探讨华蟾素通过c-Met信号通路抑制肝细胞癌的增殖与转移的机制

MA Ya-nan; JIANG Xue-mei; HU Xi-qi; WANG Ling; GAO Jian-jun; LIU Hui; QI Fang-hua; SONG Pei-pei; TANG Wei

doi:10.1007/s11655-024-4111-z

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探讨华蟾素通过c-Met信号通路抑制肝细胞癌的增殖与转移的机制

Original Article | Updated：2025-04-07

- 探讨华蟾素通过c-Met信号通路抑制肝细胞癌的增殖与转移的机制
- Cinobufacini Inhibits Survival and Metastasis of Hepatocellular Carcinoma via c-Met Signaling Pathway
- 中国结合医学杂志（英文版） 2025年31卷第4期页码：311-325
- Affiliations：
  
  1.Department of Gastroenterology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou (570311), China
  2.Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo (162-8655), Japan
  3.Central South University, Xiangya School of Medicine Affiliated Haikou Hospital, Haikou (570208), China
  4.Obstetrics and Gynecology Hospital, Fudan University, Shanghai (200011), China
  5.Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, Shandong Province (266021), China
  6.Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan (250021), China
  7.International Health Care Center, National Center for Global Health and Medicine, Tokyo (162-8655), Japan
  8.Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo (113-0033), Japan
- Author bio：
  
  Prof. QI Fang-hua, E-mail: qifanghua2006@126.com
  Prof. SONG Pei-pei, E-mail: psong@it.ncgm.go.jp;
- Funds：
  
  the National Natural Science Foundation of China(81960446;81603449);the 2023 Foreign Experts Program of Hainan Province of China(SQ2023WGZJ0002);the Natural Science Foundation of Hainan Province of China(823MS167);the Innovative Research Projects for Graduate Students of Hainan Medical University of China (2021)
- DOI：10.1007/s11655-024-4111-z
  中图分类号：
- 录用日期：2024-03-18，
  
  网络出版日期：2024-07-19，
  
  纸质出版日期：2025-04
- Accepted：
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探讨华蟾素通过c-Met信号通路抑制肝细胞癌的增殖与转移的机制[J]. 中国结合医学杂志（英文版）, 2025,31(4):311-325.

MA Ya-nan, JIANG Xue-mei, HU Xi-qi, et al. Cinobufacini Inhibits Survival and Metastasis of Hepatocellular Carcinoma via c-Met Signaling Pathway[J]. Chinese journal of integrative medicine, 2025, 31(4): 311-325.
探讨华蟾素通过c-Met信号通路抑制肝细胞癌的增殖与转移的机制[J]. 中国结合医学杂志（英文版）, 2025,31(4):311-325. DOI： 10.1007/s11655-024-4111-z.

MA Ya-nan, JIANG Xue-mei, HU Xi-qi, et al. Cinobufacini Inhibits Survival and Metastasis of Hepatocellular Carcinoma via c-Met Signaling Pathway[J]. Chinese journal of integrative medicine, 2025, 31(4): 311-325. DOI： 10.1007/s11655-024-4111-z.

摘要

目的:

研究华蟾素 (Cinobufacini

CINO) 在脱-γ-羧基凝血酶原 (Des-gamma-carboxy-prothrombin

DCP) 诱导的肝细胞癌 (Hepatocellular Carcinoma

HCC) 中的抗肿瘤作用

并阐明其可能的作用机制.

方法:

采用细胞计数试剂盒-8检测CINO对HCC细胞增殖的抑制作用

并利用流式细胞术分析细胞凋亡率. 通过免疫荧光和蛋白质印迹分析CINO处理后

与细胞生长、凋亡、迁移和侵袭相关的蛋白表达差异. 通过体内外实验验证CINO对HCC的治疗效果及其作用机制.

结果:

在DCP诱导下

CINO显著抑制HCC细胞增殖

诱导细胞凋亡

并抑制细胞迁移和侵袭. 此外

CINO在DCP诱导下调控c-Met的激活

以及磷脂酰肌醇-3激酶/蛋白激酶B (PI3K/AKT) 和丝裂原活化蛋白激酶激酶/细胞外信号调节激酶 (MEK/ERK) 信号通路的活化. 在HCC小鼠模型中

CINO可能通过抑制肿瘤组织中c-Met的磷酸化及其下游PI3K/AKT和MEK/ERK信号通路的活化

表现出显著的抗肿瘤作用.

结论:

在DCP诱导条件下

CINO可能通过靶向c-Met及PI3K/AKT和MEK/ERK信号通路

抑制HCC细胞生长

促进细胞凋亡

并抑制HCC细胞的侵袭和迁移

为HCC治疗提供潜在策略.

Abstract

Objective:

To investigate the anti-tumor effects of cinobufacini (CINO) on hepatocellular carcinoma (HCC) induced by des-gamma-carboxy-prothrombin (DCP) and to uncover the underlying mechanisms.

Methods:

The inhibitory effect of CINO on HCC cell proliferation was evaluated using the cell counting kit-8 method

and the apoptosis rate was quantified using flow cytometry. Immunofluorescence and Western blot analyses were used to investigate the differential expression of proteins associated with cell growth

apoptosis

migration

and invasion pathways after CINO treatment. The therapeutic potential of CINO for HCC was confirmed

and the possibility of combining cinobufacini with c-Met inhibitor for the treatment of primary HCC was further validated by

in vivo

experiments.

Results:

Under the induction of DCP

CINO inhibited the activity of HCC cells

induced apoptosis

and inhibited migration and invasion. Upon the induction of DCP

CINO regulated c-Met activation and the activation of the phosphatidylinositol-3 kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways. In a mouse model of HCC

CINO exhibited significant antitumor effects by inhibiting the phosphorylation of c-Met and the downstream PI3K/AKT and MEK/ERK pathways in tumor tissues.

Conclusions:

CINO inhibited HCC cell growth

promoted apoptosis

and suppressed HCC cell invasion and migration by targeting c-Met and PI3K/AKT and MEK/ERK signaling pathways under DCP induction.

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