GI Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Curr Med Sci. 2023 Oct;43(5):935-946. doi: 10.1007/s11596-023-2715-8. Epub 2023 Oct 13.
Gastrointestinal stromal tumors (GISTs) can rapidly proliferate through angiogenesis. Previous studies indicated the potential influence of microRNA on the progression of tumor immature angiogenesis. This study aimed to explore the specific mechanism by which microRNA-409-5p (miR-409-5p) contributes to GIST.
To identify genes potentially involved in the development and progression of GIST, the differences of miR-409-5p between tumors and adjacent tissues were first analyzed. Following this analysis, target genes were predicted. To further investigate the function of miRNA in GIST cells, two GIST cell lines (GIST-T1 and GIST882) were transfected with lentiviruses that stably expressed miR-409-5p and scrambled miRNA (negative control). Later, the cells were subjected to Western blotting and ELSA to determine any differences in angiogenesis-related genes.
In GISTs, there was a decrease in the expression levels of miR-409-5p compared to the adjacent tissues. It was observed that the upregulation of miR-409-5p in GIST cell lines effectively inhibited the proteins hypoxia-inducible transcription factor 1β (HIF1β) and vascular endothelial growth factor A (VEGF-A). Further investigations revealed that miR-409-5p acted as an inhibitor of angiogenesis by binding to the 3'-UTR of Lysine-specific demethylase 4D (KDM4D) mRNA. Moreover, the combination of miR-409-5p with imatinib enhanced its inhibitory effect on angiogenesis.
This study demonstrated that the miRNA-409-5p/KDM4D/HIF1β/VEGF-A signaling pathway could serve as a novel target for the development of therapeutic strategies for the treatment of imatinib-resistance in GIST patients.
胃肠道间质瘤（GIST）可通过血管生成快速增殖。先前的研究表明，microRNA 对肿瘤不成熟血管生成的进展有潜在影响。本研究旨在探讨 microRNA-409-5p（miR-409-5p）促进 GIST 的具体机制。
为了确定可能参与 GIST 发生和进展的基因，首先分析了肿瘤和相邻组织之间 miR-409-5p 的差异。在此分析之后，预测了靶基因。为了进一步研究 miRNA 在 GIST 细胞中的功能，使用稳定表达 miR-409-5p 和 scramble miRNA（阴性对照）的慢病毒转染了两种 GIST 细胞系（GIST-T1 和 GIST882）。随后，通过 Western blot 和 ELSA 检测血管生成相关基因的差异。
与相邻组织相比，GIST 中 miR-409-5p 的表达水平降低。结果表明，GIST 细胞系中 miR-409-5p 的上调有效抑制了缺氧诱导转录因子 1β（HIF1β）和血管内皮生长因子 A（VEGF-A）的蛋白表达。进一步研究表明，miR-409-5p 通过与赖氨酸特异性去甲基酶 4D（KDM4D）mRNA 的 3'-UTR 结合，作为血管生成的抑制剂。此外，miR-409-5p 与伊马替尼联合使用增强了其对血管生成的抑制作用。
本研究表明，miRNA-409-5p/KDM4D/HIF1β/VEGF-A 信号通路可作为治疗伊马替尼耐药 GIST 患者的新的治疗策略的靶点。
