title: Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET.
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.
authors.affiliation: Division of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
authors.forename: Erinn B
authors.initials: EB
authors.lastname: Rankin
authors.affiliation: Division of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Fuh
authors.affiliation: Division of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
authors.forename: Laura
authors.initials: L
authors.lastname: Castellini
authors.affiliation: Division of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
authors.forename: Kartik
authors.initials: K
authors.lastname: Viswanathan
authors.affiliation: Division of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Finger
authors.affiliation: Division of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
authors.forename: Anh N
authors.initials: AN
authors.lastname: Diep
authors.affiliation: Division of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
authors.forename: Edward L
authors.initials: EL
authors.lastname: LaGory
authors.affiliation: Division of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
authors.forename: Mihalis S
authors.initials: MS
authors.lastname: Kariolis
authors.affiliation: Division of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
authors.forename: Andy
authors.initials: A
authors.lastname: Chan
authors.affiliation: Department of Laboratory Medicine, Center for Molecular Pathology, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden; and.
authors.forename: David
authors.initials: D
authors.lastname: Lindgren
authors.affiliation: Department of Laboratory Medicine, Center for Molecular Pathology, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden; and.
authors.forename: Håkan
authors.initials: H
authors.lastname: Axelson
authors.affiliation: Division of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
authors.forename: Yu R
authors.initials: YR
authors.lastname: Miao
authors.affiliation: Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Krieg
authors.affiliation: Division of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305; giaccia@stanford.edu.
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000473:pathology / Q000556:secondary; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000201:enzymology / Q000473:pathology / Q000556:secondary*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D010641:Phenotype; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D016896:Treatment Outcome; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017228:Hepatocyte Growth Factor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D019061:src-Family Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; D000099162:Endothelial PAS Domain-Containing Protein 1; C000715470:MAS1 protein, human; C000722289:AXL protein, human
keywords: VHL; hepatocellular carcinoma; kidney cancer; targeted therapy