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

doi:10.12307/2025.514

Abstract

Abstract: 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.

Key words: gastric cancer, tumor microenvironment, exosomal miRNAs, angiogenesis, immune response, autophagy, drug resistance, diagnosis and treatment, prognosis, biomarker

CLC Number:

Wang Lei, Wang Baiyan, Zhou Chunguang, Ren Xiaoyun, Dai Yueyou, Feng Shuying. Role of different cell-derived exosomal miRNAs in progression, diagnosis, and prognosis of gastric cancer[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(25): 5434-5442.

Figures/Tables 3

2.2 外泌体及外泌体miRNAs的特征及生物学功能大量研究表明，外泌体在细胞间通讯中发挥重要作用，包括参与免疫反应、抗原呈递、细胞迁移、细胞分化以及调节远处转移位点等[14]。近年来研究证实，外泌体主要通过激活靶细胞上的细胞表面受体、与受体细胞质膜融合、内吞作用3种途径实现细胞间信号传递，在调节肿瘤微环境方面发挥着重要作用[15]。miRNAs是一类控制多个靶基因表达的、长度为19-25个核苷酸的短链miRNA，是基因表达的重要介质，其通过与蛋白质编码信使RNA配对指导基因表达，进而调控多种重要的生物学功能，如细胞的增殖、凋亡和分化等[16]。肿瘤细胞释放的外泌体miRNAs可以介导肿瘤微环境中的细胞表型变化，进而调控肿瘤细胞的生长、转移以及获得性耐药。肿瘤源性外泌体miRNAs可诱导肿瘤微环境异质性，而肿瘤微环境的改变又可促进肿瘤的发展[4]。胃癌细胞外泌体中含有丰富的miR-27a，它可以将正常成纤维细胞激活为癌相关成纤维细胞。将过表达miR-27a的HSF-1细胞与胃癌SGC-7901细胞共培养24 h后发现，与正常miR-27a组相比，过表达miR-27a组SGC-7901细胞生长速度更快，同时展现出显著的迁移与侵袭能力。体内实验发现，在注射过表达miR-27a的成纤维细胞后胃癌细胞发生了肺转移。这些作用可能与外泌体miR-27a通过抑制半胱氨酸和甘氨酸富集蛋白2表达，促进胃癌细胞的转移与侵袭有关[8]。基于外泌体miRNAs可在循环血浆和血清中被稳定地检测到，且在健康人群与胃癌患者中差异表达[17]，故外泌体miRNAs可作为胃癌不同临床分期、诊断及预后的潜在生物标志物，并为胃癌治疗提供新的潜在靶点。 2.3 外泌体miRNAs在胃癌发生发展中的作用机制 2.3.1 外泌体miRNAs与胃癌细胞凋亡凋亡是由多基因调控的程序性细胞死亡方式，外泌体miRNAs参与调控这一过程。在大多实体瘤中，M2极化型巨噬细胞在肿瘤相关巨噬细胞中占主导地位。M2极化型巨噬细胞由白细胞介素4及白细胞介素13激活，激活的M2极化型巨噬细胞衍生的外泌体miR-21可直接从M2型巨噬细胞转移至胃癌细胞中，通过下调胃癌细胞内肿瘤抑制基因磷酸酯酶与张力蛋白同源物(PTEN)水平，发挥抑制胃癌细胞凋亡作用[18]。低分化腺癌细胞BGC-823来源的外泌体高表达miR-15b-3p，在共培养体系中可转移至正常胃黏膜上皮细胞GES-1和中分化腺癌细胞SGC-7901中，通过调节DYNLT1/Caspase-3/9轴抑制受体细胞凋亡，并诱导GES-1细胞的恶性转化[19]。 miRNA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，不同细胞分泌的外泌体miRNAs具有不同的生物学功能。除了抑制细胞凋亡外，外泌体miRNAs还可诱导胃癌细胞凋亡。如胃癌细胞外泌体miR-122-5p可通过降低胃癌细胞内G蛋白偶联受体激酶2相互作用蛋白1(GIT1)水平诱导细胞凋亡，抑制胃癌细胞增殖[20]；胃癌细胞外泌体miR-101通过下调为髓样细胞白血病1(MCL1)诱导胃癌细胞凋亡，并通过下调锌指E-盒结合同源盒蛋白1(ZEB1)蛋白水平抑制胃癌细胞迁移和侵袭。在这里，miR-101及miR-122-5p在胃癌患者中表达水平下调，与胃癌发展呈负相关，见图4。miR-101抑制幽门螺杆菌相关胃癌细胞的生长，恢复miR-101a水平可能具有阻止由幽门螺杆菌引起的萎缩性胃炎癌前病变的潜力[21]。由此可见，外泌体miRNAs可通过靶向凋亡基因或影响信号转导来调节胃癌细胞凋亡，且不同外泌体miRNAs对胃癌细胞凋亡具有不同的作用。甄别不同来源外泌体中miRNAs的功能，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。"

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