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Axl activates autocrine transforming growth factor‐β signaling in hepatocellular carcinoma
Author(s) -
Reichl Patrick,
Dengler Mirko,
van Zijl Franziska,
Huber Heidemarie,
Führlinger Gerhard,
Reichel Christian,
Sieghart Wolfgang,
PeckRadosavljevic Markus,
Grubinger Markus,
Mikulits Wolfgang
Publication year - 2015
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27492
Subject(s) - cancer research , epithelial–mesenchymal transition , autocrine signalling , metastasis , gene knockdown , transforming growth factor , tumor progression , biology , axl receptor tyrosine kinase , signal transduction , hepatocellular carcinoma , cancer , medicine , receptor tyrosine kinase , endocrinology , cell culture , receptor , microbiology and biotechnology , jak stat signaling pathway , genetics
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. Conclusion : Our data suggest that Axl/14‐3‐3ζ signaling is central for TGF‐β‐mediated HCC progression and a promising target for HCC therapy. (H epatology 2015;61:930–941)