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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

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.

Detaljer

Författare
  • 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
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
Sidor (från-till)13373-13378
TidskriftProceedings of the National Academy of Sciences
Volym111
Utgivningsnummer37
StatusPublished - 2014
PublikationskategoriForskning
Peer review utfördJa