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中国癌症防治杂志

中国癌症防治杂志 ›› 2025, Vol. 17 ›› Issue (1): 40-47.doi: 10.3969/j.issn.1674-5671.2025.01.05

• 基础研究 • 上一篇    下一篇

敲低MCM5 对乳腺癌细胞增殖、侵袭、迁移及凋亡的影响

  

  1. 广西医科大学基因组与个体化医学研究中心；广西医科大学再生医学与医用生物资源开发应用省部共建协同创新中心；广西医科大学附属肿瘤医院肝胆外科
  • 出版日期:2025-02-25 发布日期:2025-03-06
  • 通讯作者: 王秋雁 E?mail：wangqiuyan@gxmu.edu.cn; 陶玉婷 E?mail：taoyuting@gxmu.edu.cn
  • 基金资助:
    国家自然科学基金项目（82260569）；广西自然科学基金项目（2024GXNSFBA010037）；广西医科大学一流学科创新驱动人才计划

Effects of MCM5 knockdown on proliferation,migration and apoptosis of breast cancer cells

  • Online:2025-02-25 Published:2025-03-06

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摘要：

目的 探讨Yes相关蛋白（Yes⁃associated protein，YAP）信号激活与肝细胞癌（hepatocellular carcinoma，HCC）患者临床特征的关联性，并分析YAP信号通过重塑细胞外基质（extracellular matrix，ECM）促进HCC进展的潜在分子机制。 方法 收集2018年5月至2019年7月在广西医科大学附属肿瘤医院接受肝切除术的116例HCC患者的组织样本及临床病理数据。基于YAP上调基因集，采用基因集变异分析方法对患者进行分型。采用转录组测序分析探讨YAP信号激活的临床意义及分子特征，并在癌症基因组图谱数据库的HCC队列中进行验证。从基因表达综合数据库下载10例HCC单细胞测序数据，分析YAP高评分肿瘤细胞的分子特征，利用CellChat算法研究YAP高评分肿瘤细胞与成纤维细胞之间的相互作用机制。结果 YAP高评分组的总生存期显著短于YAP低评分组（P<0.001），并与更多的微血管侵犯（P<0.001）、高艾德蒙森分级（P=0.005）、高巴塞罗那肝癌分期（P=0.008）相关。YAP高评分是HCC患者总生存期的独立危险因素（HR=2.467，95%CI：1.121~5.429，P=0.025）。差异基因分析显示，YAP高评分组上调基因显著富集于ECM相关信号通路。单细胞分析结果显示，ECM刚度促进肌成纤维细胞（myCAF）中的YAP信号激活，进一步升高纤维化相关基因表达，加速ECM沉积与重塑。此外，CellChat分析显示，myCAF通过COL1A1/COL1A2⁃CD44配体⁃受体轴特异性激活肿瘤细胞中的YAP信号。结论 YAP信号激活与HCC患者不良预后密切相关。YAP诱导myCAF分泌促纤维化相关基因增强ECM刚度，并通过COL1A1/COL1A2⁃CD44轴进一步激活肿瘤细胞YAP信号，形成正反馈循环。

关键词: 肝细胞癌, 细胞外基质, Yes相关蛋白, 刚度

Abstract: Objective To investigate the association between Yes⁃associated protein (YAP) signaling activation and the clinical characteristics of patients with hepatocellular carcinoma (HCC), and to analyze the potential molecular mechanism by which YAP signaling promotes HCC progression through extracellular matrix (ECM) remodeling. Methods The tissue samples and clinicopathological data of 116 HCC patients who underwent liver resection at the Guangxi Medical University Cancer Hospital from May 2018 to July 2019 were included. Patients were classified based on a YAP upregulated gene set using gene set variation analysis method. Transcriptomic sequencing was performed to investigate the clinical significance and molecular characteristics of YAP signaling activation, with validation conducted using the HCC cohort from The Cancer Genome Atlas database. Single⁃cell RNA sequencing data from 10 HCC samples were obtained from the Gene Expression Omnibus database, and molecular characteristics of malignant cells with high YAP scores were analyzed, and CellChat algorithm was employed to investigate the interaction mechanism between high YAP malignant cells and fibroblasts. Results The overall survival of patients in the high YAP score group was significantly shorter than that of the low YAP score group (P<0.001). Additionally, the high YAP score group was associated with a higher prevalence of microvascular invasion (P<0.001), advanced Edmondson grading (P=0.005), and advanced Barcelona Clinic Liver Cancer staging (P=0.008). High YAP score was an independent risk factor for overall survival in HCC patients (HR=2.467, 95%CI: 1.121-5.429, P=0.025). Differential gene expression analysis revealed that up⁃regulated genes in the high YAP score group were significantly enriched in ECM⁃related signaling pathways. Single⁃cell analysis revealed that ECM stiffness promoted YAP signaling activation in myofibroblast⁃like cancer⁃associated fibroblasts (myCAF), further enhanced the expression of fibrosis⁃related genes and accelerated ECM deposition and remodeling. Additionally, CellChat analysis demonstrated that myCAF specifically activated YAP signaling in malignant cells via the COL1A1/COL1A2⁃CD44 ligand⁃receptor axis. Conclusions YAP signaling activation was strongly associated with poor prognosis in HCC patients. It induced myCAF to secrete fibrosis⁃related genes, increasing ECM stiffness, which in turn further activated YAP signaling in malignant cells via the COL1A1/COL1A2⁃CD44 axis, forming a positive feedback loop.

Key words: Hepatocellular carcinoma, Extracellular matrix, Yes?associated protein, Stiffness

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