Interleukin-6-stimulated progranulin expression contributes to the malignancy of hepatocellular carcinoma cells by activating mTOR signaling.
Interleukin-6-stimulated progranulin expression contributes to the malignancy of hepatocellular carcinoma cells by activating mTOR signaling.
复制标题
白细胞介素6刺激的颗粒体蛋白前体表达通过激活mTOR信号通路导致肝细胞癌细胞的恶性
DOI：
10.1038/srep21260
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发表时间：
2016-02-16
影响因子：
4.6
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Liu F;Zhang W;Yang F;Feng T;Zhou M;Yu Y;Yu X;Zhao W;Yi F;Tang W;Lu Y
本研究旨在探讨白细胞介素6（IL-6）对肝癌细胞颗粒蛋白原（PGRN）表达的影响，以及PGRN在肝癌发生中的致癌活性的分子机制。肝癌组织中IL-6和PGRN水平升高，且呈正相关。IL-6剂量和时间依赖性地增加HCC细胞中的PGRN水平。IL-6驱动的PGRN表达至少部分由Erk/C/EBP β信号传导介导，并且PGRN的表达减少损害了IL-6刺激的HepG2细胞的增殖、迁移和侵袭。PGRN激活哺乳动物雷帕霉素靶标（mTOR）信号传导，如通过p70S6K、4E-BP1和Akt-Ser473/FoxO1的磷酸化增加所证明。用mTOR信号抑制剂雷帕霉素抑制mTOR信号，干扰PGRN或IL-6介导的HCC细胞体外增殖、迁移和侵袭。通过敲低TSC2持续激活mTOR信号传导恢复了PGRN敲低减弱的IL-6在HepG2细胞中的促增殖作用。此外，雷帕霉素治疗活体小鼠减缓了重组人PGRN刺激的肿瘤生长。我们的研究结果提供了一个更好的理解IL-6/PGRN/mTOR级联的生物学活性在肝癌的发生，这可能是一个新的目标，在肝癌的治疗。
This study aimed to determine the expression of progranulin (PGRN) in hepatocellular carcinoma (HCC) cells in response to interleukin 6 (IL-6), a non-cellular component of the tumor microenvironment and the molecular mechanism of PGRN oncogenic activity in hepatocarcinogenesis. Levels of IL-6 and PGRN were increased and positively correlated in HCC tissues. IL-6 dose- and time-dependently increased PGRN level in HCC cells. IL-6-driven PGRN expression was at least in part mediated by Erk/C/EBPβ signaling and reduced expression of PGRN impaired IL-6-stimulated proliferation, migration and invasion of HepG2 cells. PGRN activated mammalian target of rapamycin (mTOR) signaling, as evidenced by increased phosphorylation of p70S6K, 4E-BP1 and Akt-Ser473/FoxO1. Inhibition of mTOR signaling with rapamycin, an mTOR signaling inhibitor, disturbed PGRN- or IL-6-mediated proliferation, migration and invasion of HCC cellsin vitro. Persistent activation of mTOR signaling by knockdown of TSC2 restored PGRN-knockdown-attenuated pro-proliferation effects of IL-6 in HepG2 cells. In addition, rapamycin treatmentin vivoin mice slowed tumor growth stimulated by recombinant human PGRN. Our findings provide a better understanding of the biological activities of the IL-6/PGRN/mTOR cascade in the carcinogenesis of HCC, which may suggest a novel target in the treatment of HCC.