title: Activation of TYRO3/AXL tyrosine kinase receptors in thyroid cancer.
abstract: Thyroid cancer is the most common endocrine cancer, but its key oncogenic drivers remain undefined. In this study we identified the TYRO3 and AXL receptor tyrosine kinases as transcriptional targets of the chemokine CXCL12/SDF-1 in CXCR4-expressing thyroid cancer cells. Both receptors were constitutively expressed in thyroid cancer cell lines but not normal thyroid cells. AXL displayed high levels of tyrosine phosphorylation in most cancer cell lines due to constitutive expression of its ligand GAS6. In human thyroid carcinoma specimens, but not in normal thyroid tissues, AXL and GAS6 were often coexpressed. In cell lines expressing both receptors and ligand, blocking each receptor or ligand dramatically affected cell viability and decreased resistance to apoptotic stimuli. Stimulation of GAS6-negative cancer cells with GAS6 increased their proliferation and survival. Similarly, siRNA-mediated silencing of AXL inhibited cancer cell viability, invasiveness, and growth of tumor xenografts in nude mice. Our findings suggest that a TYRO3/AXL-GAS6 autocrine circuit sustains the malignant features of thyroid cancer cells and that targeting the circuit could offer a novel therapeutic approach in this cancer.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR G. Salvatore, Naples, Italy.
authors.forename: Elvira
authors.initials: E
authors.lastname: Avilla
authors.forename: Valentina
authors.initials: V
authors.lastname: Guarino
authors.forename: Carla
authors.initials: C
authors.lastname: Visciano
authors.forename: Federica
authors.initials: F
authors.lastname: Liotti
authors.forename: Maria
authors.initials: M
authors.lastname: Svelto
authors.forename: Gnanaprakasam
authors.initials: G
authors.lastname: Krishnamoorthy
authors.forename: Renato
authors.initials: R
authors.lastname: Franco
authors.forename: Rosa Marina
authors.initials: RM
authors.lastname: Melillo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000201:enzymology*; D014162:Transfection; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C084944:TYRO3 protein, human