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)科大學藥藥學院理學教研室 沈陽 110122; 2甘肅省衛(wèi)生學校2012級護理雙證書29班 蘭州 730000)

H19基因在腫瘤研究領域的研究進展

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)科大學藥藥學院理學教研室 沈陽 110122;2甘肅省衛(wèi)生學校2012級護理雙證書29班 蘭州 730000)

自人的印跡基因群11P15.5被發(fā)現以來,已被證明其與人體各種生理異常密切相關。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,而且H19能夠派生miRNA675的印記基因,與多種腫瘤相關,可產生反義編碼的lncRNA 91H (功能尚不清楚)而引起學者關注。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制信號軸等方面就H19基因在腫瘤發(fā)生進程中的研究現狀作一綜述。

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,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)調控[1],基因印跡的分子基礎可能是DNA在胚胎發(fā)育的早期階段的甲基化[2]和染色質結構的變化。在某些病理條件下,基因印跡異常會導致一系列病理生理學改變[3],Uribe-Lewis[4]等于2011發(fā)現其甚至會導致腫瘤的發(fā)生。哺乳動物一個等位基因突變(遺傳或表觀遺傳)會導致一個或多個基因產物的缺乏,從而導致更多的印記紊亂[5],在腫瘤相關研究方面,印跡丟失已被廣泛關注,其中H19/IGF2為最重要的研究內容之一[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,染色質重構以及RNA代謝等[7]方面具有相關性的RNA,H19基因產物加工后生成的成熟H19全長為2.3 kb,是目前發(fā)現的唯一可以編碼產生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H19基因在腫瘤研究領域的研究現狀。

H19基因的印記基因屬性與腫瘤的關系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的印記基因屬性在腫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)展過程中具有促進作用,在橫紋肌肉瘤細胞中,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,從而增加促進其擴散的IGF2表達,降低miR675表達,導致miR675的靶基因IGF1R,INSR等表達增加而使橫紋肌肉瘤細胞增殖;Gao等[9]發(fā)現腎上腺皮質惡性腫瘤組織CIMP[10](CpG island methylator phenotype)現象,據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(此文認為H19基因是抑癌基因)在內的多種腫瘤抑制基因低表達,IGF2基因高表達[9],促進腎上腺皮質腺瘤的發(fā)生,且高甲基化與不良預后相關,其原因可能是高甲基化使一些腫瘤抑制基因沉默[10]而促進了腫瘤的發(fā)生。也有學者認為IGF2和H19基因的交互印跡導致甲基化狀態(tài)差異,提出IGF2與H19基因共同競爭H19下游增強子的增強子學說[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下游的增強子激活,IGF2得以表達;在母源染色體上,H19啟動子未甲基化,則H19下游的增強子激活H19啟動子,H19得以表達。以上研究偏向于認為,H19基因上游的甲基化差異導致H19低表達,影響某些腫瘤的發(fā)展進程。二是有學者對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結合,通過這種結合可以調控下游基因是否表達而發(fā)揮作用[12-13]。三是Adriaenssens等[14]對乳腺癌和正常組織進行分析比較,觀察H19基因的表達水平,發(fā)現乳腺癌組織中其檢測陽性率遠遠高于正常乳腺組織,而在表達上調的乳腺癌組織中基質細胞占絕大多數。有研究[15]發(fā)現,雌激素在乳腺癌發(fā)展中起著至關重要的作用,lncRNAH19可誘導雌激素的產生,Berteaux等[16]進一步發(fā)現,乳腺癌組織中H19過表達并促進乳腺癌細胞由G1期向S期轉變,H19作為活躍的參與者促進細胞增殖,增加腫瘤細胞的侵襲性,提示H19在乳腺癌細胞中促進致瘤。因此lncRNA H19在一些腫瘤如腎上腺皮質腫瘤中表達減少,卻在另一些腫瘤(如乳腺癌)中表達增加,我們認為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)展進程相關。

H19基因SNP位點變異與腫瘤的關系

H19基因上游甲基化區(qū)的SNP位點變異與腫瘤的關系 許多相關研究表明,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rs2107425與乳腺癌(白人)發(fā)病風險呈負相關;而Odefrey[19]、Butt等[20]學者認為rs2107425位點變異與乳腺癌風險正相關;Riaz等[21]全基因組關聯研究荷蘭乳腺癌患者發(fā)現純合性rs2107425(AA)與乳腺癌的不良預后顯著相關;同時Barnholtz-Sloan等[22]亦發(fā)現rs2107425與非洲裔美國年輕婦女的乳腺癌積極相關聯,而在白人女性中卻呈負相關;Bhatti等[23]通過全基因組關聯研究發(fā)現對于rs2107425位點而言,基因分型相關的乳腺癌風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)病風險相關。此外,Couch等[24]運用全基因組關聯研究(GWAS)發(fā)現患者吸煙時rs2107425與胰腺癌發(fā)病風險顯著相關;Song[25]、Quaye等[26]等亦發(fā)現rs2107425位點變異與卵巢癌發(fā)病風險相關;Verhaegh等[27]研究發(fā)現rs2107425CT基因型與膀胱癌風險的降低相關,由此認為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)病風險密切相關。

rs10732516位點的相關研究主要集中在基因印記[28-29]以及新生兒的相關研究中,St-Pierre等[30]研究發(fā)現基因型為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)現位于H19基因的印記調控區(qū)CTCF結合位點上的rs10732516[A]多態(tài)性與母系H19等位基因特定CpG位點上增強的超甲基化程度相關。rs2251375[32]、rs2071094[33]兩位點的研究目前主要集中在新生兒有關研究中,在腫瘤研究領域鮮見這些位點的研究報道。

總結以上研究,我們發(fā)現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)展相關聯,目前并沒有H19基因上游甲基化與該區(qū)域SNP變異關系研究報道,也沒有二者與腫瘤進展關系的研究報道。研究[14]發(fā)現IGF2等激素可以刺激相關細胞H19的轉錄,而某些激素則抑制這種效應,H19基因的表達可由化學致癌物,視黃酸、類固醇和肽激素,生長因子如肝細胞生長因子,組織修復因子,細胞因子和低氧壓力[34]等多種因素誘導,此外,大量實驗已經確定了各種轉錄因子E2F[16],HIF-1α[35],Slug[36],p53[37]和c-myc[38],可以調節(jié)H19表達。更有學者[39]發(fā)現H19基因上游導致H19過表達的序列,并將此序列與DTA(白喉毒素)構成DTA-H19質粒,Amit等[40]進一步采用H19和IGF2-P4雙調控序列構建DTA質粒,克服了該質粒必須依賴H19高表達才能發(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錄因子或其他生物大分子在該區(qū)域的結合,導致H19基因的表達能力有差異,影響特定腫瘤發(fā)生進程。

H19基因編碼區(qū)SNP位點變異與腫瘤的關系

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水平參與細胞以及腫瘤細胞的生長過程中,其rs217727、rs2067051與rs2839698位點研究較多。在非腫瘤領域,Tragante[44],Gao[45]等研究發(fā)現H19基因rs217727與血壓及冠狀動脈疾病(CAD)風險的增加相關,具體機制尚待研究;Hewage等[46]研究發(fā)現母親H19基因rs217727TT基因型與新生兒更重的體重相關;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。在腫瘤研究領域,Yang等[47]研究發(fā)現rs217727T和rs2839698T等位基因表現出增加胃癌(GC)風險的特性;Verhaegh等[27]2008年發(fā)現rs2839698TC基因型與膀胱癌降低相關,同時發(fā)現rs217727TT基因型或攜帶T基因型攜帶者與這種降低無關,且采用生物信息學預測發(fā)現lncRNA H19的rs217727位點在TT與CC基因型下折疊結構存在差異,rs2839698位點TT與CC基因型時亦是;Li等[48]2016年發(fā)現rs2839698A基因型與大腸癌發(fā)病風險升高相關,并發(fā)現rs2839698位點有可能影響lncRNA H19的折疊而改變lncRNA H19的靶標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)病風險降低相關。以上研究結果啟示,H19基因編碼區(qū)的SNP變異可能影響lncRNA H19的二級結構,進而影響lncRNA H19的生物學功能、影響腫瘤的發(fā)生發(fā)展。因此,不僅應研究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。

lncRNA H19與腫瘤的關系 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個內含子,位于近端粒區(qū)域,與腫瘤發(fā)生有密切相關性。到目前為止,越來越多的lncRNA被證明與腫瘤的發(fā)生及轉移有關[50];研究顯示,H19作為lncRNA能使許多與腫瘤細胞的侵襲、遷移及血管形成密切相關的基因表達上調[51],在一些癌癥如乳腺癌、膀胱癌和胃癌中上調并扮演重要角色[52],并且H19的表達情況與術后早期復發(fā)現象有明顯的關系,可作為判斷術后早期復發(fā)的檢測指標。lncRNAH19在多種惡性腫瘤印跡丟失而過度表達,因此有必要從H19的lncRNA屬性去探討H19與腫瘤發(fā)生發(fā)展的關系。

lncRNA H19可通過多種機制影響腫瘤的進程。Tran等[53]指出H19在乳腺癌中反義RNA過度表達促進父源的IGF2過表達,lncRNA水平在膀胱癌組織中也顯著升高,上調的H19通過抑制E-鈣黏蛋白(E-cadherin)的表達促進膀胱癌細胞在體內外的惡變[54],更有學者發(fā)現胃癌組織表達更多的lncRNA H19,促進了胃癌細胞的擴散、惡變、侵襲和轉移[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的普遍生物學特性而影響腫瘤的發(fā)展。

LncRNA H19/miR-675信號軸與腫瘤的關系

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]等學者更是認為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lncRNA H19可以在體外促進肺癌細胞惡變,其作用原理是通過上調Slug的表達從而抑制E-cad的表達、促進上皮間質轉化過程,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ISM1以及通過miR-675間接地下調CALN1的表達從而影響腫瘤的進程;同時Tsang等[56]發(fā)現在大腸癌中H19派生miR-675,miR-675對其下游靶基因RB蛋白質產生靶向抑制促進大腸癌的發(fā)展;Zhuang等[58]研究發(fā)現H19基因通過miR-675調控抑癌基因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”促進腫瘤的發(fā)生和發(fā)展,這個結論在Liu等[59]的研究中亦得到確證。此外在神經膠質瘤中,高級神經膠質瘤組織比低級神經膠質瘤組織表達更高的lncRNAH19,H19通過派生miR-675及抑制性的CDH13[60],調節(jié)神經膠質瘤細胞的侵襲。以上研究結果說明生物大分子lncRNA H19通過“l(fā)ncRNA H19/miR-675信號軸”影響腫瘤發(fā)生發(fā)展的機制得到了廣泛的認可,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與腫瘤的關系機制的其他解釋

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

結語H19基因在正常組織鮮有表達而在異常組織(比如腫瘤組織)表達,且是目前發(fā)現的唯一屬于lncRNA的印記基因,H19基因作為腫瘤生物標記分子和治療靶點已經成為事實[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制信號軸等方面就H19基因在腫瘤發(fā)生進程中的研究現狀作了全面綜述,以全面探討H19與腫瘤的關系。我們總結認為H19基因的作用模式可以分為lncRNA H19表達前和表達后兩個時段,一是lncRNA H19表達前,H19作為印記基因,很多因素影響其表達,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化;二是lncRNAH19表達后,由于H19基因編碼區(qū)SNP變異導致lncRNA H19折疊結構的改變,可能導致產生不同的生物學效應,更重要的是lncRNA H19不僅具有普通lncRNA的一切生物學功能,而且可以派生miR-675、產生反義的91H,導致lncRNA H19在腫瘤發(fā)展過程中的機制復雜多樣,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的產生。因此,我們認為對H19基因的研究不能局限于某一個層面,而應該依據H19的各層特性交叉全面研究,全面認知H19參與腫瘤發(fā)生、發(fā)展過程中可能的調控功能和調控機制,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)。

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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).