Department of Gastrointestinal Surgery, the Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, Jiangsu 225300, China.
Department of Gastrointestinal Surgery, the Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, Jiangsu 225300, China.
Phytomedicine. 2024 Nov;134:155962. doi: 10.1016/j.phymed.2024.155962. Epub 2024 Aug 15.
Vasculogenic mimicry (VM) is a novel model for supplying blood to multiple tumors, including gastric cancer (GC), and is a potential target for its treatment. Dihydroartemisinin (DHA) is a potential natural antitumor substance that inhibits the progression of tumors in many ways. The research aimed to evaluate the impact of DHA on VM formation and its mechanisms. The IC50 of DHA, DHA's effect on proliferation, invasion, and migration in GC cells and VM formation in both cell and animal models were determined through wound healing, MTT, EdU, colony formation, and Transwell assays. Genomics was employed to identify genes related to DHA inhibition of VM formation, and to analyze their relationship to VM formation. qRT‒PCR and western blot (WB) analysis were carried out to analyze the changes in protein and mRNA levels after DHA treatment and the changes in VM-associated protein biomarkers after blocking target gene-related pathways. The mechanism by which DHA inhibits VM in GC was elucidated in vivo. DHA reduced the invasion, proliferation, and migration of GC cells and inhibited VM in cells and in vivo. A total of 220 DEGs were identified in the DHA-treated HGC-27 cells. Among the 146 downregulated genes, fibroblast growth Factor 2 (FGF2) was most closely associated with angiogenesis and VM. The level of FGF2 in GC tissues with VM was markedly greater than in VM lacking tissues. Treatment with DHA or FGFR1 blockade suppressed VM formation and reduced VM-related biomarker proteins. DHA suppressed tumor progression and VM formation by reducing FGF2 in xenograft mouse models. Per our knowledge, this is the first study to demonstrate the inhibitory effect of DHA on VM, providing a novel strategy for the treatment of GC.
血管生成拟态（VM）是为包括胃癌（GC）在内的多种肿瘤提供血液供应的新模型，也是其治疗的潜在靶点。二氢青蒿素（DHA）是一种潜在的天然抗肿瘤物质，可通过多种方式抑制肿瘤的进展。本研究旨在评估 DHA 对 VM 形成的影响及其机制。通过划痕愈合、MTT、EdU、集落形成和 Transwell 测定，确定 DHA 的 IC50、DHA 对 GC 细胞增殖、侵袭和迁移以及细胞和动物模型中 VM 形成的影响。采用基因组学方法鉴定与 DHA 抑制 VM 形成相关的基因，并分析其与 VM 形成的关系。qRT-PCR 和 Western blot（WB）分析用于分析 DHA 处理后蛋白和 mRNA 水平的变化，以及阻断靶基因相关通路后与 VM 相关的蛋白生物标志物的变化。在体内阐明了 DHA 抑制 GC 中 VM 的机制。DHA 降低了 GC 细胞的侵袭、增殖和迁移，并抑制了细胞和体内的 VM。在 DHA 处理的 HGC-27 细胞中鉴定出 220 个差异表达基因。在 146 个下调基因中，成纤维细胞生长因子 2（FGF2）与血管生成和 VM 最密切相关。具有 VM 的 GC 组织中 FGF2 的水平明显高于缺乏 VM 的组织。DHA 或 FGFR1 阻断治疗抑制了 VM 形成，并降低了 VM 相关生物标志物蛋白。DHA 通过降低异种移植小鼠模型中的 FGF2 来抑制肿瘤进展和 VM 形成。据我们所知，这是首次证明 DHA 对 VM 的抑制作用的研究，为 GC 的治疗提供了一种新策略。
