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Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET.

Author:
  • Erinn B Rankin
  • Katherine C Fuh
  • Laura Castellini
  • Kartik Viswanathan
  • Elizabeth C Finger
  • Anh N Diep
  • Edward L LaGory
  • Mihalis S Kariolis
  • Andy Chan
  • David Lindgren
  • Håkan Axelson
  • Yu R Miao
  • Adam J Krieg
  • Amato J Giaccia
Publishing year: 2014
Language: English
Pages: 13373-13378
Publication/Series: Proceedings of the National Academy of Sciences
Volume: 111
Issue: 37
Document type: Journal article
Publisher: National Acad Sciences

Abstract english

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.

Keywords

  • Cancer and Oncology

Other

Published
  • Kidney cancer research group
  • ISSN: 1091-6490
Håkan Axelson
E-mail: hakan [dot] axelson [at] med [dot] lu [dot] se

Professor

Division of Translational Cancer Research

+46 46 222 64 34

MV 404 A31A2

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