不同细胞来源外泌体miRNAs在胃癌进展及诊断和预后中的作用

Role of different cell-derived exosomal miRNAs in progression,diagnosis,and prognosis of gastric cancer

背景:肿瘤微环境可通过多种途径参与胃癌的发生发展并促进胃癌化疗耐药,其中外泌体miRNAs介导的肿瘤微环境串话可诱导基质重编程,参与肿瘤异质性,并形成有利于肿瘤增殖、迁移、侵袭、免疫逃逸和化疗耐药的微环境。目的:对近年来外泌体miRNAs在胃癌微环境中的作用机制及其在胃癌诊断及预后评估中的应用进展作一综述。方法:以“Exosomal miRNAs,gastric cancer,angiogenesis,apoptosis,proliferation,migration,autophagy,invasion,immune response,chemotherapy resistance,biomarker”为英文检索词和“外泌体miRNAs,胃癌”为中文检索词分别检索PubMed及中国知网数据库。检索时限为2017-2024年。通过阅读文题及摘要进行初步筛选,排除研究内容相关性差及内容重复的文献,最终纳入77篇文献进行归纳探讨。结果与结论:①外泌体作为细胞间信息交流的重要载体,可携带miRNA等多种信息物质,通过激活靶细胞上的细胞表面受体、与受体细胞质膜融合及内吞作用3种途径实现细胞间信号传递。②外泌体miRNAs通过调节胃癌细胞增殖、凋亡、自噬、血管形成、侵袭转移、免疫应答以及耐药性的形成等多种途径,进而在胃癌进展中发挥着重要作用。③miRNA与靶mRNA相互作用及其调控网络广泛存在于肿瘤发生和人类癌症发展中,不同类型外泌体miRNAs对调控胃癌细胞凋亡具有不同的作用,鉴别不同外泌体miRNAs对胃癌细胞凋亡相关蛋白及通路的影响,合理运用其诱导剂或抑制剂可对胃癌细胞凋亡水平进行调控。④不同细胞来源的外泌体miRNAs通过将M1极化型巨噬细胞诱导为M2型,在肿瘤微环境的建立、血管生成、免疫应答及化疗耐药中扮演重要角色。⑤外泌体miRNAs广泛稳定存在于血液及其他体液中,其在胃癌患者中的差异性表达可作为胃癌患者诊断、预后及治疗依据。目前作为生物标志物研究较多的外泌体miRNAs包括miR-379-5p,miR-590-5p,miR-29s和miR-21等,其中miR-590-5p灵敏度与特异性分别为63.7%和86%,其表达水平与胃癌患者总体生存率、浸润深度密切相关。⑥设计外泌体miRNAs模拟物或抑制物,并利用纳米递送载体(如外泌体、脂质体)将其靶向递送至肿瘤部位以恢复miRNAs正常水平,可能是治疗胃癌的一种新策略。⑦虽然外泌体miRNAs在胃癌患者诊疗中具有很大的应用前景,但仍存在一些问题亟待解决,例如外泌体miRNAs的潜在靶点及作用机制尚未完全探讨,其有效性及安全性有待进一步确认;而且外泌体的提取及纯化缺乏标准化规模化制备流程等。

BACKGROUND:Tumor microenvironment can participate in the occurrence and development of gastric cancer and promote chemotherapy resistance in various ways.Among them,the tumor microenvironment crosstalk mediated by exosomal miRNAs can induce matrix reprogramming,participate in tumor heterogeneity,and form a microenvironment conducive to tumor proliferation,migration,invasion,immune escape,and chemotherapy resistance.OBJECTIVE:To review the mechanism of action of exosomal miRNAs in the microenvironment of gastric cancer and its application in the diagnosis and prognosis assessment of gastric cancer in recent years.METHODS:“Exosomal miRNAs,gastric cancer,angiogenesis,apoptosis,proliferation,migration,autophagy,invasion,immune response,chemotherapy resistance,biomarker”for English search terms and“exosomal miRNAs,gastric cancer”for Chinese search terms were searched in PubMed and CNKI databases.The search period was from 2017 to 2024.After preliminary screening by reading the title and abstract,the articles with poor correlation and repeated content were excluded,and 77 articles were finally included for induction and discussion.RESULTS AND CONCLUSION:(1)Exosomes,as important carriers of intercellular information exchange,can carry a variety of information substances such as miRNA,and realize intercellular signal transmission through three ways:activation of cell surface receptors on target cells,fusion with the plasma membrane of recipient cells,and endocytosis.(2)Exosomal miRNAs play an important role in the progression of gastric cancer by regulating the proliferation,apoptosis,autophagy,angiogenesis,invasion and metastasis,immune response,and the formation of drug resistance of gastric cancer cells.(3)The interaction between miRNAs and target mRNA and its regulatory network are widely found in tumorigenesis and human cancer development.Different types of exosomal miRNAs have different effects on the regulation of apoptosis of gastric cancer cells,and the effects of different exosomal miRNAs on apoptosis related proteins and pathways of gastric cancer cells are screened.Rational use of its inducers or inhibitors can regulate the apoptosis level of gastric cancer cells.(4)Exosomal miRNAs of different cell origin play an important role in the establishment of tumor microenvironment,angiogenesis,immune response,and chemotherapy resistance by inducing M1-polarized macrophages to M2 type.(5)Exosomal miRNAs exist extensively and stably in blood and other body fluids,and their differential expression in patients with gastric cancer can be used as a basis for diagnosis,prognosis,and treatment of patients with gastric cancer.Currently,exosomal miRNAs widely studied as biomarkers include miR-379-5p,miR-590-5p,miR-29s,miR-21,etc.Among them,the sensitivity and specificity of miR-590-5p are 63.7%and 86%,respectively.The expression level of miR-590-5p is closely related to the overall survival rate and the depth of invasion of gastric cancer patients.(6)The design of exosomal miRNAs mimics or inhibitors and their targeted delivery to the tumor site using nano-delivery vectors(such as exosomes and liposomes)to restore the normal level of miRNAs may be a new strategy for the treatment of gastric cancer.(7)Although exosomal miRNAs have great application prospects in the diagnosis and treatment of gastric cancer patients,there are still some problems to be solved.For example,the potential targets and mechanisms of exosomal miRNAs have not been fully explored,and their effectiveness and safety need to be further confirmed.The extraction and purification of exosomes lack standardized large-scale preparation processes.