Axl activates autocrine transforming growth factor-β signaling in hepatocellular carcinoma.
Axl activates autocrine transforming growth factor-β signaling in hepatocellular carcinoma.
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DOI：
10.1002/hep.27492
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发表时间：
2015-03
期刊：
影响因子：
13.5
通讯作者：
Mikulits, Wolfgang
中科院分区：
文献类型：
--
作者：
Reichl, Patrick;Dengler, Mirko;van Zijl, Franziska;Huber, Heidemarie;Fuehrlinger, Gerhard;Reichel, Christian;Sieghart, Wolfgang;Peck-Radosavljevic, Markus;Grubinger, Markus;Mikulits, Wolfgang
在肝细胞癌中，肝内转移常与恶性肝细胞的上皮间充质转化(EMT)相关。肝细胞内胚层转化主要涉及多种机制，其中包括转化生长因子-β信号转导机制。在这里，我们展示了受体酪氨酸激酶Axl在EMT转化的肝癌细胞中的上调和激活。AXL表达下调导致间充质肝癌细胞体外侵袭和跨内皮迁移能力减弱，AXL过表达在体内诱导上皮性肝癌细胞转移定植。重要的是，AXL基因敲除严重削弱了对转化生长因子-β介导的生长抑制的抵抗。对AXL相互作用组的分析表明，AXL与14-3-3ζ结合，这是AXL介导的细胞侵袭、跨内皮细胞迁移和抵抗转化生长因子-β所必需的。AXL/14-3-3ζ信号导致Smad3连接区(Smad3L)在Ser213位发生磷酸化，导致间叶性肝癌细胞中促肿瘤转化生长因子-β靶基因PAI1、MMP9和Snail表达上调，转化生长因子-β1分泌增加。因此，肝细胞癌患者样本中Axl的高表达与肝癌细胞的血管侵袭增加、肝移植后肿瘤复发的风险更高、Smad3L的强磷酸化和生存率降低相关。此外，Ax1和14-3-3ζ的表达升高表明肝癌患者的存活率显著降低。我们的数据表明，AX1/14-3-3ζ信号通路在转化生长因子-β介导的肝细胞癌进展中起中心作用，是肝癌治疗的一个有前景的靶点。
In hepatocellular carcinoma (HCC), intrahepatic metastasis frequently correlates with epithelial to mesenchymal transition (EMT) of malignant hepatocytes. Several mechanisms have been identified to be essentially involved in hepatocellular EMT, among them transforming growth factor (TGF)-β signaling. Here we show the up-regulation and activation of the receptor tyrosine kinase Axl in EMT-transformed hepatoma cells. Knockdown of Axl expression resulted in abrogation of invasive and transendothelial migratory abilities of mesenchymal HCC cells in vitro and Axl overexpression-induced metastatic colonization of epithelial hepatoma cells in vivo. Importantly, Axl knockdown severely impaired resistance to TGF-β-mediated growth inhibition. Analysis of the Axl interactome revealed binding of Axl to 14-3-3ζ, which is essentially required for Axl-mediated cell invasion, transendothelial migration, and resistance against TGF-β. Axl/14-3-3ζ signaling caused phosphorylation of Smad3 linker region (Smad3L) at Ser213, resulting in the up-regulation of tumor-progressive TGF-β target genes such as PAI1, MMP9, and Snail as well as augmented TGF-β1 secretion in mesenchymal HCC cells. Accordingly, high Axl expression in HCC patient samples correlated with elevated vessel invasion of HCC cells, higher risk of tumor recurrence after liver transplantation, strong phosphorylation of Smad3L, and lower survival. In addition, elevated expression of both Axl and 14-3-3ζ showed strongly reduced survival of HCC patients. Our data suggest that Axl/14-3-3ζ signaling is central for TGF-β-mediated HCC progression and a promising target for HCC therapy.
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AXL 受体激酶是肝细胞癌中 YAP 依赖性致癌功能的介质
影响因子：
8
作者：
Xu, M. Z.;Chan, S. W.;Liu, A. M.;Wong, K. F.;Fan, S. T.;Chen, J.;Poon, R. T.;Zender, L.;Lowe, S. W.;Hong, W.;Luk, J. M.
通讯作者：
Luk, J. M.
影响因子：
4.7
作者：
Matsuzaki K
通讯作者：
Matsuzaki K
DOI：
10.1073/pnas.0909333107
发表时间：
2010-01-19
影响因子：
11.1
作者：
Gjerdrum, Christine;Tiron, Crina;Lorens, James B.
通讯作者：
Lorens, James B.
B-晶状体蛋白与 14-3-3 复合物诱导肝细胞癌上皮间质转化和索拉非尼耐药
影响因子：
13.5
作者：
Huang, Xiao-Yong;Ke, Ai-Wu;Zhou, Jian
通讯作者：
Zhou, Jian
影响因子：
3.1
作者：
Matsuzaki, Koichi
通讯作者：
Matsuzaki, Koichi