肝细胞癌的整合泛素组特征分析
Integrated ubiquitomics characterization of hepatocellular carcinomas
影响因子:15.80000
分区:医学1区 Top / 胃肠肝病学1区
发表日期:2025 Jul 01
作者:
Xiao-Tong Lin, Yuan-Deng Luo, Cui Mao, Yi Gong, Yu Hou, Lei-Da Zhang, Yong-Peng Gu, Di Wu, Jie Zhang, Yu-Jun Zhang, De-Hong Tan, Chuan-Ming Xie
摘要
具有侵袭性的HCC患者治疗选择有限，因此需要更深入理解HCC的发病机制以改善治疗效果。基因组研究已提升我们对癌症生物学的认识，但HCC的泛素组特征尚未充分理解。我们旨在揭示HCC的泛素组特征，并提供可用于临床诊断或治疗的侵袭性HCC的临床特征生物标志物。对85例HCC患者的肿瘤及邻近正常肝组织进行了全面的蛋白质组、磷蛋白组和泛素组分析。结果显示，HCC中药物靶点CBR1-S151和CPNE1-S55过表达。COL4A1、LAMC1和LAMA4在预后不良患者中表达升高。磷蛋白组和泛素组分析揭示代谢与转移的交叉调控。泛素组预测了多样的预后信息，并明确了HCC亚型的特异性蛋白组特征。生物标志物TUBA1A、BHMT2、BHMT和ACY1表现出不同的泛素化水平，与高风险预后相关，提示靶向这些蛋白或其修饰形式可能有助于临床治疗。验证发现，TUBA1A K370去泛素化驱动严重HCC，并标记一种侵袭性亚型。TUBA1A K370去泛素化部分归因于蛋白激酶B介导的USP14激活。在HCC中，靶向AKT-USP14-TUBA1A复合物促进TUBA1A降解，并在体内阻断肝肿瘤发生。本研究丰富了HCC的泛素组签名、生物标志物及潜在治疗靶点的知识体系。
Abstract
Patients with aggressive HCC have limited therapeutic options. Therefore, a better understanding of HCC pathogenesis is needed to improve treatment. Genomic studies of HCC have improved our understanding of cancer biology. However, the ubiquitomic characteristics of HCC remain poorly understood. We aimed to reveal the ubiquitomic characteristics of HCC and provide clinical feature biomarkers of the aggressive HCC that may be used for diagnosis or therapy in the clinic.The comprehensive proteomic, phosphoproteomic, and ubiquitomic analyses were performed on tumors and adjacent normal liver tissues from 85 patients with HCC. HCCs displayed overexpression of drugable targets CBR1-S151 and CPNE1-S55. COL4A1, LAMC1, and LAMA4 were highly expressed in the disease free survival-poor patients. Phosphoproteomic and ubiquitomic features of HCC revealed cross talk in metabolism and metastasis. Ubiquitomics predicted diverse prognosis and clarified HCC subtype-specific proteomic signatures. Expression of biomarkers TUBA1A, BHMT2, BHMT, and ACY1 exhibited differential ubiquitination levels and displayed high prognostic risk scores, suggesting that targeting these proteins or their modified forms may be beneficial for future clinical treatment. We validated that TUBA1A K370 deubiquitination drove severe HCC and labeled an aggressive subtype of HCCs. TUBA1A K370 deubiquitination was at least partly attributed to protein kinase B-mediated USP14 activation in HCC. Notably, targeting AKT-USP14-TUBA1A complex promoted TUBA1A degradation and blocked liver tumorigenesis in vivo.This study expands our knowledge of ubiquitomic signatures, biomarkers, and potential therapeutic targets in HCC.