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Advances in Clinical Medicine
Vol. 12  No. 11 ( 2022 ), Article ID: 57584 , 8 pages
10.12677/ACM.2022.12111435

IL-6/STAT3信号通路在非小细胞肺癌发生和 治疗中的进展

唐玉平1，沈存芳2

1青海大学研究生院，青海 西宁

2青海大学附属医院，青海 西宁

收稿日期：2022年10月3日；录用日期：2022年10月27日；发布日期：2022年11月8日

摘要

IL-6/STAT3通路是非小细胞肺癌发展的关键途径之一，可通过参与癌细胞的抗凋亡、增殖及肿瘤血管生成等多种恶性表型促进肿瘤发展。此外，临床研究表明，IL-6/STAT3信号通路与非小细胞肺癌的化疗、靶向及放疗耐药相关，针对IL-6/STAT3信号通路的靶向药物对非小细胞肺癌的治疗有益，有望成为治疗非小细胞肺癌的有效药物。深入了解IL-6/STAT3信号通路与非小细胞肺癌的关系有助于阐明非小细胞肺癌发病机制，并为其治疗提供新方向。本文就该通路在非小细胞肺癌发展及治疗中的最新进展作一综述。

关键词

恶性肿瘤，非小细胞肺癌，白介素-6，IL-6/STAT3信号通路

Progress of IL-6/STAT3 Signaling Pathway in the Development and Treatment of Non-Small Cell Lung Cancer

Yuping Tang1, Cunfang Shen2

1Graduate School of Qinghai University, Xining Qinghai

2Qinghai University Affiliated Hospital, Xining Qinghai

Received: Oct. 3rd, 2022; accepted: Oct. 27th, 2022; published: Nov. 8th, 2022

ABSTRACT

The IL‐6/STAT3 pathway is one of the key pathways in the development of non-small cell lung cancer (NSCLC), which can promote the development of tumor by participating in various malignant phenotypes such as anti-apoptosis, proliferation and tumor angiogenesis. In addition, clinical studies have shown that IL‐6/STAT3 signaling pathway is associated with chemotherapy, targeting and radiotherapy resistance of NSCLC. Targeted drugs targeting IL‐6/STAT3 signaling pathway are beneficial for the treatment of NSCLC and are expected to be effective drugs for the treatment of NSCLC. A deeper understanding of the relationship between IL-6/STAT3 signaling pathway and NSCLC will help clarify the pathogenesis of NSCLC and provide a new direction for its treatment. This article reviews the latest progress of this pathway in the development and treatment of non-small cell lung cancer.

Keywords:Malignant Tumor, Non-Small Cell Lung Cancer, IL-6, IL-6/STAT3 Signaling Pathway

Copyright © 2022 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

肺癌(lung cancer, LC)是威胁人们生命安全和健康最大的恶性肿瘤之一，在全球 [1]，肺癌的发病率占恶性肿瘤总发病例数的11.6%，病死率占恶性肿瘤病死例数的18.4%，发病率和病死率均居首位 [2]。在我国，肺癌也是发病率和死亡率较高的恶性肿瘤，第3次国人死亡原因调查显示，肺癌病死率为22.7%，位居首位 [3] [4]。在组织学上，肺癌分为非小细胞肺癌(non-small cell lung carcinoma, NSCLC)和小细胞肺癌(small cell lung carcinoma, SCLC)，其中NSCLC占肺癌的85%。在过去20年中，NSCLC尽管在手术、放疗、化疗和靶向治疗等治疗选择方面取得了进展，但由于大多数患者在诊断时存在局部晚期或广泛转移，所以NSCLC的总生存率和治愈率仍然较低，5年生存率约为15% [5]。因此，有必要进一步研究肺癌的生物学和恶性增殖机制，以加强对NSCLC进展的了解，提高生存率。

白介素-6 (interleukin-6, IL-6)是一种多功能的细胞因子，可介导免疫和炎症反应，IL-6信号通路通过IL-6受体、gp130和Janus蛋白酪氨酸激酶(Janus protein tyrosine kinase, JAK)发挥作用。信号转导和转录激活因子3 (Signal transducers and activators of transcription 3, STAT3)是JAK激酶家族中的成员之一，是增殖、存活、分化、凋亡、免疫功能和血管生成等多种细胞过程的关键调节因子 [6]。临床研究表明，STAT3在22%~65%的NSCLC中持续激活 [7]，并且STAT3活性与肿瘤进展、预后不良和患者生存期短相关 [8]。因此，确定IL-6/STAT3信号通路是否以及如何参与肺癌的发生发展具有重要意义。本文就IL-6/STAT3信号通路在介导肺癌中的发展及其在肺癌治疗中的研究进展进行阐述。

2. IL-6/STAT3信号通路

IL-6于1986年首次被成功克隆，作为一种多效细胞因子，在免疫调节、造血、炎症和肿瘤发生方面具有重要作用 [9]，通过与受体结合形成复合物激活下游信号通路而发挥效应。IL-6受体系统由2种跨膜蛋白组成：一种负责信号转导，相对分子质量为130000的非配基结合链糖蛋白130 (gpl30，也称CD130或IL-6R0)；另一种是可与IL-6直接结合，相对分子质量为80000的配基结合链糖蛋白80 (gp80，也称CD126或IL-6Rα)。其中IL-6Rα可分为膜结合型(mIL-6R)和可溶型(sIL-6R) 2种，研究认为mIL-6R是触发IL-6信号传导的最主要途径 [10]。IL-6信号传导途径分为经典信号通路和反式信号通路。在经典信号传导途径中，胞外IL-6与膜上的IL-6R结合形成复合物，诱导gp130聚集并与之结合，形成了由2个IL-6，2个IL-6R及2个gp130分子构成的异六聚体，随后复合体激活JAK，后者通过激活STAT3形成二聚体进入细胞核调控靶基因转录 [11]。IL-6的反式信号传导途径与经典信号传导途径基本相同，不同之处在于反式信号通路中与IL-6结合的受体是可溶性IL-6R (sIL-6R)而非mIL-6R [12]。sIL-6R由mIL-6R的有限蛋白水解或IL-6R mRNA可变剪切产生 [13] [14]。经典信号通路与反式信号通路表达范围并不相同 [15]。mIL-6R主要表达于中性粒细胞、单核细胞、活化的B细胞、CD4+ T细胞和肝细胞，因此IL-6经典信号途径表达的范围有限 [16]，而IL-6与血清中sIL-6R形成的复合物，可以作用于所有表达gp130的细胞，因此反式信号通路扩大了IL-6/STAT3信号通路的作用范围 [17]。在功能上，IL-6经典信号通路主要诱导急性期反应，具有抗炎作用，与之相反，反式信号传导与促炎反应有关 [18]。目前认为，IL-6对肿瘤的刺激主要由IL-6反式信号途径介导 [19]。

3. 非小细胞肺癌组织中IL-6的表达

IL-6是NSCLC中关键的促肿瘤细胞因子，对肺癌细胞的生长有多种调控作用，在NSCLC细胞增殖、侵袭、迁移、血管形成中IL-6均发挥促进作用，而对某些肺癌细胞有生产抑制作用，这种调控作用与肺癌细胞的自身特异性和宿主体内环境有关。有研究提示NSCLC患者血清中的IL-6水平较健康对照组明显升高，肿瘤组织中IL-6表达水平与总生存率相关，IL-6是NSCLC患者预后不良的指标 [20] [21] [22]。此外，Qihua Gu [23] 等的研究显示，IL-6水平升高与疾病进展风险增加相关，而其他炎性细胞因子与重度肺癌患者的疾病进展无关 [24]，据报道，IL-6还通过核因子κB (nuclear factor kappa-B, NF-κB)蛋白上调TIM-4，从而促进非小细胞肺癌的转移 [25]。

4. IL-6/STAT3信号通路促进肺癌发展

IL-6对肺癌具有抑制和促进双重作用，与肺癌细胞的自身特异性和宿主体内环境有关，二者均涉及其激活STAT3的能力。

IL-6通过维持肺内环境稳定和以STAT3依赖方式诱导肿瘤细胞杀伤来抑制肺癌发生。矛盾的是，IL-6也通过STAT3依赖机制促进肺癌的生长。在这种情况下，IL-6激活STAT3，在肺癌细胞中诱导细胞周期蛋白D1，从而促进癌症增殖 [26]。Jing [27] 等的研究发现IL-6/STAT3信号通过协调转移前生态位的形成和免疫抑制特性促进肺转移。Li [28] 等人研究表明，持续激活STAT3可诱导STAT3转基因小鼠发生肺肿瘤。受体酪氨酸激酶，如(EGFR和MET)、细胞因子受体(如IL-6受体)和非受体激酶(如Src)激活STAT3，可调节某些NSCLC细胞的存活途径 [29]。Zimmer [30] 等人认为STAT3活性独立于EGFR突变，有助于NSCLC的致癌潜力。Looyenga [31] 等人证明，STAT3在人类NSCLC样本和多种NSCLC细胞系中被组成性激活，与激活KRAS、EGFR和PDGFR突变或MET扩增无关。而Greulich [32] 等人报道，STAT3被各种EGFR突变激活，包括外显子19框架内缺失或外显子21 L858R点突变，并可能参与成纤维细胞和人类肺癌细胞中这些突变的致癌效应 [32]。Jiang [33] 等人通过免疫组化染色显示，发现STAT3或pSTAT3高表达是NSCLC患者预后不良的有力预测因素。Zhao [34] 等人报道，与pJAK2低表达的NSCLC患者相比，接受手术的pJAK2高表达的NSCLC患者的总体生存率明显更低。他们还发现，pJAK2和pSTAT3高表达的NSCLC样本中的微血管密度(MVD)较高，而MVD高的患者生存率较低。这些数据表明，高pSTAT3表达是NSCLC患者预后不良的有力预测因子。人类NSCLC常表现为结缔组织增生，其特征是存在肿瘤相关成纤维细胞(CAFs) [35]。在实体瘤中，CAF介导癌细胞增殖、血管生成、侵袭、转移和耐药性 [36]。从人类肺癌组织中分离的CAF分泌白细胞介素-6 (IL-6)，其刺激人类肺癌细胞中的STAT3信号，以促进肺癌的转移 [37]。Bo Jing [27] 等的研究表明，IL-6/STAT3信号诱导的免疫抑制对肺转移至关重要，研究发现IL-6/STAT3信号通过协调转移前生态位的形成和免疫抑制特性促进肺转移。

microRNA (miRNAs)是一类单链非编码RNA，由19-25个核苷酸组成，通过与靶基因的3'非翻译区(3'UTR)相互作用，作为基因表达的负调节因子 [38]。miRNAs的异常表达在包括肺癌在内的不同疾病中均有报道，它们可能作为癌基因或肿瘤抑制因子 [39]。据报道，MiR-17-92 [40]、MiR-21 [41] 和MiR-221/MiR-222 [42] 可促进肺肿瘤的发生，而let-7 [43]、MiR-126 [44]、MiR-16 [45]、MiR-340 [46]、MiR-145 [47] 和MiR-373 [48] 可作为肿瘤抑制因子。Yan Yang [49] 等的研究表明miR-218通过负性调节STAT3信号通路来调节肺癌细胞表型。研究表明，miR-218在EGFR野生型细胞中通过IL-6R和JAK3负调控STAT3信号，在EGFR突变细胞中通过IL-6R、JAK3和EGFR负调控STAT3信号。miR-218的过表达通过靶向STAT3信号降低体内肿瘤生长。

5. IL⁃6/STAT3信号通路抑制剂在肺癌治疗中的临床研究

多项研究显示，对STAT3的抑制抑制了癌细胞的生长，并增强了多种癌症对抗癌药物的敏感性，且与肿瘤治疗的耐药性相关，作为一种选择性激活的途径在治疗获得性耐药中发挥重要作用。因此，STAT3被认为是抗肿瘤治疗的潜在靶点。

据报道，STAT3与肿瘤发生和化疗耐药性有关 [7]。虽然STAT的激活在正常细胞中受到严格控制，但恶性肿瘤中酪氨酸激酶的持续激活会导致STAT的结构性激活，尤其是STAT3和STAT5 [50] [51] [52]。STAT激活后，调节癌症进展过程的基因表达将发生变化，包括不受控制的增殖、抗凋亡、持续的血管生成和逃避免疫监视 [51] [52] [53] [54]。几份报告 [55] - [61] 显示，对STAT3的抑制抑制了癌细胞的生长，并增强了多种癌症对抗癌药物的敏感性。研究 [62] [63] 显示，在NSCLC细胞中，STAT3 mRNA的过度表达与顺铂耐药性有关。通过siRNA沉默STAT3可使耐药细胞对紫杉醇、阿霉素和顺铂等细胞毒性药物更敏感 [64] [65] [66]。

其次，有研究 [67] [68] 表明，STAT3的上调直接赋予耐药表型，例如抗紫外线辐射诱导的细胞凋亡。

You [69] 等人表明，电离辐射诱导JAK2和STAT3的磷酸化，并且发现高水平的STAT3在耐辐射NSCLC细胞的细胞核中积累。他们同时发现，氯硝柳胺是一种有效的STAT3抑制剂，通过阻断STAT3的磷酸化和核转位来破坏STAT3转录活性，单独或与放疗联合使用可克服异种移植模型中的辐射抗性。Sun [70] 等人报道，JAK2的小分子抑制剂(TG101209)能够在体外抑制生存素，降低pSTAT3，并使肺癌细胞对辐射敏感。

STAT3与肿瘤靶向耐药性有关。Looyenga [31] 等人证明，舒尼替尼或环唑替尼等酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI)对STAT3活性没有影响。他们还展示了鲁索利替尼(一种JAK1/2选择性抑制剂)对NSCLC细胞系的治疗，该抑制剂在骨髓纤维化患者的I/II期研究中显示了有希望的结果，在软琼脂和异种移植试验中抑制了细胞生长。Jin等研究 [71] 表明，抑制STAT3是克服磷脂酰肌醇3-激酶(Phosphatidylinositol 3-kinase, PI3K)和哺乳动物雷帕霉素靶标(Mammalian target of rapamycin, mTOR)双重抑制剂耐药性的有效策略。这表明持续的STAT3可能导致对靶向治疗的主要耐药性。Q. Zheng等 [6] 研究表明，STAT3抑制剂W2014-S破坏了NSCLC细胞系中STAT3的二聚化，并选择性地抑制了异常的STAT3信号。W2014-S在小鼠模型中强烈抑制STAT3异常激活的肺癌细胞的增殖、存活、迁移和侵袭，并抑制人NSCLC细胞异种移植物的生长。W2014-S在体外对吉非替尼和厄洛替尼显著致敏耐药，并在体内增强吉非替尼在TKI耐药肺癌异种移植物中的抗肿瘤作用。研究 [33] [72] [73] [74] [75] 表明，将W2014-S等STAT3抑制剂与吉非替尼联合使用可能是克服NSCLC患者EGFR-TKIs获得性耐药性的一种有希望的策略。此外，具有EGFR-TKIs获得性耐药的癌症患者在一定程度上有高水平的磷酸化STAT3。虽然STAT3可以作为EGFR的下游，但在EGFR-TKIs耐药性中STAT3的激活可能与EGFR无关 [7] [76] [77] [78]。这些证据表明，靶向STAT3可能为克服肺癌中EGFR-TKI获得性耐药提供了一种新策略。尽管已经做出了大量努力来开发特异性和有效的STAT3抑制剂，但已报道的抑制剂仍然面临多种挑战，例如特异性低、结合亲和力弱、口服生物利用度低、溶解性差、结构不稳定、潜在的严重毒性，尤其是，临床上尚没有一种STAT3抑制剂被批准用于肺癌治疗 [71]。

6. 小结

人体内的细胞因子是一个复杂的网络系统，在肺癌的发生发展中起着重要作用。IL-6、STAT3和P-STAT3的异常表达可通过影响肺癌细胞的增殖、侵袭、迁移、凋亡等促进肿瘤的进展。通过IL-6单克隆抗体、GP130抑制剂、STAT3沉默和靶向miRNAs阻断该信号通路，已在抗肺癌治疗中取得初步成功。未来这一方向的深入研究将有助于肺癌的靶向治疗，为开发新的靶向药物提供新思路，并通过靶向干预结合其他药物提高临床治疗效果。

文章引用

唐玉平,沈存芳. IL-6/STAT3信号通路在非小细胞肺癌发生和治疗中的进展
Progress of IL-6/STAT3 Signaling Pathway in the Development and Treatment of Non-Small Cell Lung Cancer[J]. 临床医学进展, 2022, 12(11): 9953-9960. https://doi.org/10.12677/ACM.2022.12111435

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