肿瘤标志物在胃癌预后判断应用中的研究进展

张天瑾， 陈兆峰， 王玉平， 周永宁

兰州大学第一医院消化科 甘肃省胃肠病重点实验室，甘肃 兰州 730000

专题·胃癌

肿瘤标志物在胃癌预后判断应用中的研究进展

张天瑾， 陈兆峰， 王玉平， 周永宁

兰州大学第一医院消化科 甘肃省胃肠病重点实验室，甘肃 兰州 730000

随着对肿瘤标志物认识的不断深入，近年来发现多种肿瘤标志物与胃癌的预后有关。本文就新型的肿瘤标志物在胃癌预后判断的应用作一概述，旨在为临床病情的评估提供参考。

胃癌；预后；肿瘤标志物

胃癌是全球最常见的恶性肿瘤之一，是癌症相关死亡的第二大常见原因[1]。近年来，胃癌的诊疗水平已有了很大的提高，但因其起病较隐匿，早期无症状或症状不明显，早期易漏诊，多数患者诊断时已是临床晚期或已发生远处转移。而对于诊断为晚期胃癌的患者，化疗和靶向治疗是治疗的主要方法。不幸的是，胃癌对化疗和放疗不敏感，其预后依然很差，主要是因为缺乏具体的预后指标。因此，迫切需要确定新的更好的预后标志物以促进诊断，预测晚期胃癌患者的预后并确定其治疗反应性，从而有针对性地进行治疗和干预，以提高患者的生存率。肿瘤标志物是与肿瘤相关的抗原，在一定程度上能够反映肿瘤的发生、发展，对于肿瘤的诊断及预后判断等都具有重要意义。近年来，由于分子生物的迅猛发展，逐渐发现一些临床常用的肿瘤标志物之外的新的肿瘤标志物与胃癌预后有关。本文就新型的肿瘤标志物在胃癌预后判断的应用作一概述，旨在为临床病情的评估提供参考。

1 基因指标

1.1长链非编码RNA(longnon-codingRNA，lncRNA) lncRNA是一类长度超过200个核苷酸，因缺乏完整开放阅读框而不能编码蛋白的RNA分子。它们参与了肿瘤浸润与转移及细胞凋亡调控，在肿瘤的预防诊断中扮演了重要角色。近年来，一些学者已在胃癌中鉴定了多种lncRNA，包括lncRNA HULC、lncRNA SPRY4-IT1、lncRNA HOTTIP、lncRNA CCAT2、lncRNA H19、lncRNA LINC00261、lncRNA LINC00982，这些lncRNA与预后不良相关[2-8]。最近研究[9-12]发现，lncRNA RP11-19P22.6-001、lncRNA ZFAS1、lncRNA FEZF1-AS1、lncRNA AGAP2-AS1等可作为胃癌预后的新型生物标志物，可能是胃癌的潜在治疗靶点。

1.2环状RNA(circularRNA，circRNA) circRNA是一种缺乏5′末端帽和3′末端poly A尾的新型非编码RNA分子，其与线性RNA不同，形成共价闭合的连续环并在真核转录组中高度表达。有证据表明，circRNA可能在动脉粥样硬化性血管疾病、神经系统疾病、朊病毒疾病和癌症中起重要作用。最新的研究证实，hsa_circ_0001895[13]、circPVT1[14]等可作为胃癌临床预后预测的潜在生物标志物。

1.3微小RNA(microRNA，miRNA) miRNA是由一类内源性、长度为20～22个核苷酸构成，由一段单链RNA前体经过dicer酶加工而成。它们具有各种类型癌症诊断和预后的非侵入性生物标志物的潜力。近年来，多种miRNA，包括miRNA-22、miRNA-1271、miRNA-186、miRNA-16、miRNA-451、miRNA-1225-5p等已证实与胃癌的增殖、侵袭和转移有关[15-18]。最新的研究表明，miR-218 rs11134527[19]、miR-144-3p[20]等可用于评价胃癌治疗疗效和预后，是检测胃癌复发或转移的新型生物标志物。

1.4DNA甲基化DNA甲基化是不依赖于DNA碱基序列突变的基因表达转录前调控机制，高甲基化异常往往导致基因表达下降而发生基因沉默。有相当多的证据表明，表观遗传改变，特别是通过启动子高甲基化失活肿瘤抑制基因，在胃癌的发生、发展中起重要作用。许多研究[21-23]表明，启动子甲基化可以作为胃癌有希望的预后生物标志物。CHEN等[24]首次报道了NDRG4启动子超甲基化作为胃癌的预测生物标志物，NDRG4启动子超甲基化被认为是中国胃癌患者生存结局的独立预后因素。MA等[25]研究确定了一种新型的肿瘤抑制基因KCNMA1，其通过调节PTK2表达激活PI3K-AKT通路，发挥肿瘤抑制功能。此外，KCNMA1启动子高甲基化可作为胃癌患者的潜在预后生物标志物。

2 组织学指标

2.1钙黏蛋白(cadherin) 钙黏蛋白是一组跨膜糖蛋白，在细胞与细胞间黏附过程中起重要作用。E-钙黏蛋白的异常表达已证实参与胃癌的进展与转移，且与胃癌预后相关。R-钙黏蛋白及PCDH7属于新型的钙黏蛋白超家族成员。CHEN等[26]的一项队列研究结果显示，R-钙黏蛋白阳性表达的患者比阴性表达组显示更好的总体存活率(log-rank检验，P=0.000)。Cox多变量生存分析显示，缺乏R-钙黏蛋白的表达是胃癌临床结果差的主要独立预测因子(RR=5.680，95%CI：2.250～14.341，P<0.01)。最近的一项研究[27]发现，PCDH7的低表达与Lauren分类(P=0.0005)、淋巴结转移(P=0.0002)和肿瘤淋巴结转移期(P=0.0221)及预后差(P<0.05)显著相关。PCDH7可作为胃癌的潜在诊断和预后生物标志物。

2.2非洲爪蟾驱动蛋白样蛋白2(xenopuskinesin-likeprotein2，TPX2) TPX2是由位于人染色体带20q11.1上的基因编码的微管相关蛋白。已有学者证实，TPX2过表达可作为胃癌预后指标和治疗靶点[28]。SHAO等[29]第一次发现,TPX2是胃癌患者OS的独立预测因子。TOMII等[30]对290例接受胃切除术的胃腺癌患者的研究表明，高TPX2表达与年龄、组织学类型、肿瘤深度、淋巴结转移、分期和远处转移或复发呈正相关。高TPX2表达与较差的疾病特异性存活(P=0.004)和无复发间期(P=0.013)显著相关。

2.3驱动蛋白家族蛋白2A(kinesinfamilyprotein2A，KIF2A) KIF2A属于驱动蛋白-13家族的成员，是一种M型非微生物微管蛋白。已经证明，对于某些类型的人类癌症如结直肠癌、乳腺癌、喉鳞状细胞癌等具有高表达KIF2A的患者倾向于具有较差的预后[31-33]。SHU等[34]研究表明，KIF2A表达与胃癌患者5年生存率呈负相关。此外，多变量分析表明，KIF2A是胃癌中独立的预后因子,故高KIF2A表达可能作为胃癌患者预后不良的独立标记。

2.4半乳糖凝集素-8(galectin-8) 半乳糖凝集素-8是由LGALS8基因编码的半乳糖凝集素家族蛋白质。目前，已在透明细胞肾细胞癌、膀胱尿路上皮癌、前列腺癌和喉鳞状细胞癌中评估了半乳糖凝集素-8的预后价值。然而，其在胃癌中的预后价值尚未明确。WU等[35]研究表明，低半乳糖凝集素-8表达显示较差的OS(P<0.001)和无病生存(DFS)(P<0.001)。此外，其表达水平被认为是OS的独立有利预后因子(P<0.001)。这是第一项提出半乳糖凝集素-8表达与术后非转移性胃癌患者复发和生存恢复风险关系的研究。

2.5肺癌相关蛋白(overexpressedinlungcancer1，OLC1) OLC1是一个新型肺癌相关基因。它在肺癌和其他恶性肿瘤中均有较高表达，并与食管鳞癌、卵巢癌、乳腺癌、结直肠癌患者的不良预后相关。WANG等[36]对393个胃腺癌样本的一项回顾性研究结果显示，只有高表达的OLC1可预测不良预后(HR=1.31，P=0.04)。此外，过表达的核OLC1蛋白可能是胃腺癌的独立危险因素(单变量：HR=1.43，P=0.003；多变量：HR=1.39，P=0.011)。这是第一次调查OLC1与临床病理参数之间的相关性及胃腺癌患者的预后。

2.6RNA结合基序单链相互作用蛋白3(RNAbindingmotif,single-strandedinteractingprotein3，RBMS3) RBMS3属于c-Myc基因单链结合蛋白(MSSP)家族。ZHANG等[37]研究结果显示，RBMS3和SFRP1蛋白的低表达与组织学差异和预后差异均有统计学意义(P<0.05)，RBMS3和SFRP1共表达状态是胃癌患者OS的独立预后因素。有学者[38]证实,RBMS3可能是胃癌的独立预后因素。

2.7Wntless(Wls) Wls是近年来发现的一个Wnt配体转运蛋白，协助Wnt蛋白的分泌，是Wnt信号通路的重要成员。已经研究了Wls在某些类型人类癌症中的表达水平和作用，包括恶性星形细胞瘤、乳腺癌和卵巢癌[39-40]。STEWART等[40]分析了一组胃癌、卵巢癌和乳腺癌标本中Wls的表达，结果显示，Wls表达与胃癌中任何临床病理参数之间无显著相关性。然而，ZHANG等[41]研究结果显示，Wls的高表达与良好和中度分化的胃癌(P=0.035，rs=0.170)、淋巴结转移(P=0.001，rs=0.276)和晚期TNM期呈正相关(P=0.006，rs=0.219)，可作为胃癌预后的新标记。

2.8ArpinArpin于2013年首次被报道，是由C15ORF38基因编码，含有定位于细胞膜的220个氨基酸残基的蛋白质组成[42]。它是一种新发现的Arp2/3复合物抑制剂。相关研究[43]表明，Arpin降低与乳腺癌预后较差显著相关。LI等[44]首次报道了Arpin表达在胃癌患者中的临床意义，研究表明，Arpin表达[风险比(HR)=0.551，P=0.029]是胃癌患者OS的独立预后指标。关于3年无病生存率(DFS)、Arpin表达水平低(中位数DFS 19 mo)的胃癌患者复发率高于高Arpin表达组(中位数DFS 34 mo，P=0.022)。Arpin表达是DFS的独立预后指标。

2.9Apelin及其受体(APJ) Apelin是G蛋白偶联受体APJ的内源性配体。Apelin和APJ在包括心脏、脑、四肢、视网膜、肝、肺、皮肤、肾脏和脂肪组织在内的各种组织中广泛表达。研究[45-46]表明，Apelin与体内肿瘤生长和淋巴结转移有关，Apelin和APJ具有肿瘤血管生成的促进作用。FENG等[47]认为，Apelin可用作预测胃癌患者预后的标志物。HAO等[48]研究发现，高APJ的表达具有的肿瘤侵袭率、局部淋巴结转移、远处转移明显较高(P<0.001)，总生存期更短(P<0.001)。此外，多变量生存分析显示，APJ表达是用CRT+endostar治疗的胃癌患者OS的独立预测因子。

2.10甘露糖受体(mannosereceptor) 甘露糖受体是主要在抗原呈递细胞的表面上表达的免疫黏附分子，例如非成熟树突状细胞和巨噬细胞。LIU等[49]研究显示，胃癌细胞中甘露糖受体的表达率为45.8%(54/120)，明显高于癌旁组织(20.0%，36/120)(χ2=6.286，P=0.012)。Kaplan-Meier生存模型表明，高表达甘露糖受体组患者的生存期显著低于低表达甘露糖受体组(P>0.05)。Cox回归分析显示，高甘露糖受体表达是胃癌患者预后的独立预测因子。甘露糖受体可能是胃癌预后的重要分子标志物。

2.11趋化因子及其受体趋化因子是一些低分子量又可作为免疫调节器和化学趋向因子的分泌蛋白，各种趋化因子及其受体已被证明在癌症发病机制、进展和转移中起关键作用。研究[50-57]证实，CCR3、CCR5、CCR7、CXCR4、CCL2、CCL5、CCL17、CXCL1、CXCL8、CXCR1、CXCR2等多种趋化因子及其受体同胃癌发生、发展密切相关。WEI等[58]对273例接受胃癌根治性手术的患者术后随访1年，发现术前高CCL22水平是腹膜转移的风险因素、术后早期复发的独立危险因素。有学者[59]认为，CXCR7可能是胃癌与腹膜传播的预后指标和治疗靶标，作为SDF-1的趋化因子受体通过MAPK途径促进胃癌进展[60]。

2.12Kruppel样因子15(KLF15) KLF15也被称为肾脏富集KLF(KKLF)，是KLF转录因子家族中的一员，在多种组织中表达，包括肾脏、肝脏、心脏等。最新研究[61]显示，KLF15的过表达可以通过在胃癌细胞系中上调CDKN1A/p21和CDKN1C/p57抑制细胞增殖，可能是预测胃癌患者预后的新型生物标志物。

2.13PDZ结合激酶/T-LAK细胞起始蛋白激酶(PDZ-bindingkinase/T-LAKcell-originatedproteinkinase，PBK/TOPK) PBK/TOPK是一种丝氨酸-苏氨酸激酶，通过抑制p53和PTEN的反式激活活性，在各种类型的癌症中过表达[62-63]。OHASHI等[64]研究显示，PBK/TOPK过度表达比非表达的胃癌患者存活率差(P=0.0009，对数秩检验)，PBK/TOPK阳性与多变量分析中的不良结果独立相关(P<0.0001，风险比6.40,95%CI：2.71～14.49)，故PBK/TOPK可作为胃癌预后因素。

2.14羧肽酶A4(carboxypeptidaseA4，CPA4) CPA4属于特异性催化羧基末端氨基酸释放的含Zn金属环羧肽酶的家族。据报道，CPA4可能是前列腺癌侵袭性的强候选基因。CPA4的异常表达与胃癌侵袭和进展高度相关。SUN等[65]的研究首次表明，CPA4在胃癌组织中高度表达，CPA4的过度表达可作为胃癌独立的预后不良因素。

2.15其他组织学指标最近研究[66-75]还发现，PSMA1-7、FAM46C、SAMSN1、SCNN1B、LXRα、EPAC1、CtBP2、CD98、FAP-α、KRT17等可作为胃癌预后标志物。

3 其他

3.1循环肿瘤细胞(circulatingtumorcells，CTCs)和循环肿瘤微栓子(circulatingtumormicroemboli，CTM) CTCs于1869年由Thomas Ashworth首次发现，是从肿瘤释放到被认为在癌症转移中具有关键作用的血流中罕见的癌细胞[76]。在多种癌症中，包括乳腺癌、肺癌、结肠直肠癌和前列腺癌，CTCs与预后不良相关。CTCs与胃癌复发/转移之间存在潜在的相关性，且与OS相关[77]。LIU等[78]认为，CTCs可能是一种良好的化疗监测标志物，也是接受姑息化疗患者的理想预后标志物。ZHENG等[79]研究表明，CTM是Ⅳ期胃癌患者较短PFS(P=0.016)和OS(P=0.003)的独立预测因子，是预测Ⅳ期患者预后的有用工具。

3.2尿激肽释放酶10(urinarykallikrein10，uKLK10) 人类激肽释放酶10(KLK10)是染色体19q13.4上的激肽释放酶基因家族的成员。在胃癌方面，已有研究[80-82]报道了KLK10作为预后生物标志物。所有这些研究都使用胃癌组织样本，没有报道在胃癌患者的尿液和血清中检测到循环KLK10的存在。SHIMURA等[83]研究首次证明,KLK10在胃癌患者尿液中存在，通过使用uKLK10，肿瘤位置和大小获得的AUC达到0.859的极好水平，用于预测不可手术的胃癌，灵敏性为82.4%，特异性为86.2%。同时表明,使用uKLK10作为生物标志物比pKLK10在预测胃癌的不可逆性更有优势。

现有分子标志物为胃癌预后判断提供了可能和美好的前景。但胃癌的发生是一个多因素、多途径的过程，目前发病机制尚未完全明确，标志物的敏感性和特异性还有待进一步提高。随着对胃癌发生机制的不断认识和技术手段的不断提高，胃癌的预后将会进一步提高。

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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

国家自然科学基金(81570783)；国家科技支撑计划项目(2015BAI13B07)；甘肃省卫生行业科技管理项目(GWGL2014-43)；兰州大学中央高校基本科研业务费专项资金(Lzujbky-2015-258)

张天瑾，在读硕士，研究方向：胃肠病和肝病相关疾病的诊断及治疗。E-mail：1293335755@qq.com

周永宁，博士生导师，主任医师，研究方向：胃肠病和肝病相关疾病的诊断及治疗。E-mail：yongningzhou@sina.com

R735.2

A

1006-5709(2017)12-1321-06

2017-07-10

李 健)