TY - JOUR
T1 - Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma
AU - Capalbo, Chiara
AU - Stassi, Giorgio
AU - Miele, null
AU - Coni, null
AU - Catanzaro, null
AU - Silvano, null
AU - Cucchi, null
AU - Salvati, null
AU - Po, null
AU - Besharat, null
AU - Tartaglia, null
AU - Capalbo, Carlo
AU - De Smaele, null
AU - Di Marcotullio, null
AU - Canettieri, null
AU - Eramo, Adriana
AU - Tartaglia, Marco
AU - Ferretti, null
AU - Screpanti, null
AU - Vacca, null
AU - De Maria, Ruggero
AU - Tartaglia, Anna Maria
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Adenocarcinoma; Animals; Carcinoma
KW - Non-Small-Cell Lung; Cell Line
KW - SCID; Mitogen-Activated Protein Kinase Kinases; Neoplastic Stem Cells; Neuropilin-2; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; RNA Interference; RNA
KW - Small Interfering; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1; Molecular Biology; Genetics; Cancer Research
KW - Tumor; Female; Humans; Lung Neoplasms; Mice; Mice
KW - Adenocarcinoma; Animals; Carcinoma
KW - Non-Small-Cell Lung; Cell Line
KW - SCID; Mitogen-Activated Protein Kinase Kinases; Neoplastic Stem Cells; Neuropilin-2; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; RNA Interference; RNA
KW - Small Interfering; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1; Molecular Biology; Genetics; Cancer Research
KW - Tumor; Female; Humans; Lung Neoplasms; Mice; Mice
UR - http://hdl.handle.net/10447/252358
UR - http://www.nature.com/onc/index.html
M3 - Article
VL - 36
SP - 4641
EP - 4652
JO - Oncogene
JF - Oncogene
SN - 0950-9232
ER -