title: Inactivation of GSK3β and activation of NF-κB pathway via Axl represents an important mediator of tumorigenesis in esophageal squamous cell carcinoma.
abstract: The receptor tyrosine kinase Axl has been described as an oncogene, and its deregulation has been implicated in the progression of several human cancers. While the role of Axl in esophageal adenocarcinoma has been addressed, there is no information about its role in esophageal squamous cell carcinoma (OSCC). In the current report, we identified, for the first time, deregulation of Axl expression in OSCC. Axl is consistently overexpressed in OSCC cell lines and human tumor samples, mainly in advanced stages of the disease. Blockage of Axl gene expression by small interfering RNA inhibits cell survival, proliferation, migration, and invasion in vitro and esophageal tumor growth in vivo. Additionally, repression of Axl expression results in Akt-dependent inhibition of pivotal genes involved in the nuclear factor-kappaB (NF-κB) pathway and in the induction of glycogen synthase kinase 3β (GSK3β) activity, resulting in loss of mesenchymal markers and induction of epithelial markers. Furthermore, treatment of esophageal cancer cells with the Akt inhibitor wortmannin inhibits NF-κB signaling, induces GSK3β activity, and blocks OSCC cell proliferation in an Axl-dependent manner. Taken together, our results establish a clear role for Axl in OSCC tumorigenesis with potential therapeutic implications.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South Africa Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa.
authors.forename: Juliano D
authors.initials: JD
authors.lastname: Paccez
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South Africa Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa.
authors.forename: Kristal
authors.initials: K
authors.lastname: Duncan
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South Africa Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa.
authors.forename: Akhona
authors.initials: A
authors.lastname: Vava
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Ricardo G
authors.initials: RG
authors.lastname: Correa
authors.affiliation: BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115.
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South Africa Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa.
authors.forename: M Iqbal
authors.initials: MI
authors.lastname: Parker
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South Africa Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa luiz.zerbini@icgeb.org.
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Zerbini
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D000077277:Esophageal Squamous Cell Carcinoma; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D000094963:Axl Receptor Tyrosine Kinase