title: miR-17-92/p38α Dysregulation Enhances Wnt Signaling and Selects Lgr6+ Cancer Stem-like Cells during Lung Adenocarcinoma Progression.
abstract: Defining the molecular and cellular roots of lung cancer relapse after initial treatment remains an imperative to improve survival. Here we report that the lung stem cell marker Lgr6 becomes enriched in non-small cell lung cancer (NSCLC) cells during malignant progression. Lgr6(+) NSCLC cells displayed self-renewal and differentiation properties along with a higher tumorigenic potential. Mechanistic investigations suggested that a defective repression of the miR-17-92 gene cluster was responsible for evolution of a selection for outgrowth of Lgr6(+) NSCLC cells. High levels of expression of miR-19 family members were found to target and downregulate levels of p38α kinase, providing a specific survival signal for Lgr6(+) cells as mediated by increased Wnt/ß-catenin activity. Our results identify a specific stem-like cell population in NSCLC with increased malignant potential, the elucidation of which may enable earlier prognosis and possibly the development of more effective targeted treatments. Cancer Res; 76(13); 4012-22. ©2016 AACR.
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Guinot
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Feride
authors.initials: F
authors.lastname: Oeztuerk-Winder
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom. Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Belgium. juanjose.ventura@kuleuven.be.
authors.forename: Juan-Jose
authors.initials: JJ
authors.lastname: Ventura
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D063646:Carcinogenesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D062085:RNA, Long Noncoding; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C417544:LGR6 protein, human; C568997:MIR17HG, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D048308:Mitogen-Activated Protein Kinase 14