Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, China.
Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, China.
Int J Biochem Cell Biol. 2024 Mar;168:106516. doi: 10.1016/j.biocel.2024.106516. Epub 2024 Jan 12.
In view of the tumor-inhibiting effect of α-santalol in various cancers and the role of E2F transcription factor 1 (E2F1) as an important target for anticancer research, this study investigates the relation between α-santalol and E2F1, as well as the effect of α-santalol on liver cancer progression and the corresponding mechanism. Concretely, liver cancer cells were treated with different concentrations of α-santalol. The IC value of α-santalol was determined using Probit regression analysis. Then, transcription factors that are targeted by α-santalol and differentially expressed in liver cancer were screened out. The clinicopathological impact of E2F1 and its targets were evaluated and predicted. The expressions of E2F1 and high-mobility group box 2 (HMGB2) and their correlation in the liver cancer tissues were analyzed by bioinformatics. The effects of E2F1 and HMGB2 on the biological characteristics of liver cancer cells were examined through loss/gain-of-function and molecular assays. With the extension of treatment time, the inhibitory effects of 10 μmol/L and 20 μmol/L α-santalol on cancer cell survival rate were enhanced (P < 0.001). E2F1 and HMGB2 were highly expressed and positively correlated in liver cancer tissues (P < 0.05). High E2F1 expression was correlated with large tumors and high TNM stages (P < 0.05). E2F1 knockdown promoted the effects of α-santalol on dose-dependently inhibiting viability, colony formation, invasion and migration (P < 0.05). Moreover, E2F1 knockdown reduced the IC value and HMGB2 level, while HMGB2 overexpression produced opposite effects. HMGB2 overexpression and E2F1 knockdown mutually counteracted their effects on the IC value and on the viability and apoptosis of α-santalol-treated liver cancer cells (P < 0.01). Collectively, blocking the E2F1/HMGB2 pathway enhances the intervention effects of α-santalol on the proliferation, migration and invasion of liver cancer cells.
鉴于 α-檀香醇在各种癌症中的抑瘤作用以及 E2F 转录因子 1（E2F1）作为抗癌研究的重要靶点，本研究探讨了 α-檀香醇与 E2F1 之间的关系，以及 α-檀香醇对肝癌进展的影响及其相应的机制。具体而言，用不同浓度的 α-檀香醇处理肝癌细胞。采用概率单位回归分析确定 α-檀香醇的 IC 值。然后筛选出 α-檀香醇靶向的转录因子和肝癌中差异表达的转录因子。评估和预测 E2F1 及其靶标的临床病理影响。通过生物信息学分析，分析肝癌组织中 E2F1 和高迁移率族蛋白 2（HMGB2）的表达及其相关性。通过基因敲除/过表达和分子检测研究 E2F1 和 HMGB2 对肝癌细胞生物学特性的影响。随着治疗时间的延长，10 μmol/L 和 20 μmol/L α-檀香醇对癌细胞存活率的抑制作用增强（P<0.001）。E2F1 和 HMGB2 在肝癌组织中高表达且呈正相关（P<0.05）。E2F1 高表达与肿瘤较大和 TNM 分期较高相关（P<0.05）。E2F1 敲低促进了 α-檀香醇依赖剂量抑制活力、集落形成、侵袭和迁移的作用（P<0.05）。此外，E2F1 敲低降低了 IC 值和 HMGB2 水平，而 HMGB2 过表达则产生相反的效果。HMGB2 过表达和 E2F1 敲低相互拮抗其对 IC 值以及 α-檀香醇处理肝癌细胞活力和凋亡的影响（P<0.01）。总之，阻断 E2F1/HMGB2 通路增强了 α-檀香醇对肝癌细胞增殖、迁移和侵袭的干预作用。
