药物资讯  >> Vol. 10 No. 3 (May 2021)

ESM1:一个癌症治疗的新靶点
ESM1: A New Target for Cancer Therapy

DOI: 10.12677/PI.2021.103016, PDF, HTML, XML, 下载: 29  浏览: 78 

作者: 梁 雪, 刘 煜*:中国药科大学生命科学与技术学院,江苏 南京

关键词: ESM1血管生成癌症ESM1 Angiogenesis Cancers

摘要: ESM1,又称Endocan,是一种50 kDa的富含半胱氨酸的分泌型蛋白聚糖,包含一个20 kDa的蛋白质核心和一条与其共价结合的硫酸皮肤素糖链。正常组织中,ESM1在血管内皮细胞、肾远端小管上皮细胞、支气管和肺粘膜下腺表达。近年来研究发现,ESM1在肺癌、肾癌、肝癌、乳腺癌、脑胶质母细胞瘤等多种恶性肿瘤中高表达,且与肿瘤血管生成、转移和预后不良相关。有研究者认为,ESM1可能成为癌症治疗的新靶点。本文旨在对ESM1的结构、功能,及其在多种炎症疾病和癌症中的研究进展进行综述。
Abstract: ESM1, also called Endocan, is a 50 kDa cysteine-rich secreted proteoglycan, containing a 20 kDa core protein and a single dermatan sulfate chain. In normal tissues, ESM1 is secreted by vascular endothelial cells, epithelial cells lining renal distal tubules, bronchi, and lung submucosal glands. Recent research has shown that ESM1 expression is overexpressed in lung cancer, kidney cancer, liver cancer, breast cancer, brain glioblastoma and other tumors. Tumor angiogenesis, metastasis and prognosis were shown to be associated with Endocan expression. Investigators believe that ESM1 may be a new target for cancer therapy. This article aims to review the structure and function of ESM1, as well as the research progress in a variety of inflammatory diseases and cancers.

文章引用: 梁雪, 刘煜. ESM1:一个癌症治疗的新靶点[J]. 药物资讯, 2021, 10(3): 121-128. https://doi.org/10.12677/PI.2021.103016

1. ESM1起源

内皮细胞特异性分子1 (endothelial cell specific molecular-1, ESM1)又称Endocan,最早由Lassalle团队从人脐静脉内皮细胞HUVEC细胞cDNA文库中克隆得到其基因,并在猴、小鼠、大鼠、兔子和牛中鉴定出相似的条带,证明在人类和灵长类之间存在一个高度保守的ESM1基因,且在其他哺乳动物物种中也存在一个相关基因 [1]。由于该分子在血管内皮细胞中的高度限制性分布,其最初被命名为内皮细胞特异性分子ESM1,进一步研究发现ESM1是一种硫酸皮肤素蛋白聚糖(dermatan sulfate proteoglycan, DSPG),并将其编码蛋白命名为Endocan [2]。ESM1主要表达于血管内皮细胞,在支气管上皮和肾上皮等上皮细胞中也检测到有表达 [3]。有研究表明ESM1在一些肾脏疾病 [4]、血管炎症 [5]、肺炎 [6] 和多种癌症肿瘤 [7] [8] [9] 中高表达,其在炎症,血管生成与肿瘤进展中发挥着重要作用。

2. ESM1分子结构

ESM1编码基因位于人类5号染色体上(5q11.2),其完整cDNA序列长度为2006 bp,包含一个552个核苷酸构成的开放阅读框 [1]。该基因含有3个外显子和2个内含子,3个外显子的长度分别是362 bp、150 bp和1560 bp,启动子从5'侧翼区3888 bp开始。ESM1蛋白氨基末端包含110个氨基酸且富含半胱氨酸,由第1个外显子和第2个外显子的一部分编码;同时第2个外显子还编码一个特定的区域,该区域富含苯丙氨酸,据研究与ESM1蛋白功能相关;羧基末端由第3个外显子编码,含50个氨基酸,具有该部分早期终止密码子和137位丝氨酸O-糖基化位点 [10]。研究表明ESM1基因启动子具有典型的TATA框,包括3个Ets基序,1个cAMP反应元件样元件和1个回文序列(GCATGC) [11]。另一项研究中指出ESM1启动子区有3个GATA基序,3个AP4 (activating protein-4)基序和2个AP1 (activating protein-1)基序,且该基因可以被转录成两种可变剪接体:一种包含完整的蛋白质核心和DSPG单链;另一种则是缺失了外显子2,虽然与前一种拥有相同的氨基端和羧基端,但缺少了外显子2编码的50个氨基酸,且丧失了ESM1蛋白促肿瘤生长的能力 [12]。目前,尚未有研究对这两种蛋白形式在疾病中的相对表达进行分析。

ESM1是蛋白聚糖(proteoglycans, PGs)家族的一员,包含一个蛋白质核心和与其共价相连的糖链部分。ESM1的蛋白质核心由165个氨基酸组成,一条单一的硫酸皮肤素(DS)糖链,通过翻译后修饰过程连接到蛋白质核心的第137位丝氨酸上 [13]。与其他PGs家族成员不同的是,ESM1是一种分泌型蛋白分子,不属于细胞外基质(extracellular matrix, ECM)成分,不为细胞提供结构支持,也与其他细胞外PGs缺乏显著的同源性 [14]。与其他具有多条糖链的PGs大分子相比,ESM1分子量只有20 kDa且只含有一条DS糖链,该DS糖链由32个二糖单元组成,与其他天然存在的DSPG相比,ESM1中非硫酸化和二硫酸化单元的比例更高 [15]。

3. ESM1在炎症疾病中发挥作用

研究表明ESM1在炎症疾病中发挥重要作用。ESM1可以与白细胞上的淋巴细胞功能相关抗原-1 (lymphocyte function-associated antigen-1, LFA1)结合,从而阻断LFA1与血管内皮细胞上表达的细胞间粘附分子-1 (intercellular adhesion molecule-1, ICAM1)之间的相互作用 [16]。LFA1和ICAM1是一组粘附分子伴侣,在白细胞自发粘附于内皮细胞以及白细胞沿着血管壁的迁移行为中起重要作用 [17]。当发生急性损伤时,血管内皮细胞分泌出的ESM1与LFA1结合,干扰LFA1/ICAM1之间粘附,从而抑制白细胞向炎症部位募集、迁移、激活,显示出抗炎特性 [16]。但是众多临床数据显示ESM1在包括肺炎 [18],脓毒症 [19],心血管疾病 [5] 和肾脏疾病 [4] 等病理情况中参与促炎反应。使用ESM1基因敲除(Esm1KO)小鼠进行实验,发现ESM1不仅不会在体内影响白细胞的迁移和粘附,反而是介导白细胞外渗的必需因素 [20]。

3.1. 肺炎

通过持续监测呼吸机插管通气患者体内ESM1含量,探究ESM1水平与呼吸机相关性肺炎(VAP)之间是否存在关联。随着插管时间推移,ESM1水平逐渐升高,确认患者血浆中高水平ESM1与VAP发生发展有关 [18],且更适合作为诊断获得性肺炎的筛查工具 [21]。针对慢性阻塞性肺病(COPD)患者的临床试验表明,病情加重期间血清ESM1水平升高,且这种升高与呼吸功能下降有关 [22] [23],ESM1可作为COPD患者病情加重的新型生物标志物 [24]。最近有研究表明在肺动脉高压(PAH)的炎症部位miR-181a/b-5p直接靶向ESM1抑制其表达,可减轻TNFα刺激产生的炎症反应,这一新发现为治疗PAH提供了新思路 [6]。

3.2. 心血管疾病

内皮功能障碍是众多心血管疾病(CVD)进展中的主要病变 [25],因为内皮功能障碍会破坏内皮屏障通透性和血管内皮保护作用,促进炎症发生。已知ESM1在调节细胞粘附中起重要作用,可能参与了内皮功能障碍,有研究表明ESM1可以上调HUVEC细胞上ICAM1、VCAM1等细胞粘附分子的表达,介导白细胞牢固粘附在内皮细胞上,发挥促炎作用 [26],同时ESM1还可以通过MAPK和NF-κB信号通路引发促炎反应 [27]。因此,ESM1可以作为一种与心血管疾病相关的潜在内皮功能障碍炎症标记物。还有研究表明ESM1在激活的内皮细胞和动脉粥样硬化(AS)斑块中高表达 [28],急性冠状动脉综合症(ACS)患者体内血清ESM1水平明显高于健康对照组 [29],高血压患者血清中ESM1水平与冠状动脉疾病(CAD)的严重程度相关 [30]。

3.3. 脓毒症

白细胞外渗失调是导致脓毒症等急性炎症疾病的主要原因,临床数据表明ESM1在新生儿脓毒症病例 [31] 和脓毒症重症患者 [32] 体内的表达水平显著升高,并可能引起严重的促炎反应。此前,研究人员在脓毒症患者血清中检测到一种ESM1分解代谢产物,由中性粒细胞表达的组织蛋白酶G切割ESM1而生成的一个14 kDa的肽片段,并命名为p14,p14在结构上失去了ESM1的羧基末端片段以及羧基末端连接的糖链 [33]。最新研究表明,p14和ESM1结合在LFA1一个共同的位点上,这个结合位点位于ICAM1/LFA1的结合位点附近,ESM1是通过聚糖链的空间位阻阻碍了ICAM1/LFA1的相互作用,而p14由于丧失聚糖链,没有空间位阻的阻碍,导致ICAM1/LFA1的相互作用得以恢复 [19]。p14与ESM1相互竞争,p14会逆转ESM1的抗迁移作用,这些结果解释了为何ESM1的高表达与促炎作用相关——p14拮抗ESM1与LFA1结合,帮助白细胞募集与迁移作用,同时ESM1作为促炎因子进一步增加细胞粘附分子的表达,从而引发严重的急性炎症反应。

4. ESM1在癌症中的作用

ESM1参与癌症进展、迁移、侵袭和血管生成等病理过程,是多种癌症的潜在生物标志物 [34]。在小鼠皮下接种正常的HEK293细胞不会成瘤,但是接种过表达ESM1的HEK293细胞可以形成肿瘤,且在血清中检测到了循环ESM1水平随时间变化上调 [10]。即ESM1可以诱导肿瘤生长,并且这种作用由蛋白质核心连接的聚糖链介导 [10]。

血管生成是癌症进展的关键步骤,内皮细胞分泌的VEGFA刺激ESM1表达上调 [35],同时ESM1可取代VEGFA与纤连蛋白结合,增加VEGFA生物利用度 [20],增强其促有丝分裂作用和迁移活性,形成正反馈回路。还有研究表明ESM1在新生血管“尖端细胞(tip cells)”中高表达,介导血管生长,引导肿瘤部位血管网络的形成 [36]。

4.1. 膀胱癌

ESM1在浸润性膀胱癌肿瘤组织的血管中高表达 [37],对膀胱癌患者的血清和尿液进行检测,ESM1水平也高于健康人样本 [9]。研究称膀胱癌肿瘤部位血管内皮细胞分泌VEGFA增多,VEGFA可诱导表达ESM1ESM1又促进VEGFA与VEGFR2之间的结合,增强VEGFA介导的内皮细胞增殖和血管生成,ESM1通过这种方式参与肿瘤进展和扩散 [37]。最近有学者发现一些microRNA参与调节膀胱癌中ESM1的表达,miR-9-3p [38] 和miR-211-3p [39] 可以下调肿瘤部位ESM1水平,抑制膀胱癌细胞集落形成、迁移、侵袭,促进肿瘤细胞凋亡,从而阻止癌症的进展和转移,这为膀胱癌的治疗提供了潜在靶点。

4.2. 乳腺癌

鉴定ESM1以及另外70个基因,为乳腺癌早期转移(<5年)发展的标志,且ESM1与肿瘤的不良预后相关 [40]。在不同转移表型的人三阴性乳腺癌细胞系中均检测到ESM1的高表达 [41],特别是在MDA-MB-231BR (脑转移表型)细胞系的相关研究中,检测到细胞培养上清及携带异种移植物的小鼠血浆中ESM1高表达,肿瘤细胞表现出更强的侵略性和转移能力 [8]。作者认为这种高表达归因于ESM1启动子处的DNA去甲基化,促进基因转录和随后的蛋白产生,但尚不清楚是什么触发了这种表观遗传学的改变 [8]。在放疗耐药MDA-MB-231细胞中ESM1水平最为上调,其显示出强致瘤性和侵袭性。ESM1通过刺激ICAM1、VCAM1、MMP9、VEGFA表达上调并激活ERK1/2、PKC、PDK1信号通路,在肿瘤发生中起重要作用 [42]。

4.3. 肺癌

有研究指出ESM1在非小细胞肺癌(NSCLC)肿瘤血管中高表达,特别是在肿瘤侵袭前沿部位表达强烈,并鉴定出VEGF和ESM1之间存在关联,VEGF刺激内皮细胞中ESM1的mRNA水平升高 [43]。此外,NSCLC患者的临床数据显示,血清中的ESM1水平升高,与不良预后和肿瘤转移相关 [44]。已知EGFR突变是NSCLC的关键驱动突变 [45],ESM1可与EGFR结合,促进EGF与EGFR相互作用,从而增强EGFR的磷酸化和下游信号通路传导。同时EGFR信号轴级联JAK/STAT3和ERK/ELK又上调ESM1的表达,从而形成正调控闭环,促进肿瘤生长和转移,且与患者较差的生存期相关 [46]。

4.4. 胃癌

与正常胃部组织相比,胃癌肿瘤部位ESM1的蛋白水平和mRNA水平显著提高(p < 0.01),胃癌晚期患者(III和IV期)血清中ESM1水平也显著高于胃癌早期患者(I和II期) (p < 0.05),且血清ESM1水平高低与患者5年生存率之间存在明显相关性(p < 0.001),ESM1或可作为预测胃癌患者生存的肿瘤生物标志物 [47]。最近有研究者评估了在接受辅助S-1化疗的II/III期胃癌患者中,ESM1基因表达与预后之间的关系,发现胃癌组织高表达ESM1的患者复发风险更高,说明ESM1是胃癌的一个重要预后指标 [7]。

4.5. 结直肠癌

在结直肠癌细胞中使用siRNA抑制ESM1表达可减轻肿瘤细胞的侵袭性,ESM1-siRNA通过调节MMP蛋白和EMT相关基因来抑制肿瘤转移过程 [48]。临床分析表明结直肠癌患者肿瘤部位ESM1的表达水平与癌症分化之间存在相关性 [49]。通过建立分析算法,研究者为结直肠癌患者的血液、尿液、唾液分别鉴定出了有效的候选生物标志物ESM1、CTHRC1、AZGP1,从而帮助理解结直肠癌的分子机制,为临床治疗提供理论基础 [50]。

4.6. 肝癌

肝癌组织中ESM1的mRNA水平与其患者的淋巴结转移和肿瘤血管浸润相关 [51],ESM1在肿瘤血管中的表达反映了血管生成和肿瘤侵袭能力 [52],通过ESM1标记测得的微血管密度,比通过CD34标记测得的微血管密度,更显著地与缩短的生存期相关 [53]。在肝癌细胞中沉默ESM1,可通过抑制NF-κB通路降低细胞存活率,并通过PTEN诱导细胞周期停滞,调节肿瘤进展 [54],ESM1或可在肝癌中作为一种诊断和治疗的标志物。

4.7. 垂体腺瘤

垂体腺瘤是一种良性肿瘤,但具有侵袭性和恶性表型,可导致术后复发 [55]。正常垂体血管中不表达ESM1,在垂体组织中出现ESM1可能是肿瘤形成的标志 [56]。垂体腺瘤肿瘤部位的肿瘤细胞和血管内皮细胞中都检测到有ESM1的表达,而肿瘤细胞中表达的ESM1更能准确反映侵袭性,此外ESM1也与垂体腺瘤Knosp分级密切相关 [57]。

4.8. 肾癌

使用VEGFA处理血管内皮细胞和人肾癌细胞,ESM1的mRNA水平和蛋白水平都上调,使用PI3K信号通路的抑制剂处理细胞也会上调ESM1的表达,即ESM1是VEGFA和PI3K调控的基因 [58]。在肾癌患者的肿瘤部位血管组织和血清中都检测到ESM1高表达,ESM1或可用于评估肾癌肿瘤对抗VEGF的抗血管生成疗法的反应 [59]。

4.9. 头颈部鳞状细胞癌

对头颈部鳞状细胞癌(HNSCC)临床肿瘤样本及癌旁组织进行转录组分析,ESM1是差异最明显的基因,可以在TCGA数据库中类似的结论,研究人员还发现在HNSCC中ANGPT2是与ESM1共表达的基因,高表达ESM1的HNSCC细胞中MAPK、TGFβ信号通路富集,这为探究调控HNSCC进展的作用机制提供了重要的线索 [60]。

5. 总结与展望

对生物标志物的研究探索,不仅有助于疾病的早期发现,也有助于及时监测疾病的发生发展。ESM1作为一种循环分泌蛋白,天然具有在血液、尿液、唾液中易被检测和定量的优点,可作为一种生物标志物。对ESM1研究表明,其在人体内主要参与了炎症反应和血管生成,在多种疾病和不同肿瘤中检测到ESM1的表达有显著差异,不仅影响肿瘤血管内皮细胞的免疫学特性,而且与肿瘤血管生成有着密切的联系,在肿瘤的发生发展和转移中有重要意义,ESM1或可成为一种新颖的,基于血液或组织的,与疾病进展或不良预后相关的生物标志物。此外,ESM1所发挥的血管生成作用与VEGF密切相关,而抗VEGF药物是肿瘤抗血管生成疗法中最为成熟的方法,故ESM1有望作为一种监测患者对抗血管生成疗法治疗反应的关键标记分子。同时,ESM1信号通路本身也为抗血管生成疗法提供了有效的新靶点。

NOTES

*通讯作者。

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