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摘要:
环状RNA（circRNA）是一类单链非编码RNA，通过非经典剪接或反向剪接事件形成环状构象。最近，已在多种癌症中观察到circRNA的异常表达，且越来越多的研究提示circRNA通过多种分子机制不同程度地参与抑癌或促癌进程，表明它们在肿瘤的发生发展中发挥关键作用。本文系统总结了circRNA在消化系统恶性肿瘤中的功能和分子机制的最新研究进展，发现circRNA有望作为靶分子在未来消化系统癌症治疗领域得到进一步探索。
Abstract:Circular RNAs (circRNAs) are a class of single-stranded non-coding RNAs that form circular conformations through non-canonical splicing or reverse splicing events. Recently, aberrant expression of circRNA has been observed in several cancers. An increasing number of studies suggested that circRNA is involved in tumor suppression or tumor promotion to varying degrees through diverse molecular mechanisms, highlighting its key role in the occurrence and development of tumors. In this review, we systematically summarize the latest research progress on the function and molecular mechanism of circRNA in malignant tumors of the digestive system. circRNA is expected to be further explored as a target molecule in the treatment of digestive system cancers in the future.
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Key words:
- Circular RNA /
- Malignancies of the digestive system /
- Tumorigenesis /
- Biomarker /
- Prognosis
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0 引言
环状RNA（circRNA）是一类以pre-mRNA为模板经反向剪切后，通过3’和5’末端共价结合形成的环形RNA[1]。circRNA在遗传信息调控及生物体内复杂进程中展现出独特的角色，它们作为microRNA（miRNA）的海绵分子，深度参与基因转录的精细调节、非典型翻译机制如滚环式翻译，以及假基因形成的调控网络[2]。近年来，研究发现circRNA与一系列重大疾病如阿尔茨海默氏病、心血管疾病及恶性肿瘤的发生发展密切相关。尤其在癌症领域，circRNA的功能被揭示为影响肿瘤起始、进展的关键因素。本文综述了circRNA的特征、类型及其生物学功能，并概述了一系列最新的circRNA在消化系统恶性肿瘤的作用及分子机制研究，从而证实circRNA可以在消化系统恶性肿瘤中作为未来探索的新型生物标志物和治疗靶点。
1 circRNA的简介
1.1 circRNA的发现
circRNA是共价闭合的环状RNA分子。1979年，科学家们首次通过电子显微镜捕捉到了几种RNA病毒在特定变性环境下的环状形态图像[3]，这一发现预示着RNA结构学的新篇章。1986年，科学界在肝炎δ病毒（HDV）的研究中鉴定出了首个自然存在的环状RNA分子[4]，尽管当时对单链RNA如何形成环状结构的机制尚属未知领域，但这一发现被视作RNA研究进展的里程碑式事件。有假说提出，这些RNA末端的特殊“盘柄”结构可能是病毒RNA复制循环的启动平台[3,5]。随后的数年间，随着研究的深入，真核生物体内也陆续发现了更多circRNA的存在[6-8]，然而，关于这些环状RNA的确切生物学功能及其作用机制仍未被完全阐明。
长久以来，circRNA常被视作基因表达过程中的副产物，被误解为异常RNA剪接或转录噪音的残余，且其丰度被严重低估[9]。随着高通量测序技术的革新与生物信息学分析方法的精进，科学家们在多种生物体内挖掘出更多样化的circRNA种类。这一进展激发了研究者们对circRNA在疾病发生发展中潜在功能的深入探索[9]。2012年，Salzman等首次提出已知的非编码RNA中有极多数属于环状构象[10]。之后，Jeck等从蛋白质编码基因的外显子中鉴定出超过25 000种circRNAs[11]，揭示了外显子circRNA作为RNA剪接产物的丰富性、稳定性、保守性及非随机性，预示着它们在基因表达调控中的潜在关键角色[11]。Memczak等后续发现circRNA在动物基因组中的存在模式复杂多变，展现出高度的组织、细胞类型及发育阶段特异性[1]。这三项里程碑式的研究共同掀开了circRNA生物学研究的崭新篇章。
1.2 circRNA的亚型及功能
迄今为止，根据circRNA的生物发生方式，基本上确定了三个circRNA亚型[12]：外显子circRNA[13-14]；内含子[8]和外显子-内含子环状RNA[15]。此外，最新研究表明，存在一种由线粒体直接编码的circRNA，其生成机制不依赖于传统的RNA剪接过程，而是作为分子伴侣促进核内编码的蛋白质有效转运至线粒体内部[16]。
目前已知circRNA通过以下几种机制发挥生物学功能[12]：（1）充当miRNA海绵：某些circRNA在细胞中吸附miRNA起到miRNA海绵的作用，进而解除miRNA对其靶基因的抑制作用；（2）作为蛋白质海绵：circRNA通过结合某些蛋白影响其表达及定位；（3）编码小肽：某些circRNA具有开放阅读框，具有编码蛋白质的潜能；（4）定位于核内的circRNA参与调控基因的转录和RNA剪切过程；（5）circRNA在体内反转录后融合至基因组形成假基因。
2 cricRNA与消化系统恶性肿瘤
最近的证据表明，几乎所有的癌症都存在circRNA的异常表达，circRNA作为癌基因或抑癌基因在癌症发病机制中发挥不可或缺的作用[17]。circRNA已被揭示为调控癌细胞增殖、迁移、侵袭及凋亡过程的关键分子，其多样化的作用机制为癌症生物学研究提供了新视角[18-20]。鉴于癌症早期诊断对于患者预后的重要性，开发高效、特异的生物标志物成为迫切需求。circRNA以其与线性RNA截然不同的特性，例如组织或细胞特异性、发育阶段特异性、对RNase R的抗性以及更长的半衰期，提示circRNA可能作为临床治疗中潜在的靶向标志物。
2.1 食管癌
食管鳞癌（Esophageal squamous cell carcinoma, ESCC）在全球范围内的发病率与致死率均居高不下，构成了严重的公共卫生挑战。Shi等[18]证明circLPAR3在ESCC中上调，circLPAR3通过海绵miR-198激活RAS/MAPK和PI3K/Akt通路，从而促进ESCC细胞的迁移、侵袭和转移。Wang等[19]发现circ-LRP6与食管癌恶性临床病理特征和不良预后相关，circ-LRP6海绵化miR-182以缓解对原癌基因myc的抑制，从而促进食管癌进展。Zhang等[20]发现hsa_circRNA6448-14可能通过竞争性结合miR-455-3p促进细胞增殖、迁移、侵袭并抑制食管癌细胞凋亡。circRNA_001275在顺铂耐药的食管癌组织和细胞中显著上调，通过与miR-370-3p结合并上调Wnt7a的表达，促进了食管癌细胞的增殖、侵袭和对顺铂的耐药性[21]。Song等[22]利用GEO和TCGA的数据集构建了与食管癌相关的circRNA、miRNA和mRNA的调控网络，发现circRNA相关调控网络与免疫细胞浸润有关，为预测食管癌患者的临床结果和评估其免疫状态提供了一个circRNA相关的模型。
2.2 胃癌
胃癌是全球，尤其是中国恶性肿瘤相关死亡的主要原因之一[23]。在过去的几年里，circRNA被认为是胃癌临床治疗中潜在的靶点。Zhao等[24]发现了一种新的N6-甲基腺苷（m6A）修饰的circRNA—circPAK2，它在胃癌组织和转移性淋巴结组织中显著上调，circPAK2的高表达与胃癌淋巴结转移和预后不良呈正相关，有希望作为胃癌的治疗靶点和预后生物标志物。Xu等[25]发现circUSP1在胃癌组织和循环血液中表达增加，并与临床病理因素和不良预后相关。circSLC4A7在胃癌组织中高表达，促进了胃癌细胞增殖、侵袭和迁移，进一步研究发现通过circSLC4A7与HSP90相互作用激活NOTCH1信号通路，从而加速胃癌的干性和进展[26]。Dai等[27]发现circFGD4在人胃癌组织和细胞系中下调，进一步分析证实circFGD4作为miR-532-3p的海绵，可缓解miR-532-3p对其靶标腺瘤性结肠息肉病（Adenomatous polyposis coli, APC）基因的肿瘤促进作用。Huang等[28]的研究独立证实了circFN1在对顺铂治疗产生抗性的胃癌细胞及组织中呈现高表达状态，这一特征性改变与肿瘤的高侵袭性生物学行为紧密相关。Miao等[29]发现circ_0088300通过上调RNA结合蛋白BOLL促进线粒体代谢重编程促进胃癌生长和转移。Xing等[30]揭示了hsa_circ_0136666在胃癌中起致癌作用，其通过miR-375/PRKDC信号轴驱动PD-L1磷酸化，促进肿瘤细胞免疫逃逸。胃癌细胞的外泌体衍生的circATP8A1通过circATP8A1/miR-1-3p/STAT6轴诱导巨噬细胞M2极化和肿瘤进展，证实了circATP8A1是胃癌的潜在预后生物标志物和治疗靶点[31]。以上系列研究揭示了circRNA作为免疫靶点的新作用，并为增强抗PD-L1治疗胃癌的疗效提供了理论依据。
2.3 肝癌、胆管癌
肝细胞癌（Hepatocellular carcinoma, HCC）是最常见的原发性肝癌，是癌症相关性死亡的重要原因。研究发现circASH2通过介导核结合蛋白YBX1液相分离，从而靶向调控原肌球蛋白4（TPM4）的mRNA/pre-mRNA剪接过程，并诱导其发生无义介导的mRNA降解，最终改变肿瘤细胞的骨架结构以抑制HCC的侵袭和转移[32]。Wu等[33]发现circPETH-147aa可调节肝癌细胞代谢重编程，重塑免疫抑制微环境，从而促进肿瘤发展。机制研究表明，circPETH-147aa通过增加SLC43A2 mRNA的稳定性，导致细胞毒性CD8+ T细胞中甲硫氨酸和亮氨酸缺乏，从而损害抗肝细胞癌免疫。Han等[34]发现circMTO1在HCC中下调，并通过海绵化miR-9促进p21表达，进而抑制HCC进展。类似的研究还有，CircTRIM33-12通过海绵化miR-191上调TET1表达，导致HCC细胞中5-羟甲基胞嘧啶（5hmC）水平显著降低[35]。CircTMEM45A在体外和体内作为海绵分子与miR-665结合以解除其在HCC中对靶基因IGF2的降解作用[36]。除了ceRNA网络外，最近在HCC中还报道了通过与RNA结合蛋白相互结合发挥功能的circRNA。Wang等发现circRHOT1在HCC中显著上调，促进HCC的增殖和转移，且circRHOT1将TIP60募集到NR2F6启动子上，从而启动NR2F6转录[37]。据报道，CircRNAs还可以通过调节细胞干性影响癌症发生发展进程[38]。Zhu等研究发现circZKSCAN1可以竞争性地结合FMRP，抑制HCC中Wnt信号转导[39]。Sheng等通过高通量RNA测序技术（RNA-seq）在HCC中发现了一系列失调的circRNA[40]。
肝内胆管癌（Intrahepatic cholangiocarcinoma, ICC）是第二常见的原发性肝癌，近几十年来其发病率和死亡率持续上升[41]。近年的研究显示，多种circRNAs在胆管癌中表达异常，可能成为胆管癌的治疗靶点和预后生物标志物[42]。circPCNXL2一方面通过与STRAP相互作用，激活ERK信号通路，另一方面通过调节miR-766-3p/SRSF1轴，影响下游靶基因的表达，从而协同促进ICC的发生发展[43]，这为研究circRNA在胆管癌免疫微环境中的代谢重编程调控提供了借鉴。
2.4 胰腺癌
大多数胰腺癌患者诊断时已属晚期， 5年生存率较低。2020年，Wong等[44]证实circFOXK2在胰腺导管腺癌细胞和组织中显著上调。Guo等[45]发现circBFAR在胰腺导管腺癌患者组织中显著上调，circBFAR通过海绵吸附作用调控miR-34b-5p，进而上调间充质−上皮转化因子的表达，最终激活MET/PI3K/Akt信号通路，促进肿瘤细胞的增殖和转移。MET抑制剂PHA-665752可能会抑制circBFAR促肿瘤功能，这表明靶向circBFAR及相关信号通路可能是胰腺癌的潜在治疗手段[45]。有研究发现，hsa_circ_0001846通过海绵吸附miR-204-3p间接调节KRAS的表达，从而发挥其致癌作用，这一分子机制的阐明为后续研究提供了理论依据和潜在的靶点。CircRREB1作为一种致癌circRNA，在胰腺导管腺癌中显著上调，并与患者不良预后相关。分子机制研究表明，CircRREB1刺激PGK1诱导糖酵解并激活Wnt/β-catenin信号通路以维持胰腺癌的干性，表明circRREB1作为生物标志物和治疗靶点的潜力[46]。近期还报道了其他几种“可靶向”的circRNA，如hsa_circ_0001846和circPDAC在胰腺癌中的作用[47-48]。
2.5 结直肠癌
结直肠癌（Colorectal cancer, CRC）作为全球范围内发病率第三、致死率第二的癌症类型[49]，其发病机制与多种分子调控机制密切相关。研究表明circSKA3在CRC中显著上调，并通过特异性细胞基序元件在CRC细胞中存在。细胞基序元件也是circSKA3与SLUG相互作用的位点，抑制SLUG泛素化降解并促进CRC上皮-间充质转化，体内外实验表明，circSKA3促进CRC的增殖、侵袭和转移[50]。Zhang等[51]的研究揭示了has_circ_0000231在CRC肿瘤组织中的异常高表达，预示与患者不良预后相关；同时还阐明了其作为miR-375的海绵分子，促进细胞周期蛋白D2的累积，通过与IGF2BP3结合稳定该蛋白，共同驱动CRC进展的双重作用。另一方面，Li等[52]的研究揭示了has_circ_ITGA7在CRC中显著下调，通过海绵化miR-3187-3p间接上调ASXL1表达，抑制CRC的进展。Geng等[53]聚焦于hsa_circ_0009361，发现其在CRC中的低表达可通过竞争miR-582的结合，促进腺瘤性息肉病大肠杆菌2（APC2）的表达，进而抑制Wnt/β-catenin信号通路，为CRC治疗提供了新的分子靶标网络（hsa_circ_0009361/miR-582/Wnt/β-catenin）。circRNF216在CRC组织中的表达水平显著降低，具有潜在肿瘤抑制作用，其与miR-576-5p结合，降低了后者对靶基因ZC3H12C的抑制作用，进而降低N-cadherin的表达水平，通过上调ZC3H12C促进CD8+T细胞的浸润，最终抑制CRC的进展[54]。这一系列发现不仅深化了对circRNA在CRC中复杂调控机制的理解，还凸显了circRNA-miRNA调控网络在恶性肿瘤发生发展中的核心地位，为CRC的精准医疗提供了新的视角和策略。
3 结论与展望
在过去的几年里，环状RNA从“垃圾”到“宝藏”发生了戏剧性的转变。总的来说，在消化系统常见恶性肿瘤中，尽管目前部分研究揭示了circRNA在消化系统肿瘤发生发展过程中的重要调节功能，但关于circRNA在其中具体的调控途径研究有限，且仅在少数实体瘤中进行了circRNA表达谱的全面分析，circRNA表达谱与驱动癌基因突变之间的关系通常知之甚少。此外，缺乏单细胞水平和空间位置的circRNA表达数据。针对以上方面的研究对于理解circRNA功能以及推动未来生物标志物的开发至关重要。
Competing interests: The authors declare that they have no competing interests.利益冲突声明：所有作者均声明不存在利益冲突。作者贡献：姜玉娟：文章选题、资料收集与论文撰写田艳涛：选题设计、论文审校 -
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