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肝细胞癌转化治疗的策略及实践
DOI: 10.12449/JCH240902
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：马驰负责设计论文框架及起草；谭广负责论文修改，拟定写作思路，指导撰写并最后定稿。
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摘要: 原发性肝癌因发病隐匿及预后较差，多数初始诊断即为不可切除。近些年，随着靶向治疗、免疫治疗及局部治疗等转化治疗方案的兴起，部分中晚期肝癌患者成功转化并行根治性手术切除，但同时也带来了诸多问题，如潜在转化人群的界定、转化方案的选择、转化后手术切除的必要性及时机、转化手术后辅助治疗的必要性及持续时间等。本文将结合笔者的自身经验，针对肝癌转化治疗中上述问题进行探讨。Abstract: Due to the insidious onset and poor prognosis of primary liver cancer， most patients are found to have unresectable primary liver cancer at initial diagnosis. In recent years， with the advent of targeted therapy， immunotherapy， and local therapy， some patients with advanced liver cancer have achieved successful conversion and undergone radical surgical resection， but at the same time， such treatment has brought many issues， such as the identification of potential population for conversion， the selection of conversion regimen， the necessity and timing of surgical resection after conversion， and the necessity and duration of adjuvant therapy after conversion surgery. This article discusses the above problems in conversion therapy for liver cancer based on the author’s own experience.
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肝细胞癌（HCC）是临床常见的恶性肿瘤之一。HCC早期治疗以手术切除为主，但侵袭性HCC的治疗策略目前选择有限，索拉非尼、仑伐替尼及程序性细胞死亡受体1及其配体免疫抑制剂治疗HCC的效果不佳，临床有效率不足30%。因此，亟需进一步探究HCC的发病机制与治疗靶点。随着基因组学研究的发展，对HCC肿瘤生物学的认识逐渐深入，但HCC的泛素化特征尚不明晰。本研究旨在揭示HCC的泛素化特征，并探寻可指导侵袭性HCC临床诊断和治疗的潜在生物标志物。
陆军军医大学第一附属医院（重庆西南医院）谢传明教授、张雷达教授与重庆医科大学侯宇教授等通过对85例HCC患者肿瘤及相邻正常肝组织进行蛋白质组学、磷酸化修饰组学和泛素化修饰组学测序与分析发现，COL4A1、LAMC1和LAMA4在无病生存期较差患者中高表达。磷酸化与泛素化修饰在代谢和转移相关信号通路中存在关联。利用泛素化组学和蛋白质组学数据对HCC进行分子分型，发现具有不同临床特征的3个亚型：S-Ⅰ、S-Ⅱ和S-Ⅲ。S-Ⅰ亚型以代谢相关蛋白高表达为特征，预后最好；S-Ⅲ亚型与增殖/转移信号通路密切相关，预后最差，表现为总生存期最短和复发率最高；而S-Ⅱ亚型则介于两者之间。研究发现，生物标志物TUBA1A、BHMT2、BHMT和ACY1的表达表现出不同的泛素化水平，与HCC患者预后不良密切相关，表明靶向这些蛋白质或其泛素化修饰蛋白可能对临床治疗有益。此外，研究证实TUBA1A K370去泛素化可驱动HCC发生与转移，这主要归因于AKT介导的USP14激活。TUBA1A K370去泛素化标志着一类高侵袭性HCC亚型。值得注意的是，靶向AKT-USP14-TUBA1A复合物可促进TUBA1A降解，并在体内阻断HCC发生。
总之，本研究从泛素化组学、磷酸化组学和蛋白质组学角度对HCC进行了全面的整合分析，该研究不仅加深了对HCC中泛素化特征的了解，并为开发新的HCC生物标志物和潜在的治疗靶点提供了依据。
摘译自LIN XT, LUO YD, MAO C, et al. Integrated ubiquitomics characterization of hepatocellular carcinomas[J]. Hepatology, 2024. DOI: 10.1097/HEP.0000000000001096. [Online ahead of print]
(陆军军医大学第一附属医院肝胆外科 谢传明 报道） -
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