Critical role of Myc activation in mouse hepatocarcinogenesis induced by the activation of AKT and RAS pathways.
Critical role of Myc activation in mouse hepatocarcinogenesis induced by the activation of AKT and RAS pathways.
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DOI：
10.1038/onc.2017.114
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发表时间：
2017-09-07
期刊：
影响因子：
8
通讯作者：
Nishikawa Y
中科院分区：
文献类型：
--
作者：
Xin B;Yamamoto M;Fujii K;Ooshio T;Chen X;Okada Y;Watanabe K;Miyokawa N;Furukawa H;Nishikawa Y
在肝细胞癌中经常发现中等水平的MYC激活。然而，其在肝癌发生中的意义仍不清楚。在这里，我们研究了Myc激活在小鼠肝肿瘤诱导的豆蔻酰化AKT（AKT）和/或突变HRASV 12（HRAS）通过转座子介导的基因整合的肝细胞表达的作用。单独使用AKT或HRAS需要5个月才能诱导肝肿瘤，而它们的组合在8周内产生肝细胞癌。AKT和HRAS的共同引入诱导了载脂的癌前细胞，这些细胞生长成由具有或不具有胞浆内脂质的肿瘤细胞组成的结节，后者更具增殖性并且与自发Myc表达相关。AKT/HRAS诱导的肿瘤发生几乎完全取消时，MadMyc，一个竞争性的Myc抑制剂，同时表达。Tet-On在癌前细胞中对MadMyc的诱导显著抑制了AKT/HRAS诱导的肿瘤的进展;其在转化细胞中的诱导抑制了其增殖活性，并改变了脂质代谢和蛋白质翻译。转座子介导的Myc过表达促进了AKT或HRAS的肿瘤发生，当它与AKT和HRAS共同引入时，早在2周就出现了无脂质积累的弥漫性浸润肿瘤。对Myc在AKT/HRAS诱导的肿瘤发生增强中的剂量反应的检查显示，减少到三分之一保留了增强作用，但三倍以上的引入抑制了该过程，增加了凋亡。Myc过表达抑制参与脂肪酸合成的蛋白质的mRNA表达，并且当与HRAS引入结合时，其还抑制参与其降解的蛋白质的mRNA表达。最后，MYC阳性的人肝细胞癌的特征是细胞质中没有脂质积聚，核仁突出，增殖活性较高。我们的研究结果表明，在由激活的AKT和HRAS诱导的肝癌发生中，内源性Myc的激活是一个增强因素，适当水平的Myc失调进一步促进细胞代谢改变的过程。
MYC activation at modest levels has been frequently found in hepatocellular carcinoma. However, its significance in hepatocarcinogenesis has remained obscure. Here we examined the role of Myc activation in mouse liver tumours induced by hepatocytic expression of myristoylated AKT (AKT) and/or mutant HRASV12 (HRAS) via transposon-mediated gene integration. AKT or HRAS alone required 5 months to induce liver tumours, whereas their combination generated hepatocellular carcinoma within 8 weeks. Co-introduction of AKT and HRAS induced lipid-laden preneoplastic cells that grew into nodules composed of tumour cells with or without intracytoplasmic lipid, with the latter being more proliferative and associated with spontaneous Myc expression. AKT/HRAS-induced tumorigenesis was almost completely abolished when MadMyc, a competitive Myc inhibitor, was expressed simultaneously. The Tet-On induction of MadMyc in preneoplastic cells significantly inhibited the progression of AKT/HRAS-induced tumours; its induction in transformed cells suppressed their proliferative activity with alterations in lipid metabolism and protein translation. Transposon-mediated Myc overexpression facilitated tumorigenesis by AKT or HRAS, and when it was co-introduced with AKT and HRAS, diffusely infiltrating tumours without lipid accumulation developed as early as 2 weeks. Examination of the dose-responses of Myc in the enhancement of AKT/HRAS-induced tumorigenesis revealed that a reduction to one-third retained enhancing effect but three-times greater introduction damped the process with increased apoptosis. Myc overexpression suppressed the mRNA expression of proteins involved in the synthesis of fatty acids, and when combined with HRAS introduction, it also suppressed the mRNA expression of proteins involved in their degradation. Finally, the MYC-positive human hepatocellular carcinoma was characterized by the cytoplasm devoid of lipid accumulation, prominent nucleoli and a higher proliferative activity. Our results demonstrate that in hepatocarcinogenesis induced by both activated AKT and HRAS, activation of endogenous Myc is an enhancing factor and adequate levels of Myc deregulation further facilitate the process with alterations in cellular metabolism.
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