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Dysregulation of the von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) signaling pathway promotes clear cell renal cell carcinoma (ccRCC) progression and metastasis. The protein kinase GAS6/AXL signaling pathway has recently been implicated as an essential mediator of metastasis and receptor tyrosine kinase crosstalk in cancer. Here we establish a molecular link between HIF stabilization and induction of AXL receptor expression in metastatic ccRCC. We found that HIF-1 and HIF-2 directly activate the expression of AXL by binding to the hypoxia-response element in the AXL proximal promoter. Importantly, genetic and therapeutic inactivation of AXL signaling in metastatic ccRCC cells reversed the invasive and metastatic phenotype in vivo. Furthermore, we define a pathway by which GAS6/AXL signaling uses lateral activation of the met proto-oncogene (MET) through SRC proto-oncogene nonreceptor tyrosine kinase to maximize cellular invasion. Clinically, AXL expression in primary tumors of ccRCC patients correlates with aggressive tumor behavior and patient lethality. These findings provide an alternative model for SRC and MET activation by growth arrest-specific 6 in ccRCC and identify AXL as a therapeutic target driving the aggressive phenotype in renal clear cell carcinoma.

Original publication

DOI

10.1073/pnas.1404848111

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

16/09/2014

Volume

111

Pages

13373 - 13378

Keywords

VHL, hepatocellular carcinoma, kidney cancer, targeted therapy, Basic Helix-Loop-Helix Transcription Factors, Carcinoma, Renal Cell, Cell Hypoxia, Cell Line, Tumor, Enzyme Activation, Hepatocyte Growth Factor, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Intercellular Signaling Peptides and Proteins, Kidney Neoplasms, Models, Biological, Neoplasm Invasiveness, Phenotype, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-met, Receptor Protein-Tyrosine Kinases, Signal Transduction, Treatment Outcome, Von Hippel-Lindau Tumor Suppressor Protein, src-Family Kinases