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中国癌症防治杂志

中国癌症防治杂志 ›› 2025, Vol. 17 ›› Issue (2): 164-171.doi: 10.3969/j.issn.1674-5671.2025.02.06

• 论著 • 上一篇    下一篇

胶原交联介导的细胞外基质重塑在肝细胞癌去分化中的作用#br# 机制及临床意义

  

  1. 广西医科大学第一附属医院检验科；广西医科大学基因组与个体化医学研究中心；广西医科大学第一附属医院肝胆外科；4.广西医科大学附属肿瘤医院肝胆胰腺外科
  • 出版日期:2025-04-25 发布日期:2025-05-15
  • 通讯作者: 王秋雁 E-mail：wangqiuyan@gxmu.edu.cn； 陶玉婷 E-mail：tytxzxh@126.com
  • 基金资助:
    国家自然科学基金项目（82403412）；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

Mechanism and clinical significance of collagen crosslinking-mediated extracellular matrix remodeling in hepatocellular carcinoma dedifferentiation


  • Online:2025-04-25 Published:2025-05-15

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摘要： 目的 探讨细胞外基质（extracellular matrix,ECM）重塑对肝细胞癌（hepatocellular carcinoma,HCC）预后的影响及潜在分子机制。方法 纳入2018年至2019年于广西医科大学附属肿瘤医院接受肝切除术的116例HCC患者的组织标本及临床资料。采用非负矩阵分解法对患者进行分子分型。采用全转录组测序数据分析并探讨分型患者的临床意义及分子特征。利用成像质谱技术分析胶原交联状态和肿瘤细胞的蛋白组学特征。从GEO（The Gene Expression Omnibus）数据库获取10例HCC单细胞测序数据，使用Monocle2结合CytoTRACE方法分析肿瘤细胞分化轨迹和状态。结果 成功将HCC患者分为S1（n=25）和S2（n=91）两种亚型。相较于S2型HCC患者，S1型患者预后更差，甲胎蛋白水平（P<0.001）、巴塞罗那临床肝癌分期（P=0.040）及微血管侵犯发生率（P=0.010）均更高。转录组结果表明，S1型HCC呈显著的ECM重塑和胶原信号活跃特征。S1型HCC的Type2和Type3交联模式的胶原比例更高（P<0.001），且ECM机械转导通路活性增强。S1型HCC肿瘤组织肝细胞标志物表达降低，干细胞和胆管细胞标志物增加，呈现去分化状态，且表现出E⁃钙粘蛋白降低和波形蛋白增加的侵袭性表型（均P<0.001）。其中，YAP和Hippo信号通路的关键调控因子高表达与患者预后不良显著相关。结论 S1亚型HCC预后较差，其特征为胶原过度交联和基质刚度增强，并通过激活YAP信号通路促进肿瘤细胞去分化。

关键词:  , 肝细胞癌；细胞外基质；胶原交联；机械力；YAP信号通路

Abstract: Objective To investigate the effects of extracellular matrix (ECM) remodeling on the prognostic of in hepatocellular carcinoma (HCC) and explore its potential molecular mechanisms. Methods Tissue specimens and clinical data from 116 HCC patients who underwent hepatectomy in Guangxi Medical University Cancer Hospital from 2018 to 2019 were included. Non⁃negative matrix factorization (NMF) was performed for molecular subtyping. Bulk RNA sequencing (bulk RNA⁃seq) data analyzed to investigate the clinical significance and molecular characteristics of the patients with different molecular subtyping. Imaging mass cytometry (IMC) was employed to analyze the collagen cross⁃linking status and tumor proteomic profiles. Single⁃cell transcriptome sequencing (scRNA⁃seq) data from 10 cases of HCC were obtained from the Gene Expression Omnibus (GEO) database, and the differentiation trajectory and state of tumor cells were analyzed using the Monocle2 algorithm in conjunction with the CytoTRACE method. Results HCC patients were successfully stratified into 2 subtypes: S1 (n=25) and S2 (n=91). Compared with S2,  S1 subtype patients demonstrated poorer prognosis, with higher alpha⁃fetoprotein levels (AFP, P<0.001), advanced Barcelona Clinic Liver Cancer (BCLC) stage (P=0.040), and increased microvascular invasion (MVI) incidence (P=0.010). Transcriptomic analysis revealed significant ECM remodeling and collagen signaling activation in S1 HCC. S1 HCC subtype exhibited significantly higher proportions of Type2 and Type3 collagen crosslinking patterns （P<0.001）, and enhanced mechanotransduction pathway activity. S1 HCC tissues displayed decreased expression of hepatocyte markers but increased stem cell and cholangiocyte markers, indicating a dedifferentiation state. These tumors also showed aggressive phenotypes characterized by E⁃cadherin downregulation and vimentin upregulation (all P<0.001). High expression of key regulators of the YAP and Hippo signaling pathways were significantly associated with poor prognosis of patients. Conclusions The S1 HCC subtype demonstrates poor prognosis, characterized by excessive collagen crosslinking and increased matrix stiffness, which facilitates tumor cell dedifferentiation by activating the YAP signaling pathway.

Key words: Hepatocellular carcinoma, Extracellular matrix, Collagen, Mechanical force, YAP signaling pathway

中图分类号: 

  • R735.7