Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
Hubei Key Laboratory of Tumour Biological Behaviours, Wuhan, China.
Clin Transl Med. 2022 Aug;12(8):e992. doi: 10.1002/ctm2.992.
Regulatory T (Treg) cells are important components of the tumour microenvironment (TME) that play roles in gastric cancer (GC) metastasis. Although tumour cells that undergo epithelial-mesenchymal transition (EMT) regulate Treg cell function, their regulatory mechanism in GC remains unclear.
The miR-192-5p was identified by examining three Gene Expression Omnibus GC miRNA expression datasets. RNA immunoprecipitation (RIP) and dual-luciferase reporter assays were conducted to identify interactions between miR-192-5p and RB1. The role of miR-192-5p/RB1 in GC progression was evaluated based on EdU incorporation, wound healing and Transwell assays. An in vitro co-culture assay was performed to measure the effect of miR-192-5p/RB1 on Treg cell differentiation. In vivo experiments were conducted to explore the role of miR-192-5p in GC progression and Treg cell differentiation.
MiR-192-5p was overexpressed in tumour and was associated with poor prognosis in GC. MiR-192-5p bound to the RB1 3'-untranslated region, resulting in GC EMT, proliferation, migration and invasion. MiR-192-5p/RB1 mediated interleukin-10 (IL-10) secretion by regulating nuclear factor-kappaBp65 (NF-κBp65), affecting Treg cell differentiation. NF-κBp65, in turn, promoted miR-192-5p expression and formed a positive feedback loop. Furthermore, in vivo experiments confirmed that miR-192-5p/RB1 promotes GC growth and Treg cell differentiation.
Collectively, our studies indicate that miR-192-5p/RB1 promotes EMT of tumour cells, and the miR-192-5p/RB1/NF-κBp65 signaling axis induces Treg cell differentiation by regulating IL-10 secretion in GC. Our results suggest that targeting miR-192-5p/RB1/NF-κBp65 /IL-10 may pave the way for the development of new immune treatments for GC.
调节性 T（Treg）细胞是肿瘤微环境（TME）的重要组成部分，在胃癌（GC）转移中发挥作用。尽管经历上皮-间充质转化（EMT）的肿瘤细胞调节 Treg 细胞功能，但它们在 GC 中的调节机制尚不清楚。
通过检查三个基因表达组学 GC miRNA 表达数据集，鉴定出 miR-192-5p。通过 RNA 免疫沉淀（RIP）和双荧光素酶报告基因测定鉴定 miR-192-5p 与 RB1 之间的相互作用。基于 EdU 掺入、划痕愈合和 Transwell 测定，评估 miR-192-5p/RB1 在 GC 进展中的作用。进行体外共培养测定以测量 miR-192-5p/RB1 对 Treg 细胞分化的影响。进行体内实验以探索 miR-192-5p 在 GC 进展和 Treg 细胞分化中的作用。
miR-192-5p 在肿瘤中过度表达，与 GC 的不良预后相关。miR-192-5p 与 RB1 的 3'-非翻译区结合，导致 GC EMT、增殖、迁移和侵袭。miR-192-5p/RB1 通过调节核因子-κBp65（NF-κBp65）介导白细胞介素-10（IL-10）的分泌，影响 Treg 细胞分化。NF-κBp65 反过来又促进 miR-192-5p 的表达，形成正反馈环。此外，体内实验证实 miR-192-5p/RB1 促进 GC 生长和 Treg 细胞分化。
总之，我们的研究表明 miR-192-5p/RB1 促进肿瘤细胞的 EMT，miR-192-5p/RB1/NF-κBp65 信号轴通过调节 IL-10 的分泌诱导 GC 中的 Treg 细胞分化。我们的结果表明，靶向 miR-192-5p/RB1/NF-κBp65/IL-10 可能为 GC 的新免疫治疗开辟道路。
