后顯著相關(guān);同時Barnholtz-Sloan等[22]亦發(fā)現(xiàn)rs2107425與非洲裔美國年輕婦女的乳腺癌積極相關(guān)聯(lián),而在白人女性中卻呈負(fù)相關(guān);Bhatti等[23]通過全基因組關(guān)聯(lián)研究發(fā)現(xiàn)對于rs2107425位點而言,基因分型相關(guān)的乳腺癌風(fēng)險隨輻射劑量變化顯著(P=0.001),以上研究提示rs2107425位點變異與乳腺癌發(fā)病風(fēng)險相關(guān)。此外,Couch等[24]運用全基因組關(guān)聯(lián)研究(GWAS)發(fā)現(xiàn)患者吸煙時rs2107425與胰腺癌發(fā)病風(fēng)險顯著相關(guān);Song[25]、Quaye等[26]等亦發(fā)現(xiàn)rs2107425位點變異與卵巢癌發(fā)病風(fēng)險相關(guān);Verhaegh等[27]研究發(fā)現(xiàn)rs2107425CT基因型與膀胱癌風(fēng)險的降低相關(guān),由此認(rèn)為H19基因的rs2107425位點基因型與胰腺癌、乳腺癌、膀胱癌、卵巢癌等腫瘤的發(fā)病風(fēng)險密切相關(guān)。

rs10732516位點的相關(guān)研究主要集中在基因印記[28-29]以及新生兒的相關(guān)研究中,St-Pierre等[30]研究發(fā)現(xiàn)基因型為rs10732516(CC/CT)或者rs2107425(AA/AG)的母親較基因型為rs10732516(TT)與rs2107425(GG)的母親分娩的嬰兒體重更重;而Coolen等[31]發(fā)現(xiàn)位于H19基因的印記調(diào)控區(qū)CTCF結(jié)合位點上的rs10732516[A]多態(tài)性與母系H19等位基因特定CpG位點上增強(qiáng)的超甲基化程度相關(guān)。rs2251375[32]、rs2071094[33]兩位點的研究目前主要集中在新生兒有關(guān)研究中,在腫瘤研究領(lǐng)域鮮見這些位點的研究報道。

總結(jié)以上研究,我們發(fā)現(xiàn)H19基因上游甲基化區(qū)SNP變異與多種類型腫瘤的發(fā)生發(fā)展相關(guān)聯(lián),目前并沒有H19基因上游甲基化與該區(qū)域SNP變異關(guān)系研究報道,也沒有二者與腫瘤進(jìn)展關(guān)系的研究報道。研究[14]發(fā)現(xiàn)IGF2等激素可以刺激相關(guān)細(xì)胞H19的轉(zhuǎn)錄,而某些激素則抑制這種效應(yīng),H19基因的表達(dá)可由化學(xué)致癌物,視黃酸、類固醇和肽激素,生長因子如肝細(xì)胞生長因子,組織修復(fù)因子,細(xì)胞因子和低氧壓力[34]等多種因素誘導(dǎo),此外,大量實驗已經(jīng)確定了各種轉(zhuǎn)錄因子E2F[16],HIF-1α[35],Slug[36],p53[37]和c-myc[38],可以調(diào)節(jié)H19表達(dá)。更有學(xué)者[39]發(fā)現(xiàn)H19基因上游導(dǎo)致H19過表達(dá)的序列,并將此序列與DTA(白喉毒素)構(gòu)成DTA-H19質(zhì)粒,Amit等[40]進(jìn)一步采用H19和IGF2-P4雙調(diào)控序列構(gòu)建DTA質(zhì)粒,克服了該質(zhì)粒必須依賴H19高表達(dá)才能發(fā)揮作用的局限,使這一方法成功運用于卵巢癌、胰腺癌等多種腫瘤并進(jìn)入臨床試驗[41-42]。綜合Medrzycki等[43]的研究我們猜測,H19基因上游印記狀態(tài)、某些狀態(tài)下的印記丟失和SNP變異影響不同類型腫瘤中轉(zhuǎn)錄因子或其他生物大分子在該區(qū)域的結(jié)合,導(dǎo)致H19基因的表達(dá)能力有差異,影響特定腫瘤發(fā)生進(jìn)程。

H19基因編碼區(qū)SNP位點變異與腫瘤的關(guān)系

基因的SNP不僅存在于基因的非編碼區(qū),也存在于基因的編碼序列中,lncRNA H19在RNA水平參與細(xì)胞以及腫瘤細(xì)胞的生長過程中,其rs217727、rs2067051與rs2839698位點研究較多。在非腫瘤領(lǐng)域,Tragante[44],Gao[45]等研究發(fā)現(xiàn)H19基因rs217727與血壓及冠狀動脈疾病(CAD)風(fēng)險的增加相關(guān),具體機(jī)制尚待研究;Hewage等[46]研究發(fā)現(xiàn)母親H19基因rs217727TT基因型與新生兒更重的體重相關(guān);rs2067051的研究主要集中在冠狀動脈疾病(CAD)[45]和新生兒體重[32]方面。在腫瘤研究領(lǐng)域,Yang等[47]研究發(fā)現(xiàn)rs217727T和rs2839698T等位基因表現(xiàn)出增加胃癌(GC)風(fēng)險的特性;Verhaegh等[27]2008年發(fā)現(xiàn)rs2839698TC基因型與膀胱癌降低相關(guān),同時發(fā)現(xiàn)rs217727TT基因型或攜帶T基因型攜帶者與這種降低無關(guān),且采用生物信息學(xué)預(yù)測發(fā)現(xiàn)lncRNA H19的rs217727位點在TT與CC基因型下折疊結(jié)構(gòu)存在差異,rs2839698位點TT與CC基因型時亦是;Li等[48]2016年發(fā)現(xiàn)rs2839698A基因型與大腸癌發(fā)病風(fēng)險升高相關(guān),并發(fā)現(xiàn)rs2839698位點有可能影響lncRNA H19的折疊而改變lncRNA H19的靶標(biāo)microRNAs,從而影響腫瘤的發(fā)生發(fā)展;Xia等[49]的研究顯示rs217727CT+TT基因型與懷孕2次以上的女性患乳腺癌的發(fā)病風(fēng)險降低相關(guān)。以上研究結(jié)果啟示,H19基因編碼區(qū)的SNP變異可能影響lncRNA H19的二級結(jié)構(gòu),進(jìn)而影響lncRNA H19的生物學(xué)功能、影響腫瘤的發(fā)生發(fā)展。因此,不僅應(yīng)研究lncRNA H19作為RNA生物大分子在腫瘤發(fā)展中的功能,而且要研究其SNP變異的不同基因型,為腫瘤的個體化診斷和施治奠定理論和實踐基礎(chǔ)。

lncRNA H19與腫瘤的關(guān)系 lncRNAH19基因全長2.5 kb,共含有5個外顯子(第一個外顯子派生出miR675)和4個內(nèi)含子,位于近端粒區(qū)域,與腫瘤發(fā)生有密切相關(guān)性。到目前為止,越來越多的lncRNA被證明與腫瘤的發(fā)生及轉(zhuǎn)移有關(guān)[50];研究顯示,H19作為lncRNA能使許多與腫瘤細(xì)胞的侵襲、遷移及血管形成密切相關(guān)的基因表達(dá)上調(diào)[51],在一些癌癥如乳腺癌、膀胱癌和胃癌中上調(diào)并扮演重要角色[52],并且H19的表達(dá)情況與術(shù)后早期復(fù)發(fā)現(xiàn)象有明顯的關(guān)系,可作為判斷術(shù)后早期復(fù)發(fā)的檢測指標(biāo)。lncRNAH19在多種惡性腫瘤印跡丟失而過度表達(dá),因此有必要從H19的lncRNA屬性去探討H19與腫瘤發(fā)生發(fā)展的關(guān)系。

lncRNA H19可通過多種機(jī)制影響腫瘤的進(jìn)程。Tran等[53]指出H19在乳腺癌中反義RNA過度表達(dá)促進(jìn)父源的IGF2過表達(dá),lncRNA水平在膀胱癌組織中也顯著升高,上調(diào)的H19通過抑制E-鈣黏蛋白(E-cadherin)的表達(dá)促進(jìn)膀胱癌細(xì)胞在體內(nèi)外的惡變[54],更有學(xué)者發(fā)現(xiàn)胃癌組織表達(dá)更多的lncRNA H19,促進(jìn)了胃癌細(xì)胞的擴(kuò)散、惡變、侵襲和轉(zhuǎn)移[55]。lncRNA H19作為RNA分子,在腫瘤中主要通過以下幾條途徑發(fā)揮作用:一是通過lncRNA H19/miR-675信號軸影響腫瘤發(fā)展,二是lncRNA H19發(fā)揮lncRNA的“miRNA sponge”作用影響腫瘤發(fā)展,三是由于發(fā)揮具有l(wèi)ncRNA的普遍生物學(xué)特性而影響腫瘤的發(fā)展。

LncRNA H19/miR-675信號軸與腫瘤的關(guān)系

H19基因通過miR-675發(fā)揮作用[2],且H19/miR-675信號軸在腫瘤發(fā)生過程中具有重要作用[56],Cai[57]和Wang[52]等學(xué)者更是認(rèn)為lncRNA H19以miR-675的pri-miRNA發(fā)揮促腫瘤生長的功能。近期研究[36]發(fā)現(xiàn)lncRNA H19可以在體外促進(jìn)肺癌細(xì)胞惡變,其作用原理是通過上調(diào)Slug的表達(dá)從而抑制E-cad的表達(dá)、促進(jìn)上皮間質(zhì)轉(zhuǎn)化過程,miR-675參與該過程;也有人[55]推斷H19在胃癌中的作用可能通過上調(diào)ISM1以及通過miR-675間接地下調(diào)CALN1的表達(dá)從而影響腫瘤的進(jìn)程;同時Tsang等[56]發(fā)現(xiàn)在大腸癌中H19派生miR-675,miR-675對其下游靶基因RB蛋白質(zhì)產(chǎn)生靶向抑制促進(jìn)大腸癌的發(fā)展;Zhuang等[58]研究發(fā)現(xiàn)H19基因通過miR-675調(diào)控抑癌基因RUNX1來影響胃癌的發(fā)生發(fā)展,即通過“l(fā)ncRNA H19派生miR-675,miR-675靶向抑制其下游靶基因”的“l(fā)ncRNA H19/miR-675信號軸”促進(jìn)腫瘤的發(fā)生和發(fā)展,這個結(jié)論在Liu等[59]的研究中亦得到確證。此外在神經(jīng)膠質(zhì)瘤中,高級神經(jīng)膠質(zhì)瘤組織比低級神經(jīng)膠質(zhì)瘤組織表達(dá)更高的lncRNAH19,H19通過派生miR-675及抑制性的CDH13[60],調(diào)節(jié)神經(jīng)膠質(zhì)瘤細(xì)胞的侵襲。以上研究結(jié)果說明生物大分子lncRNA H19通過“l(fā)ncRNA H19/miR-675信號軸”影響腫瘤發(fā)生發(fā)展的機(jī)制得到了廣泛的認(rèn)可,通過“l(fā)ncRNA H19/miR-675信號軸”解釋腫瘤發(fā)展日趨成熟,并可能成為新的腫瘤治療靶點。

LncRNA H19與腫瘤的關(guān)系機(jī)制的其他解釋

癌細(xì)胞內(nèi)H19作用機(jī)制還存在其他相關(guān)假說。研究發(fā)現(xiàn)H19通過抑制E-鈣黏蛋白表達(dá),也可抑制miR-630表達(dá)而使EZH2表達(dá)量上升,促進(jìn)鼻咽癌的侵襲[61]。Wu等[62]亦通過研究發(fā)現(xiàn)H19基因的上調(diào)可以抑制miR-148a-3p的表達(dá)導(dǎo)致miR-148a-3p下游靶基因的DNMT1表達(dá)上調(diào),促進(jìn)喉鱗狀細(xì)胞癌的進(jìn)展,說明H19發(fā)揮miRNA海綿(miRNA sponge)作用促進(jìn)腫瘤發(fā)展。此外,Han等[63]也通過研究發(fā)現(xiàn)lncRNA H19可通過招募eIF4A3促進(jìn)結(jié)直腸癌細(xì)胞的增殖,因此lncRNA H19同樣具有作為新的結(jié)直腸癌和其他腫瘤治療靶標(biāo)的潛在可能。H19作為lncRNA,可以通過發(fā)揮lncRNA普遍具有的生物學(xué)功能而促進(jìn)腫瘤的發(fā)生發(fā)展,H19作為lncRNA促腫瘤的更多作用機(jī)制有待深入研究。

結(jié)語H19基因在正常組織鮮有表達(dá)而在異常組織(比如腫瘤組織)表達(dá),且是目前發(fā)現(xiàn)的唯一屬于lncRNA的印記基因,H19基因作為腫瘤生物標(biāo)記分子和治療靶點已經(jīng)成為事實[64]。本文首次從H19基因的印記屬性、SNP變異、lncRNA屬性及其可能的作用機(jī)制信號軸等方面就H19基因在腫瘤發(fā)生進(jìn)程中的研究現(xiàn)狀作了全面綜述,以全面探討H19與腫瘤的關(guān)系。我們總結(jié)認(rèn)為H19基因的作用模式可以分為lncRNA H19表達(dá)前和表達(dá)后兩個時段,一是lncRNA H19表達(dá)前,H19作為印記基因,很多因素影響其表達(dá),比如H19基因上游甲基化區(qū)的印記狀態(tài)、特定環(huán)境下的印記丟失、SNP變異、生物大分子等都會影響H19基因編碼,造成lncRNA H19的生成量差異,影響腫瘤發(fā)生發(fā)展,這方面的研究將有助于腫瘤治療的個體化和精準(zhǔn)化;二是lncRNAH19表達(dá)后,由于H19基因編碼區(qū)SNP變異導(dǎo)致lncRNA H19折疊結(jié)構(gòu)的改變,可能導(dǎo)致產(chǎn)生不同的生物學(xué)效應(yīng),更重要的是lncRNA H19不僅具有普通lncRNA的一切生物學(xué)功能,而且可以派生miR-675、產(chǎn)生反義的91H,導(dǎo)致lncRNA H19在腫瘤發(fā)展過程中的機(jī)制復(fù)雜多樣,這方面的研究將有助于腫瘤的個體化施治和一批新腫瘤治療靶標(biāo)的產(chǎn)生。因此,我們認(rèn)為對H19基因的研究不能局限于某一個層面,而應(yīng)該依據(jù)H19的各層特性交叉全面研究,全面認(rèn)知H19參與腫瘤發(fā)生、發(fā)展過程中可能的調(diào)控功能和調(diào)控機(jī)制,將十分有助于未來將H19運用于腫瘤臨床診治各個環(huán)節(jié)。

[1] MURPHY R,THOMPSON JM,TOST J,etal.No evidence for copy number and methylation variation in H19 and KCNQ10T1 imprinting control regions in children born small for gestational age[J].BMCMedGenet,2014,15:67.

[2] MATOUK IJ,HALLE D,GILON M,etal.The non-coding RNAs of the H19-IGF2 imprinted loci:A focus on biological roles and therapeutic potential in Lung cancer[J].JTranslMed,2015,13(1):113.

[3] BARROW TM,BARAULT L,ELLSWORTH RE,etal.Aberrant methylation of imprinted genes is associated with negative hormone receptor status in invasive breast cancer[J].IntJCancer,2015,137(3):537-547.

[4] URIBE-LEWIS S,WOODFINE K,STOJIC L,etal.Molecular mechanisms of genomic imprinting and clinical implications for cancer[J].ExpertRevMolMed,2011,13:e2.

[5] BARTOLOMEI MS.Genomic imprinting:employing and avoiding epigenetic processes[J].GenesDev,2009,23(18):2124-2133.

[6] TIAN F,TANG Z,SONG G,etal.Loss of imprinting of IGF2 correlates with hypomethylation of the H19 differentially methylated region in the tumor tissue of colorectal cancer patients[J].MolMedRep,2012,5(6):1536-1540.

[7] REN C,LI X,WANG T,etal.Functions and mechanisms of long noncoding RNAs in ovarian cancer[J].IntJGynecolCancer,2015,25(4):566-569.

[8] TARNOWSKI M,TKACZ M,CZEREWATY M,etal.5Azacytidine inhibits human rhabdomyosarcoma cell growth by downregulating insulinlike growth factor 2 expression and reactivating the H19 gene product miR675,which negatively affects insulinlike growth factors and insulin signaling[J].IntJOncol,2015,46(5):2241-2250.

[9] GAO ZH,SUPPOLA S,LIU J,etal.Association of H19 promoter methylation with the expression of H19 and IGF-II genes in adrenocortical tumors[J].JClinEndocrinolMetab,2002,87(3):1170-1176.

[10] BARREAU O,ASSIE G,WILMOT-ROUSSEL H,etal.Identification of a CpG island methylator phenotype in adrenocortical carcinomas[J].JClinEndocrinolMetab,2013,98(1):E174-E184.

[11] ISHIHARA K,HATANO N,FURUUMI H,etal.Comparative genomic sequencing identifies novel tissue-specific enhancers and sequence elements for methylation-sensitive factors implicated in Igf2/H19 imprinting[J].GenomeRes,2000,10(5):664-671.

[12] KURUKUTI S,TIWARI VK,TAVOOSIDANA G,etal.CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2[J].ProcNatlAcadSciUSA,2006,103(28):10684-10689.

[13] TEIF VB,BESHNOVA DA,VAINSHTEIN Y,etal.Nucleosome repositioning links DNA (de)methylation and differential CTCF binding during stem cell development[J].GenomeRes,2014,24(8):1285-1295.

[14] ADRIAENSSENS E,DUMONT L,LOTTIN S,etal.H19 overexpression in breast adenocarcinoma stromal cells is associated with tumor values and steroid receptor status but independent of p53 and Ki-67 expression[J].AmJPathol,1998,153(5):1597-1607.

[15] SUN H,WANG G,PENG Y,etal.H19 lncRNA mediates 17beta-estradiol-induced cell proliferation in MCF-7 breast cancer cells[J].OncolRep,2015,33(6):3045-3052.

[16] BERTEAUX N,LOTTIN S,MONTE D,etal.H19 mRNA-like noncoding RNA promotes breast cancer cell proliferation through positive control by E2F1[J].JBiolChem,2005,280(33):29625-29636.

[17] KIM SJ,PARK SE,LEE C,etal.Alterations in promoter usage and expression levels of insulin-like growth factor-II and H19 genes in cervical carcinoma exhibiting biallelic expression of IGF-II[J].BiochimBiophysActa,2002,1586(3):307-315.

[18] O′BRIEN KM,COLE SR,POOLE C,etal.Replication of breast cancer susceptibility loci in whites and African Americans using a Bayesian approach[J].AmJEpidemiol,2014,179(3):382-94.

[19] ODEFREY F,STONE J,GURRIN LC,etal.Common genetic variants associated with breast cancer and mammographic density measures that predict disease[J].CancerRes,2010,70(4):1449-1458.

[20] BUTT S,HARLID S,BORGQUIST S,etal.Genetic predisposition,parity,age at first childbirth and risk for breast cancer[J].BMCResNotes,2012,5:414.

[21] RIAZ M,BERNS EM,SIEUWERTS AM,etal.Correlation of breast cancer susceptibility loci with patient characteristics,metastasis-free survival,and mRNA expression of the nearest genes[J].BreastCancerResTreat,2012,133(3):843-851.

[22] BARNHOLTZ-SLOAN JS,SHETTY PB,GUAN X,etal.FGFR2 and other loci identified in genome-wide association studies are associated with breast cancer in African-American and younger women[J].Carcinogenesis,2010,31(8):1417-1423.

[23] BHATTI P,DOODY MM,ALEXANDER BH,etal.Breast cancer risk polymorphisms and interaction with ionizing radiation among U.S.radiologic technologists[J].CancerEpidemiolBiomarkersPrev,2008,17(8):2007-2011.

[24] COUCH FJ,WANG X,MC WILLIAMS RR,etal.Association of breast cancer susceptibility variants with risk of pancreatic cancer[J].CancerEpidemiolBiomarkersPrev,2009,18(11):3044-3048.

[25] SONG H,RAMUS SJ,KJAER SK,etal.Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study[J].HumMolGenet,2009,18(12):2297-2304.

[26] QUAYE L,TYRER J,RAMUS SJ,etal.Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer[J].PLoSOne,2009,4(6):e5983.

[27] VERHAEGH GW,VERKLEIJ L,VERMEULEN SH,etal.Polymorphisms in the H19 gene and the risk of bladder cancer[J].EurUrol,2008,54(5):1118-1126.

[28] HERNANDEZ-VALERO MA,ROTHER J,GORLOV I,etal.Interplay between polymorphisms and methylation in the H19/IGF2 gene region may contribute to obesity in Mexican-American children[J].JDevOrigHealthDis,2013,4(6):499-506.

[29] RENTERIA ME,COOLEN MW,STATHAM AL,etal.GWAS of DNA methylation variation within imprinting control regions suggests parent-of-origin association[J].TwinResHumGenet,2013,16(4):767-781.

[30] ST-PIERRE J,HIVERT MF,PERRON P,etal.IGF2 DNA methylation is a modulator of newborn's fetal growth and development[J].Epigenetics,2012,7(10):1125-1132.

[31] COOLEN MW,STATHAM AL,QU W,etal.Impact of the genome on the epigenome is manifested in DNA methylation patterns of imprinted regions in monozygotic and dizygotic twins[J].PLoSOne,2011,6(10):e25590.

[32] ADKINS RM,SOMES G,MORRISON JC,etal.Association of birth weight with polymorphisms in the IGF2,H19,and IGF2R genes[J].PediatrRes,2010,68(5):429-434.

[33] PETRY CJ,SEEAR RV,WINGATE DL,etal.Maternally transmitted foetal H19 variants and associations with birth weight[J].HumGenet,2011,130(5):663-670.

[34] MATOUK I,RAVEH E,OHANA P,etal.The increasing complexity of the oncofetal h19 gene locus:functional dissection and therapeutic intervention[J].IntJMolSci,2013,14(2):4298-4316.

[35] MATOUK IJ,MEZAN S,MIZRAHI A,etal.The oncofetal H19 RNA connection:hypoxia,p53 and cancer[J].BiochimBiophysActa,2010,1803(4):443-451.

[36] MATOUK IJ,RAVEH E,ABU-LAIL R,etal.Oncofetal H19 RNA promotes tumor metastasis[J].BiochimBiophysActa,2014,1843(7):1414-1426.

[37] DUGIMONT T,MONTPELLIER C,ADRIAENSSENS E,etal.The H19 TATA-less promoter is efficiently repressed by wild-type tumor suppressor gene product p53[J].Oncogene,1998,16(18):2395-2401.

[38] WANG C,LISANTI MP,LIAO DJ.Reviewing once more the c-myc and Ras collaboration:converging at the cyclin D1-CDK4 complex and challenging basic concepts of cancer biology[J].CellCycle,2011,10(1):57-67.

[39] BANET G,BIBI O,MATOUK I,etal.Characterization of human and mouse H19 regulatory sequences[J].MolBiolRep,2000,27(3):157-165.

[40] AMIT D,HOCHBERG A.Development of targeted therapy for a broad spectrum of cancers (pancreatic cancer,ovarian cancer,glioblastoma and HCC) mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences[J].IntJClinExpMed,2012,5(4):296-305.

[41] SORIN V,OHANA P,MIZRAHI A,etal.Regional therapy with DTA-H19 vector suppresses growth of colon adenocarcinoma metastases in the rat liver[J].IntJOncol,2011,39(6):1407-1412.

[42] SCAIEWICZ V,SORIN V,FELLIG Y,etal.Use of H19 gene regulatory sequences in DNA-based therapy for pancreatic cancer[J].JOncol,2010,2010:178174.

[43] MEDRZYCKI M,ZHANG Y,ZHANG W,etal.Histone h1.3 suppresses H19 noncoding RNA expression and cell growth of ovarian cancer cells[J].CancerRes,2014,74(22):6463-6473.

[44] TRAGANTE V,BARNES MR,GANESH SK,etal.Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci[J].AmJHumGenet,2014,94(3):349-360.

[45] GAO W,ZHU M,WANG H,etal.Association of polymorphisms in long non-coding RNA H19 with coronary artery disease risk in a Chinese population[J].MutatRes,2015,772:15-22.

[46] HEWAGE AS,JAYANTHINY P,TENNEKOON KH,etal.H19 rs217727 genotype and IGF-1/intron-2 dinucleotide CT repeat polymorphism are independently associated with birth weight[J].Endocrine,2015,48(3):1010-1012.

[47] YANG C,TANG R,MA X,etal.Tag SNPs in long non-coding RNA H19 contribute to susceptibility to gastric cancer in the Chinese Han population[J].Oncotarget,2015,6(17):15311-15320.

[48] LI S,HUA Y,JIN J,etal.Association of genetic variants in lncRNA H19 with risk of colorectal cancer in a Chinese population[J].Oncotarget,2016,7(18):25470-25477.

[49] XIA Z,YAN R,DUAN F,etal.Genetic polymorphisms in long noncoding RNA H19 are associated with susceptibility to breast cancer in Chinese population[J].Medicine(Baltimore),2016,95(7):e2771.

[50] WANG GY,ZHU YY,ZHANG YQ.The functional role of long non-coding RNA in digestive system carcinomas[J].BullCancer,2014,101(9):E27-E31.

[51] AYESH S,MATOUK I,SCHNEIDER T,etal.Possible physiological role of H19 RNA[J].MolCarcinog,2002,35(2):63-74.

[52] WANG L,CAI Y,ZHAO X,etal.Down-regulated long non-coding RNA H19 inhibits carcinogenesis of renal cell carcinoma[J].Neoplasma,2015,62(3):412-418.

[53] TRAN VG,COURT F,DUPUTIE A,etal.H19 antisense RNA can up-regulate Igf2 transcription by activation of a novel promoter in mouse myoblasts[J].PLoSOne,2012,7(5):e37923.

[54] LUO M,LI Z,WANG W,etal.Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression[J].CancerLett,2013,333(2):213-221.

[55] LI H,YU B,LI J,etal.Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer[J].Oncotarget,2014,5(8):2318-2329.

[56] TSANG WP,NG EK,NG SS,etal.Oncofetal H19-derived miR-675 regulates tumor suppressor RB in human colorectal cancer[J].Carcinogenesis,2010,31(3):350-358.

[57] CAI B,MA W,BI C,etal.Long non-coding RNA H19 mediates melatonin inhibition of premature senescence of c-kit cardiac progenitor cells by promoting miR-675[J].JPinealRes,2016,61(1):82-95.

[58] ZHUANG M,GAO W,XU J,etal.The long non-coding RNA H19-derived miR-675 modulates human gastric cancer cell proliferation by targeting tumor suppressor RUNX1[J].BiochemBiophysResCommun,2014,448(3):315-322.

[59] LIU G,XIANG T,WU QF,etal.Long Noncoding RNA H19-derived miR-675 enhances proliferation and invasion via RUNX1 in gastric cancer Cells[J].OncolRes,2016,23(3):99-107.

[60] SHI Y,WANG Y,LUAN W,etal.Long non-coding RNA H19 promotes glioma cell invasion by deriving miR-675[J].PLoSOne,2014,9(1):e86295.

[61] LI XL,LIN YL,YANG X,etal.Long noncoding RNA H19 regulates EZH2 expression by interacting with miR-630 and promotes cell invasion in nasopharyngeal carcinoma[J].BiochemBiophysResCommun,2016,473(4):913-919.

[62] WU T,QU L,HE G,etal.Regulation of laryngeal squamous cell cancer progression by the lncRNA H19/miR-148a-3p/DNMT1 axis[J].Oncotarget,2016,7(10):11553-11566.

[63] HAN D,GAO X,WANG M,etal.Long noncoding RNA H19 indicates a poor prognosis of colorectal cancer and promotes tumor growth by recruiting and binding to eIF4A3[J].Oncotarget,2016,7(16):22159-22173.

[64] ARIEL I,SUGHAYER M,FELLIG Y,etal.The imprinted H19 gene is a marker of early recurrence in human bladder carcinoma[J].MolPathol,2000,53(6):320-323.

Research progress ofH19 gene in the field of tumor research

WANG Xiao-dong1, WANG Xiao-juan2, ZHAO Peng-fei1, CHEN Wen-jie1, WU Hui-zhe1, WEI Min-jie1△

(1DepartmentofPharmacology,SchoolofPharmacy,ChinaMedicalUniversity,Shenyang110122,LiaoningProvince,China;2NursingDouble-CertificateClass29,Grade2012,GansuProvinceHealthSchool,Lanzhou730000,GansuProvince,China)

Since human imprinted genes in 11P15.5 was found,it had been proved that various human physiological abnormality associated with it.As one of the first identified imprinted non-coding RNA genes,more attention is paid to lncRNA H19 by many scholars not only because it’s linked with Beckwith-Wiedemann syndrome (BWS) and Russell syndrome (SRS),but alsoH19 gene is the only imprinted gene belonging to long non-coding RNA related with a variety of tumors which can also produce microRNA675 and lncRNA 91H coming fromH19 gene antisense-coding.This paper will review possible mechanisms ofH19 gene in tumorigenesis process and its research status in Cancer therapy from four aspects:imprinting feature,single nucleotide polymorphisms,lncRNA character and its possible action signal axis in cancer.

gene imprinting; tumor; lncRNAH19; miR675

國家自然科學(xué)基金(81572898,81402948)

R730

B

10.3969/j.issn.1672-8467.2017.02.017

2016-04-14;編輯:張秀峰)

△Corresponding author E-mail:mjwei@hotmail.com

*This work was supported by the National Natural Science Foundation of China (81572898,81402948).