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Hepatology:清华大学陈立功课题组报道氨基酸转运蛋白在肝癌发生过程中的重要调节作用

2017-04-28 16:01  
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2017年3月30日,国际肝病学领域著名学术期刊《Hepatology》在线发表了清华大学药学院陈立功课题组及其合作者题为“A functional mTORC1 signaling is indispensable for c-Myc driven hepatocarcinogenesis”的文章,阐述了氨基酸转运蛋白在肝癌发生过程受原癌基因c-Myc调控进而激活mTORC1信号通路诱导肝癌形成。清华大学生命科学院博士生葛梦梦和UCSF刘玭为论文共同第一作者,药学院研究生程丽丽、孙焜和本科生黄越冬为本论文的合作作者,清华大学药学院陈立功研究员以及UCSF Xin Chen教授为论文通讯作者。

Hepatocellular carcinoma (HCC)肝细胞癌是最常见的恶性肿瘤之一。原癌基因c-Myc是引发肝癌主要基因之一,促进细胞恶变,最后导致肿瘤的发生在小鼠肝脏中过表达c-Myc能引起肿瘤的形成,但是c-Myc致癌的分子机制仍然知之甚少。我们发现mTORC1信号通路的激活是c-Myc诱导肝癌形成的必要条件, mTOR 下游效应器真核细胞翻译启始因子4E 结合蛋白1 4EBP1 / eIF4E和核糖体蛋白S6 激酶1 p70S6K 共同调节细胞增殖。氨基酸作为细胞生长和增殖的必要条件,对mTORC1正常发挥功能起着至关作用,转录组学数据分析表明c-Myc能够上调多种氨基酸转运蛋白的表达,如SLC1A5和SLC7A6,它们属于膜转运蛋白的溶质载体(SLC)家族,这些转运蛋白在各种生理和病理过程中具有关键的作用。代谢组学分析表明c-Myc直接上调SLC1A5和SLC7A6,导致肝癌细胞对氨基酸的吸收增加进而激活mTORC1信号通路。在人类HCC标本中,c-Myc的水平和SLC1A5 / SLC7A6表达之间有很大的相关性。总之,这些数据表明在肝癌的治疗过程中,除了靶向mTOR信号通路以外,SLC氨基酸转运蛋白家族也渐渐成为有效的药物的靶标,成为治疗HCC有效选择。


原文链接:

A functional mTORC1 signaling is indispensable for c-Myc driven hepatocarcinoGENEsis

原文摘要:

Amplification and/or activation of the c-Myc protooncogene is one of the leading genetic events along hepatocarcinogenesis. The oncogenic potential of c-Myc has been proven experimentally by the finding that its overexpression in the mouse liver triggers tumor formation. However, the molecular mechanism whereby c-Myc exerts its oncogenic activity in the liver remains poorly understood. Here, we demonstrate that the mammalian target of rapamycin complex 1 (mTORC1) cascade is activated and necessary for c-Myc dependent hepatocarcinogenesis. Specifically, we found that ablation of Raptor, the unique member of the mTORC1 complex, strongly inhibits c-Myc liver tumor formation. Also, p70S6K/ribosomal protein S6 (RPS6) and eukaryotic translation initiation factor 4E-binding protein 1/eukaryotic translation initiation factor 4E (4EBP1/eIF4E) signaling cascades downstream of mTORC1 are required for c-Myc-driven tumorigenesis. Intriguingly, microarray expression analysis revealed the upregulation of multiple amino acid transporters, including SLC1A5 and SLC7A6, leading to robust uptake of amino acids, including glutamine, into c-Myc tumor cells. Subsequent functional studies showed that amino acids are critical for activation of mTORC1, as their inhibition suppressed mTORC1 in c-Myc tumor cells. In human HCC specimens, levels of c-Myc directly correlate with those of mTORC1 activation as well as of SLC1A5 and SLC7A6. Conclusion: Our current study indicates that an intact mTORC1 axis is required for c-Myc-driven hepatocarcinogenesis. Thus, targeting mTOR pathway or amino acid transporters may be an effective and novel therapeutic option for the treatment of HCC with activated c-Myc signaling.

DOI:10.1002/hep.29183

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