II 期酶配体的异质性控制人胃癌类器官作为干细胞治疗模型的进展。
Heterogeneity of Phase II Enzyme Ligands on Controlling the Progression of Human Gastric Cancer Organoids as Stem Cell Therapy Model.
发表日期:2023 Nov 02
作者:
Deng-Chyang Wu, Chia-Chen Ku, Jia-Bin Pan, Kenly Wuputra, Ya-Han Yang, Chung-Jung Liu, Yi-Chang Liu, Kohsuke Kato, Shigeo Saito, Ying-Chu Lin, Inn-Wen Chong, Michael Hsiao, Huang-Ming Hu, Chao-Hung Kuo, Kung-Kai Kuo, Chang-Shen Lin, Kazunari K Yokoyama
来源:
Stem Cell Research & Therapy
摘要:
胃癌 (GC) 类器官经常用于检查细胞增殖和死亡以及癌症的发展。采用侵袭/迁移测定、异种移植和活性氧 (ROS) 产生来检查抗氧化药物,包括紫苏醛 (PEA)、肉桂醛 (CA) 和萝卜硫素 (SFN) 对 GC 的影响。 PEA 和 CA 抑制人 GC 类器官的增殖,而 SFN 则增强其增殖。用 PEA 和 CA 处理后,Caspase 3 活性也受到抑制。此外,PEA 和 CA 治疗可抑制肿瘤形成和侵袭活性,而 SFN 治疗可增强肿瘤形成和侵袭活性。三维 (3D)-GC 类器官的这些结果显示了 2D-GC 细胞中 II 相酶配体的不同癌症发展。 PEA 和 CA 处理后,ROS 产生以及 TP53、核因子红细胞 2 相关因子 (NRF2) 和 Jun 二聚蛋白 2 的表达也下调,但 SFN 则没有下调。 NRF2 敲除逆转了这些抗氧化剂药物对 3D-GC 类器官侵袭活性的影响。此外,PEA 和 CA 处理也抑制了 ROS 的产生,但 SFN 则没有。因此,NRF2 在这些抗氧化药物对 3D-GC 类器官中癌症进展的不同影响中发挥着关键作用。 PEA 和 CA 可能成为 GC 的新抗肿瘤疗法。
Gastric cancer (GC) organoids are frequently used to examine cell proliferation and death as well as cancer development. Invasion/migration assay, xenotransplantation, and reactive oxygen species (ROS) production were used to examine the effects of antioxidant drugs, including perillaldehyde (PEA), cinnamaldehyde (CA), and sulforaphane (SFN), on GC. PEA and CA repressed the proliferation of human GC organoids, whereas SFN enhanced it. Caspase 3 activities were also repressed on treatment with PEA and CA. Furthermore, the tumor formation and invasive activities were repressed on treatment with PEA and CA, whereas they were enhanced on treatment with SFN. These results in three-dimensional (3D)-GC organoids showed the different cancer development of phase II enzyme ligands in 2D-GC cells. ROS production and the expression of TP53, nuclear factor erythroid 2-related factor (NRF2), and Jun dimerization protein 2 were also downregulated on treatment with PEA and CA, but not SFN. NRF2 knockdown reversed the effects of these antioxidant drugs on the invasive activities of the 3D-GC organoids. Moreover, ROS production was also inhibited by treatment with PEA and CA, but not SFN. Thus, NRF2 plays a key role in the differential effects of these antioxidant drugs on cancer progression in 3D-GC organoids. PEA and CA can potentially be new antitumorigenic therapeutics for GC.