| 杨 震,赵志杰,冯宗妹,张春和,曹永生.葫芦巴碱调节HIF-1α/VEGF信号通路对非小细胞肺癌增殖、迁移和侵袭能力的影响[J].现代生物医学进展英文版,2024,(18):3429-3436. |
| 葫芦巴碱调节HIF-1α/VEGF信号通路对非小细胞肺癌增殖、迁移和侵袭能力的影响 |
| Effects of Trigonelline on the Proliferation, Migration and Invasion of Non-Small Cell Lung Cancer by Regulating HIF-1α/VEGF Signaling Pathway |
| Received:March 06, 2024 Revised:March 28, 2024 |
| DOI：10.13241/j.cnki.pmb.2024.18.005 |
| 中文关键词: 葫芦巴碱 HIF-1α/VEGF信号通路 非小细胞肺癌 细胞增殖 细胞迁移 细胞侵袭 |
| 英文关键词: Trigonelline HIF-1α/VEGF signaling pathway Non small cell lung cancer Cell proliferation Cell migration Cell invasion |
| 基金项目:河北省卫生健康委科研项目（20220323） |
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| 中文摘要: |
| 摘要 目的：探究葫芦巴碱（TRG）调节缺氧诱导因子-1α（HIF-1α）/血管内皮生长因子（VEGF）信号通路对非小细胞肺癌（NSCLC）细胞增殖、迁移和侵袭能力的影响。方法：（1）体外实验：将NSCLC细胞株（A549）随机分为对照组（Control组，正常培养）、TRG低浓度组（TRG-Low组，25 μM）、TRG高浓度组（TRG-High组，50 μM）、TRG高浓度+HIF-1α激活剂二甲基草酰甘氨酸组（TRG-High+DMOG组，50 μM TRG+10 μM DMOG）。分别采用细胞计数试剂盒-8（CCK-8）法、细胞划痕实验以及转移小室（Transwell）实验检测各组细胞的增殖能力、迁移能力以及侵袭能力。（2）体内实验：将60只SPF级雄性Rowett裸鼠随机分为正常组（NC组）、原位NSCLC模型组（Model组），TRG低剂量组（TRG-Low组，40 mg/kg TRG）、TRG高剂量组（TRG-High组，80 mg/kg TRG）和TRG高剂量+DMOG组（TRG-High+DMOG组，80 mg/kg TRG+40 mg/kg DMOG），TRG、DMOG采用腹腔注射的方式，每组12只。实验结束后摘取各组大鼠肺部组织进行肺重量指数和肿瘤总负荷的测量。苏木精-伊红（HE）染色观察各组大鼠肺部病理学变化；原位末端标记法（TUNEL）实验评估肺组织中的细胞凋亡率；免疫印迹实验（Western Blot）实验检测各组大鼠肺组织中HIF-1α、VEGF、细胞周期蛋白D1（cyclinD1）、E-钙黏蛋白（E-cadherin）、波形蛋白（Vimentin）的表达。结果：（1）体外实验：TRG-Low组和TRG-High组A549细胞存活率、细胞迁移率和细胞侵袭数目显著低于Control组（P＜0.05）。TRG-High+DMOG组A549细胞存活率、细胞迁移率和细胞侵袭数目显著高于TRG-High组（P＜0.05）。（2）体内实验：Model组大鼠肺重量指数、肿瘤总负荷、HIF-1α、VEGF、CyclinD1、Vimentin蛋白表达显著高于NC组（P＜0.05），细胞凋亡率、E-cadherin蛋白表达显著降低（P＜0.05），肺组织病理损伤严重，有明显NSCLC病灶；TRG-High组大鼠肺重量指数、肿瘤总负荷、HIF-1α、VEGF、CyclinD1、Vimentin蛋白表达显著低于Model组（P＜0.05），细胞凋亡率、E-cadherin蛋白表达水平显著高于Model组（P＜0.05），肺组织病理学损伤减轻，NSCLC病灶减小。DMOG减轻了TRG对NSCLC的抑制作用（P＜0.05）。结论：TRG可能在体内外通过抑制HIF-1α/VEGF信号通路抑制NSCLC细胞增殖、迁移和侵袭以阻止NSCLC进展。 |
| 英文摘要: |
| ABSTRACT Objective: To investigate the effects of trigonelline (TRG) on the proliferation, migration and invasion of non-small cell lung cancer (NSCLC) cells by regulating hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway. Methods: (1) In vitro experiments: NSCLC cell lines (A549) were randomly divided into control group (Control group, normal culture), TRG low concentration group (TRG-Low group, 25 μM), TRG high concentration group (TRG-High group, 50 μM), TRG high concentration+HIF-1α activator dimethyloxalylglycine group (TRG-High+DMOG group, 50 μM TRG+10 μM DMOG). The proliferation, migration and invasion abilities of cells in each group were detected by Cell Counting Kit-8 (CCK-8) method, cell scratch assay, and transfer the chamber (Transwell), respectively. (2) In vivo experiment: 60 SPF male Rowett nude mice were randomly divided into normal group (NC group), in situ NSCLC model group (Model group), TRG low dose group (TRG-Low group, 40 mg/kg TRG), TRG high dose group (TRG-High group, 80 mg/kg TRG) and TRG high dose+DMOG group (TRG-High+DMOG group, 80 mg/kg TRG+40 mg/kg DMOG), TRG and DMOG were injected intraperitoneally, with 12 mice in each group. The lung tissue in each group of rats was taken for lung weight index and total tumor load measurement at the end of the experiment. The pathological changes of lung in each group were observed by hematoxylin-eosin (HE) staining. The apoptosis rate in lung tissue was evaluated by in situ end labeling (TUNEL) assay. The expression of HIF-1α, VEGF, cyclin D1 (cyclinD1), E-cadherin (E-cadherin) and vimentin (Vimentin) in lung tissue of rats in each group were detected by immunoblot experiments (Western Blot). Results: (1) In vitro experiments: The survival rate, cell migration rate and cell invasion number of A549 cells in TRG-Low group and TRG-High group were significantly lower than those in control group (P<0.05). The survival rate, cell migration rate and cell invasion number of A549 cells in TRG-High+DMOG group were significantly higher than those in TRG-High group(P<0.05). (2) In vivo experiment: The lung weight index, total tumor load, HIF-1α, VEGF, CyclinD1 and Vimentin protein expression in Model group were significantly higher than those in NC group(P<0.05), and the apoptosis rate and E-cadherin protein expression were significantly decreased (P<0.05). The pathological damage of lung tissue was serious, and there were obvious NSCLC lesions. The lung weight index, total tumor load, HIF-1α, VEGF, CyclinD1 and Vimentin protein expression in TRG-High group were significantly lower than thoes in Model group(P<0.05), the apoptosis rate and E-cadherin protein expression level were significantly higher than those in Model group (P<0.05), the pathological damage of lung tissue was reduced, and the NSCLC lesions were reduced. DMOG alleviated the inhibitory effect of TRG on NSCLC (P<0.05). Conclusion: TRG may inhibit the proliferation, migration and invasion of NSCLC cells by inhibiting the HIF-1α/VEGF signaling pathway in vitro and in vivo to prevent progression of NSCLC. |
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