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   中国临床医学  2020, Vol. 27 Issue (1): 127-131      DOI: 10.12025/j.issn.1008-6358.2020.20190397
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具核梭杆菌促进结直肠癌发病相关机制的研究进展
吕振涛 , 钟芸诗 , 陈涛 , 周平红     
复旦大学附属中山医院内镜中心, 上海 200032
摘要:具核梭杆菌(fusobacterium nucleatum,Fn)与结直肠癌(colorectal cancer,CRC)发生有关。有研究发现人类CRC中有过量的Fn,并阐明了Fn在体外和小鼠模型中参与CRC发生可能的机制。Fn参与CRC癌变的机制主要包括:通过增加髓系来源的抑制细胞和减少自然杀伤细胞等发挥的免疫调节;由FadA、Fap2和脂多糖介导的毒力作用;促进肿瘤相关microRNA(如miR-21)表达;代谢作用。本文就Fn在CRC中的作用机制作一综述。
关键词结直肠癌    具核梭杆菌    机制    
Research progress on mechanisms of fusobacterium nucleatum promoting colorectal cancer
LV Zhen-tao , ZHONG Yun-shi , CHEN Tao , ZHOU Ping-hong     
Department of Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Abstract: Fusobacterium nucleatum (Fn) has been linked to colorectal cancer (CRC). Several studies showed an overabundance of Fn in human CRC and elucidated the possible mechanisms of Fn involved in CRC in vitro and in mouse models. The mechanisms of Fn involved in CRC carcinogenesis mainly include immune modulation by increasing myeloid-derived suppressor cells and decreasing natural killer cells, toxic effect mediated by FadA, Fap2, and lipopolysaccharide, increasing tumor-associated microRNAs (such as miR-21), and metabolism modulation. This article reviews the mechanisms of Fn in CRC.
Key words: colorectal cancer    fusobacterium nucleatum    mechanisms    

结直肠癌(colorectal cancer, CRC)是全球发病率第4、死亡率第2的癌症[1]。年龄、性别、遗传等危险因素会导致CRC的发病。多种微生物与癌症的发病相关,如幽门螺杆菌与胃癌、人乳头状病毒与宫颈癌等。因此,肠道菌群在CRC中的作用引起了广泛关注。大约有1 000种不同的微生物栖息在人类胃肠道内[2]。这些微生物对肠道环境稳态的维持具有重要作用。但这个作用是相对的,当肠道微生物菌群发生迁移时,可能导致包括CRC、炎症性肠病(inflammatory bowel disease, IBD)和肥胖在内的各种疾病[3-4]。值得注意的是,肠道菌群分布不均匀,大肠内的细菌密度(每毫升约1 012个细菌)远高于小肠(每毫升约102个细菌)。大肠中的癌症风险也比小肠高12倍[2]

CRC患者肠道菌群的构成与正常人群存在差异[5],主要表现为益生菌减少和具核梭杆菌(fusobacterium nucleatum,Fn)、大肠杆菌、肠球菌等机会致病菌增多,提示这些微生物可能参与CRC的发病过程[5-6]。为了明确微生物与CRC之间的关系,Castellarin等[7]对CRC组织进行了RNA测序,并与邻近的正常组织进行比较。结果显示,肿瘤组织中Fn的数量显著增加。最近的重复研究[8]也证明了这一点。Fn是专性厌氧的格兰阴性杆菌,广泛分布于口腔、肠道、上呼吸道和阴部[9],也是临床样本中分离出的最常见的微生物之一,常与牙周病、阑尾炎、IBD、呼吸道感染、类风湿关节炎、心血管疾病、绒毛膜羊膜炎、早产、死产、阿尔茨海默病和勒米尔综合征等有关[9-10]。此外,Fn在结肠腺瘤中过度增殖,其在CRC发展的初级阶段起重要作用,且可能影响患者的生存[11]。虽然多项研究表明Fn与CRC之间存在联系,但是其中的机制仍然不明确,本文就相关研究结果作一综述。

1 髓源性抑制细胞(myeloid-derived suppressor cells,MDSCs)和自然杀伤细胞(natural killer cell,NK)细胞介导的免疫机制 1.1 MDSC相关免疫机制

Kostic等[12]发现,与周围非腺瘤组织相比,人类结直肠腺瘤组织中Fn的含量明显增高;与健康对照组相比,结直肠腺瘤患者的粪便中Fn的含量也增加。Chiu等[13]在CRC小鼠模型中发现,Fn能增加肿瘤负荷、促进炎症标志物表达,促进CD11b+MDSCs浸润。而MDSCs作为免疫抑制细胞在癌症中起抑制免疫反应、促进癌症进展的作用。研究[14]表明,MDSCs可以抑制T细胞向肿瘤浸润,增加基质金属蛋白酶9及血管生成,且能保持干细胞特性。

MDSC是肿瘤相关巨噬细胞(M2型巨噬细胞)、粒细胞和树突状细胞(dendritic cell, DC)的前体[12],在促进肿瘤发展和血管生成中起关键作用(图 1)。巨噬细胞能对肿瘤环境中的不同信号作出反应,可分化为2种不同的功能表型(M1与M2),其中M1表型有阻碍肿瘤进展的功能,而M2表型则可促进肿瘤增殖、迁移和血管生成[15-16]。喂食了Fn的小鼠结直肠肿瘤微环境中M2型巨噬细胞数量增加了7.8倍,导致CD4+T细胞被抑制[12]。Chen等[17]的实验表明,在人类CRC中,M2型是巨噬细胞的主要表型,而Fn感染促进肿瘤微环境内M2型巨噬细胞极化和肿瘤生长。Toll样受体4(TLR4)抑制剂TAK-242预处理能显著降低Fn引起的肿瘤微环境中M2巨噬细胞的极化;在此基础上进行免疫荧光检测,发现TLR4依赖的IL-6/p-STAT3/c-MYC信号通路参与Fn对M2巨噬细胞的极化作用。另一项研究[18]表明,肿瘤组织中Fn DNA的富集与高频度微卫星不稳定(high frequencymicrosatellite instability,MSI-H) CRC中巨噬细胞浸润和CDKN2A甲基化显著相关。Través等的研究[19]则表明,可变读框基因(alternative reading frame, ARF)是CDKN2A的INK4a/ARF位点编码的肿瘤抑制因子,缺乏ARF会使M1型通路受损,导致M2型极化,进而产生致癌作用。由此推测在Fn感染的CRC中,启动子甲基化对CDKN2A的抑制可能与M2巨噬细胞的增加有关。肿瘤相关中性粒细胞(tumor-associated neutrophil,TAN)也参与肿瘤的发展、转移和血管生成[20]。另一种Fn喂食的小鼠肠内增加的骨髓免疫细胞是CD103+DCs,这些细胞通过增加Foxp3+调节性T细胞而降低肿瘤免疫[21]

1.2 NK相关免疫机制

Fn能减少体内具有细胞毒作用的NK细胞,从而引起肿瘤细胞免疫逃逸[22]。NK细胞属于固有免疫系统,有激活和抑制2种受体[23]。激活受体可以被肿瘤蛋白、病毒成分、自体分子和应激诱导分子激活[23]。免疫受体尾酪氨酸抑制基序(TIGIT)是一种抑制NK细胞和其他免疫细胞的受体,可被脊髓灰质炎病毒受体(poliovirus receptor, PVR)和nectin-2分子激活。这些配体与TIGIT结合后,通过细胞质结构域、免疫受体酪氨酸基抑制基序(immunoreceptor tyrosine-based inhibition motif,ITIM)启动抑制信号[24]。在NK细胞上,Fn表面的Fap2蛋白与人TIGIT (hTIGIT)受体相互作用,导致抑制性级联反应。CD4+和CD8+细胞也表达TIGIT受体。Gur等[22]研究表明,Fn通过Fap2与TIGIT相互作用抑制T辅助细胞和细胞毒性T淋巴细胞的活性。此外,已有研究[25]表明,Fn能够诱导Jurkat T细胞和外周血单核细胞凋亡。Fn通过抑制相关蛋白表达使人T细胞阻滞在G1[26]。相关免疫机制见图 1

图 1 MDSCs和NK细胞介导的促肿瘤发生的部分相关免疫机制
2 FadA、Fap2和脂多糖(lipopolysaccharide,LPS)介导的毒力机制

细菌的毒力因子分为侵袭因子和毒素因子(内外毒素),这些物质帮助细菌侵袭宿主细胞,并对宿主细胞造成毒性作用,这个过程可能影响细胞的信号通路,使其出现癌变倾向。Fn的毒力因子在肠道中也具有这样的作用(图 2)。

图 2 Fn中FadA、Fap2和LPS介导的毒力机制
2.1 蛋白FadA

FadA是存在于Fn上的一种毒性蛋白,具有帮助细菌黏附和破坏上皮细胞、内皮细胞的作用,对于细菌传播至关重要[27]。Rubinstein等[28]利用免疫沉淀和缺失分析来检验野生型Fn 12230上的FadA是否与非癌变人类胚胎肾细胞(HEK-293)和CRC细胞系SW480、DLD1、HCT116、HT29中的E-cadherin细胞外区域结合(除外不表达E-cadherin的RKO细胞系)。结果表明,FadA特异性地与E-cadherin结合,诱导β-catenin/Wnt信号的激活;用E-cadherin的单克隆抗体HECD-1或siRNA下调E-cadherin的表达明显阻碍了HEK-293中野生型Fn 12230的附着和侵袭;同时,野生型Fn 12230可以附着和侵袭全长E-cadherin (CDH1) cDNA转染的RKO细胞。该研究表明,E-cadherin是FadA的特异性结合受体,两者结合引发的β-catenin/Wnt信号激活可导致癌基因、Wnt基因和炎症基因表达水平升高。在上述过程中,网格蛋白参与激活Wnt信号通路,促进CRC的癌变过程。

2.2 蛋白Fap2

Fap2是一种半乳糖敏感的血凝素和黏附蛋白,在Fn感染中发挥重要作用[29]。除通过与TIGIT相互作用抑制NK细胞外,Abed等[30]在研究CRC患者肠道中Fn的定植机制时发现,Fn的Fap2蛋白可通过与CRC中高表达的Gal-GalNAc结合介导细菌富集,而用O-聚糖酶降低Gal-GalNAc的表达可减少CRC中Fn的积累。此外,在多种其他类型的腺癌中也发现了高水平的Gal-GalNAc,表明其可能是富含Fn癌症治疗中一个潜在的靶点[30]

2.3 LPS

LPS可与TLR4结合,而TLR4在CRC中过度表达,有促进肿瘤的作用[31]。Wu等[32]发现,用Fn加抗生素喂食组小鼠的肿瘤数量及大小均超过仅用抗生素的控制组。此外,通过用TLR4抑制剂TAK-242阻滞TLR4/p-PAK1/β-catenin信号通路,可以减少Fn诱导的肠肿瘤发生[32],说明Fn通过TLR4/ p-PAK1级联激活β-catenin信号通路可促进肠道肿瘤的起始和发展。β-catenin在CRC发展中具有重要促进作用[33]。已有研究表明,Ser675磷酸化的β-catenin更加稳定和活跃,而在CRC细胞中PAK1可以使其Ser675磷酸化,进而增加β-catenin水平[34]。上述证据提示,LPS介导的TLR4/p-PAK1/β-catenin信号通路是预防和治疗Fn相关CRC的潜在靶点。

3 Fn调节多种致瘤microRNA的表达

有多种microRNA在CRC的发生中发挥作用,其中一些还被用于诊断CRC的发生和进展[35-37]。其中,miR-21可以促进肠慢性炎症和结肠炎相关CRC的进展[37]。Yang等[38]发现,Fn可以通过激活TLR4/MYD88/NF-κB通路调节CRC细胞中miR-21的表达。该研究用Fn处理APCMin/+小鼠后,CRC肿瘤数量、肿瘤负荷和肿瘤大小均增加;用Fn处理CRC细胞株后,通过微阵列分析发现,miR-21在所有miRNA中的表达率最高。OHTA等[39]进一步发现,类GTPase转运蛋白(RAS GTPase)活化蛋白家族中的RASA1是miR-21的直接靶点,miR-21被抑制后,RASA1表达增加;而RASA1可以与RAS癌蛋白结合并使其失活。同时,Yu等[40]发现,Fn在CRC细胞系中诱导LC3-Ⅱ表达,进而能扩增自噬通量和促进自噬体合成,并刺激自噬相关蛋白pULK1、ULK1、ATG7在CRC中的表达;而自噬抑制增强了经Fn处理的CRC细胞对5-氟尿嘧啶(5-FU)和奥沙利铂的敏感性。因此,Fn能通过调节TLR4/MYD88、miR-18a*、miR-4802与ULK1/ATG7自噬网络之间的关系,导致CRC化疗抵抗,从而介导CRC的复发。

4 Fn在微卫星不稳定性(MSI)状态下的致瘤作用

MSI指与正常组织相比,肿瘤中的某一微卫星由于重复单位的插入或缺失而造成长度改变,出现新的微卫星等位基因现象。MSI特点是在肿瘤微环境中,由于移码突变和免疫原多肽高表达,产生了强烈的抗肿瘤免疫反应。人CRC病理和分子研究[41-42]显示,Fn DNA在MSI-H CRC分子亚型中富集,提示两者存在联系。但是,Park等[18]发现,CD3+肿瘤浸润淋巴细胞密度、程序性死亡配体1(programmed cell death 1 ligand 1,PD-L1)表达水平与MSI-H CRC组织中Fn DNA水平无显著相关性;Mima等[42]发现,Fn的数量与CD3+T细胞的密度负相关。最近,Hamada等[43]的研究提示,MSI状态对Fn感染介导的CRC免疫反应有重要影响。该结果也许可以解释这种对立情况。该研究[43]表明,在MSI-H的CRC中,Fn对小鼠自适应性抗肿瘤免疫反应具有显性抑制作用,而在非MSI-H的CRC中则表现为明显的促炎作用。虽然其中的具体机制还不清楚,但上述研究表明MSI表型可能是Fn感染引起CRC的独立影响因素。

5 Fn肠道代谢相关致瘤机制

Fn在肿瘤微环境中将多肽和氨基酸作为营养物质的来源。短链脂肪酸和甲酰基亮氨酸苯丙氨酸作为Fn的氨基酸代谢产物,是髓源性细胞的激活剂[12]。此外,Fn特有的电子传递链使其能够在肿瘤微环境缺氧条件下复制生存[44]

6 小结

Fn感染作为CRC的危险因素,相关研究提出了多种可能的机制。其中,TLR4参与多种途径,其介导的IL-6/p-STAT3/c-MYC信号通路参与Fn感染免疫反应[15]; TLR4/p-PAK1级联激活的β-catenin信号通路参与Fn感染毒力机制[32];TLR4/MYD88/NF-κB信号通路以及TLR4/MYD88自噬通路[40]均参与MicroRNA相关作用机制。因此,TLR4可能是Fn影响CRC的重要作用点。另外,MSI状态的不同对Fn感染CRC免疫反应产生不同的影响[43],但具体的机制还不清楚。总之,Fn感染与CRC的关系及相关机制需要更多的研究来揭示。

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引用本文
吕振涛, 钟芸诗, 陈涛, 周平红. 具核梭杆菌促进结直肠癌发病相关机制的研究进展[J]. 中国临床医学, 2020, 27(1): 127-131.
LV Zhen-tao, ZHONG Yun-shi, CHEN Tao, ZHOU Ping-hong. Research progress on mechanisms of fusobacterium nucleatum promoting colorectal cancer[J]. Chinese Journal of Clinical Medicine, 2020, 27(1): 127-131.
通信作者(Corresponding authors).
钟芸诗, Tel:021-64041990. E-mail:zhongyunshi@yahoo.com.
Corresponding author
ZHONG Yun-shi, Tel:021-64041990. E-mail:zhongyunshi@yahoo.com.

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