Stratification of Hepatocellular Carcinoma Patients Based on Acetate Utilization
Stratification of Hepatocellular Carcinoma Patients Based on Acetate Utilization
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DOI：
10.1016/j.celrep.2015.10.045
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发表时间：
2015-12-01
期刊：
影响因子：
8.8
通讯作者：
Mardinoglu, Adil
中科院分区：
文献类型：
--
作者：
Bjornson, Elias;Mukhopadhyay, Bani;Mardinoglu, Adil
肝细胞癌（HCC）是一种致命的肝癌形式，越来越普遍。我们通过基于组合网络的分析方法分析了361个HCC肿瘤和49个邻近非癌肝脏样本的全局基因表达谱。我们研究了肝癌转录组和蛋白质组之间的相关性，并建立了一个功能性基因组代谢模型（GEM）。我们使用GEM提供的网络中心视图确定了细胞增殖所需的基本代谢过程。我们的分析揭示了肝癌中脂肪酸生物合成（FAB）的严格调节和脂肪酸氧化的高度显著失调。我们预测线粒体乙酸盐是通过上调肝细胞癌中线粒体乙酰辅酶A合成酶（ACSS 1）而产生FAB的一种新兴底物。我们分析了ACSS1和ACSS2在HCC患者中的异质性表达，这些HCC患者通过ACSS1和ACSS2的高表达和低表达分层，并揭示了ACSS1与人HCC在缺氧条件下的肿瘤生长和恶性程度相关。
Hepatocellular carcinoma (HCC) is a deadly form of liver cancer that is increasingly prevalent. We analyzed global gene expression profiling of 361 HCC tumors and 49 adjacent noncancerous liver samples by means of combinatorial network-based analysis. We investigated the correlation between transcriptome and proteome of HCC and reconstructed a functional genome-scale metabolic model (GEM) for HCC. We identified fundamental metabolic processes required for cell proliferation using the network centric view provided by the GEM. Our analysis revealed tight regulation of fatty acid biosynthesis (FAB) and highly significant deregulation of fatty acid oxidation in HCC. We predicted mitochondrial acetate as an emerging substrate for FAB through upregulation of mitochondrial acetyl-CoA synthetase (ACSS1) in HCC. We analyzed heterogeneous expression of ACSS1 and ACSS2 between HCC patients stratified by high and low ACSS1 and ACSS2 expression and revealed that ACSS1 is associated with tumor growth and malignancy under hypoxic conditions in human HCC.