宋妮娜,瞿全新
宮頸上皮內(nèi)瘤變分子生物學(xué)指標(biāo)的研究進(jìn)展
宋妮娜,瞿全新△
宮頸癌是婦科最常見的惡性腫瘤之一,近年來宮頸癌的發(fā)病率逐年上升,且有年輕化趨勢(shì)。宮頸上皮內(nèi)瘤變(CIN)是由高危型人乳頭瘤病毒(HPV)的持續(xù)性感染引起的,是宮頸癌的癌前病變,其反映宮頸癌發(fā)生發(fā)展中的連續(xù)過程,從CIN發(fā)展為宮頸癌需要較長(zhǎng)的時(shí)間。在CIN的進(jìn)展過程中,許多基因結(jié)構(gòu)和功能都會(huì)發(fā)生變化。近年來的研究發(fā)現(xiàn),在CIN和宮頸癌的組織中存在著一些表達(dá)異常的生物學(xué)標(biāo)記物,這些生物學(xué)標(biāo)記物與前驅(qū)病變級(jí)別和腫瘤是否發(fā)生轉(zhuǎn)移相關(guān),將這些基因作為CIN進(jìn)展的分子生物學(xué)標(biāo)志物進(jìn)行檢測(cè),早期發(fā)現(xiàn)和診斷宮頸癌已成為目前研究的熱點(diǎn)。綜述CIN研究的前沿性分子生物學(xué)指標(biāo)。
宮頸上皮內(nèi)瘤樣病變;宮頸腫瘤;生物學(xué)標(biāo)記;端粒,末端轉(zhuǎn)移酶;白細(xì)胞介素類;Toll樣受體
20世紀(jì)70年代,Richart等提出宮頸上皮內(nèi)瘤變(cervical intraepithelial neoplasia,CIN)這一概念,隨著對(duì)宮頸癌前病變發(fā)生機(jī)制及其進(jìn)展的認(rèn)識(shí),目前世界衛(wèi)生組織(WHO)將其更名為鱗狀上皮內(nèi)病變(squamous intraepithelial lesion,SIL),根據(jù)病變程度,再將其分為低度鱗狀上皮內(nèi)病變(low-grade squamous intraepithelial lesion,LSIL)和高度鱗狀上皮內(nèi)病變(high-grade squamous intraepithelial lesion,HSIL),前者對(duì)應(yīng)尖銳濕疣與CINⅠ、后者對(duì)應(yīng)CINⅡ與CINⅢ[1],其中HSIL是宮頸癌的癌前病變。
分子生物學(xué)研究結(jié)果顯示,高危型人乳頭瘤病毒(HPV)持續(xù)感染是宮頸癌的主要危險(xiǎn)因素,90%以上的宮頸癌伴有高危型HPV感染。從HPV感染發(fā)展到宮頸癌是一個(gè)較長(zhǎng)的過程,有報(bào)道CINⅠ、CINⅡ、CINⅢ進(jìn)展為宮頸浸潤(rùn)癌的概率分別為15%、30%、45%,此過程大約歷經(jīng)10年。大多數(shù)HPV感染是一過性的,國(guó)外研究顯示約90%的HPV感染在2年內(nèi)自然消退,僅有不足5%的病例進(jìn)展為高級(jí)別CIN。CIN并非是單向發(fā)展過程,其發(fā)展有3種可能:直接發(fā)展為浸潤(rùn)癌,局限在鱗狀上皮內(nèi)持續(xù)不變,逆轉(zhuǎn)乃至消退。在LSIL患者中,1~2年出現(xiàn)自發(fā)消退者達(dá)80%[2-3],10%~15%的患者進(jìn)展為HSIL,而HSIL患者逆轉(zhuǎn)為正常者達(dá)30%~50%。HSIL的治療通常包括切除病灶和轉(zhuǎn)化區(qū),防止進(jìn)展為宮頸癌,而LSIL的治療較為保守[4-5]。因此,篩選LSIL患者中可能進(jìn)展為HSIL的高危者并采取有效治療措施變得尤為重要。目前,臨床上嘗試應(yīng)用某些特異性標(biāo)志物輔助判定宮頸病變的轉(zhuǎn)歸,以期更好地預(yù)測(cè)患者預(yù)后,指導(dǎo)臨床分流與管理。本文就與CIN進(jìn)展有關(guān)的分子標(biāo)志物的研究進(jìn)展進(jìn)行綜述。
端粒酶(telomerase)是一種將5′-TTAGGG-3′增加到人染色體末端的核糖酶復(fù)合物,由多個(gè)亞基組成,包括作為端粒延伸和催化亞基模板的端粒酶(如hTERC)、具有逆轉(zhuǎn)錄酶活性的人端粒酶逆轉(zhuǎn)錄酶(human telomerase reverse transcriptase,hTERT)和端粒酶相關(guān)蛋白1(human telomoraseassociated protein 1,hTP1)。端粒酶活性主要依賴于hTERT和hTERC基因表達(dá),hTERC位于染色體3q26,編碼端粒酶RNA亞基,通過細(xì)胞分裂維持端粒長(zhǎng)度,參與惡性腫瘤的發(fā)生與進(jìn)展。hTERC基因擴(kuò)增可以阻止細(xì)胞凋亡,從而導(dǎo)致腫瘤發(fā)生。近年來研究發(fā)現(xiàn),hTERC表達(dá)是宮頸癌生物標(biāo)志物[6]。在從非典型增生向癌癥轉(zhuǎn)化過程中,幾乎所有宮頸上皮細(xì)胞都表現(xiàn)出異常hTERC基因擴(kuò)增。hTERC基因突變改變端粒酶功能,從而導(dǎo)致染色體異常[7]。因此,檢測(cè)hTERC基因可作為判斷病變進(jìn)展的標(biāo)志。Heselmeyer-Haddad等[8]經(jīng)過1~3年隨訪發(fā)現(xiàn),CINⅠ/Ⅱ患者中有hTERC基因擴(kuò)增者比無擴(kuò)增者更易進(jìn)展為CINⅢ,提示hTERC基因異常表達(dá)可能是進(jìn)展為浸潤(rùn)癌的關(guān)鍵。
p16INK4a是一種腫瘤抑制蛋白,抑制細(xì)胞周期蛋白依賴性激酶(CPK),通過視網(wǎng)膜母細(xì)胞瘤蛋白(pRb)磷酸化調(diào)節(jié)細(xì)胞周期。p16INK4a參與pRb負(fù)反饋調(diào)節(jié),由于HPV E7滅活pRb,從而導(dǎo)致p16INK4a表達(dá)增強(qiáng)[9]。因此,p16INK4a基因可作為判斷HPV致病能力及CIN患者預(yù)后的標(biāo)志物[10]。
有學(xué)者對(duì)CINⅠ患者進(jìn)行回顧性研究,發(fā)現(xiàn)p16INK4a表達(dá)水平與CINⅠ進(jìn)展為CINⅡ/Ⅲ有關(guān),提示p16INK4a是判定CINⅠ病變轉(zhuǎn)歸的有價(jià)值的標(biāo)志物[11]。以往許多研究發(fā)現(xiàn),幾乎所有HSIL中都能檢測(cè)到p16INK4a表達(dá),而在不成熟化生或萎縮等反應(yīng)性病變中,p16INK4a表達(dá)都是陰性或僅有局灶性表達(dá)。因此,p16INK4a表達(dá)在HSIL病變中具有無可爭(zhēng)議的重要意義[12-13]。
但是,近來Sagasta等[14]進(jìn)行了一個(gè)大型的前瞻性研究,對(duì)入選的507例患者(其中LSIL 416例)做了平均28個(gè)月的隨訪后發(fā)現(xiàn),所有患者的p16INK4a染色陽性率是48%(245/507),而LSIL患者的p16INK4a染色陽性率是50%(210/416),認(rèn)為p16INK4a作為評(píng)價(jià)LSIL進(jìn)展的標(biāo)志物價(jià)值有限,在LSIL病變中,p16INK4a染色僅用于診斷可疑的病例,協(xié)助排除HSIL病變的可能性。
緊密連接(TJS)是細(xì)胞間連接復(fù)合體,是正常上皮細(xì)胞穩(wěn)態(tài)的關(guān)鍵結(jié)構(gòu),該結(jié)構(gòu)包括膜和膜相關(guān)蛋白[15]。Caudin-1蛋白是緊密連接的主要封閉蛋白,參與細(xì)胞間信號(hào)傳導(dǎo)。在癌變過程中,已證實(shí)Caudin-1基因及其蛋白水平發(fā)生改變,可作為癌癥進(jìn)展的標(biāo)志物。緊密連接缺失與腫瘤發(fā)生與進(jìn)展密切相關(guān),緊密連接蛋白表達(dá)減少可以預(yù)測(cè)癌癥進(jìn)展。研究發(fā)現(xiàn),在CIN和浸潤(rùn)性宮頸癌中,Caudin-1表達(dá)增加[16]。Caudin-1蛋白持續(xù)表達(dá)可能是LSIL向HSIL、浸潤(rùn)癌進(jìn)展的重要因素,可作為宮頸SIL進(jìn)展的可靠標(biāo)志物。
細(xì)胞因子在炎癥和免疫調(diào)節(jié)方面起著重要作用。在細(xì)胞免疫中,輔助性T細(xì)胞分為Th1和Th2兩種亞型,Th1細(xì)胞分泌白細(xì)胞介素2(interleukin-2,IL-2)、γ干擾素(interferon-γ,INF-γ)和腫瘤壞死因子β(tumor necrosis factorβ,TNF-β),其中IL-2是免疫應(yīng)答和調(diào)節(jié)的主要核心因子,參與T細(xì)胞凋亡,促進(jìn)T細(xì)胞增殖,具有免疫抑制作用,可造成腫瘤細(xì)胞凋亡,其活性高低直接影響免疫細(xì)胞的功能及宮頸局部免疫狀態(tài)[17];IFN-γ具有較強(qiáng)的抗腫瘤作用和免疫調(diào)節(jié)作用,因此Th1細(xì)胞有抗腫瘤作用。Th2細(xì)胞主要分泌IL-1β、IL-4、IL-5、IL-6、IL-8、IL-9和IL-10。其中IL-4、IL-6、IL-10能直接作用于靶細(xì)胞,還能通過旁分泌與其他細(xì)胞因子間接發(fā)揮作用,破壞機(jī)體免疫系統(tǒng),促進(jìn)腫瘤細(xì)胞浸潤(rùn)和轉(zhuǎn)移,因此Th2細(xì)胞會(huì)嚴(yán)重干擾機(jī)體抗腫瘤免疫[18]。HPV持續(xù)感染是CIN進(jìn)展的必需條件,HPV感染降低了Th1/ Th2平衡,導(dǎo)致Th2細(xì)胞相對(duì)優(yōu)勢(shì)和樹突狀細(xì)胞(DCs)抑制未成熟DCs分化,從而改變免疫抑制微環(huán)境[19],促進(jìn)CIN進(jìn)展。Sharma等[20]用植物血凝素(PHA)刺激試驗(yàn)檢測(cè)65例患者外周血單核細(xì)胞,觀察到CIN患者IL-2降低,IL-4以及IL-10增加。Iwata等[21]研究發(fā)現(xiàn),宮頸黏膜IL-1β、IL-8水平在HSIL組中高于NILM組(無上皮內(nèi)病變或惡性病變)+ LSIL組,表明高水平的炎癥細(xì)胞因子IL-8、IL-1β可促進(jìn)持續(xù)性HPV感染與CIN進(jìn)展。因此,宮頸黏液細(xì)胞因子可作為評(píng)價(jià)CIN病變進(jìn)展的觀察指標(biāo)。
aPKCλ/ι是一種絲氨酸/蘇氨酸激酶,為上皮細(xì)胞極性和增殖調(diào)節(jié)所必需。aPKCλ/ι有增強(qiáng)癌細(xì)胞增殖、生存、運(yùn)動(dòng)的作用[22-23]。aPKCλ/ι過度表達(dá)加速癌細(xì)胞生長(zhǎng)、侵襲和轉(zhuǎn)移[24-26]。CIN組織學(xué)特點(diǎn)包括細(xì)胞極性喪失和細(xì)胞增殖,aPKCλ/ι可能參與CIN的發(fā)生和發(fā)展,在CIN轉(zhuǎn)變?yōu)榻?rùn)癌的過程中發(fā)揮重要作用。研究證明,在人宮頸和皮膚角化細(xì)胞中,aPKCλ/ι過度表達(dá)與HPV16 E6/E7基因上調(diào)無關(guān)[27],提示HPV E6/E7表達(dá)不足以支持CIN病變中aPKCλ/ι的過度表達(dá),aPKCλ/ι可能是不依賴于HPV E6/E7蛋白表達(dá)的獨(dú)立致癌因素。Liu等[28]用免疫組織化學(xué)法觀察CIN和宮頸浸潤(rùn)癌中aPKC表達(dá),結(jié)果證明隨著CIN級(jí)別進(jìn)展,aPKC在宮頸上皮細(xì)胞中的表達(dá)增加。而且Mizushima等[29]研究表明,aPKCλ/ι異常表達(dá)及其在亞細(xì)胞中的定位可以作為預(yù)測(cè)CINⅠ預(yù)后的指標(biāo),aPKCλ/ι是CINⅠ進(jìn)展的獨(dú)立危險(xiǎn)因素,與非HPV16/18感染所致CINⅠ的高進(jìn)展率和低逆轉(zhuǎn)率相關(guān)。aPKCλ/ι表達(dá)及其細(xì)胞內(nèi)定位可能對(duì)非HPV16/18型感染的CINⅠ有分流作用。
TLRs是IL-1受體家族成員,是機(jī)體識(shí)別病毒、細(xì)菌和其他病原體感染的模式識(shí)別受體,是天然免疫反應(yīng)的重要分子,通過病原相關(guān)分子模式(PAMPs)在宿主-病原體相互作用和識(shí)別中發(fā)揮核心作用。以往研究證實(shí),TLRs在許多人類惡性腫瘤和宮頸癌中,通過病毒識(shí)別和體內(nèi)炎性反應(yīng)而發(fā)揮作用。進(jìn)化保守的TLRs在一系列人類疾病,包括癌癥的病理過程中發(fā)揮關(guān)鍵性作用。研究發(fā)現(xiàn),不同TLRs識(shí)別不同配體。TLR2位于細(xì)胞膜,可以識(shí)別細(xì)菌脂蛋白、脂磷壁酸、真菌酵母多糖和病毒衣殼蛋白;TLR9位于內(nèi)涵體,能識(shí)別病毒基因組CpG基序。TLR2由HPV衣殼蛋白激活,通過腫瘤壞死因子受體相關(guān)因子6(TRAF6)途徑激活中間體IKB激酶催化亞基α(IKKα)、IKKβ和核因子κB(NF-κB)關(guān)鍵調(diào)節(jié)因子(NEMO),最后激活NF-κB,導(dǎo)致炎性細(xì)胞因子分泌。HPV E6 CpG序列能刺激TLR9反應(yīng),TLR9激活干擾素調(diào)節(jié)因子7(IRF7),形成復(fù)雜的IRF3/7,導(dǎo)致INF-γ的產(chǎn)生[30],發(fā)揮抗HPV感染作用。
在正常組織中,幾乎檢測(cè)不到TLRs表達(dá)。Aggarwal等[31]研究證實(shí),在宮頸鱗狀細(xì)胞癌中,TLR2、TLR9表達(dá)稍高。Ghosh等[32]研究發(fā)現(xiàn),盡管TLR2、TLR9在宮頸癌不同時(shí)期表達(dá)差異較小,但是TLR2和TLR9可以通過特異性曲線分析評(píng)估疾病進(jìn)展程度,TLR2和TLR9表達(dá)隨宮頸病變程度加重和浸潤(rùn)性癌進(jìn)展而增加。
CIN雖然是一種連續(xù)發(fā)展的病變,但存在極大的可逆性。CIN篩查直接關(guān)系到宮頸癌的預(yù)防及治療,因此早期診斷和治療CIN是阻止宮頸癌發(fā)生的關(guān)鍵。檢測(cè)某些特異性分子生物學(xué)指標(biāo)可提高診斷特異性,但這一研究領(lǐng)域至今還未發(fā)現(xiàn)一種CIN特異性的非常理想的分子生物學(xué)標(biāo)志物。臨床上可采用標(biāo)志物聯(lián)合檢測(cè)等方法提高敏感度與特異度。隨著對(duì)腫瘤病因?qū)W和CIN進(jìn)展、消退機(jī)制的深入研究以及分子生物學(xué)的進(jìn)一步發(fā)展,在不久的將來,宮頸癌有望達(dá)到全面預(yù)防和根除。
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Research Advances in Molecular Biological Indicators of Cervical Intraepithelial Neoplasia
SONG Ni-na,QU Quan-xin.
Center of Clinical College,Medical University of Tianjin,Tianjin 300192,China(SONG Ni-na,QU Quan-xin);Tianjin Huanghe Hospital,Tianjin 300110,China(SONGNi-na)
Cervical cancer is one of themost common gynecologicalmalignant tumors.In recent years,the incidence of cervical cancer has increased year by year,and there is a trend of youth.Cervical intraepithelial neoplasia(CIN)is caused by persistent infection of high risk human papillomavirus(HPV).It is a precancerous lesion of cervical cancer,and it reflects the continuous processof the developmentof cervical cancer.From the developmentofCIN to cervical cancer needs a long time.In the progress of CIN,many gene structure and function will change.Recent studies have found that there are some abnormal expression ofbiologicalmarkers between the CIN and cervical cancer tissue,which are related to the levelof the precursor and themetastasis of the tumor.These genes as CIN progression ofmolecular biomarkers for testing to early detectand diagnosis of cervical cancerhasbecome a hot research.In thisarticle,we reviewed the research on the frontiermolecularbiology ofCIN.
Cervical intraepithelialneoplasia;Uterine cervicalneoplasms;Biologicalmarkers;Telomerase;Interleukins;Toll-like receptors(JInt Obstet Gynecol,2016,43:524-527)
2016-01-21)
[本文編輯王琳]
300192天津醫(yī)科大學(xué)一中心臨床學(xué)院(宋妮娜,瞿全新);天津市黃河醫(yī)院(宋妮娜)
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