張?zhí)扈?陳兆峰， 王玉平， 周永寧

蘭州大學(xué)第一醫(yī)院消化科 甘肅省胃腸病重點(diǎn)實(shí)驗(yàn)室，甘肅 蘭州 730000

專題·胃癌

腫瘤標(biāo)志物在胃癌預(yù)后判斷應(yīng)用中的研究進(jìn)展

張?zhí)扈?陳兆峰， 王玉平， 周永寧

蘭州大學(xué)第一醫(yī)院消化科 甘肅省胃腸病重點(diǎn)實(shí)驗(yàn)室，甘肅 蘭州 730000

隨著對(duì)腫瘤標(biāo)志物認(rèn)識(shí)的不斷深入，近年來發(fā)現(xiàn)多種腫瘤標(biāo)志物與胃癌的預(yù)后有關(guān)。本文就新型的腫瘤標(biāo)志物在胃癌預(yù)后判斷的應(yīng)用作一概述，旨在為臨床病情的評(píng)估提供參考。

胃癌；預(yù)后；腫瘤標(biāo)志物

胃癌是全球最常見的惡性腫瘤之一，是癌癥相關(guān)死亡的第二大常見原因[1]。近年來，胃癌的診療水平已有了很大的提高，但因其起病較隱匿，早期無癥狀或癥狀不明顯，早期易漏診，多數(shù)患者診斷時(shí)已是臨床晚期或已發(fā)生遠(yuǎn)處轉(zhuǎn)移。而對(duì)于診斷為晚期胃癌的患者，化療和靶向治療是治療的主要方法。不幸的是，胃癌對(duì)化療和放療不敏感，其預(yù)后依然很差，主要是因?yàn)槿狈唧w的預(yù)后指標(biāo)。因此，迫切需要確定新的更好的預(yù)后標(biāo)志物以促進(jìn)診斷，預(yù)測(cè)晚期胃癌患者的預(yù)后并確定其治療反應(yīng)性，從而有針對(duì)性地進(jìn)行治療和干預(yù)，以提高患者的生存率。腫瘤標(biāo)志物是與腫瘤相關(guān)的抗原，在一定程度上能夠反映腫瘤的發(fā)生、發(fā)展，對(duì)于腫瘤的診斷及預(yù)后判斷等都具有重要意義。近年來，由于分子生物的迅猛發(fā)展，逐漸發(fā)現(xiàn)一些臨床常用的腫瘤標(biāo)志物之外的新的腫瘤標(biāo)志物與胃癌預(yù)后有關(guān)。本文就新型的腫瘤標(biāo)志物在胃癌預(yù)后判斷的應(yīng)用作一概述，旨在為臨床病情的評(píng)估提供參考。

1 基因指標(biāo)

1.1長鏈非編碼RNA(longnon-codingRNA，lncRNA) lncRNA是一類長度超過200個(gè)核苷酸，因缺乏完整開放閱讀框而不能編碼蛋白的RNA分子。它們參與了腫瘤浸潤與轉(zhuǎn)移及細(xì)胞凋亡調(diào)控，在腫瘤的預(yù)防診斷中扮演了重要角色。近年來，一些學(xué)者已在胃癌中鑒定了多種lncRNA，包括lncRNA HULC、lncRNA SPRY4-IT1、lncRNA HOTTIP、lncRNA CCAT2、lncRNA H19、lncRNA LINC00261、lncRNA LINC00982，這些lncRNA與預(yù)后不良相關(guān)[2-8]。最近研究[9-12]發(fā)現(xiàn)，lncRNA RP11-19P22.6-001、lncRNA ZFAS1、lncRNA FEZF1-AS1、lncRNA AGAP2-AS1等可作為胃癌預(yù)后的新型生物標(biāo)志物，可能是胃癌的潛在治療靶點(diǎn)。

1.2環(huán)狀RNA(circularRNA，circRNA) circRNA是一種缺乏5′末端帽和3′末端poly A尾的新型非編碼RNA分子，其與線性RNA不同，形成共價(jià)閉合的連續(xù)環(huán)并在真核轉(zhuǎn)錄組中高度表達(dá)。有證據(jù)表明，circRNA可能在動(dòng)脈粥樣硬化性血管疾病、神經(jīng)系統(tǒng)疾病、朊病毒疾病和癌癥中起重要作用。最新的研究證實(shí)，hsa_circ_0001895[13]、circPVT1[14]等可作為胃癌臨床預(yù)后預(yù)測(cè)的潛在生物標(biāo)志物。

1.3微小RNA(microRNA，miRNA) miRNA是由一類內(nèi)源性、長度為20～22個(gè)核苷酸構(gòu)成，由一段單鏈RNA前體經(jīng)過dicer酶加工而成。它們具有各種類型癌癥診斷和預(yù)后的非侵入性生物標(biāo)志物的潛力。近年來，多種miRNA，包括miRNA-22、miRNA-1271、miRNA-186、miRNA-16、miRNA-451、miRNA-1225-5p等已證實(shí)與胃癌的增殖、侵襲和轉(zhuǎn)移有關(guān)[15-18]。最新的研究表明，miR-218 rs11134527[19]、miR-144-3p[20]等可用于評(píng)價(jià)胃癌治療療效和預(yù)后，是檢測(cè)胃癌復(fù)發(fā)或轉(zhuǎn)移的新型生物標(biāo)志物。

1.4DNA甲基化DNA甲基化是不依賴于DNA堿基序列突變的基因表達(dá)轉(zhuǎn)錄前調(diào)控機(jī)制，高甲基化異常往往導(dǎo)致基因表達(dá)下降而發(fā)生基因沉默。有相當(dāng)多的證據(jù)表明，表觀遺傳改變，特別是通過啟動(dòng)子高甲基化失活腫瘤抑制基因，在胃癌的發(fā)生、發(fā)展中起重要作用。許多研究[21-23]表明，啟動(dòng)子甲基化可以作為胃癌有希望的預(yù)后生物標(biāo)志物。CHEN等[24]首次報(bào)道了NDRG4啟動(dòng)子超甲基化作為胃癌的預(yù)測(cè)生物標(biāo)志物，NDRG4啟動(dòng)子超甲基化被認(rèn)為是中國胃癌患者生存結(jié)局的獨(dú)立預(yù)后因素。MA等[25]研究確定了一種新型的腫瘤抑制基因KCNMA1，其通過調(diào)節(jié)PTK2表達(dá)激活PI3K-AKT通路，發(fā)揮腫瘤抑制功能。此外，KCNMA1啟動(dòng)子高甲基化可作為胃癌患者的潛在預(yù)后生物標(biāo)志物。

2 組織學(xué)指標(biāo)

2.1鈣黏蛋白(cadherin) 鈣黏蛋白是一組跨膜糖蛋白，在細(xì)胞與細(xì)胞間黏附過程中起重要作用。E-鈣黏蛋白的異常表達(dá)已證實(shí)參與胃癌的進(jìn)展與轉(zhuǎn)移，且與胃癌預(yù)后相關(guān)。R-鈣黏蛋白及PCDH7屬于新型的鈣黏蛋白超家族成員。CHEN等[26]的一項(xiàng)隊(duì)列研究結(jié)果顯示，R-鈣黏蛋白陽性表達(dá)的患者比陰性表達(dá)組顯示更好的總體存活率(log-rank檢驗(yàn)，P=0.000)。Cox多變量生存分析顯示，缺乏R-鈣黏蛋白的表達(dá)是胃癌臨床結(jié)果差的主要獨(dú)立預(yù)測(cè)因子(RR=5.680，95%CI：2.250～14.341，P<0.01)。最近的一項(xiàng)研究[27]發(fā)現(xiàn)，PCDH7的低表達(dá)與Lauren分類(P=0.0005)、淋巴結(jié)轉(zhuǎn)移(P=0.0002)和腫瘤淋巴結(jié)轉(zhuǎn)移期(P=0.0221)及預(yù)后差(P<0.05)顯著相關(guān)。PCDH7可作為胃癌的潛在診斷和預(yù)后生物標(biāo)志物。

2.2非洲爪蟾驅(qū)動(dòng)蛋白樣蛋白2(xenopuskinesin-likeprotein2，TPX2) TPX2是由位于人染色體帶20q11.1上的基因編碼的微管相關(guān)蛋白。已有學(xué)者證實(shí)，TPX2過表達(dá)可作為胃癌預(yù)后指標(biāo)和治療靶點(diǎn)[28]。SHAO等[29]第一次發(fā)現(xiàn),TPX2是胃癌患者OS的獨(dú)立預(yù)測(cè)因子。TOMII等[30]對(duì)290例接受胃切除術(shù)的胃腺癌患者的研究表明，高TPX2表達(dá)與年齡、組織學(xué)類型、腫瘤深度、淋巴結(jié)轉(zhuǎn)移、分期和遠(yuǎn)處轉(zhuǎn)移或復(fù)發(fā)呈正相關(guān)。高TPX2表達(dá)與較差的疾病特異性存活(P=0.004)和無復(fù)發(fā)間期(P=0.013)顯著相關(guān)。

2.3驅(qū)動(dòng)蛋白家族蛋白2A(kinesinfamilyprotein2A，KIF2A) KIF2A屬于驅(qū)動(dòng)蛋白-13家族的成員，是一種M型非微生物微管蛋白。已經(jīng)證明，對(duì)于某些類型的人類癌癥如結(jié)直腸癌、乳腺癌、喉鱗狀細(xì)胞癌等具有高表達(dá)KIF2A的患者傾向于具有較差的預(yù)后[31-33]。SHU等[34]研究表明，KIF2A表達(dá)與胃癌患者5年生存率呈負(fù)相關(guān)。此外，多變量分析表明，KIF2A是胃癌中獨(dú)立的預(yù)后因子,故高KIF2A表達(dá)可能作為胃癌患者預(yù)后不良的獨(dú)立標(biāo)記。

2.4半乳糖凝集素-8(galectin-8) 半乳糖凝集素-8是由LGALS8基因編碼的半乳糖凝集素家族蛋白質(zhì)。目前，已在透明細(xì)胞腎細(xì)胞癌、膀胱尿路上皮癌、前列腺癌和喉鱗狀細(xì)胞癌中評(píng)估了半乳糖凝集素-8的預(yù)后價(jià)值。然而，其在胃癌中的預(yù)后價(jià)值尚未明確。WU等[35]研究表明，低半乳糖凝集素-8表達(dá)顯示較差的OS(P<0.001)和無病生存(DFS)(P<0.001)。此外，其表達(dá)水平被認(rèn)為是OS的獨(dú)立有利預(yù)后因子(P<0.001)。這是第一項(xiàng)提出半乳糖凝集素-8表達(dá)與術(shù)后非轉(zhuǎn)移性胃癌患者復(fù)發(fā)和生存恢復(fù)風(fēng)險(xiǎn)關(guān)系的研究。

2.5肺癌相關(guān)蛋白(overexpressedinlungcancer1，OLC1) OLC1是一個(gè)新型肺癌相關(guān)基因。它在肺癌和其他惡性腫瘤中均有較高表達(dá)，并與食管鱗癌、卵巢癌、乳腺癌、結(jié)直腸癌患者的不良預(yù)后相關(guān)。WANG等[36]對(duì)393個(gè)胃腺癌樣本的一項(xiàng)回顧性研究結(jié)果顯示，只有高表達(dá)的OLC1可預(yù)測(cè)不良預(yù)后(HR=1.31，P=0.04)。此外，過表達(dá)的核OLC1蛋白可能是胃腺癌的獨(dú)立危險(xiǎn)因素(單變量：HR=1.43，P=0.003；多變量：HR=1.39，P=0.011)。這是第一次調(diào)查OLC1與臨床病理參數(shù)之間的相關(guān)性及胃腺癌患者的預(yù)后。

2.6RNA結(jié)合基序單鏈相互作用蛋白3(RNAbindingmotif,single-strandedinteractingprotein3，RBMS3) RBMS3屬于c-Myc基因單鏈結(jié)合蛋白(MSSP)家族。ZHANG等[37]研究結(jié)果顯示，RBMS3和SFRP1蛋白的低表達(dá)與組織學(xué)差異和預(yù)后差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)，RBMS3和SFRP1共表達(dá)狀態(tài)是胃癌患者OS的獨(dú)立預(yù)后因素。有學(xué)者[38]證實(shí),RBMS3可能是胃癌的獨(dú)立預(yù)后因素。

2.7Wntless(Wls) Wls是近年來發(fā)現(xiàn)的一個(gè)Wnt配體轉(zhuǎn)運(yùn)蛋白，協(xié)助Wnt蛋白的分泌，是Wnt信號(hào)通路的重要成員。已經(jīng)研究了Wls在某些類型人類癌癥中的表達(dá)水平和作用，包括惡性星形細(xì)胞瘤、乳腺癌和卵巢癌[39-40]。STEWART等[40]分析了一組胃癌、卵巢癌和乳腺癌標(biāo)本中Wls的表達(dá)，結(jié)果顯示，Wls表達(dá)與胃癌中任何臨床病理參數(shù)之間無顯著相關(guān)性。然而，ZHANG等[41]研究結(jié)果顯示，Wls的高表達(dá)與良好和中度分化的胃癌(P=0.035，rs=0.170)、淋巴結(jié)轉(zhuǎn)移(P=0.001，rs=0.276)和晚期TNM期呈正相關(guān)(P=0.006，rs=0.219)，可作為胃癌預(yù)后的新標(biāo)記。

2.8ArpinArpin于2013年首次被報(bào)道，是由C15ORF38基因編碼，含有定位于細(xì)胞膜的220個(gè)氨基酸殘基的蛋白質(zhì)組成[42]。它是一種新發(fā)現(xiàn)的Arp2/3復(fù)合物抑制劑。相關(guān)研究[43]表明，Arpin降低與乳腺癌預(yù)后較差顯著相關(guān)。LI等[44]首次報(bào)道了Arpin表達(dá)在胃癌患者中的臨床意義，研究表明，Arpin表達(dá)[風(fēng)險(xiǎn)比(HR)=0.551，P=0.029]是胃癌患者OS的獨(dú)立預(yù)后指標(biāo)。關(guān)于3年無病生存率(DFS)、Arpin表達(dá)水平低(中位數(shù)DFS 19 mo)的胃癌患者復(fù)發(fā)率高于高Arpin表達(dá)組(中位數(shù)DFS 34 mo，P=0.022)。Arpin表達(dá)是DFS的獨(dú)立預(yù)后指標(biāo)。

2.9Apelin及其受體(APJ) Apelin是G蛋白偶聯(lián)受體APJ的內(nèi)源性配體。Apelin和APJ在包括心臟、腦、四肢、視網(wǎng)膜、肝、肺、皮膚、腎臟和脂肪組織在內(nèi)的各種組織中廣泛表達(dá)。研究[45-46]表明，Apelin與體內(nèi)腫瘤生長和淋巴結(jié)轉(zhuǎn)移有關(guān)，Apelin和APJ具有腫瘤血管生成的促進(jìn)作用。FENG等[47]認(rèn)為，Apelin可用作預(yù)測(cè)胃癌患者預(yù)后的標(biāo)志物。HAO等[48]研究發(fā)現(xiàn)，高APJ的表達(dá)具有的腫瘤侵襲率、局部淋巴結(jié)轉(zhuǎn)移、遠(yuǎn)處轉(zhuǎn)移明顯較高(P<0.001)，總生存期更短(P<0.001)。此外，多變量生存分析顯示，APJ表達(dá)是用CRT+endostar治療的胃癌患者OS的獨(dú)立預(yù)測(cè)因子。

2.10甘露糖受體(mannosereceptor) 甘露糖受體是主要在抗原呈遞細(xì)胞的表面上表達(dá)的免疫黏附分子，例如非成熟樹突狀細(xì)胞和巨噬細(xì)胞。LIU等[49]研究顯示，胃癌細(xì)胞中甘露糖受體的表達(dá)率為45.8%(54/120)，明顯高于癌旁組織(20.0%，36/120)(χ2=6.286，P=0.012)。Kaplan-Meier生存模型表明，高表達(dá)甘露糖受體組患者的生存期顯著低于低表達(dá)甘露糖受體組(P>0.05)。Cox回歸分析顯示，高甘露糖受體表達(dá)是胃癌患者預(yù)后的獨(dú)立預(yù)測(cè)因子。甘露糖受體可能是胃癌預(yù)后的重要分子標(biāo)志物。

2.11趨化因子及其受體趨化因子是一些低分子量又可作為免疫調(diào)節(jié)器和化學(xué)趨向因子的分泌蛋白，各種趨化因子及其受體已被證明在癌癥發(fā)病機(jī)制、進(jìn)展和轉(zhuǎn)移中起關(guān)鍵作用。研究[50-57]證實(shí)，CCR3、CCR5、CCR7、CXCR4、CCL2、CCL5、CCL17、CXCL1、CXCL8、CXCR1、CXCR2等多種趨化因子及其受體同胃癌發(fā)生、發(fā)展密切相關(guān)。WEI等[58]對(duì)273例接受胃癌根治性手術(shù)的患者術(shù)后隨訪1年，發(fā)現(xiàn)術(shù)前高CCL22水平是腹膜轉(zhuǎn)移的風(fēng)險(xiǎn)因素、術(shù)后早期復(fù)發(fā)的獨(dú)立危險(xiǎn)因素。有學(xué)者[59]認(rèn)為，CXCR7可能是胃癌與腹膜傳播的預(yù)后指標(biāo)和治療靶標(biāo)，作為SDF-1的趨化因子受體通過MAPK途徑促進(jìn)胃癌進(jìn)展[60]。

2.12Kruppel樣因子15(KLF15) KLF15也被稱為腎臟富集KLF(KKLF)，是KLF轉(zhuǎn)錄因子家族中的一員，在多種組織中表達(dá)，包括腎臟、肝臟、心臟等。最新研究[61]顯示，KLF15的過表達(dá)可以通過在胃癌細(xì)胞系中上調(diào)CDKN1A/p21和CDKN1C/p57抑制細(xì)胞增殖，可能是預(yù)測(cè)胃癌患者預(yù)后的新型生物標(biāo)志物。

2.13PDZ結(jié)合激酶/T-LAK細(xì)胞起始蛋白激酶(PDZ-bindingkinase/T-LAKcell-originatedproteinkinase，PBK/TOPK) PBK/TOPK是一種絲氨酸-蘇氨酸激酶，通過抑制p53和PTEN的反式激活活性，在各種類型的癌癥中過表達(dá)[62-63]。OHASHI等[64]研究顯示，PBK/TOPK過度表達(dá)比非表達(dá)的胃癌患者存活率差(P=0.0009，對(duì)數(shù)秩檢驗(yàn))，PBK/TOPK陽性與多變量分析中的不良結(jié)果獨(dú)立相關(guān)(P<0.0001，風(fēng)險(xiǎn)比6.40,95%CI：2.71～14.49)，故PBK/TOPK可作為胃癌預(yù)后因素。

2.14羧肽酶A4(carboxypeptidaseA4，CPA4) CPA4屬于特異性催化羧基末端氨基酸釋放的含Zn金屬環(huán)羧肽酶的家族。據(jù)報(bào)道，CPA4可能是前列腺癌侵襲性的強(qiáng)候選基因。CPA4的異常表達(dá)與胃癌侵襲和進(jìn)展高度相關(guān)。SUN等[65]的研究首次表明，CPA4在胃癌組織中高度表達(dá)，CPA4的過度表達(dá)可作為胃癌獨(dú)立的預(yù)后不良因素。

2.15其他組織學(xué)指標(biāo)最近研究[66-75]還發(fā)現(xiàn)，PSMA1-7、FAM46C、SAMSN1、SCNN1B、LXRα、EPAC1、CtBP2、CD98、FAP-α、KRT17等可作為胃癌預(yù)后標(biāo)志物。

3 其他

3.1循環(huán)腫瘤細(xì)胞(circulatingtumorcells，CTCs)和循環(huán)腫瘤微栓子(circulatingtumormicroemboli，CTM) CTCs于1869年由Thomas Ashworth首次發(fā)現(xiàn)，是從腫瘤釋放到被認(rèn)為在癌癥轉(zhuǎn)移中具有關(guān)鍵作用的血流中罕見的癌細(xì)胞[76]。在多種癌癥中，包括乳腺癌、肺癌、結(jié)腸直腸癌和前列腺癌，CTCs與預(yù)后不良相關(guān)。CTCs與胃癌復(fù)發(fā)/轉(zhuǎn)移之間存在潛在的相關(guān)性，且與OS相關(guān)[77]。LIU等[78]認(rèn)為，CTCs可能是一種良好的化療監(jiān)測(cè)標(biāo)志物，也是接受姑息化療患者的理想預(yù)后標(biāo)志物。ZHENG等[79]研究表明，CTM是Ⅳ期胃癌患者較短PFS(P=0.016)和OS(P=0.003)的獨(dú)立預(yù)測(cè)因子，是預(yù)測(cè)Ⅳ期患者預(yù)后的有用工具。

3.2尿激肽釋放酶10(urinarykallikrein10，uKLK10) 人類激肽釋放酶10(KLK10)是染色體19q13.4上的激肽釋放酶基因家族的成員。在胃癌方面，已有研究[80-82]報(bào)道了KLK10作為預(yù)后生物標(biāo)志物。所有這些研究都使用胃癌組織樣本，沒有報(bào)道在胃癌患者的尿液和血清中檢測(cè)到循環(huán)KLK10的存在。SHIMURA等[83]研究首次證明,KLK10在胃癌患者尿液中存在，通過使用uKLK10，腫瘤位置和大小獲得的AUC達(dá)到0.859的極好水平，用于預(yù)測(cè)不可手術(shù)的胃癌，靈敏性為82.4%，特異性為86.2%。同時(shí)表明,使用uKLK10作為生物標(biāo)志物比pKLK10在預(yù)測(cè)胃癌的不可逆性更有優(yōu)勢(shì)。

現(xiàn)有分子標(biāo)志物為胃癌預(yù)后判斷提供了可能和美好的前景。但胃癌的發(fā)生是一個(gè)多因素、多途徑的過程，目前發(fā)病機(jī)制尚未完全明確，標(biāo)志物的敏感性和特異性還有待進(jìn)一步提高。隨著對(duì)胃癌發(fā)生機(jī)制的不斷認(rèn)識(shí)和技術(shù)手段的不斷提高，胃癌的預(yù)后將會(huì)進(jìn)一步提高。

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Researchprogressoftumormarkersintheprognosisofgastriccancer

ZHANG Tianjin, CHEN Zhaofeng, WANG Yuping, ZHOU Yongning

Department of Gastroenterology, the First Affiliated Hospital of Lanzhou University, Key Laboratory of Gastrointestinal Diseases of Gansu Province, Lanzhou 730000, China

With the increasing of understanding of tumor markers, several tumor markers have been found to be related to the prognosis of gastric cancer. The application of new tumor markers in the prognosis of gastric cancer was reviewed, to provide references for the evaluation of clinical conditions.

Gastric cancer; Prognosis; Tumor markers

10.3969/j.issn.1006-5709.2017.12.001

國家自然科學(xué)基金(81570783)；國家科技支撐計(jì)劃項(xiàng)目(2015BAI13B07)；甘肅省衛(wèi)生行業(yè)科技管理項(xiàng)目(GWGL2014-43)；蘭州大學(xué)中央高?；究蒲袠I(yè)務(wù)費(fèi)專項(xiàng)資金(Lzujbky-2015-258)

張?zhí)扈谧x碩士，研究方向：胃腸病和肝病相關(guān)疾病的診斷及治療。E-mail：1293335755@qq.com

周永寧，博士生導(dǎo)師，主任醫(yī)師，研究方向：胃腸病和肝病相關(guān)疾病的診斷及治療。E-mail：yongningzhou@sina.com

R735.2

A

1006-5709(2017)12-1321-06

2017-07-10

李 健)