2023, Vol. 50
RNA修饰在胃癌发生发展中的作用机制研究进展
本刊由国家卫生和计划生育委员会主管，湖北省卫生厅、中国抗癌协会、湖北省肿瘤医院主办。
文章信息
- RNA修饰在胃癌发生发展中的作用机制研究进展
- RNA Modification in Carcinogenesis and Development of Gastric Cancer
- 肿瘤防治研究, 2023, 50(8): 738-744
- Cancer Research on Prevention and Treatment, 2023, 50(8): 738-744
- http://www.zlfzyj.com/CN/10.3971/j.issn.1000-8578.2023.23.0067
- 收稿日期: 2023-02-01
- 修回日期: 2023-03-21
引用本文 |
徐佳雯, 王强, 王守宇. RNA修饰在胃癌发生发展中的作用机制研究进展[J]. 肿瘤防治研究, 2023, 50(8): 738-744.
XU Jiawen, WANG Qiang, WANG Shouyu. RNA Modification in Carcinogenesis and Development of Gastric Cancer[J]. Cancer Research on Prevention and Treatment, 2023, 50(8): 738-744.
RNA修饰在胃癌发生发展中的作用机制研究进展
1. 210093 南京，南京大学医学院;
2. 230000 合肥，安徽医科大学第一附属医院医学转化研究院
2. 230000 合肥，安徽医科大学第一附属医院医学转化研究院
摘要: 胃癌的发生与环境、遗传和表观遗传因素密切相关。目前，RNA修饰是表观遗传领域的研究前沿和热点。随着分析化学和高通量测序技术的进步，解析RNA修饰的新技术和新方法不断涌现。大量研究已经证实RNA修饰参与多种疾病的发生和发展。最近研究发现m6A、m5C、ac4C等RNA修饰调控胃癌、肝癌、结直肠癌、白血病等多种肿瘤的恶性进程。本文就RNA修饰在胃癌发生发展中的研究现状和作用机制作系统综述，并讨论其在胃癌诊断和治疗方面的潜在价值。
关键词:
RNA修饰 胃癌 m6A m5C ac4C
RNA Modification in Carcinogenesis and Development of Gastric Cancer
1. Medical School of Nanjing University, Nanjing 210093, China;
2. Institute of Medical Transformation, the First Affiliated Hospital of Anhui Medical University, Hefei 230000, China
2. Institute of Medical Transformation, the First Affiliated Hospital of Anhui Medical University, Hefei 230000, China
Abstract: The occurrence of gastric cancer is closely related to environmental, genetic, and epigenetic factors. Currently, RNA modification is a research frontier and hotspot in the field of epigenetics. With the advancements in analytical chemistry and high-throughput sequencing technologies, new technologies and methods of exploring RNA modification are constantly being presented. Numerous studies have confirmed the involvement of RNA modifications in the occurrence and development of various diseases. Recent studies have shown that RNA modifications such as m6A, m5C, and ac4C regulate the malignant progression of various tumors, including gastric cancer, liver cancer, colorectal cancer, and leukemia. This article systematically reviews the research status and mechanism of different RNA modifications in the occurrence and development of gastric cancer, as well as discusses its potential value in the diagnosis and treatment of gastric cancer.
Key words:
RNA modification Gastric cancer m6A m5C ac4C
0 引言
胃癌（gastric cancer, GC）是常见的恶性肿瘤之一，我国胃癌的发病率和死亡率在各种恶性肿瘤排名中均位居前三。尽管早期内镜筛查、手术、放化疗和靶向治疗等综合治疗方案的实施，胃癌发病率和死亡率呈下降趋势，但总体预后仍不容乐观[1-2]。胃癌的致病因素主要包括环境因素（幽门螺杆菌感染、吸烟、饮酒和不良饮食习惯等）、遗传因素以及表观遗传因素等。其中，表观遗传因素在肿瘤发生发展过程中发挥重要作用。表观遗传是指DNA序列不发生改变，但是调控模式和基因表达可以发生遗传且可逆的改变[3]。表观遗传主要包括DNA甲基化、非编码RNA调控、RNA修饰、组蛋白修饰和染色质重塑等[3]。近年来，随着高通量技术的快速发展及分析化学相关技术的进步，越来越多的RNA修饰被鉴定，包括N6-甲基腺苷（N6-methyladenosine, m6A）、N4-乙酰胞苷（N4-acetylcytidine, ac4C）、5-甲基胞苷（5-methylcytosine, m5C）等，这些修饰在基因转录后调控过程中发挥着极为重要的作用，参与包括肿瘤在内的多种疾病的发生发展[4]。本文就不同的RNA修饰在胃癌发生发展中的作用和调控机制进行综述。
1 N6-甲基腺苷m6A修饰是真核生物中普遍存在且丰度最高的RNA化学修饰[5]。m6A修饰是一种动态可逆的过程，由甲基转移酶复合物（writers）催化RNA发生甲基化，RNA甲基转移酶复合物主要由甲基转移酶样蛋白3/14（methyltransferase-like 3/14，METTL3/14）[6-7]、甲基转移酶样蛋白16（methyltransferase-like 16, METTL16）[8]和肾母细胞瘤1相关蛋白（wilms tumor 1-associated protein, WTAP）[9]组成，可能还包括病毒样m6A甲基转移酶相关蛋白（vir-like m6A methyltransferase-associated protein, VIRMA）[10]、锌指CCCH结构域蛋白13（zinc finger CCCH domain-containing protein 13, ZC3H13）[11]和RNA结合基序蛋白15/15B（RNA-binding motif protein 15/15B, RBM15/15B）[12]等。同时，脂肪含量和肥胖相关蛋白（fat mass and obesity-associated protein, FTO）[13]和α酮戊二酸依赖性双加氧酶同系物5（alpha-ketoglutarate-dependent dioxygenase alkB homolog 5, ALKBH5）[14]是去甲基化酶（erasers），可以擦除RNA上的m6A修饰。在此过程中，需要特异的RNA结合蛋白（readers）识别并结合m6A修饰位点从而调控RNA代谢。RNA readers主要包括一些YTH结构域蛋白1/2（YTH domain-containing protein 1/2, YTHDC1/2）[15]、胰岛素样生长因子2结合蛋白1/2/3（insulin-like growth factor 2 binding protein 1/2/3, IGF2BP1/2/3）[16]、异质核糖核蛋白（heterogeneous nuclear ribonucleoprotein A2B1, hnRNPA2B1）[17]、真核起始因子3（eukaryotic initiation factor 3, eIF3）[18]等。不同的RNA结合蛋白通过调控RNA剪接、出核、翻译、稳定性和降解等过程参与RNA代谢[19-21]。在此，本文系统回顾了m6A相关蛋白在胃癌恶性进展中的作用。
1.1 m6A甲基转移酶METTL3是最早发现的m6A甲基转移酶。近年来，关于METTL3上下游调控机制和功能研究已有很多报道。胃癌组织中METTL3的表达显著增加，并与胃癌患者的不良预后显著相关[22]。有研究发现敲减METTL3可以抑制AKT磷酸化及下游p70S6K和细胞周期蛋白D1（Cyclin D1）的表达，进而抑制胃癌细胞增殖和迁移[23]。此外，乙型肝炎X-相互作用蛋白（hepatitis B X interacting protein, HBXIP）通过促进METTL3表达增强癌基因MYC mRNA上的m6A修饰，促进MYC翻译，对胃癌细胞的增殖和迁移起促进作用[24-25]。最近研究发现P300介导组蛋白H3乙酰化（H3K27ac）促进METTL3转录激活，随后METTL3介导肝癌衍生生长因子（hepatoma-derived growth factor, HDGF）mRNA上m6A修饰，同时IGF2BP3识别并结合m6A修饰位点，维护HDGF mRNA的稳定性。HDGF可以分泌到细胞外促进肿瘤血管生成，还能进入细胞核促进糖酵解相关蛋白葡萄糖转运蛋白4（glucose transporter 4, GLUT4）和神经元变性烯醇化酶（neurone specific enolase-2, ENO2）的转录，增强胃癌细胞糖酵解能力，共同促进胃癌细胞的生长和肝转移[26]。此外，转录因子HOXA10能与转化生长因子TGFβ2基因的启动子区结合，激活TGFβ/Smad信号通路并促进METTL3表达，在胃癌转移中发挥着重要作用[27]。METTL3可以介导锌指MYM型蛋白1（zinc finger MYM-type containing 1, ZMYM1）mRNA上m6A修饰来维护其mRNA稳定性，随后ZMYM1通过与CtBP/LSD1/CoREST复合物结合并抑制E-钙粘蛋白（E-cadherin）表达，促进胃癌细胞上皮间质转化（EMT）和转移[22]。METTL3也可通过YTHDF1依赖性的方式促进鞘氨醇激酶2（sphingosine kinase 2, SPHK2）mRNA的翻译，介导Kruppel样因子2（KLF transcription factor 2, KLF2）磷酸化，导致KLF2蛋白发生泛素化降解，发挥促癌作用[28]。最近研究报道METTL3参与调控胃癌化疗敏感度，CD133阳性的胃癌干细胞通过METTL3介导PARP1 mRNA上的m6A修饰维护其mRNA稳定性，增强DNA损伤修复能力，导致胃癌细胞对奥沙利铂产生耐药[29]。可见，METTL3可以通过调控不同信号通路或下游关键节点分子促进胃癌发生发展，提示其可以作为胃癌临床诊断的分子标志物和潜在治疗靶点。
此外，一些非编码RNA被揭示可以调控METTL3表达。如miR-4429和miR-1269b可以负调控METTL3表达，抑制胃癌进展[30-31]。胚胎外胚层发育蛋白（embryonic ectoderm development, EED）介导组蛋白甲基化抑制miR-338-5p的表达，激活下游METTL3表达，进一步增加CUB结构域蛋白1（CUB domain containing protein 1, CDCP1）mRNA的m6A修饰，促进CDCP1翻译，促进胃癌细胞增殖和侵袭[32]。LncRNA BLACAT2通过吸附miR-193b-5p正调控METTL3，促进胃癌恶性进展[33]。最近有报道EB病毒（EBV）可产生多种环状RNA（circRNA），如ebv-circRPMS1与含KH结构域的RNA结合信号通路关联蛋白1（KHDRBS1）相互作用，将KHDRBS1招募到METTL3启动子促进METTL3表达，增加EB病毒感染的胃癌细胞增殖、迁移和侵袭，并抑制细胞凋亡[34]。这些研究提示靶向调控METTL3的非编码RNA也可能成为胃癌治疗的潜在分子靶标。
METTL14是RNA甲基转移酶复合物中的另一个核心分子，它与METTL3协同促进m6A修饰，发挥RNA结合支架、变构激活和增强METTL3催化活性的作用[7, 35]。有研究发现METTL14表达增强促使PI3K/AKT/mTOR和EMT通路失活，从而抑制胃癌细胞增殖和侵袭[36]。METTL14也能增强磷酸酶及张力蛋白同源物基因（PTEN）mRNA上的m6A修饰水平，维持PTEN mRNA的稳定，抑制胃癌生长和转移[37]。此外，METTL14介导LINC01320发生m6A修饰，LINC01320通过吸附miR-495-5p促进RAS癌基因家族蛋白RAB19的表达，促进胃癌细胞的增殖、迁移和侵袭[38]。METTL14介导CircORC5的m6A修饰可以抑制其表达，降低对miR-30c-2-3p吸附进而抑制富含脯氨酸AKT1底物蛋白（AKT1 substrate 1, AKT1S1）和真核翻译起始因子4B（eukaryotic translation initiation factor 4B, EIF4B）的表达，抑制胃癌生长和转移[39]。
WTAP作为m6A甲基转移酶复合物中的一个关键分子，其主要通过调节甲基转移酶复合物募集到RNA底物来稳定核心复合物并促进m6A修饰[9]。有研究发现WTAP可以抑制T淋巴细胞浸润，导致胃癌患者不良预后[40]。此外，WTAP介导己糖激酶2（hexokinase 2, HK2）3’-UTR附近的m6A修饰维护HK2 mRNA的稳定性，增强胃癌的糖酵解，促进胃癌发生发展[41]。
METTL16是第二个被鉴定出具有m6A甲基转移酶活性的蛋白，是一种独立于METTL3/METTL14复合物的“编码器”。研究发现METTL16介导细胞周期蛋白D1（cyclin D1）的m6A修饰促进其表达，加快胃癌细胞增殖[42]。
KIAA1429是新发现的m6A甲基化转移酶，其参与特定位点的m6A甲基转移酶复合物催化核心组分METTL3-METTL14-WTAP的募集[10]。KIAA1429与原癌基因蛋白/活化蛋白1抗体（c-Jun）的3’-UTR结合，以m6A非依赖性的方式稳定c-Jun mRNA和调节c-Jun的表达，促进胃癌发生[43]。KIAA1429也能催化LINC00958上的m6A修饰，并介导其与GLUT1 mRNA相互作用增加GLUT1 mRNA稳定性，促进胃癌细胞葡萄糖代谢和恶性进展[44]。可见，METTL3/14、WTAP、METT16及KIAA1429可能以复合物的形式存在共同调控下游分子的m6A修饰，影响胃癌的恶性进程。所以，利用多分子联合评估胃癌预后可能提高其预测效能，针对复合物的药物研发也将为胃癌治疗提供新思路。
1.2 m6A去甲基化酶FTO作为第一个被发现的m6A去甲基化酶，在胃癌中的表达显著上调，且FTO高表达与胃癌患者预后不良显著相关，可能作为胃癌诊断和预后评价的潜在分子标志物[45-46]。有研究发现FTO抑制下游靶基因同源盒蛋白B13（homeobox B13, HOXB13）的m6A修饰促进其表达，激活PI3K/AKT/mTOR信号通路，促进胃癌细胞的迁移、侵袭和增殖[47]。转录因子叉头框蛋白A2（forkhead box A2, FOXA2）与FTO基因启动子结合抑制其表达，降低MYC癌基因的m6A修饰水平，增强MYC mRNA的稳定性，促进胃癌进展[48]。此外，FTO以m6A修饰依赖的方式促进微囊蛋白1（caveolin-1, CAV-1）mRNA的降解，调节线粒体的分裂融合和代谢，促进胃癌生长和转移[49]。然而，也有少量研究报道FTO抑制胃癌细胞增殖、迁移和侵袭[50-51]。
ALKBH5是FTO的同源物，介导m6A的去甲基化，影响mRNA加工、出核和RNA代谢等多个过程[52]。研究发现ALKBH5结合并降低lncRNA NEAT1（nuclear paraspeckle assembly transcript 1, NEAT1）的m6A水平，促进胃癌转移[53]。髓鞘转录因子1激酶（protein kinase, membrane associated tyrosine/threonine 1, PKMYT1）是ALKBH5的下游靶基因，IGF2BP3通过识别和结合PKMYT1的m6A修饰位点维持其mRNA稳定性，促进胃癌侵袭和转移[54]。目前ALKBH5在胃癌中的系统研究还较少，其在胃癌恶性进展中的作用机制值得深入探索。
1.3 m6A阅读蛋白YTH家族蛋白通过特定RNA结构域以m6A依赖性方式识别和结合RNA，调控RNA的剪接、核输出、翻译和mRNA降解等过程[15]，其高表达与胃癌恶性进展和预后不良显著相关[55]。YTHDF1通过与翻译机制相互作用积极促进蛋白质合成[56]。YTHDF1促进卷曲蛋白家族受体7（frizzled drosophila homolog of 7, FZD7）翻译表达，激活Wnt/β-catenin信号通路从而促进胃癌的发生发展[57]。此外，YTHDF1能识别泛素特异性肽酶14（ubiquitin specific peptidase 14, USP14）mRNA上的m6A修饰，促进USP14翻译，增加胃癌生长和转移[58]。YTHDF2是最先被发现，也是研究最多的m6A阅读器蛋白，抑制叉头框基因C2（forkhead box proteinC2, FOXC2）的表达，从而抑制胃癌恶性进展，其可作为判断胃癌预后的分子标志物[59]。
2 N4-乙酰胞苷ac4C修饰主要存在于稳定且高丰度的转运RNA（transfer RNA, tRNA）和核糖体RNA（ribosome RNA, rRNA）上。N-乙酰基转移酶10（N-acetyltransferase 10, NAT10）是目前唯一被鉴定具有催化mRNA发生ac4C修饰的酶[60-61]。最近研究发现胃癌中NAT10高表达，且与胃癌患者不良预后相关。NAT10催化Ⅴ型胶原蛋白a1链（collagen type Ⅴ alpha 1 chain, COL5A1）mRNA上发生ac4C修饰，提高其mRNA稳定性和表达，促进胃癌细胞迁移和侵袭[62]。另有研究发现幽门螺杆菌可以诱导NAT10的表达，NAT10通过催化鼠双微体2（murine double minute 2, MDM2）mRNA上的ac4C修饰，促进其表达并介导P53泛素化降解，增加胃癌恶性进展[63]。目前关于ac4C修饰的生物学功能和调控机制研究尚在起步阶段，介导ac4C去乙酰化的酶以及特异识别ac4C修饰的阅读器蛋白还有待鉴定。
3 N6, 2’-O-二甲基腺苷N6, 2’-O-二甲基腺苷（N6, 2’-O-dimethyladenosine, m6Am）修饰是脊椎生物mRNA上一种含量丰富的RNA甲基化修饰，存在于mRNA的转录起始区域，通常mRNA的5’末端7-甲基鸟苷（m7G）帽子结构后的第一个2’-O-甲基腺苷（Am）会被催化为m6Am[64]。磷酸化CTD相互作用因子1（phosphorylated CTD interacting factor 1, PCIF1）是目前唯一被鉴定可以催化mRNA发生m6Am修饰的酶，能特异性识别mRNA上的m7G结构，发挥m6Am甲基转移酶活性作用[65]。最近研究发现m6Am修饰和PCIF1表达在胃癌中显著增加，而且PCIF1可以作为判断胃癌预后的独立风险因子。PCIF1促进跨膜蛋白9超家族成员1（transmembrane 9 superfamily member 1, TM9SF1）mRNA上m6Am修饰以抑制其mRNA翻译，抑制TM9SFl的蛋白表达，促进胃癌恶性发展[66]。目前，识别m6Am修饰的阅读器蛋白还未发现，m6Am的调控机制值得深入研究，其在胃癌恶性进程中的生物学作用还待阐明。
4 5-甲基胞嘧啶m5C修饰也是一种常见且重要的RNA修饰，在tRNA、rRNA和mRNA上广泛分布。m5C修饰可以调控RNA结构稳定、RNA加工和翻译效率以及mRNA出核等，与人类疾病的发生密切相关[67]。
NOP2/Sun甲基转移酶6（NOP2/Sun RNA methyltransferase 6, NSUN6）是一个特异催化tRNA-Thr和tRNA-Cys发生m5C修饰的甲基转移酶[67]。NOP2/Sun甲基转移酶2（NOP2/Sun RNA methyltransferase 2, NSUN2）可以增强周期依赖激酶抑制子1C（cyclin dependent kinase inhibitor 1C, CDKN1C）mRNA发生m5C修饰进而促进胃癌恶性进展[68]。小泛素样调节蛋白2/3（small ubiquitin like modifier 2/3, SUMO2/3）通过非共价键与NSUN2的SIM（236-240aa）结构域相互作用，调节其核转运，增加其致癌活性[69]。LncRNA-FOXC2-AS1介导NSUN2催化FOXC2 mRNA上发生m5C修饰，随后被Y-框结合蛋白1（Y-box binding protein 1, YBX1）识别促进FOXC2的表达，增加胃癌的恶性进展[70]，提示NSUN2可能成为胃癌诊断新的生物标志物及潜在的治疗靶点。目前m5C修饰调控肿瘤发生发展的作用机制研究还不够深入，这可能与m5C修饰在细胞中整体丰度不高有关，但是随着检测灵敏度的提高以及测序技术的改进，这一领域一定会有更多的发现。
5 小结与展望目前临床上治疗胃癌的可用靶点和药物较少、受众较窄。因此，深入研究调控胃癌发生发展关键分子的作用机制，评估其作为预测胃癌风险及预后的分子标志物和潜在治疗靶点的价值，将对制定胃癌防治策略具有重要意义。RNA修饰作为当前表观遗传学领域的研究前沿和热点，其相关基因和蛋白表达水平的变化有可能成为肿瘤分子诊断的潜在标志物，针对关键分子的药物研发可能为肿瘤临床靶向治疗提供新的思路。目前关于RNA新修饰的鉴定和功能研究正如火如荼地展开，其中m6A修饰作为丰度最高且研究较早的转录后修饰，调控包括胃癌在内的多个肿瘤发生发展，调节肿瘤的增殖、转移、侵袭、糖酵解、自噬和EMT等过程。
开发靶向RNA修饰相关蛋白的抑制剂用于癌症临床治疗已有突破，其中一些候选药物在临床前研究中显示出较好的疗效。例如FAO抑制剂大黄酸能够可逆性地结合FTO，竞争性阻止m6A底物的识别，增加mRNA的m6A修饰水平，抑制胃癌进展[51]。研究发现奥美拉唑可以诱导FTO失活，激活mTORC1信号通路，从而增强5-氟尿嘧啶、顺铂和紫杉醇对胃癌细胞的抗肿瘤效果[71]。mTOR抑制剂依维莫司靶向胃癌细胞中METTL3/miR-17-92/TMEM127和PTEN/mTOR信号通路，在METTL3高表达的肿瘤中抑制作用更为显著。一项Ⅱ期临床研究结果显示依维莫司对晚期胃癌患者显示出较好的疗效[72]。小分子抑制剂CS1（Bisantrene）和CS2（Brequinar）可以直接与FTO的酶促反应中心结合，阻断其与靶基因mRNA的结合，抑制其去甲基酶活性。CS1和CS2化合物具有广谱抗癌特性，并对多种实体瘤（乳腺癌、胰腺癌和胶质母细胞瘤）表现出显著的抑制效果[73]。但是由于METTL3广泛调控基因的表达，靶向METTL3药物的潜在不良反应也需要密切关注。
免疫治疗是当前肿瘤治疗的研究热点。微卫星不稳定型MSI-H患者在胃癌中占有一定的比例，这部分患者可在免疫治疗中获益。有研究发现，m6A修饰可能与MSI阳性胃癌患者免疫治疗的效果相关[74]，其机制研究也是未来一个新的研究方向。m6A修饰与PD-1/L1免疫疗法响应也显著相关，抑制FTO表达可以增强肿瘤细胞对INF-γ和抗PD-L1治疗敏感度[75]。研究提示m6A修饰参与调控肿瘤免疫微环境，在肿瘤免疫治疗中可能发挥重要作用。
RNA表观遗传研究的兴起扩展了我们对肿瘤病因学的认知。然而，在胃癌中m6A修饰的机制研究才刚刚起步，有许多问题还未完全阐明。例如，在胃癌发生发展的不同阶段，RNA修饰的变化特征，不同类型RNA修饰之间，是否存在相互影响尚不清楚，甲基化酶和去甲基化酶如何实现对不同靶RNA的准确调控，RNA修饰类型与表型之间的调控关系等。我们相信，随着对RNA修饰调控机制的深入研究，越来越多新型、特异、有效的RNA修饰抑制剂和激活剂有望被开发和批准用于临床，更好地造福肿瘤患者。
利益冲突声明:
所有作者均声明不存在利益冲突。
作者贡献：
徐佳雯：论文构思和撰写
王强：论文修改
王守宇：论文指导、修改和审校
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