PO.MCB11.01 · 分子与细胞生物学
AMBRA1介导的核质控制促进肝癌的早期发生
AMBRA1-mediated nucleocytoplasmic control promotes early onset of liver cancer
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作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肝细胞癌(HCC)是全球癌症相关死亡的主要原因之一,主要由不受控制的细胞增殖和肝脏抑癌活性丧失所驱动。通过分析公开可用的全基因组CRISPR筛选数据集,我们鉴定出AMBRA1为一个强有力的抗增殖候选因子。对一个临床HCC患者队列的分析显示,AMBRA1表达在肿瘤组织中显著降低,且其下调与患者不良结局密切相关。AMBRA1的下调在多个通过体细胞突变和高脂饮食刺激建立的早期HCC小鼠模型中得到了一致验证。在功能上,CRISPR介导的AMBRA1敲除在体内加速了早期自发性肝肿瘤的起始。AMBRA1与参与核质转运的关键蛋白发生共免疫沉淀,提示AMBRA1在HCC中调节核质运输方面具有新功能。总之,我们的发现确立了AMBRA1是一个真正的抑癌因子,在HCC中具有临床和功能上的重要性。
查看英文原文 English abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, largely driven by uncontrolled cell proliferation and the loss of tumor suppressor activity in the liver. By analyzing publicly available genome-wide CRISPR screening datasets, we identified AMBRA1 as a strong anti-proliferative candidate. Analysis of a clinical HCC patient cohort revealed that AMBRA1 expression was significantly reduced in tumor tissues, and its downregulation was tightly associated with poor patient outcomes. The downregulation of AMBRA1 was consistently validated in multiple HCC mouse models established through somatic mutations and high-fat diet challenge at early stages. Functionally, CRISPR-mediated knockout of AMBRA1 accelerated early spontaneous liver tumor initiation in vivo. AMBRA1 co-immunoprecipitated with key proteins involved in nucleocytoplasmic transport, suggesting a novel function for AMBRA1 in modulating nucleocytoplasmic trafficking in HCC. Collectively, our findings establish AMBRA1 as a bona fide tumor suppressor with clinical and functional importance in HCC.
利益披露 Disclosure
Y. He, None..
Y. Xie, None..
M. Zhang, None..
M. Tong, None.