Department of Biosystems Science and Engineering, ETH Zürich, 4058, Basel, Switzerland.
Swiss Institute of Bioinformatics, Basel, Switzerland.
BMC Genomics. 2021 Aug 4;22(1):592. doi: 10.1186/s12864-021-07876-9.
Genetic aberrations in hepatocellular carcinoma (HCC) are well known, but the functional consequences of such aberrations remain poorly understood.
Here, we explored the effect of defined genetic changes on the transcriptome, proteome and phosphoproteome in twelve tumors from an mTOR-driven hepatocellular carcinoma mouse model. Using Network-based Integration of multi-omiCS data (NetICS), we detected 74 'mediators' that relay via molecular interactions the effects of genetic and miRNA expression changes. The detected mediators account for the effects of oncogenic mTOR signaling on the transcriptome, proteome and phosphoproteome. We confirmed the dysregulation of the mediators YAP1, GRB2, SIRT1, HDAC4 and LIS1 in human HCC.
This study suggests that targeting pathways such as YAP1 or GRB2 signaling and pathways regulating global histone acetylation could be beneficial in treating HCC with hyperactive mTOR signaling.
肝细胞癌 (HCC) 的遗传异常众所周知，但这些异常的功能后果仍知之甚少。
在这里，我们在一个 mTOR 驱动的肝细胞癌小鼠模型的 12 个肿瘤中探索了明确的遗传变化对转录组、蛋白质组和磷酸化蛋白质组的影响。使用基于网络的多 omics 数据综合分析 (NetICS)，我们检测到 74 个“中介物”，通过分子相互作用传递遗传和 miRNA 表达变化的影响。检测到的中介物解释了致癌性 mTOR 信号对转录组、蛋白质组和磷酸化蛋白质组的影响。我们证实了人类 HCC 中 YAP1、GRB2、SIRT1、HDAC4 和 LIS1 中介物的失调。
这项研究表明，靶向 YAP1 或 GRB2 信号通路以及调节组蛋白乙酰化的通路可能有益于治疗具有过度活跃 mTOR 信号的 HCC。
