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Advances in Clinical Medicine
Vol. 13  No. 04 ( 2023 ), Article ID: 64083 , 7 pages
10.12677/ACM.2023.134832

IGFBP7在消化系统肿瘤中的研究进展

任怀静1，马臻棋2*，王学红2，张梦迪1，李重杰1

1青海大学研究生院，青海 西宁

2青海大学附属医院消化内科，青海 西宁

收稿日期：2023年3月17日；录用日期：2023年4月12日；发布日期：2023年4月19日

摘要

消化系统肿瘤发病率及病死率高，对人类生命健康造成严重威胁。胰岛素样生长因子结合蛋白7 (insulin-like growth factor binding-protein 7, IGFBP7)是胰岛素样生长因子结合蛋白超家族中的一员，参与肿瘤的生长、增殖、侵袭、转移及小血管生成等过程，其在不同肿瘤中表现为激活或抑制肿瘤发生发展的双重生物学特性。IGFBP7有望成为消化系统肿瘤早期诊断、靶向治疗及评估预后的标志物，本文就近年来IGFBP7在消化系统中的研究进展及可能的致癌机制作一综述。

关键词

消化系统肿瘤，IGFBP7，致癌机制

Research Progress of IGFBP7 in Digestive System Tumors

Huaijing Ren1, Zhenqi Ma2*, Xuehong Wang2, Mengdi Zhang1, Chongjie Li1

1Graduate School of Qinghai University, Xining Qinghai

2Department of Gastroenterology, Affiliated Hospital of Qinghai University, Xining Qinghai

Received: Mar. 17th, 2023; accepted: Apr. 12th, 2023; published: Apr. 19th, 2023

ABSTRACT

The high incidence rate and mortality of digestive system tumors pose a serious threat to human life and health. Insulin-like growth factor binding protein 7 (IGFBP7) is a member of the insulin-like growth factor binding protein superfamily, which is involved in the growth, proliferation, invasion, metastasis and small angiogenesis of tumors. It has the dual biological characteristics of activating or inhibiting tumor development in different tumors. IGFBP7 is expected to become a marker for early diagnosis, targeted treatment and evaluation of prognosis of digestive system tumors. This article reviews the research progress of IGFBP7 in digestive system and its possible carcinogenic mechanism in recent years.

Keywords:Digestive System Tumor, IGFBP7, Carcinogenic Mechanism

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

随着社会经济的发展以及人们生活环境和方式的改变，恶性肿瘤成为造成严重疾病负担、损害生命健康的主要病种。2020年全球癌症新发1929万例，死亡996万例，其中消化系统恶性肿瘤新增病例超过500万，新增死亡病例约占肿瘤相关死亡的36.5% [1] 。虽然传统的外科手术、放化疗和药物治疗等方法可提高患者生存率 [2] ，但治疗效果不容乐观，因此探讨肿瘤标志物对肿瘤早期诊断、靶向治疗及评估预后尤为重要。

胰岛素样生长因子结合蛋白是胰岛素样生长因子(insulin-like growth factor, IGF)系统的一类肽类激素，可与IGF受体结合并阻断IGF的激活。目前共发现15个家族成员，IGFBP-1至IGFBP-6与IGF具有较高的结合能力，而IGFBP-7至IGFBP-15结合力较低，因此也被称为IGFBP相关蛋白 。IGFBP7作为第一个被发现的相关蛋白，可通过诱导细胞衰老凋亡、抑制肿瘤增殖及小血管生成而发挥抑制肿瘤的作用 [3] ，近年被认为是肿瘤抑癌基因而成为国内外的研究热点。但随着不断深入的研究，IGFBP7在消化系统肿瘤中出现相矛盾的结果，提示其可能在不同肿瘤中具有激动或抑制肿瘤发生发展的双重特性，IGFBP7有望成为消化系统肿瘤早期诊断、靶向治疗及评估预后的标志物。本文回顾性分析相关文献，就IGFBP7在消化系统肿瘤中的研究进展及可能的致癌机制作一综述，以期为消化系统肿瘤的诊断、治疗及预后提供方向和思路。

2. IGFBP7结构、功能和分布

2.1. IGFBP7结构

IGFBP7基因位于染色体4q12-13上，编码277个氨基酸的前蛋白，具有类似于IGFBP1-6高度保守的N端结构域，含12个保守半胱氨酸(cysteine, Cys)的“GCGCCXXC”氨基酸序列，是富含Cys的最高区域，偶数个Cys在N端内部形成二硫键，此二硫键有利于维持IGFBPs三级结构的稳定性。近N端结构域的是一段30-45个氨基酸残基，因与丝氨酸蛋白酶抑制剂Kazal家族有30%的相似性，被称为KI结构域(kazal-type serineproteinase inhibitor, KI) [3] [4] 。因IGFBP7缺乏保守的C端和中间结构域，IGFBP7较IGFBP1-6对IGF-I、IGF-II的亲和力分别弱5倍和20~25倍，但同时C端结构域的缺失导致N端的胰岛素结合位点暴露，和胰岛素的亲和力要强500倍，从而阻断胰岛素与其受体间的结合，阻止后者自身磷酸化及其他后续反应的发生 [5] ，进而参与糖代谢功能的紊乱和2型糖尿病的发生过程。

2.2. IGFBP7生物学功能

IGFBP的作用主要涉及到两方面：1) IGF依赖(IGF-dependent)方式：IGFBP作为IGFs的转运蛋白，限制IGFs与其受体的结合，并调节体液及肿瘤组织中IGFs的浓度、活性和半衰期，从而影响IGFs的功能发挥。2) IGF非依赖(IGF-independent)方式：IGFBP可以直接通过调节细胞分泌生长因子、与细胞表面非IGF受体直接作用、入核调控基因转录以及鞘磷脂作用途径等多种机制调控细胞增殖、凋亡、衰老和自噬等过程 [6] ，IGFBP7与肿瘤的关系多数取决于IGF非依赖方式。

2.3. IGFBP7分布

IGFBP7分布十分广泛，在肾脏、胃肠道、乳腺和前列腺等多个器官表达量较高，在大多数内皮细胞、平滑肌细胞和成纤维细胞都有较强的免疫荧光染色，但脂肪细胞、浆细胞和淋巴细胞为染色为阴性 [7] 。此外，在循环血液、细胞外组织液和细胞内组织中也可检测到IGFBP7的存在 [8] ，推测其具有成为早期无创诊断肿瘤的潜力。

3. IGFBP7和消化系统恶性肿瘤的关系

3.1. 食管癌

食管癌(esophageal cancer, EC)以食管鳞状细胞癌(esophageal squamous cell carcinoma, ESCC)和食管腺癌(esophageal adenocacinoma, EAC)为主，与配对的正常组织相比，IGFBP7在两种组织学类型均出现过表达 [9] [10] 。采用酶联免疫吸附测定(enzymelinked immunosorbent assay, ELASA)检测ESCC患者和正常对照的循环血清样本，并通过ROC曲线进一步确定了血清IGFBP7对ESCC具有早期诊断价值 [11] ，以便早期诊断、治疗和更有利的预后。IGFBP7的增加可通过激活TGFβ1/SMAD信号通路上调，诱导肿瘤微环境(tumor microenvironment, TME)重要的细胞成分如转化生长因子-β1 (transforming growth factor-β1, TGFβ1)、α-平滑肌肌动蛋白(α-smooth muscle actin, α-SMA)和I型胶原蛋白上调和细胞外基质(extracellular matrix, ECM)产生 [12] ，从而可能通过重塑TME加快ESCC的发生发展。Smith E等人 [1] 发现EC组织中IGFBP7启动子的甲基化与基因表达的沉默相关，且随着IGFBP7蛋白表达升高，患者的生存期逐渐缩短。腺苷脱氨酶2 (adenosine deaminase acting on RNA2, ADAR2)可通过改变基质酶的蛋白酶识别点从而编辑和稳定IGFBP7的表达进一步抑制肿瘤生长并诱导细胞凋亡 [13] ，从而抑制ESCC的进一步发展。IGFBP7可能在EC发生发展过程中充当原癌基因的重要角色。

3.2. 胃癌

胃癌是源于胃黏膜上皮细胞的恶性肿瘤，主要是胃腺癌，是侵袭性强和转移率高的肿瘤。研究表明IGFBP7在胃癌组织中的表达水平显著上调 [14] [15] [16] ，与临床分期、分级、免疫细胞浸润和幽门螺杆菌感染状态存在相关。晚期GC的IGFBP7 mRNA水平显着高于早期GC，有淋巴结转移和存在远处转移的肿瘤高于无淋巴结转移和无远处转移的肿瘤，推测IGFBP7可能是GC分化的关键功能成分。IGFBP7表达上调与GC预后不良和免疫抑制细胞浸润相关基因有关 [14] ，尤其是肿瘤相关巨噬细胞。部分研究出现相矛盾的结果，GC组织中IGFBP7 mRNA和蛋白均显着低于癌旁非肿瘤组织，IGFBP7下调可诱导GC细胞增殖、浸润和去分化，可作为预测患者的不良预后 [17] [18] 。有趣的是，IGFBP7的表达与Ki-67呈负相关，但与p53呈正相关。IGFBP7甲基化与GC中IGFBP7表达呈负相关，敲低IGFBP7后加速GC细胞的生长、侵袭和迁移，而GC细胞中的IGFBP7过表达可诱导细胞生长抑制和凋亡。IGFBP7可通过表观遗传途径在GC中发挥抑癌作用 [19] 。GC发生发展的生物学步骤复杂多样，尚未拥有清晰的描述，需进一步探讨。

3.3. 结直肠癌

结直肠癌(colorectal cancer, CRC)的临床类型以腺癌最为普遍，与正常组织相比，CRC组织中IGFBP7的表达普遍显著上调 [20] [21] ，尤其是空腹血糖水平升高和患有糖尿病的受试者。部分研究发现IGFBP7在CRC中表达下调 [22] ，且在晚期才表现显著差异。IGFBP7的表达可反应分化程度 [23] ，是CRC分化的潜在关键分子。虽然已有研究报道了CRC中IGFBP7的表达情况，但具体的生物学功能尚不明确。Lin等人认为表观遗传失活是部分CRC患者IGFBP7下调的原因 [24] ，去甲基化激活IGFBP7可抑制人CRC细胞的体外生长，DNA甲基化可能是负责IGFBP-7基因沉默的机制。IGFBP7的表观遗传失活似乎通过从p53诱导的衰老中逃脱而在CPG岛甲基化(cpg island methylation phenotype, CIMP)的CRC肿瘤发生中起关键作用 [25] 。IGFBP7通过诱导其下游分子热休克蛋白60 (heat shock protein60, HSP-60)效应的下调 [23] ，在CRC中发挥抑制肿瘤的生物学行为。与之矛盾的是，CRC细胞以Smad2/3-Dvl2/3依赖性方式共同调节TGF-β和Wnt信号传导，促进成纤维细胞中IGFBP7的高表达 [26] 。远处转移是CRC患者癌症相关死亡的主要原因。IGFBP7的过表达通过TGF-β/Smad依赖性通路在抑制上皮–间充质转化(epithelial mesenchymal transition, EMT)相关基因的表达，如E-钙粘蛋白和N-钙粘蛋白 [22] [27] ，可能对CRC细胞的转移行为起到预防作用。采用ELISA检测了CRC患者与正常对照的血清IGFBP7水平，发现在CRC患者血清中的升高 [28] ，在CRC诊断中有一定价值，并具有作为CRC早期无创诊断性肿瘤标记物的潜力，与癌胚抗原(carcinoembryonic antigen, CEA)联合应用可能提高诊断的准确性。上述结果表明IGFBP7可能是结直肠癌早期诊断、发生发展和远处转移的生物标志物。

3.4. 肝癌

肝癌(hepatocellular carcinoma, HCC)的发生发展是一个长期多阶段的过程，其中以肝细胞肝癌最为普遍。研究人员发现与正常肝细胞相比，HCC样本和细胞系中IGFBP7的表达随着HCC的晚期和分化程度的降低而显著下调 [29] ，被认为是一种肿瘤抑制因子。血清IGFBP7基因启动子CpG岛的甲基化可作为HCC诊断的非侵入性生物标志物和HCC肝切除术后中总生存期及早期肿瘤复发的独立预后预测因子 [30] 。值得注意的是，IGFBP7甲基化和甲胎蛋白(alpha-fetoprotein, AFP)的组合可提高肝癌的早期诊断率及弥补AFP较为单一的情况 [31] ，同时也可以增强AFP区分乙型肝炎病毒相关HCC和慢性乙型肝炎(chronic hepatitis B, CHB)的诊断能力。IGFBP7不仅可以通过与IGF1受体结合来抑制IGF信号传导，通过抑制血管生成和诱导癌症特异性衰老和凋亡来消除肿瘤，而且还能调节肿瘤微环境 [5] ，这种双重作用可能具有比较持久的抑制肿瘤生长和远处转移的作用。在过表达星形胶质细胞上调基因-1 (astrocyte elevated gene-1, AEG-1)的人HCC细胞的背景下建立IGFBP7过表达克隆后，细胞系增殖和集落形成明显减少，AEG-1表达升高可导致IGFBP7的表达显著下调 [32] ，从而介导了AEG-1的肿瘤促进功能。目前针对肝癌的治疗方案较为单一，以外科手术和药物治疗居多，开发全新有效的靶向治疗以延长患者的生存期尤为重要。IGFBP7的复制缺陷型腺病毒通过诱导活性氧(reactive oxygen species, ROS)及激活DNA损伤应答(DNA-damage response, DDR)和p38 MAPK，抑制多种HCC细胞系的活力并诱导细胞凋亡。在小鼠静脉中注射腺病毒递送IGFBP7 (adenovirus-delivered IGFBP7, Ad.IGFBP7)可显著抑制原发性肿瘤生长、肝内转移和血管生成 [32] ，提示Ad.IGFBP7可能是一种有效根除原发性HCC和远处转移的治疗方法。

3.5. 胆管癌

胆管癌(cholangiocarcinoma, CCA)是继肝细胞癌后的第二大常见肝癌类型，一种高度致死性的促增生性癌症 [33] 。IGFBP7在胆管癌(CCA)中的相关报道较少，Yue等人 [34] 发现IGFBP7的过表达可抑制肿瘤细胞增殖并将间充质表型逆转为上皮表型从而降低细胞侵袭性，这可能与phorsphor-p38MAPK升高及IGF-1R，IRS-1和phosphor-AKT蛋白水平降低存在一定的联系，敲除IGFBP7后促进CCA细胞增殖。推测IGFBP7可能与CCA的发生具有一定的相关性。

3.6. 胰腺癌

胰腺癌(pancreatic cancer, PC)是具有侵袭性和致命性的消化道肿瘤 [35] ，由于胰腺特殊的解剖位置及疾病进展迅速，绝大多数患者发现时已发生远处转移，是预后最差的恶性肿瘤之一。IGFBP7在胰腺癌中的相关报道较少，IGFBP7在PC中表达相较于正常组织显著下调，同时IGFBP7的低表达与增殖增加和术后生存不良有关 [36] ，提示IGFBP7在PC中可能扮演着抑癌基因的角色。

4. 总结和展望

综上所述，在不同消化系统恶性肿瘤中IGFBP7表现出不同的表达模式，不同分型、分化程度的肿瘤中也表现出差异。这些存在争议的结果提示其在不同肿瘤中可能通过不同的信号通路发挥生物学作用，这种模糊的表达模式或许能够在临床上不易判断原发肿瘤病灶时提供定位帮助，以达到辅助诊断的作用。血清IGFBP7的诊断价值已在多种消化系统肿瘤中得到相应的验证，因此IGFBP7有望成为消化系统肿瘤早期非侵入性诊断标志物、新治疗靶点及预后标志物，但具体的作用机制，因此需进行大样本、多中心分析，找到更充分的循证医学依据。

基金项目

青海大学附属医院重点专科项目。

文章引用

任怀静,马臻棋,王学红,张梦迪,李重杰. IGFBP7在消化系统肿瘤中的研究进展
Research Progress of IGFBP7 in Digestive System Tumors[J]. 临床医学进展, 2023, 13(04): 5894-5900. https://doi.org/10.12677/ACM.2023.134832

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    37. NOTES

    *通讯作者。

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