Rheumatic Immune-related Adverse Events and Treatment of Immune Checkpoint Inhibitors
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摘要:
免疫检查点抑制剂（ICIs）在癌症治疗中显示出较好的疗效，但随着ICIs的快速应用，免疫相关不良事件（irAE）也越来越引起人们的关注。几乎全身器官皆可发生irAE，但风湿性irAE似乎具有不同的临床特征。本文就ICIs治疗引起的风湿性irAE的流行病学、临床特征及管理原则进行综述，并探讨其可能的潜在致病机制。
Abstract:Immune checkpoint inhibitors(ICIs) has revolutionized the treatment of cancer. However, with the rapid application of CPIs, the immune-related adverse events (irAE) have attracted more and more attention. irAE can occur in almost all organs, but rheumatic irAE seems to have different clinical characteristics. This article reviews the epidemiology, clinical characteristics and management principles of rheumatic irAE caused by ICIs treatment, and discusses its potential pathogenesis.
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0 引言
宫颈癌是妇科常见恶性肿瘤，是导致女性因癌症死亡的主要原因之一[1-2]。据统计，全球每年宫颈癌的新发病例高达529 800人，有275 100人死于宫颈癌[3]。发展中国家是宫颈癌的高发地区，超过80%的宫颈癌患者都出现在发展中国家[1]。放化疗及手术是目前治疗宫颈癌的常用方法，但并未能提高宫颈癌患者的生存率[4]。阐明宫颈癌发生发展机制是治疗宫颈癌的关键。近年来研究表明，微小型RNA（microRNAs, miRNAs）在调控细胞增殖、凋亡、分化和侵袭的过程中发挥重要作用，也可通过调控下游靶基因的表达影响癌症的发展[5]。miR-198是一类抑癌基因，在肝癌、胃癌及肺癌等多种癌症中表达下调[6-8]。上调miR-198表达可通过调控CDCP1表达抑制乳腺癌细胞增殖和侵袭，还可通过下调FGFR1表达抑制肺癌细胞增殖、诱导肺癌细胞凋亡[9-10]。但miR-198在宫颈癌细胞中的表达及对宫颈癌细胞增殖、凋亡和侵袭的作用还未见报道。本研究以宫颈癌细胞HeLa为对象，探讨miR-198对HeLa细胞增殖、凋亡和侵袭的作用及机制。
1 材料与方法
1.1 试剂与仪器
RPMI1640培养液、胎牛血清和胰蛋白酶购自美国Gibco公司；TRIzol试剂、TaqMan miRNA反转录试剂盒、TaqMan miRNA定量PCR试剂盒和Lipofectamine 2000转染试剂盒购自美国Thermo Fisher公司；TaKaRa 6210A反转录试剂盒和实时定量PCR试剂盒购自日本TaKaRa公司；miR-198 mimic购自美国Invitrogen公司；pcDNA3.0-丝裂原活化蛋白激酶1（Mitogen-activated protein kinase 1, MAPK1）重组质粒构建由北京BioGeek公司设计完成；抗核糖体S6激酶2（Ribosomal S6 kinase 2, RSK2）、c-Myc和c-fos抗体购自英国Abcam公司，货号分别为ab32123，ab39688和ab190289；辣根过氧化物酶（Horseradish peroxidase, HRP）标记的山羊抗兔二抗购自北京博奥森生物技术有限公司。PCR扩增仪购自美国Applied Biosystems公司，CytoFLEX流式细胞仪购自美国Beckman Coulter公司，电泳仪、转膜仪和凝胶成像系统购自美国Bio-Rad公司。
1.2 细胞培养
人宫颈癌细胞系HeLa细胞购自中国科学院细胞库（上海）。用含有10%胎牛血清的RPMI 1640培养液将HeLa细胞培养于37℃、5%CO2的恒温培养箱中，隔天换液一次。细胞融合度达到85%以上时进行传代培养。
1.3 细胞转染
将细胞以每毫升1×106个的密度传代培养于12孔板中，24 h后取出细胞，根据转染试剂盒说明书用Lipofectamine 2000将miR-198 mimic和pc-MAPK1转染入HeLa细胞。转染4 h后更换正常细胞培养液继续培养。
1.4 qRT-PCR检测
将细胞分为HeLa组、miR-198 scram组和miR-198 mimic组。用不含目标基因的载体转染miR-198 scram组细胞，miR-198 mimic转染miR-198 mimic组细胞。48 h后，用TRIzol试剂提取各组细胞总RNA，用TaqMan miRNA反转录试剂盒或Takara反转录试剂盒合成cDNA，用PCR进行扩增，根据试剂盒说明书用TaqMan miRNA定量PCR试剂盒或实时定量PCR试剂盒进行定量分析。实验所用到的引物均由上海生工设计合成。以GAPDH为参照，实验至少重复3次。
1.5 荧光素酶报告实验
通过生物信息预测miR-198上存在MAPK1的结合位点，用RT-PCR扩增MAPK1上miR-198的结合位点基因片段，将该片段插入pMIR-REPORT荧光素酶载体，构建MAPK1野生质粒；再利用基因位点图片技术对结合位点的部分核苷酸进行突变，构建MAPK1突变质粒。用MAPK1野生质粒或MAPK1突变质粒与miR-198 mimic对HeLa细胞进行共转染，根据Dual Luciferase报告基因试剂盒说明书避光测定荧光素酶活性。
1.6 CCK-8检测细胞活性
将细胞传代培养于96孔板中，随机分为HeLa组、miR-198 mimic组、pc-MAPK1组和mimic+pc-MAPK1组，用miR-198 mimic和pc-MAPK1分别或同时转染细胞后，分别于转染后的第0、1、2、3和4 d用MTT法检测细胞增殖活性。每孔加入10 μl CCK-8试剂，于37℃继续孵育2 h后用酶标仪检测细胞吸光度。
1.7 流式细胞术检测细胞凋亡
用胰酶收集后转染细胞，将细胞密度调整至1×106个每毫升，用结合缓冲液清洗细胞三次后，将100 μl细胞加入到Falcon试管中，分别加入Annexin V和PI试剂，室温避光孵育15 min后，各试管分别加入400 μl结合缓冲液，用流式细胞仪检测细胞凋亡情况。
1.8 Transwell检测细胞侵袭能力
将转染后的HeLa细胞用无血清培养液培养12 h后，传代于基质胶包被的Transwell小室上层，细胞密度为每毫升1×105个，小室下层则加入含胎牛血清的正常细胞培养液。继续培养24 h后用无菌棉签刮去上层细胞，用结晶紫对小室下层细胞染色，每孔随机选取5个视野进行计数统计。
1.9 Western blot检测蛋白表达
用RIPA裂解液提取各组细胞蛋白。用BCA试剂盒检测各组总蛋白浓度，调平蛋白浓度后，取等量蛋白用10%SDS-PAGE分离蛋白，半干法转移蛋白至PVDF膜。5%脱脂牛奶室温封闭PVDF膜2 h，随后加入一抗，4℃封闭过夜，第2 d弃去一抗，加入HRP标记的山羊抗兔二抗室温封闭1 h，滴加显色液显色，用凝胶成像系统获取蛋白质条带图片。
1.10 统计学方法
用SPSS19.0对实验数据进行统计分析，实验结果用均数±标准差表示，组间差异用One-Way ANOVA检测。P < 0.05为差异有统计学意义。
2 结果
2.1 miR-198过表达对宫颈癌细胞MAPK1表达的影响
用miR-198 mimic转染细胞后，miR-198 mimic组细胞miR-198表达水平与miR-198 scram组比较明显升高（P=0.0012）；miR-198 mimic组细胞MAPK1 mRNA表达水平明显低于miR-198 scram组，差异有统计学意义（P=0.0004），见图 1。
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图 1 miR-198 mimic对HeLa细胞miR-198和MAPK1 mRNA表达水平的影响Figure 1 Effects of miR-198 mimic on mRNA levels of miR-198 and MAPK1 in HeLa cells**: P < 0.01, ***: P < 0.001, compared with miR-198 scram group2.2 miR-198与MAPK1的靶向关系
生物信息预测结果表明，miR-198序列上存在MAPK1连续的结合位点。荧光素酶报告实验结果表明，miR-198 mimic能显著减弱MAPK1野生质粒的荧光素酶活性（P=0.011）；结合位点突变后，miR-198 mimic对MAPK1荧光素酶活性的调控作用消失，表明miR-198和MAPK1之间存在靶向调控关系，见图 2。
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图 2 荧光素酶报告实验检测miR-198与MAPK1之间的靶向关系Figure 2 Relationship between miR-198 and MAPK1 detected by luciferase reporter assay2.3 miR-198过表达对宫颈癌细胞增殖的影响
miR-198 mimic转染细胞4 d后，miR-198 mimic组HeLa细胞增殖倍数显著低于HeLa组（P=0.016）；pc-MAPK1能显著促进HeLa细胞增殖（P=0.023）；与miR-198 mimic组比较，mimic+pc-MAPK1组细胞增殖倍数明显升高（P=0.019），见图 3。
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图 3 CCK-8法检测miR-198过表达对HeLa细胞增殖的影响Figure 3 Effect of miR-198 mimic on proliferation of HeLa cells measured by CCK-8 assay*: P < 0.05, compared with HeLa group; #: P < 0.01, compared with miR-198 mimic group2.4 miR-198过表达对宫颈癌细胞凋亡的影响
与HeLa组比较，miR-198 mimic组宫颈癌细胞凋亡率明显升高（P=0.001），pc-MAPK1组细胞凋亡率明显降低（P=0.0024）；与miR-198 mimic组比较，mimic+pc-MAPK1组HeLa细胞凋亡率明显降低（P=0.0031），见图 4。
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图 4 流式细胞术检测miR-198过表达对HeLa细胞凋亡的影响Figure 4 Effect of miR-198 mimic on apoptosis of HeLa cells detected by flow cytometry**: P < 0.01, ***: P < 0.0001, compared with HeLa group; ##: P < 0.01, compared with miR-198 mimic group2.5 miR-198过表达对宫颈癌细胞侵袭能力的影响
miR-198 mimic组HeLa细胞侵袭数显著低于HeLa组（P=0.026），pc-MAPK1组细胞侵袭数明显高于HeLa组（P=0.012），差异有统计学意义。与miR-198 mimic组比较，mimic+pc-MAPK1组HeLa细胞侵袭数明显升高（P=0.0036），见图 5。
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图 5 Transwell实验检测各组HeLa细胞侵袭能力Figure 5 Invasion ability of cervical cancer HeLa cells measured by Transwell assay*: P < 0.05, compared with HeLa group; ##: P < 0.01, compared with miR-198 mimic group2.6 miR-198过表达对MAPK1下游蛋白表达的影响
Western blot实验结果表明，miR-198高表达能显著抑制MAPK1下游蛋白RSK2、c-Myc和c-fos的表达（P=0.00045, 0.00020, 0.00016）；MAPK1能显著升高RSK2、c-Myc和c-fos的蛋白表达水平（P=0.00024, 0.00036, 0.00086）；pc-MAPK1能显著减弱miR-198 mimic对RSK2、c-Myc和c-fos表达的抑制作用（P=0.00048, 0.00022, 0.00031），见图 6。
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图 6 Western blot检测RSK2、c-Myc和c-fos的蛋白表达水平Figure 6 Expression levels of RSK2, c-Myc and c-fos detected by Western blot***: P < 0.001, compared with HeLa group; ###: P < 0.001, compared with miR-198 mimic group3 讨论
大量研究表明，miRNAs的异常表达与癌症的发生发展有关[11]。miRNAs通过调控下游靶基因的表达影响癌症的发展，可作为预测癌症发生发展的指标[12-13]。因此，寻找与癌症发生相关的miRNAs及下游靶标将有助于癌症的治疗。本研究中，我们发现miR-198在宫颈癌细胞中表达异常减少，上调miR-198表达能显著降低宫颈癌细胞MAPK1的mRNA表达水平，提示miR-198可能可靶向调控MAPK1的表达。MAPK1是MAPK的下游靶基因，主要参与细胞增殖、凋亡和侵袭的调控[14]。miRNAs可通过调控MAPK1活性影响癌细胞增殖、凋亡和迁移的过程[15]。为了验证miR-198与MAPK1的靶向调控关系，本研究首先采用生物信息预测两者之间的关系，表明miR-198序列上存在MAPK1连续的结合位点。荧光素酶报告实验进一步表明miR-198与MAPK1之间存在靶向调控关系，提示MAPK1是miR-198的下游靶基因。
miR-198是一类癌症抑制基因，在多种癌细胞中表达降低[11, 16-17]。在结肠癌中，miR-198的表达水平与患者的预后呈负相关，上调miR-198表达水平能通过抑制岩藻糖转移酶8的表达抑制结肠癌皮下瘤的生长[18]。miR-198还与胰腺导管腺癌患者的生存率及生存时间长短密切相关[19]。Wu等研究发现，miR-198在47例肺腺癌患者癌组织中表达水平均明显降低[20]。本研究发现，miR-198 mimic转染细胞后4 d，宫颈癌细胞增殖速度明显降低，提示miR-198过表达能抑制宫颈癌细胞增殖。同时转染pc-MAPK1后，宫颈癌细胞增殖速度有所升高，表明miR-198抑制宫颈癌细胞增殖与靶向抑制MAPK1表达有关。
研究表明，miR-198调控癌症发展还与诱导癌细胞凋亡有关。上调miR-198表达能通过调控纤维生长因子受体的表达诱导肺癌细胞增殖，从而降低肺癌细胞活性[10]。miR-198表达下调可降低胶质瘤细胞凋亡率，与胶质瘤患者较差的预后密切相关[21]。但miR-198对宫颈癌细胞凋亡的作用还未见报道。本研究采用miR-198 mimic转染细胞，用流式细胞术检测转染后宫颈癌细胞的凋亡率，发现上调miR-198表达能显著升高HeLa细胞凋亡率，表明miR-198能诱导宫颈癌细胞凋亡。上调MAPK1表达后，miR-198诱导细胞凋亡的作用明显被减弱，提示miR-198能通过抑制MAPK1表达诱导宫颈癌细胞凋亡，从而减缓宫颈癌发展。
大量研究表明，miR-198高表达能抑制癌细胞的转移[9, 22]。癌细胞转移是导致癌症恶化和癌症患者死亡的主要原因。上调miR-198表达能降低肝癌细胞侵袭和迁移能力，作用机制与抑制肝细胞生长因子、下调p44/42 MAPK活性有关[23]。miR-198还可通过靶向调控ROCK1的表达降低骨肉瘤细胞的转移率[24]。本研究发现，上调miR-198表达水平能显著降低宫颈癌细胞HeLa的侵袭能力，表明miR-198低表达可能是宫颈癌出现远端转移的机制之一。MAPK1能显著减弱miR-198 mimic对宫颈癌细胞侵袭能力的抑制作用，表明miR-198可通过抑制MAPK1表达来抑制宫颈癌细胞转移。
MAPK信号通路是调控细胞增殖、凋亡、分化和转录的基本信号通路，MAPK1是MAPK的下游靶标，又称为p42 MAPK、ERK2[25]。抑制MAPK1表达可抑制肺癌细胞侵袭和迁移，研究表明敲除MAPK1下游靶基因RSK2后，癌细胞侵袭和转移能力明显减弱[26]。此外，RSK2激活可直接诱导c-Myc和c-fos表达，诱导细胞增殖及癌症的发生[27]。Li等研究发现，长链非编码RNA促进前列腺癌细胞增殖和转移与下调miR-198表达促进MAPK1信号通路激活有关[28]。本研究发现上调miR-198表达能显著抑制MAPK1下游蛋白RSK2、c-Myc和c-fos表达，上调MAPK1表达后，miR-198对RSK2、c-Myc和c-fos蛋白表达的抑制作用明显减弱，进一步表明miR-198抑制宫颈癌细胞增殖、侵袭，诱导癌细胞凋亡与靶向下调MAPK1的表达有关。
综上所述，miR-198可抑制宫颈癌HeLa细胞增殖和侵袭，并诱导宫颈癌细胞凋亡，作用机制与miR-198靶向调控MAPK1的表达有关。本研究阐明了miR-198在宫颈癌中的表达及miR-198对宫颈癌细胞增殖、凋亡和侵袭的作用，并初步探讨了miR-198对宫颈癌细胞的作用机制，可能为宫颈癌的治疗提供了又一新的治疗靶标。
Competing interests: The authors declare that they have no competing interests.作者贡献张雪：文献调研、整理及论文撰写李大可：文章审核及修改 -
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