Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Molecular Cell Biology & Toxicology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
Clin Transl Med. 2022 May;12(5):e780. doi: 10.1002/ctm2.780.
Cisplatin resistance is the main cause of poor clinical prognosis in patients with gastric cancer (GC). Yet, the exact mechanism underlying cisplatin resistance remains unclear. Recent studies have suggested that exocrine miRNAs found in the tumor microenvironment participate in tumor metastasis and drug resistance.
Exosomes isolated from BGC823 and BGC823/DDP culture medium were characterized by transmission electron microscopy and differential ultracentrifugation, and miRNA expression profiles of BGC823 and BGC823/DDP cells derived exosomes were analyzed using miRNA microarray. In vivo and in vitro assays were used to identify roles of exosomal miR-769-5p and clarify the mechanism of exosomal miR-769-5p regulated the crosstalk between sensitive and resistant GC cells.
In this study, we found that cisplatin-resistant GC cells communicated with the tumor microenvironment by secreting microvesicles. MiR-769-5p was upregulated in GC tissues and enriched in the serum exosomes of cisplatin-resistant patients. The biologically active miR-769-5p could be integrated into exosomes and delivered to sensitive cells, spreading cisplatin resistance. Underlying cellular and molecular mechanism was miR-769-5p targeting CASP9, thus inhibiting the downstream caspase pathway and promoting the degradation of the apoptosis-related protein p53 through the ubiquitin-proteasome pathway. Targeting miR-769-5p with its antagonist to treat cisplatin-resistant GC cells can restore the cisplatin response, confirming that exosomal miR-769-5p can act as a key regulator of cisplatin resistance in GC.
These findings indicate that exosome-transmitted miR-769-5p confers cisplatin resistance and progression in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53. These findings reveal exosomal miR-769-5p derived from drug-resistant cells can be used as a potential therapeutic predictor of anti-tumor chemotherapy to enhance the effect of anti-cancer chemotherapy, which provides a new treatment option for GC.
顺铂耐药是胃癌（GC）患者临床预后不良的主要原因。然而，顺铂耐药的确切机制尚不清楚。最近的研究表明，肿瘤微环境中发现的外泌体 miRNA 参与肿瘤转移和耐药。
通过透射电子显微镜和差速超速离心法对 BGC823 和 BGC823/DDP 培养上清液中分离的外泌体进行了表征，并使用 miRNA 微阵列分析了 BGC823 和 BGC823/DDP 细胞衍生的外泌体中的 miRNA 表达谱。通过体内和体外实验鉴定了外泌体 miR-769-5p 的作用，并阐明了外泌体 miR-769-5p 调节敏感和耐药 GC 细胞之间串扰的机制。
在这项研究中，我们发现顺铂耐药的 GC 细胞通过分泌微泡与肿瘤微环境进行通讯。miR-769-5p 在 GC 组织中上调，并富集在顺铂耐药患者的血清外泌体中。具有生物活性的 miR-769-5p 可以整合到外泌体中，并传递给敏感细胞，从而传播顺铂耐药性。潜在的细胞和分子机制是 miR-769-5p 靶向 CASP9，从而抑制下游 caspase 途径，并通过泛素-蛋白酶体途径促进凋亡相关蛋白 p53 的降解。用其拮抗剂靶向 miR-769-5p 治疗顺铂耐药 GC 细胞可以恢复顺铂的反应，证实外泌体 miR-769-5p 可以作为 GC 中顺铂耐药的关键调节剂。
这些发现表明，外泌体传递的 miR-769-5p 通过靶向 CASP9 并促进 p53 的泛素化降解，赋予胃癌顺铂耐药性和进展。这些发现揭示了来自耐药细胞的外泌体 miR-769-5p 可作为抗肿瘤化疗的潜在治疗预测因子，以增强抗癌化疗的效果，为 GC 提供了一种新的治疗选择。
