壳多糖酶3样蛋白1在癌症发展中的作用及其应用价值

2020-08-04 13:55陈羽熊娟
中国当代医药 2020年17期
关键词:肿瘤标志物应用价值癌症

陈羽 熊娟

[摘要]壳多糖酶3样蛋白1(CHI3L1)是一种不具有壳多糖酶活性的壳多糖酶样蛋白(CLPs),近年来,国际上关于CHI3L1与癌症的关系的研究逐渐增多。CHI3L1在免疫应答、炎症和细胞外基质组成等方面都有重要作用,其可以调节肿瘤微环境影响肿瘤的生长、转移和对治疗的反应等。有研究者推荐CHI3L1成为一种新的肿瘤标志物,用于预测肿瘤的发生发展及预后。目前,人们对CHI3L1及其与癌症关系等方面的认识还比较匮乏。本文从CHI3L1在癌症发展中的作用机制、在人类癌症中的表达情况、在癌症发展中相关的信号通路、在治疗癌症中的研究价值等方面入手,收集近几年国际上前沿的有关CHI3L1与癌症的研究结果并进行归纳总结,旨在阐述CHI3L1在癌症发展中的作用及应用价值。

[关键词]壳多糖酶3样蛋白1;癌症;应用价值;肿瘤标志物

[中图分类号] R735.7          [文献标识码] A          [文章编号] 1674-4721(2020)6(b)-0021-04

[Abstract] Chitinase-3-like protein 1 (CHI3L1) is a chitinase like proteins (CLPs) without chitinase activity. In recent years, international researches on the relationship between CHI3L1 and cancer have gradually increased. CHI3L1 plays an important role in immune response, inflammation, and extracellular matrix composition, which can affect tumor growth, metastasis, and response to treatment by regulating the tumor microenvironment. Some researchers have recommended CHI3L1 as a new tumor marker for predicting the occurrence, development and prognosis of tumors. At present, people′s understanding of CHI3L1 and its relationship with cancer is not enough. This paper collects and summarizes the internationally advanced research results on CHI3L1 and cancer in recent years, from the aspects of  the mechanism of CHI3L1 in cancer development, expression in human cancer, related signaling pathways in cancer development and research value in cancer treatment, so as to explain the role and application value of CHI3L1 in the development of cancer.

[Key words] Chitinase-3-like protein 1; Cancer; Application value; Tumor marker

壳多糖酶3样蛋白1(chitinase-3-like protein 1,CHI3L1)从属于糖苷水解酶18基因家族,是一种分泌型糖蛋白,分子量约为40 kDa,具有碳水化合物结合域,有类似凝集素的作用,在不同物种均有表达并发挥重要的生物学作用[1]。在人体内多种细胞可表达CHI3L1,包括巨噬细胞、中性粒细胞、软骨细胞、滑膜细胞、成骨细胞和血管平滑肌细胞等,但对于其配体及其特性仍有待探索[2-4]。有研究表明,CHI3L1与癌症的发生发展密切相关,其可通过调节一些生物过程,包括但不限于氧化损伤反应,细胞凋亡,Th1/Th2炎症平衡和M2巨噬细胞分化等来发挥作用[5-6]。近年来,有关CHI3L1与癌症关系的研究逐年增多。

CHI3L1有结合多个受体的能力,可参与多种细胞反应[7]。如,CHI3L1可以与晚期糖基化终产物受体(receptor of advanced glycation endproducts,RAGE)、白细胞介素-13受体α2链(interleukin-13 receptor α2 chain,IL-13Rα2)受体结合,诱导炎性小体激活,细胞凋亡,癌变和肿瘤血管生成[8],在免疫应答、炎症和细胞外基质组成等方面都有重要的作用,可以调节肿瘤微环境影响肿瘤的生长、转移和对治疗的反应等。因此,有研究者推荐CHI3L1可作为一种新的肿瘤标志物,应用于胶质母细胞瘤、骨肉瘤、结直肠癌、肺腺癌、乳腺癌和宫颈癌等[9-12]。

1 CHI3L1在癌症发展中的作用机制

CHI3L1可能通过免疫应答和细胞因子来影响癌症的生长。研究表明,T细胞中CHI3L1的表达降低会激活Th1反应并增加γ-干扰素(interferon-γ,IFN-γ)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)和白细胞介素-2(interleukin-2,IL-2)的表达,从而抑制肺转移[6]。在胃癌和乳腺癌中,M2巨噬细胞分泌的CHI3L1可以激活IL-13Rα2并激活丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信號通路,从而促进与癌症进展相关的金属蛋白酶基因的表达[13]。

另有研究表明,CHI3L1相关信号通路与癌症发展直接相关。在胆管癌细胞系中,CHI3L1通过蛋白激酶B(protein kinase B,Akt)/细胞外调节蛋白激酶(extracellular signal-regulated kinases,ERK)介导途径,促进肿瘤生长和迁移[14]。下调CHI3L1的表达可以降低前列腺癌侵袭和转移的发生率,相反其过表达会增加细胞锚定非依赖性生长能力,导致更多侵袭和转移发生[15]。

氧化应激也可能是CHI3L1影响癌症进展的一种潜在机制。Ma等[16]研究表明,CHI3L1可以通过增加活性氧和氧化性DNA损伤,促进结肠炎相关癌进展。

此外,CHI3L1在癌症的血管生成和肿瘤微环境的调节中具有促进作用。癌症相关成纤维细胞分泌的CHI3L1可以介导乳腺癌的生长和转移[17]。CHI3L1还可能通过使机体产生免疫抑制微环境来诱导癌症发展。如,CHI3L1可以调节2型免疫,包括促进巨噬细胞募集和转变,从而使肿瘤进展和转移[17]。突变型CHI3L1的表达会减少乳腺癌细胞生长和血管形成[18]。此外,在人胶质母细胞瘤的内皮细胞血管生成和肿瘤特征形成方面,血管内皮生长因子(vascular endothelial growth factor,VEGF)可能与CHI3L1有协同作用[19]。有研究还发现CHI3L1在宫颈癌患者中可诱导血管生成和血管生成拟态形成[18]。而在广泛期小细胞肺癌患者的循环肿瘤细胞中,CHI3L1可通过对巨噬细胞和炎症因子的调节,介导肿瘤的侵袭和进展[20]。在神经胶质瘤中,茴香霉素诱导的CHI3L1表达降低可以使癌症侵袭性特征减弱[21]。此外,信号传导与转录激活因子3(signal transducer and activator of transcription 3,STAT3)抑制剂可调节CHI3L1表达来抑制胶质母细胞瘤细胞系的生长[22]。

2人类癌症中CHI3L1的表达情况

CHI3L1在多种癌症患者组织或血浆中的表达增加。Wang等[23]报道过在非小细胞肺癌组织中,CHI3L1的表达显著上调。有研究者建议将其作为一种预后不良的肿瘤标志物。在人类胶质母细胞瘤患者中,CHI3L1表达水平较高的生存率较差[19]。最近的一项研究表明,在脑室下区Ⅱ型胶质母细胞瘤中CHI3L1的表达率为58%(77个样本中有45例)[24]。在人星形细胞瘤组织中CHI3L1也为高表达水平[12]。在人乳头状甲状腺癌组织中CHI3L1也表达增加,且其表达水平与肿瘤大小、淋巴结转移和侵袭有关[25]。在黑色素瘤患者中CHI3L1表达与预后不良相关,在这个研究中值得注意的是,肿瘤相关巨噬细胞表达CHI3L1的水平显着高于黑色素瘤细胞[26]。在胆管癌患者中血清CHI3L1升高往往意味着存活期变短,但癌细胞本身仅表达低水平CHI3L1[14]。CHI3L1在早期子宫内膜癌中也有表达,并推荐作为高危患者的预后标志物[27]。在结肠直肠癌患者中常可检测到CHI3L1,但在健康个体的结肠中很少有CHI3L1的表达,Johansen等[28]推荐其作为预测患结肠直肠癌风险的生物标志物。

与之前提到的研究报道结果相反,在Thorn等[29]的研究中,肿瘤细胞/基质CHI3L1表达高比值与骨肉瘤患者较长的总体生存成正相关。另有研究表明,血清学CHI3L1与发生第二原发癌的风险无显著相关性[30]。这些结果表明CHI3L1在不同肿瘤细胞和微环境中的表达不尽相同。

因此,CHI3L1与肿瘤不良预后之间的关系仍没有定论,亟需进一步研究CHI3L1表达水平与癌症预后的相关性。

3癌症发展中CHI3L1相关的信号通路

CHI3L1具有调节癌症微环境和免疫应答的作用。有研究表明CHI3L1在Th2细胞中显著增高,调节多种细胞因子表达,包括IL-2、IFN-γ和IL-4[6]。

血管生成是CHI3L1影响癌症进程的另一可能机制。CHI3L1通过激活粘着斑激酶(focal adhesion kinase,FAK)和ERK-1/ERK-2活性从而使VEGF和血管生成增加[19]。特别是膜受体syndecan-1和整合素αvβ5作为触发分子引发CHI3L1信号传导级联反应。CHI3L1与RAGE结合并诱导癌细胞增殖,其中ERK1/2-MAPK途径在RAGE-CHI3L1下游信号级联反应中起作用[19]。

已发现CHI3L1在胶质母细胞瘤衍生的细胞系U87和内皮细胞中直接诱导VEGF和VEGF受体2的表达[19,31]。还有研究表明,在胶质母细胞瘤患者中肿瘤血管稳定性和通透性与CHI3L1表达相关[32]。

此外,CHI3L1可使U87细胞中磷脂酰肌醇3-激酶(phosphoinositide-3 kinae,PI3K)-AKT途径激活[19,31],并能与巨噬细胞中的IL-13Rα2结合[7]。这些信号传导途径能够增强射线抗性减少肿瘤细胞死亡,并且在黑素瘤肺转移中起到重要作用[19,31]。

CHI3L1在小细胞肺癌循环肿瘤细胞中高表达,有報道显示,通过上调上游刺激因子-1(upstream stimulatory factor 1,USF1)使CHI3L1表达减少可以抑制肺癌转移[33]。在人成纤维细胞中,CHI3L1有类胰岛素样生长因子-1的作用,能增加基质金属蛋白酶-1的表达和细胞外基质重塑[34]。这些研究表明CHI3L1可通过血管生成和炎症相关的信号传导途径调节肿瘤微环境和基质反应性。

4 CHI3L1用于治疗癌症的研究

依据相关研究结果,CHI3L1有希望成为治疗癌症的新靶点。已证实,咖啡因可通过调节氧化应激来抑制CHI3L1,减少结肠炎相关癌的肿瘤进展[16]。咖啡因通过抑制CHI3L1/AKT和PI3K信号通路发挥对炎症性肠病的保护作用[35]。此外,通过对CHI3L1的抑制作用,咖啡因可减少氧化造成的DNA损伤。因此,有研究者建议将CHI3L1作为结肠炎相关癌的治疗靶点。在胶质母细胞瘤患者中,CHI3L1的表达下调可增加患者对PI3K/AKT抑制剂的敏感性[36]。CHI3L1的另一种抑制剂茶碱,也被证实具有抗肿瘤活性。茶碱可使细胞周期G1期阻滞和血管生成素-2的下调,从而抑制人直肠癌细胞的增殖[37]。

在Chiang等[38]的研究中,CHI3L1通過调节一种特殊的蛋白质表达干扰紫杉醇的抗肿瘤作用,减少人卵巢癌细胞的凋亡。在脑肿瘤模型中,抗CHI3L1抗体联合放射治疗,是抑制肿瘤血管形成和进展的协同治疗方法[31]。这些研究表明,CHI3L1是一个治疗耐药性癌症的潜在靶点。

CHI3L1靶向治疗用于抑制肿瘤转移方面,目前已有不少研究。在肺癌转移中,CHI3L1与小干扰RNA(small interfering RNA,siRNA)结合后可显着增强抗肿瘤免疫力,如可增强Th1和细胞毒性T淋巴细胞(cytotoxic lymphocyte,CTL)的免疫应答和抑制黑素瘤肺转移[6]。另一项研究报道显示,CHI3L1与乳腺癌转移相关[39]。甲壳素[β-(1-4)-聚-N-乙酰基D-葡糖胺]可通过产生IFN-γ和减少趋化因子2和基质金属蛋白酶9表达来阻断CHI3L1的作用并抑制乳腺癌的转移。上述研究表明,CHI3L1诱导的血管生成与癌细胞抗药(射线)性相关。还有研究表明,CHI3L1的下调减少了肺肿瘤的发展和转移[33]。

5小结

癌症作为21世纪人类的主要死亡原因之一,现代医学一直在寻找治疗癌症的有效方法。而CHI3L1因其在免疫应答、炎症和细胞外基质组成等方面的重要作用,对肿瘤的生长、转移和对治疗的反应等都有重要影响,有希望成为治疗癌症的一个重要靶点,用于抑制肿瘤进展、转移等方面。针对CHI3L1的新型治疗方法或将为癌症的治疗开辟一条新的道路。

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(收稿日期:2019-12-10  本文編辑:任秀兰)

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