蛋白质组学标记了早期肝细胞癌的新治疗靶点

StephenW

Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma

    Ying Jiang, Aihua Sun, […]Chinese Human Proteome Project (CNHPP) Consortium

Naturevolume 567, pages257–261 (2019) | Download Citation
Abstract

Hepatocellular carcinoma is the third leading cause of deaths from cancer worldwide. Infection with the hepatitis B virus is one of the leading risk factors for developing hepatocellular carcinoma, particularly in East Asia1. Although surgical treatment may be effective in the early stages, the five-year overall rate of survival after developing this cancer is only 50–70%2. Here, using proteomic and phospho-proteomic profiling, we characterize 110 paired tumour and non-tumour tissues of clinical early-stage hepatocellular carcinoma related to hepatitis B virus infection. Our quantitative proteomic data highlight heterogeneity in early-stage hepatocellular carcinoma: we used this to stratify the cohort into the subtypes S-I, S-II and S-III, each of which has a different clinical outcome. S-III, which is characterized by disrupted cholesterol homeostasis, is associated with the lowest overall rate of survival and the greatest risk of a poor prognosis after first-line surgery. The knockdown of sterol O-acyltransferase 1 (SOAT1)—high expression of which is a signature specific to the S-III subtype—alters the distribution of cellular cholesterol, and effectively suppresses the proliferation and migration of hepatocellular carcinoma. Finally, on the basis of a patient-derived tumour xenograft mouse model of hepatocellular carcinoma, we found that treatment with avasimibe, an inhibitor of SOAT1, markedly reduced the size of tumours that had high levels of SOAT1 expression. The proteomic stratification of early-stage hepatocellular carcinoma presented in this study provides insight into the tumour biology of this cancer, and suggests opportunities for personalized therapies that target it.

StephenW

蛋白质组学标记了早期肝细胞癌的新治疗靶点

Ying Jiang，Aihua Sun，[...]中国人类蛋白质组计划（CNHPP）联盟

Naturevolume 567，pages257-261（2019）|下载引文
抽象

肝细胞癌是全球癌症死亡的第三大原因。感染乙型肝炎病毒是发展肝细胞癌的主要危险因素之一，特别是在东亚地区1。虽然手术治疗可能在早期阶段有效，但五 - 发生这种癌症后的总生存率仅为50-70％2。在这里，我们使用蛋白质组学和磷酸化蛋白质组学分析，我们描述了与乙型肝炎病毒感染有关的临床早期肝细胞癌的110对肿瘤组织和非肿瘤组织我们的定量蛋白质组学数据突出了早期肝细胞癌的异质性：我们用它来将队列分为SI，S-II和S-III亚型，每种亚型具有不同的临床结果。 S-III的特征在于破坏胆固醇稳态，与一线手术后最低的总生存率和预后不良的风险最大相关。降低甾醇O-酰基转移酶1（SOAT1） - 其高表达是S-III亚型特异性的特征 - 改变细胞胆固醇的分布，并有效抑制肝细胞癌的增殖和迁移。最后，基于患者来源的肝细胞癌肿瘤异种移植小鼠模型，我们发现用SOAS1抑制剂avasimibe治疗显着减少了具有高水平SOAT1表达的肿瘤的大小。本研究中提出的早期肝细胞癌的蛋白质组学分层提供了对这种癌症的肿瘤生物学的深入了解，并提出了针对它的个性化治疗的机会。