文章信息
- DNA甲基化影响鼻咽癌侵袭转移相关信号通路的研究进展
- Research Progress on Influence of DNA Methylation on Signal Pathways Related to Invasion and Metastasis of Nasopharyngeal Carcinoma
- 肿瘤防治研究, 2022, 49(9): 956-960
- Cancer Research on Prevention and Treatment, 2022, 49(9): 956-960
- http://www.zlfzyj.com/CN/10.3971/j.issn.1000-8578.2022.22.0052
- 收稿日期: 2022-01-14
- 修回日期: 2022-04-24
2. 310006 杭州,浙江大学医学院附属杭州市第一人民医院耳鼻咽喉科
2. Department of Otorhinolaryngology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
鼻咽癌具有明确的地理分布特点,在东亚和东南亚尤为常见,是一种起源于鼻咽黏膜的恶性肿瘤。过去研究证实,表观遗传改变,尤其是DNA甲基化改变在鼻咽癌的发生发展中起着不可忽视的作用,使用去甲基化剂恢复多种鼻咽癌相关基因(如ZNF671、ZNF750、UCHL1、SHISA3、ARNTL、NFAT1、RIP3等)的表达后,均可在体内外抑制鼻咽癌细胞的侵袭与转移[1-7],此外,多种鼻咽癌相关基因(如TIPE3、LATS2、RAB37等)因启动子高甲基化而在鼻咽癌细胞中低表达,相比于甲基化水平低的患者,高甲基化水平的鼻咽癌患者的预后更差[8-10]。DNA甲基化在鼻咽癌侵袭与转移中具体的作用机制尚未阐明。近期有文献报道[4-6],DNA甲基化可能通过作用于多种信号转导通路进而影响鼻咽癌细胞的侵袭与转移。本文拟总结此类研究进展,为进一步探究DNA甲基化在鼻咽癌侵袭转移中具体的作用机制提供思路,并讨论其在鼻咽癌治疗中的应用前景。
1 DNA甲基化与鼻咽癌的侵袭转移DNA甲基化研究是目前机体细胞表观遗传学研究的一大热点。DNA甲基化基本发生在CpG二核苷酸的胞嘧啶上,通过DNA甲基转移酶(DNA methyltransferase, DNMT),包括DNMT1、DNMT3A和DNMT3B的催化作用,以S-腺苷甲硫氨酸(S-adenosyl methionine, SAM)作为甲基供体共价结合到需要甲基化的部位,形成5-甲基胞嘧啶(5mC),通常抑制靶基因的转录水平下调其表达。有研究显示,全基因组DNA低甲基化与抑癌基因启动子DNA高甲基化是癌细胞的一个关键特征[11]:一方面基因组整体甲基化水平降低可能导致原癌基因(如Ras、Myc、HOX11等)表达增加,促进癌症的发生发展[12];另一方面抑癌基因启动子高甲基化会抑制抑癌基因(如RASSF1、CDKN2A等)的表达,导致癌细胞增殖、抗凋亡能力增强,信号通路异常激活以及促进血管生成[13-14],使癌细胞的存活率大大增加[15],且增强其侵袭与转移能力。DNA甲基化与诸多实体肿瘤(如结直肠癌、胃癌、甲状腺癌及头颈部鳞癌包括鼻咽癌)的发生发展密切相关,在胃癌中DNA甲基化可通过作用于PI3K/AKT信号通路进而影响癌细胞的侵袭转移[16],DNA甲基化还可能通过TGF-β信号通路与Wnt/β-catenin信号通路促进结直肠癌的肝转移[17]。最近一些研究发现,DNA甲基化可能通过Wnt/β-catenin、PI3K/AKT及MAPK等信号通路影响鼻咽癌细胞的侵袭和转移[4, 6, 18-20]。
2 DNA甲基化影响鼻咽癌侵袭转移相关信号通路鼻咽癌发生侵袭转移与癌基因异常表达、肿瘤血管生成、细胞外基质降解、细胞黏附降低等因素有关,多种信号转导通路参与其中,目前研究较多的有Wnt、MAPK、PI3K、JAK/STAT、TGF-β等信号通路,初步阐明了DNA甲基化影响鼻咽癌侵袭转移的具体机制。
2.1 Wnt/β-catenin信号通路Wnt/β-catenin信号通路也称经典Wnt信号通路,是一种高度保守的信号通路,参与人体的多种生理过程,如细胞增殖、分化、凋亡、迁移、浸润和组织稳态[21-23]。相关研究证实Wnt/β-catenin信号通路的失调参与了部分实体肿瘤和血液系统恶性肿瘤的发生与发展[24-28],其中也包括鼻咽癌。转录因子β-catenin的调节异常导致了早期癌变的发生[29-32]。Wnt/β-catenin信号通路可以概括为Wnt蛋白与其FZD受体以及LRP-5/6受体结合,诱导胞质中的蓬乱蛋白(DVL),导致复合物(AXIN、GSK3β、CK1、APC)和受体聚集,进而使细胞质中β-catenin蛋白浓度升高迁移到细胞核中积聚,在细胞核中,β-catenin蛋白与T细胞因子(TCF)和淋巴增强因子(LEF)相互作用,诱导Wnt靶基因c-Myc、Cyclin D1和CDKN1A的表达[33]。Wnt/β-catenin信号通路不仅通过自身介导的信号通路促进肿瘤转移,还与其他信号协同通路直接或间接诱导上皮间充质转化(EMT)[34],且涉及多个关键蛋白,如钙黏素(Cadherin)、转化生长因子-β(TGF-β)、内皮素(ET)和基质金属蛋白(MMP)等。在鼻咽癌细胞中,SOX1与SEPT9_v2的过表达均可以降低β-catenin的表达,同时下调Wnt/β-catenin信号通路的下游靶点Cyclin D1和c-Myc,通过抑制Wnt/β-catenin信号通路进而抑制鼻咽癌的侵袭与转移。甲基化特异性PCR检测鼻咽癌组织与细胞系中SOX1与SEPT9_v2启动子甲基化状态后发现,两者在鼻咽癌细胞中的低表达与其启动子高甲基化密切相关[18, 20]。此外,ZNF154在鼻咽癌组织与细胞系中的表达经常由于其启动子高甲基化而下调,并且ZNF154在体外与体内均可抑制鼻咽癌细胞的侵袭与转移,可能与ZNF154下调鼻咽癌细胞中β-catenin的表达,使Wnt/β-catenin信号通路失活,以此抑制上皮间充质转化(EMT)有关[35]。DACT2作为Wnt通路的拮抗剂,可降低鼻咽癌细胞中活性β-catenin及其下游基因的表达,并且抑制β-catenin/LEF复合体的活性,同时DACT2过表达还会导致鼻咽癌细胞中的MMP下调。Zhang等[36]通过RT-PCR检测证实了鼻咽癌组织中DACT2较正常组织低表达,通过甲基化特异性聚合酶链反应(MSP)检测鼻咽癌组织与正常组织中DACT2启动子甲基化状态,发现DACT2低表达与其启动子高甲基化密切相关。有研究者发现TET1可以导致Wnt拮抗剂(DACT2、SFRP2)启动子去甲基化,恢复其在鼻咽癌细胞中的表达,以此发挥抑制肿瘤侵袭转移的作用[19]。尽管相关的研究仍然比较缺乏,但上述研究初步阐明了DNA甲基化通过Wnt/β-catenin信号通路影响鼻咽癌侵袭与转移的具体作用机制,鼻咽癌相关基因可因其启动子高甲基化而表达下调,而这些基因可以作用于Wnt/β-catenin信号通路的各个阶段,使其失活或下调其靶基因的表达,从而抑制鼻咽癌细胞的侵袭与转移。这些研究揭示Wnt/β-catenin信号通路中可能存在潜在的鼻咽癌治疗靶点,并为后续的研究提供方向。
2.2 PI3K/AKT信号通路PI3K是一种胞内磷脂酰肌醇激酶,具有丝氨酸/苏氨酸活性和磷脂酰肌醇激酶活性,当接收到酪氨酸激酶和G蛋白偶联受体的信号后,PI3K调节亚基的p85聚集到细胞膜周围,蛋白激酶B(AKT)在丙酮酸脱氢酶激酶同工酶1和2(PDK1和PDK2)的介导下由细胞质转移到细胞膜并被激活[37]。在正常细胞中,PI3K/AKT信号通路受到抑癌基因PTEN的严格调控,而在肿瘤细胞中,异常激活的PI3K/AKT信号通路可以诱导PTEN泛素化及降解,加速肿瘤的发展[38]。该信号通路主要与细胞运动以及血管生成有关。已有研究发现PI3K/AKT信号通路在多种实体肿瘤中促进肿瘤细胞的增殖、存活与运动[39-40],且该信号通路在鼻咽癌中过度表达与激活[15],并通过下调E-钙黏蛋白的表达降低细胞之间以及细胞与间质之间的黏附性,促进鼻咽癌细胞的侵袭与转移[41]。同Wnt/β-catenin信号通路类似,PI3K/AKT信号通路也可以激活MMP、诱导EMT,以此促进鼻咽癌的侵袭与转移[42]。Chen等[43]发现CHL1在鼻咽癌细胞系与组织中由于其启动子高甲基化而表达下调,在功能研究中,CHL1在鼻咽癌细胞中的过表达可以抑制癌细胞增殖与细胞运动,并且CHL1还可以通过上调上皮标志物和下调间质标志物,诱导间充质上皮转化(MET),同时抑制EMT,以此来抑制鼻咽癌细胞的侵袭与转移。进一步的机制研究表明,CHL1通过与整合素β1和Merlin的相互作用,导致下游PI3K/AKT信号通路的失活,从而发挥其肿瘤抑制作用。鼻咽癌组织与细胞系中Fibulin-3的表达与磷酸化AKT的活性负相关,过表达Fibulin-3可以抑制磷酸化AKT的活性,进而使PI3K/AKT信号通路失活,以此来抑制鼻咽癌细胞的侵袭与转移[44]。Fibulin-3经常在鼻咽癌细胞系和组织中表达下调,可能是由于其启动子高甲基化导致的。综上,DNA甲基化可以通过PI3K/AKT信号通路影响鼻咽癌侵袭与转移,但仍然需要更多的证据支持。
2.3 MAPK信号通路MAPK信号通路是调控多种细胞过程的关键信号通路,包括增殖、分化、凋亡和应激反应。MAPK通路包括三个主要的激酶:MAPK、MAPK激酶和MAPK激酶激酶,来激活和磷酸化下游蛋白。Ras/Raf/MAPK(MEK)/ERK通路是MAPK信号通路中最重要的信号级联,与肿瘤细胞外基质降解和肿瘤血管生成有关,在肿瘤增殖,侵袭与转移中发挥重大作用[45]。现有研究表明,在卵巢癌、结肠癌、乳腺癌、肺癌等多种肿瘤中均可以检测到ERK通路的过度激活[46-49]。Zhang等[4]在鼻咽癌细胞与组织中发现,SHISA3经常由于启动子高甲基化而表达下调,而SHISA3在体内外均可以抑制鼻咽癌细胞的侵袭与转移,进一步的机制研究发现,SHISA3的过表达抑制了磷酸化细胞外信号调节激酶(p-ERK)、磷酸化MEK的活化和Ras-GTP的活性,导致MAPK信号通路的失活,因此抑制鼻咽癌细胞的侵袭与转移。此外RERG过表达可抑制ERK和NF-κB信号通路及其下游的效应分子,进而下调MMPs和促血管生成细胞因子,以此来抑制鼻咽癌细胞的侵袭与转移[50]。RERG在鼻咽癌细胞和组织中由于启动子高甲基化而表达下调,使用DNA甲基转移酶抑制剂恢复其表达后,RERG可在体内外抑制鼻咽癌细胞的侵袭与转移。分泌型金属蛋白酶ADAMTS8抑制表皮生长因子受体(EGFR)信号转导,并且降低磷酸化MEK和ERK的水平,通过破坏肌动蛋白应激纤维组织抑制肿瘤细胞的迁移,Choi等[51]发现ADAMTS8在正常组织中广泛表达,但在常见癌细胞系(包括鼻咽癌、食管鳞状细胞癌、胃癌和结肠癌)中经常因启动子高甲基化而表达下调,应用去甲基化剂处理后可恢复ADAMTS8的表达,进而抑制癌细胞的迁移。目前这些研究初步揭示了DNA甲基化如何通过MAPK信号通路影响鼻咽癌侵袭与转移,可以为后续进一步研究该通路中更多的分子靶点提供思路。
3 其他可能的相关信号通路除了上述已经明确了的DNA甲基化影响鼻咽癌侵袭与转移具体的信号通路,还有许多相关信号通路可能参与其中。前期的一项鼻咽癌全基因组测序研究中,研究者采用了甲基化DNA免疫沉淀(methylated DNA immunoprecipitation, MeDIP)技术对鼻咽癌细胞系和原发肿瘤以及正常鼻咽上皮细胞的甲基化基因进行了分析,结果观察到了广泛的、全基因组的CpG甲基化。进一步采用京都基因和基因组百科全书数据库(KEGG)进行通路分析发现,鼻咽癌中Wnt、TGF-β、Hedgehog和MAPK等关键信号通路被DNA甲基化破坏[52]。如前文所述,已有研究证实DNA甲基化可通过Wnt和MAPK通路影响鼻咽癌的侵袭与转移,然而,尚未有研究证明DNA甲基化可通过TGF-β和Hedgehog通路影响鼻咽癌的侵袭与转移。此外,尚有诸多鼻咽癌的相关基因也可以通过去甲基化剂恢复其表达进而抑制鼻咽癌的侵袭与转移,但这一过程中涉及的具体信号通路仍未明确,如HOPX和NFAT1可能通过靶向EMT抑制鼻咽癌细胞的侵袭与转移[6, 53],Fibulin-2通过抑制血管生成进而抑制肿瘤的增殖与转移[54],CLDN11通过干扰微管蛋白聚合发挥其抑制肿瘤细胞迁移的作用[55],ZNF582可以通过下调细胞黏附分子Nectin-3和上调细胞黏附分子NRXN3抑制鼻咽癌细胞的侵袭与转移[56]。而这些可以为后续的研究提供理论基础,未来可以进一步探寻上述基因究竟是作用于何种信号通路进而影响鼻咽癌的侵袭与转移,并明确其在各个信号通路中具体的作用靶点。
4 总结与展望综上所述,DNA甲基化通过多种信号通路作用于诸如细胞运动、细胞黏附、细胞外基质降解、肿瘤血管生成等各个环节,最终影响鼻咽癌的侵袭与转移。目前早期鼻咽癌依靠放疗能取得满意的疗效,然而一旦肿瘤发生远处转移,不论是联合放化疗还是手术治疗,均难以有效改善患者的预后。DNA甲基化是一种可以逆转的表观遗传调控机制,尽管存在一定的局限性,但上述研究初步阐明了鼻咽癌相关基因DNA甲基化影响鼻咽癌细胞侵袭与转移具体信号通路的分子机制,有助于通过进一步研究构建信号转导通路网络,并探寻各个通路潜在的治疗靶点。早在1970年左右,欧美国家就开始使用去甲基化剂5-氮杂胞苷(azacitidine AZA)和5-氮杂-2-脱氧胞苷(decitabine DAC)进行治疗血液系统肿瘤与实体肿瘤的临床试验,结果表明,联合应用AZA和DAC治疗急性髓系白血病(AML)是有效的,但是对于其他实体肿瘤并没有显著作用[57]。2004年研究人员调整了去甲基化剂的剂量以降低其毒性和提高效率之后,其被批准用于临床治疗骨髓异常增生综合征(MDS)[58]。尽管去甲基化剂尚未应用于鼻咽癌的临床治疗,但我们希望上述研究可以为相关靶向药物的研发指明方向,从而有效控制肿瘤转移,延长患者的生存时间,改善患者的预后。
作者贡献:
王梓合:文献检索、论文撰写
李锃亮、方许哲:文献检索
朱瑾:文章修改
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