侵袭性肝细胞癌 (HCC) 患者的治疗选择有限。因此，需要更好地了解 HCC 发病机制以改善治疗。 HCC 的基因组研究提高了我们对癌症生物学的理解。然而，人们对 HCC 的普遍特征仍知之甚少。我们的目的是揭示 HCC 的泛素组学特征，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。对来自 85 个肿瘤和邻近正常肝组织进行了全面的蛋白质组学、磷酸化蛋白质组学和泛素组学分析。肝癌患者。 HCC 显示可药物靶点 CBR1-S151 和 CPNE1-S55 的过度表达。 COL4A1、LAMC1和LAMA4在DFS较差的患者中高表达。 HCC 的磷酸化蛋白质组学和泛素组学特征揭示了代谢和转移中的串扰。泛素组学预测了不同的预后并阐明了 HCC 亚型特异性蛋白质组学特征。生物标志物 TUBA1A、BHMT2、BHMT 和 ACY1 的表达表现出不同的泛素化水平，并显示出高预后风险评分，表明针对这些蛋白质或其修饰形式可能有利于未来的临床治疗。我们验证了 TUBA1A K370 去泛素化会导致严重的 HCC 并标记为侵袭性 HCC 亚型。 HCC 中 TUBA1A K370 去泛素化至少部分归因于 AKT 介导的 USP14 激活。值得注意的是，靶向 AKT-USP14-TUBA1A 复合物可促进 TUBA1A 降解并阻断体内肝脏肿瘤发生。这项研究扩展了我们对 HCC 泛素特征、生物标志物和潜在治疗靶点的了解。版权所有 © 2024 美国肝病研究协会。

Patients with aggressive hepatocellular carcinoma (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 HCC patients. HCCs displayed overexpression of drugable targets CBR1-S151 and CPNE1-S55. COL4A1, LAMC1 and LAMA4 were highly expressed in the DFS poor patients. Phosphoproteomic and ubiquitomic features of HCC revealed crosstalk 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 AKT-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.Copyright © 2024 American Association for the Study of Liver Diseases.