6533b852fe1ef96bd12aac5a
RESEARCH PRODUCT
Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma
Marco TartagliaGiuseppina CatanzaroL Di MarcotullioZein Mersini BesharatElisabetta FerrettiDanilo CucchiMarianna SilvanoAdriana EramoCarlo CapalboAlessandra VaccaEvelina MieleR De MariaR De MariaAgnese PoGianluca CanettieriGiorgio StassiIsabella ScrepantiMatilde TodaroE De SmaeleValentina SalvatiSonia Conisubject
0301 basic medicineMAPK/ERK pathwayCancer ResearchLung NeoplasmsPyridinesPyridineMitogen-Activated Protein Kinase KinaseMice SCIDMiceCarcinoma Non-Small-Cell LungRNA Small InterferingNon-Small-Cell LungMolecular Biology; Genetics; Cancer ResearchTumorbiologyintegumentary systemHedgehog signaling pathwayCell biologyNeoplastic Stem CellsFemaleRNA InterferenceOriginal ArticleHumanXenograft Model Antitumor AssayAdenocarcinomaSCIDSmall InterferingZinc Finger Protein GLI1Cell LineProto-Oncogene Proteins p21(ras)Adenocarcinoma; Animals; Carcinoma Non-Small-Cell Lung; Cell Line Tumor; Female; Humans; Lung Neoplasms; Mice; Mice SCID; Mitogen-Activated Protein Kinase Kinases; Neoplastic Stem Cells; Neuropilin-2; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; RNA Interference; RNA Small Interfering; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1; Molecular Biology; Genetics; Cancer Research03 medical and health sciencesParacrine signallingGeneticSettore MED/04 - PATOLOGIA GENERALEstem cellsCancer stem cellGLI1Cell Line TumorGeneticsAnimalsHumansAutocrine signallingMolecular BiologyMitogen-Activated Protein Kinase KinasesSettore MED/06 - ONCOLOGIA MEDICAAnimalCarcinomaXenograft Model Antitumor AssaysNeuropilin-2Lung Neoplasmlung cancer030104 developmental biologyPyrimidinesPyrimidineCancer cellbiology.proteinRNANeoplastic Stem CellSmootheneddescription
Aberrant Hedgehog/GLI signaling has been implicated in a diverse spectrum of human cancers, but its role in lung adenocarcinoma (LAC) is still under debate. We show that the downstream effector of the Hedgehog pathway, GLI1, is expressed in 76% of LACs, but in roughly half of these tumors, the canonical pathway activator, Smoothened, is expressed at low levels, possibly owing to epigenetic silencing. In LAC cells including the cancer stem cell compartment, we show that GLI1 is activated noncanonically by MAPK/ERK signaling. Different mechanisms can trigger the MAPK/ERK/GLI1 cascade including KRAS mutation and stimulation of NRP2 by VEGF produced by the cancer cells themselves in an autocrine loop or by stromal cells as paracrine cross talk. Suppression of GLI1, by silencing or drug-mediated, inhibits LAC cells proliferation, attenuates their stemness and increases their susceptibility to apoptosis in vitro and in vivo. These findings provide insight into the growth of LACs and point to GLI1 as a downstream effector for oncogenic pathways. Thus, strategies involving direct inhibition of GLI1 may be useful in the treatment of LACs.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2016-09-22 |