miR-34a在胶质瘤化疗耐药中的研究进展.pdf

临床神经外科杂志2 0 2 3年第2 0 卷第5期581D0I:10.3969/j.issn.1672-7770.2023.05.020综述miR-34a在胶质瘤化疗耐药中的研究进展童彬,黄延林，田新华,刘忠，童俊江,孙瑾【摘要】胶质瘤是一种严重威胁人类健康的脑恶性肿瘤，因发现miR-34a在大脑中表达丰富,其在脑肿瘤领域的地位逐渐提高。miR-34a能调控胶质瘤相关基因的表达,参与胶质瘤形成，阐明miR-34a在胶质瘤中的作用机制，寻找到新的药物治疗靶点,对胶质瘤治疗极为重要。本文通过介绍miR-34a的生理特性、信号通路、替莫唑胺化疗耐药、化疗给药载体等方面的综述，总结了miR-34a在胶质瘤化疗耐药机制中的研究新进展并展望未来研究方向。【关键词】miR-34a；胶质瘤；化疗耐药；研究进展【中图分类号】R739.41Research progress of miR-34a in chemoresistance of glioma TONG Bin,HUANG Yanlin,TIAN Xinhua,et al.Department of Neurosurgery,Zhongshan Hospital Xiamen University,Xiamen 361004,ChinaCorresponding author:SUN JinAbstract:Glioma is a brain malignant tumor that seriously threatens human health.MiR-34a is found abundantin the brain,and its position in the field of brain tumors is gradually improved.MiR-34a can regulate the expressionof glioma related genes,participate in glioma formation,clarify the mechanism of miR-34a in glioma,and find newdrug therapeutic targets,which is very important for glioma treatment.By introducing the physiologicalcharacteristics,signal pathway,temozolomide chemoresistance and chemotherapeutic delivery vector of miR-34a,thispaper summarizes the new research progress of miR-34a in the mechanism of chemoresistance of glioma,and looksforward to the future research direction.Key words:miR-34a;glioma;chemoresistance;research progress胶质瘤是中枢神经系统最常见的恶性肿瘤，胶质母细胞瘤（glioblastoma,GBM)是胶质瘤中恶性程度最高的分型,因其高度恶性的生物学行为常导致疗效的不佳，患者预后极差;7 0%8 0%患者病程在3 6 个月,病程超过1年者仅10%。因为血脑屏障的存在和神经中枢强大的免疫监视系统,导致胶质瘤药物化疗非常困难。microRNA是一类高度保守的、小的、单链非编码RNA，已在各种癌症中被发现存在表达失调的现象。本文将目光聚焦于miR-34a，它是第一个被发现能被抑癌基因Tp53直接调控的microRNA,与胶质瘤的增殖、调亡密切相关,近期有多篇关于miR-34a在胶质瘤药物化疗耐药机制研究方面的文章，本文就miR-34a在胶质瘤化疗耐药中的研究进展进行综述,并探讨其在临床研究方面的应用前景。1miR-34a 生理特性miR-34s包含3个家族成员，miR-34a、m i R-34b 和miR-34c。m i R-34a 在脑中表达最高，位于染色体1q36.22,具有一个独特的序列转录区,特异于miR-34b和miR-34cl)。Srinivasan等2 研究黑腹果蝇发现miR-34通过抑制基金项目：国家青年科学基金资助项目（8 2 10 140 3）；厦门市医疗卫生指导性项目（350 2 Z20214ZD1045）作者单位：36 10 0 4厦门，厦门大学附属中山医院神经外科通信作者：孙瑾【文献标志码】A【文章编号】16 7 2-7 7 7 0(2 0 2 3)0 5-0 58 1-0 4H3K27me3表达增加SCA3神经毒性及通过调节TORC1的亚基3 UTR影响大脑中蛋白质稳态,因此miR-34是大脑衰老和神经变性的修饰剂，对调节蛋白质稳态和防治大脑衰老十分重要。2miR-34a在胶质瘤中化疗相关通路的研究进展2.1p53通路miR-34a受p53的直接调控，当细胞受到外来刺激,p53基因便被激活，以维持细胞内环境稳态。miR-34a被认为是p53的下游多个效应器中最重要的一个，它通过调控多种与肿瘤发生相关的细胞周期基因或癌基因,如细胞周期蛋白（cyclin，CCN）、周期蛋白依赖性激酶（cyclindependentkinase，C D K）、沉默信息调节因子（silentinformation regulator,SIRT）、Bc l-2 等多种基因,诱导 Go/G,期阻滞和肿瘤细胞凋亡，提高替莫唑胺（temozolomide,TMZ）化疗敏感性,从而达到肿瘤抑制作用3-6 1。miR-34a 还可通过抑制下游靶基因的表达反作用于p53，形成类似正反馈激活的闭环效应。Fan等7 研究发现,GBM 细胞中高表达的miR-34a通过抑制SIRT1对p53的去乙酰化,间接使p53产生乙酰化效应。目前研究发现,p53通路多态化参与调节胶质瘤的化疗耐药，如辐射暴露（脉冲电磁场）8 、相关基因敲除（TRIM32）【9 、药物联合使用（二甲双胍+TMZ）【10 等多种方式都能改善胶质瘤的TMZ化疗耐药。2.2?PD-L1 通路PD-L1 在肿瘤细胞中高表达,可以和免582疫T细胞表面的PD-1结合后抑制机体的免疫应答,因此阻断PD-1/PD-L1通路可恢复机体的抗肿瘤免疫达到治疗肿瘤的效果。有研究发现与正常脑组织相比 GBM组织标本中miR-34a水平较低，但PD-L1表达水平较高，两者表达水平呈负相关 。miR-34a的异位表达可以拮抗PD-L1 的作用，从而抑制 GBM细胞增殖,促进了细胞周期在G,/S期停滞及调亡,并提高对紫杉醇的化疗敏感性。2.3Wnt通路Wnt信号通路由Wnt和膜蛋白受体结合激活细胞表面受体,从而将胞外信号传递到胞内。Ma等12 1发现p53突变的 GBM中突变p53丧失调节miR-34a表达的功能,却可通过直接与WNT6mRNA的3 UTR结合来抑制WNT6的转录，导致WNT信号传导的激活,并最终引起WNT介导的TMZ化疗耐药。这一改变可通过提高mir-34a的表达而被逆转。2.4?DRD4/Akt/mTOR通路Wen等13 研究开发了一种新的5-(2 ,4-二氟苯基)-水杨酰苯胺衍生物，称为LCC-09,发现该小分子物质可透过血脑屏障进入细胞，通过增加miR-34a和解除DRD4/Akt/mTOR信号轴来抑制胶质母细胞的生物活性和治疗耐药性表型。2.5其他可能信号通路2.5.1Notch通路Notch1作为Notch家族的一员，广泛参与细胞增殖、分化和调亡过程,在肿瘤发生、侵袭和转移中发挥重要作用。研究发现，基于由miR-34a-5p介导的负向调控模块M2受体具有干扰Notch-1/ECFR信号通路的能力14。过度表达的circNFIX在胶质瘤中通过海绵miR-34a-5p降低miR-34a-5p对Notchl信号通路的调节作用，从而影响 GBM 细胞的生物学行为15。Pan 等16 在研究胰腺癌发病机制时发现,miR-34a通过抑制胰腺癌干细胞中的 Notch1信号通路提高胰腺癌细胞对吉西他滨化疗敏感度16 ，这些证据都表明Notch通路具有改善胶质瘤化疗耐药的潜力。2.5.2细胞内活性氧ROS通路ROS通路积极参与调节肿瘤细胞的生长、增殖和凋亡。有研究发现,miR-34a通过增强ROS和NOX2表达诱导人胶质瘤细胞系A172细胞凋亡,证实胶质瘤细胞存在 ROS 通路17 。Chen 等18 发现,敲低SIRT1或SIRT1抑制剂可以显著提高CBM细胞对 TMZ治疗的敏感性,虽未明确指出miR-34a的存在,但基于现有研究可大胆推测miR-34a在ROS通路中起关键作用。3miR-34a与胶质瘤TMZ化疗耐药研究TMZ是一种DNA烷基化抗肿瘤药,目前是胶质瘤最常用化疗药物，能起到延缓肿瘤进展、延长患者生存期等作用，但TMZ的治疗效能因肿瘤的化学耐药性而受到限制,这已成为治疗神经胶质瘤的主要障碍。内源性竞争RNA（c o mp e t i n g e n d o g e n o u s,Ce R NA）是指通过应答元件竞争性结合microRNA导致microRNA的基因沉默。Shree 等19 发现lncRNA-MUF作为miR-34a的CeRNA靶向TCF-调节smad2/3磷酸化及 snail1的表达，得出结论敲低lncRNA-MUF可以减少胶质瘤细胞增殖、迁移和侵袭，提高TMZ化疗敏感性。高迁移率族蛋白A2（h i g h mo b i l i t y g r o u p p r o t e i n s，J Clin Neurosurg,October 2023,Vol.20,No.5HMGA2)可促进胶质瘤的活性、侵袭性和肿瘤发生。研究发现HMGA2在胶质瘤细胞中的表达显著上调,并且与胶质瘤分级和预后不良呈正相关2 0 。Ma等2 指出,miR-34a-5p是HMGA2的上游调节分子，miR-34a-5p靶向降低HMGA2表达抑制神经胶质瘤细胞的增殖、迁移和侵袭,并增强了TMZ介导的对体外胶质瘤细胞活性和体内胶质瘤异种移植生长的抑制作用,HMGA2水平降低，miR-34a-5p水平升高。4miR-34a与胶质瘤化疗耐药给药载体的研究4.1纳米载体血脑屏障是中枢神经系统内的天然结构，然而其存在限制了药物递送的效果。Khan等2 2 研发了基于三向连接的RNA纳米颗粒，搭载miR-34a的纳米颗粒优先被位于血管周围区域的GBM 细胞吸收,随后细胞将miR-34a包人细胞外囊泡，通过旁分泌转移到肿瘤的其余部分，最终使miR-34a在整个肿瘤组织内发挥作用,以此抵消GBM细胞对 TMZ的耐药。Shatsberg等2 3 为克服miRNA的体内递送问题,设计了基于聚甘油支架的聚合物纳米凝胶（nanogel,NG）,用 NG-miR-34a纳米多链处理的U-87MG显示出miR-34a下游靶基因显著的下调,从而调节细胞凋亡和细胞周期停滞,并诱导抑制细胞增殖和迁移。同样,Ofek等2 4 开发了阳离子载体系统树突状聚甘油胺(dPG-NH2）。m i R NA-34a 与 dPG-NH2结合后,显著提高了自身的稳定性、细胞内运输和活性,并能够穿过血脑屏障,疗效明显优于传统方式，且无明显的毒性迹象。纳米载体在穿透血脑屏障到达病灶区释放药物方面起到了十分有效的作用，然而其给药方式、药物扩散及纳米材料代谢方面仍需进一步研究。4.2生物载体介导改善胶质瘤化疗耐药外泌体通过转运各种生物分子介导肿瘤微环境中的细胞间通讯而被熟知，由于其纳米级大小,可以穿过血脑屏障,防止miR-34a降解,减少其与细胞结构的相互作用,使肿瘤细胞最大限度地摄取miR-34a,改善细胞内环境，提高肿瘤化疗敏感性，外泌体具有良好的生物载体潜力2 5。Wang等2 6 发现富集miR-25的外泌体能转移并靶向FBXW7促进胶质母细胞瘤细胞的增殖和TMZ耐药性。最近Benecke 等2 7 的研究指出由于外泌体的结构功能特性，不仅有资格成为获得更好的肿瘤分子解析的重要工具,而且还可以作为专门针对恶性肿瘤细胞的治疗工具。Aili 等2 8 也指出,外泌体能通过其中所含的microRNA的特性影响胶质瘤的生物学行为，如增殖、侵袭、血管生成、肿瘤代谢、免疫微环境、自噬、化疗耐药等。Wang等2 9 用miR-34a模拟物转染骨髓间充质干细胞分泌的外泌体，体外、体内检测均发现含miR-34a的外泌体抑制GBM细胞的增殖、侵袭、迁移和肿瘤发生，同时通过沉默MYCN促进GBM细胞对TMZ的化疗敏感性。5miR-34a在改善胶质瘤干细胞耐药的研究胶质母细胞瘤的耐药性和复发可能归因于胶质瘤干细胞（glioma stem cell,GSC)的存在,通过规避死亡信号和诱导细胞再聚集而在放疗和化疗中存活。Sun 等30 通过培养临床神经外科杂志2 0 2 3年第2 0 卷第5期U87胶质瘤细胞株发现,miR-34a可以抑制U87GSCs增殖并诱导凋亡。随后Rathod等31 发现，miR-34a通过靶向Akt和Wnt信号通路抑制胶质瘤干细胞的细胞增殖。Wen等13 还在其实验中发现LCC-09携带的miR-34a 能逆转 GCSs 的TMZ 耐药性。另外,Guessous 等32 指出miR-34a 能抑制CSCs并诱导干细胞分化的观点。该观点被Jin等33 探究GSCs转分化为血管内皮细胞的实验中，发现了miR-34a作为GSC分化诱导剂的潜力,并同样可以改变GCS的TMZ耐药性。6总结和展望miR-34a可能是胶质瘤患者个性化治疗的重要靶点，因为在胶质瘤中miR-34a的靶基因数量有限,故而它的上调表达只会影响一定数量的信号通路，这使它的作用是针对且易控的,这是一个重要的优势。并且随着生物纳米材料开发和外泌体方面取得的进展,使得穿透血脑屏障达到病灶部位给药的困难大大减少。因此,基于miR-34a的克服化疗耐药作用机制和穿透血脑屏障的载体结合的药物递送体系,研发设计以miR-34a为核心的改善肿瘤耐药的药物，可以联合应用化疗、靶向治疗或免疫治疗等药物，在患者出现药物耐药后或预见性使用可以尽可能减少患者因耐药而增加化疗药物剂量或种类而造成的药物毒副作用，降低胶质瘤耐药性并达到增强抗肿瘤疗效的目的,从而有望达到延长患者生存时间，提高患者生存质量，提升患者幸福指数。本文为胶质瘤治疗带来新的见解，相信随着对miR-34a的不断研究将为胶质瘤化疗耐药治疗提供更多的指导和帮助。利益冲突：所有作者均声明不存在利益冲突。参考 文献1 Wang C,Jia QJ,Guo XJ,et al.MicroRNA-34 family:frommechanism to potential applications J.Int J Biochem Cell Biol,2022,144(3):106168.2Srinivasan AR,Tran TT,Bonini NM.Loss of miR-34 in Drosophiladysregulates protein translation and protein turnover in the agingbrainJ.Aging Cell,2022,21(3):e13559.3Hermeking H.p53 enters the microRNA world J.Cancer Cell,2007,12(5):414-418.4He L,He XY,Lowe SW,et al.MicroRNAs join the p53 networkanother piece in the tumour-suppression puzzle J.Nat 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