蟾毒灵通过阻断egfr介导的RAS-RAF-MEK-ERK通路激活抑制肝细胞癌的进展。

IF 12.8 1区 医学 Q1 ONCOLOGY
Jingwen Liu, Jia Jiang, Ju Huang, Zhi-E Fang, Lexi Liu, Yong Liu, Weiqi Nian, Jianyuan Tang, Zhilei Wang
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引用次数: 0

摘要

背景:肝细胞癌(HCC)仍然是最具挑战性的恶性肿瘤之一,尽管在诊断和治疗策略方面取得了多学科的进展,但其长期生存预后一直很差。Cinobufacini制剂作为HCC综合治疗策略的辅助治疗剂已引起越来越多的关注。蟾毒灵(BF)是蟾毒杆菌中的有效成分,因其有效的抗肿瘤作用而受到广泛关注。然而,其抗肿瘤作用的精确分子机制仍不完全清楚。方法:进行临床回顾性队列分析,以确定Cinobufacini在改善HCC患者治疗结果方面的明确临床益处。基于这些临床见解,我们实施了多维方法来阐明由Cinobufacini的生物活性成分BF介导的抗hcc分子机制。结果:西药联合Cinobufacini对HCC患者的总生存期(OS)和无进展生存期(PFS)均有改善趋势。此外,我们的探索性分析表明潜在的剂量-反应关系,即更长时间的累积暴露于Cinobufacini似乎与改善的临床结果相关。体外实验表明,BF能显著抑制HepG2和HCCLM3细胞活力和增殖,诱导细胞凋亡。网络药理学分析鉴定出20个核心靶点,分子对接发现BF与EGFR、GRB2、SRC、MAPK1等关键蛋白具有高亲和力结合。肝细胞癌组织芯片证实了EGFR和GRB2在肝细胞癌组织中的过表达。进一步的机制研究表明,BF抑制egfr介导的HepG2和HCCLM3中RAS/RAF/MEK/ERK通路的激活。BF干预可显著降低C57BL/6小鼠皮下肝癌异种移植和BALB/c裸鼠原位肝癌异种移植模型的肿瘤体积。此外,BF抑制了肿瘤组织中EGFR、RAF、MEK和ERK的磷酸化水平,进一步证实了其对RAS/RAF/MEK/ERK信号通路的抑制作用。结论:我们的观察数据表明,HCC患者使用Cinobufacini与OS和PFS的有利趋势之间存在潜在关联。BF通过干扰egfr介导的RAS/RAF/MEK/ERK信号通路对HCC发挥抗肿瘤作用。这些发现不仅阐明了BF抗肿瘤作用的分子机制,而且强调了Cinobufacini制剂作为HCC治疗的一种有价值的选择的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Bufalin inhibits hepatocellular carcinoma progression by blocking EGFR-mediated RAS-RAF-MEK-ERK pathway activation.

Background: Hepatocellular carcinoma (HCC) remains one of the most challenging malignancies with persistently dismal long-term survival outcomes despite multidisciplinary advances in diagnostic and therapeutic strategies. Cinobufacini preparations have garnered increasing attention as adjunctive therapeutic agents in integrated management strategies for HCC. Bufalin (BF), the active ingredient in Cinobufacini, has garnered substantial attention due to its potent antitumor effects. However, the precise molecular mechanisms underlying its antitumor actions remain incompletely characterized.

Methods: A clinical retrospective cohort analysis was conducted to establish the definitive clinical benefit of Cinobufacini in improving treatment outcomes among HCC patients. Building upon these clinical insights, a multi-dimensional approach was implemented to elucidate the anti-HCC molecular mechanisms mediated by the bioactive component BF of Cinobufacini.

Results: Western medical treatment combined with Cinobufacini shows an improving trend in the overall survival (OS) and progression free survival (PFS) of HCC patients. Moreover, our exploratory analysis suggests a potential dose-response relationship where longer cumulative exposure to Cinobufacini appears to be associated with improved clinical outcomes. In vitro experiments demonstrated that BF significantly inhibited cell viability and proliferation, and induced apoptosis in HepG2 and HCCLM3. Network pharmacology analysis identified 20 core targets, and molecular docking revealed high-affinity binding between BF and key proteins, including EGFR, GRB2, SRC, and MAPK1. HCC tissue microarrays confirmed the overexpression of EGFR and GRB2 in HCC tissues. Further mechanistic investigations revealed that BF suppressed the EGFR-mediated RAS/RAF/MEK/ERK pathway activation in HepG2 and HCCLM3. BF intervention significantly reduced tumor volumes in C57BL/6 mouse subcutaneous HCC xenograft and BALB/c Nude mouse orthotopic HCC xenograft models. Moreover, BF inhibited the phosphorylation levels of EGFR, RAF, MEK, and ERK in tumor tissues, further corroborating its inhibitory effects on the RAS/RAF/MEK/ERK signaling pathway.

Conclusions: Our observational data suggest a potential association between Cinobufacini use and favorable trends in OS and PFS among HCC patients. BF exerts its antitumor effects against HCC by interfering with the EGFR-mediated RAS/RAF/MEK/ERK signaling pathway. These findings not only elucidate the molecular mechanisms underlying the antitumor actions of BF but also highlight the potential of Cinobufacini preparations as a valuable therapeutic option for HCC.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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