title: Epithelial-mesenchymal transition induces an antitumor immune response mediated by NKG2D receptor.
abstract: Epithelial-mesenchymal transition (EMT) is a morphogenetic process characterized by the acquisition of mesenchymal properties linked with an invasive phenotype and metastasis of tumor cells. NK group 2, member D (NKG2D) is an NK cell-activating receptor crucially involved in cancer immunosurveillance. In this study, we show that induction of EMT by TGF-β stimulation of human keratinocytes, by glycogen synthase kinase-3β inhibition in several epithelial tumor cell lines, and by Snail1 overexpression in colorectal cancer cells strongly upregulated the expression of NKG2D ligands (NKG2DLs), MHC class I chain-related molecules A and B (MICA/B) and ULBP1-3. Overexpression of Snail1 and inhibition of glycogen synthase kinase-3β in colorectal tumor cells markedly induced the activity of Sp1 transcription factor, which plays a key role in the upregulation of NKG2DL expression during EMT. The stimulation of MICA/B expression by TGF-β treatment was independent of Sp1, but it involved posttranslational mechanisms mediated by mammalian target of rapamycin pathway. Accordingly, with the increased expression of NKG2DLs, triggering of EMT rendered cancer cells more susceptible to NKG2D-mediated killing by NK cells. In agreement, MICA/B were expressed in vivo in well-differentiated colorectal tumors with retained epithelial characteristics, whereas no expression of MICA/B was detected in poorly differentiated and invasive colorectal tumors that have lost epithelial characteristics. This decrease of MICA/B expression was associated with a dramatic increase of NKG2D(+)-tumor infiltrating lymphocytes. Overall, our findings indicate that EMT is a relevant checkpoint in the control of tumor progression through NKG2D-mediated immune responses.
authors.affiliation: Departamento de Biología Funcional, Universidad de Oviedo, Instituto Universitario de Oncología del Principado de Asturias, 33006 Oviedo, Spain. lopezsalejandro@uniovi.es
authors.forename: Alejandro
authors.initials: A
authors.lastname: López-Soto
authors.forename: Leticia
authors.initials: L
authors.lastname: Huergo-Zapico
authors.forename: José Alberto
authors.initials: JA
authors.lastname: Galván
authors.forename: Luis
authors.initials: L
authors.lastname: Rodrigo
authors.forename: Antonio García
authors.initials: AG
authors.lastname: de Herreros
authors.forename: Aurora
authors.initials: A
authors.lastname: Astudillo
authors.forename: Segundo
authors.initials: S
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019073:HT29 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D016130:Immunophenotyping; D008648:Mesoderm / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000276:immunology / Q000473:pathology
chemical_list: D055655:NK Cell Lectin-Like Receptor Subfamily K