Cao Jun-Feng, Hang Kuan, Tan Chunlu, Wu Zuowei, Guo Ziheng, Men Jie, Tian Jin, Li Kezhou
College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan, China.
Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
Bioorg Chem. 2025 Aug;163:108729. doi: 10.1016/j.bioorg.2025.108729. Epub 2025 Jul 5.
Gastric adenocarcinoma is a highly aggressive malignant tumor characterized by a complex tumor microenvironment and significant degradation of extracellular matrix. Studies highlighted the critical role of MMP14 in tumor metastasis and cell proliferation within gastric adenocarcinoma. Furthermore, dihydroartemisinin has demonstrated a significant ability to reduce tumor invasiveness and promote apoptosis. However, the specific mechanism of dihydroartemisinin in gastric adenocarcinoma treatment remains unclear. This study investigated key targets of dihydroartemisinin and its signaling pathway through inhibiting tumor metastasis and promoting apoptosis in gastric adenocarcinoma.
The human gastric adenocarcinoma AGS cell was selected to establish cell experiments with CCK-8, V-FITC/PI and scratch assay in order to investigate effects of dihydroartemisinin on cell proliferation, apoptosis and migration. We screened differential gene targets by machine learning and bioinformatics analysis of GSE27342 and GeneCards database. RT-qPCR, survival analysis, pan-tumor analysis and immune infiltration analysis were also performed on the differential gene targets. The stability of dihydroartemisinin binding to key proteins was verified using computer simulations.
The results of cellular experiments showed that dihydroartemisinin at 10 μg/mL significantly inhibited proliferation and invasiveness and promoted apoptosis of AGS cells. Bioinformatics and machine learning analysis screened the key target MMP14. RT-qPCR revealed that dihydroartemisinin significantly inhibited the gene expression of MMP14. The results of molecular dynamics showed binding free energy of MMP14/Dihydroartemisinin was -30.61 ± 1.29 kcal/mol.
In this study, we found dihydroartemisinin not only reduced invasiveness of gastric adenocarcinoma cells by down-regulating MMP14 expression and interfering with degradation of extracellular matrix, but also promoted apoptosis by inducing activation of relevant apoptotic signaling pathways, thus effectively inhibiting the growth and progression of gastric adenocarcinoma.
胃腺癌是一种侵袭性很强的恶性肿瘤，其特征是肿瘤微环境复杂且细胞外基质显著降解。研究强调了基质金属蛋白酶14（MMP14）在胃腺癌肿瘤转移和细胞增殖中的关键作用。此外，双氢青蒿素已显示出显著降低肿瘤侵袭性和促进细胞凋亡的能力。然而，双氢青蒿素在胃腺癌治疗中的具体机制仍不清楚。本研究通过抑制胃腺癌的肿瘤转移和促进细胞凋亡来探究双氢青蒿素的关键靶点及其信号通路。
选择人胃腺癌AGS细胞，进行CCK-8、V-FITC/PI和划痕试验以建立细胞实验，从而研究双氢青蒿素对细胞增殖、凋亡和迁移的影响。我们通过对GSE27342和GeneCards数据库进行机器学习和生物信息学分析来筛选差异基因靶点。还对差异基因靶点进行了RT-qPCR、生存分析、泛肿瘤分析和免疫浸润分析。使用计算机模拟验证双氢青蒿素与关键蛋白结合的稳定性。
细胞实验结果表明，10μg/mL的双氢青蒿素显著抑制AGS细胞的增殖和侵袭性，并促进其凋亡。生物信息学和机器学习分析筛选出关键靶点MMP14。RT-qPCR显示双氢青蒿素显著抑制MMP14的基因表达。分子动力学结果显示MMP14/双氢青蒿素的结合自由能为-30.61±1.29kcal/mol。
在本研究中，我们发现双氢青蒿素不仅通过下调MMP14表达和干扰细胞外基质降解来降低胃腺癌细胞的侵袭性，还通过诱导相关凋亡信号通路的激活来促进细胞凋亡，从而有效抑制胃腺癌的生长和进展。
