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

Rankin, Erinn B; Fuh, Katherine C; Castellini, Laura; Viswanathan, Kartik; Finger, Elizabeth C; Diep, Anh N; LaGory, Edward L; Kariolis, Mihalis S; Chan, Andy and Lindgren, David LU , et al. (2014) In Proceedings of the National Academy of Sciences 111(37). p.13373-13378
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... (More)
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. (Less)
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publication status
published
subject
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Proceedings of the National Academy of Sciences
volume
111
issue
37
pages
13373 - 13378
publisher
National Acad Sciences
external identifiers
  • pmid:25187556
  • wos:000341630000041
  • scopus:84907192193
ISSN
1091-6490
DOI
10.1073/pnas.1404848111
language
English
LU publication?
yes
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5552a374-3cf1-4ec4-a776-22c4fd1cb18d (old id 4692359)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25187556?dopt=Abstract
date added to LUP
2014-10-01 18:01:08
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2017-11-19 03:04:22
@article{5552a374-3cf1-4ec4-a776-22c4fd1cb18d,
  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.},
  author       = {Rankin, Erinn B and Fuh, Katherine C and Castellini, Laura and Viswanathan, Kartik and Finger, Elizabeth C and Diep, Anh N and LaGory, Edward L and Kariolis, Mihalis S and Chan, Andy and Lindgren, David and Axelson, Håkan and Miao, Yu R and Krieg, Adam J and Giaccia, Amato J},
  issn         = {1091-6490},
  language     = {eng},
  number       = {37},
  pages        = {13373--13378},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET.},
  url          = {http://dx.doi.org/10.1073/pnas.1404848111},
  volume       = {111},
  year         = {2014},
}