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

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

Research output: Contribution to journalArticlepeer-review

137 Scopus citations

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 ki-nase 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 meta-static 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-onco-gene 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 languageEnglish
Pages (from-to)13373-13378
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number37
DOIs
StatePublished - Sep 16 2014

Keywords

  • Hepatocellular carcinoma
  • Kidney cancer
  • Targeted therapy
  • VHL

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