Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma

Giorgio Stassi, Chiara Capalbo, Miele, Coni, Catanzaro, Silvano, Cucchi, Salvati, Po, Besharat, Carlo Capalbo, De Smaele, Di Marcotullio, Canettieri, Adriana Eramo, Marco Tartaglia, Ferretti, Screpanti, Vacca, Ruggero De MariaAnna Maria Tartaglia

Risultato della ricerca: Article

24 Citazioni (Scopus)

Abstract

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.
Lingua originaleEnglish
pagine (da-a)4641-4652
Numero di pagine12
RivistaOncogene
Volume36
Stato di pubblicazionePublished - 2017

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cita questo

Stassi, G., Capalbo, C., Miele, Coni, Catanzaro, Silvano, Cucchi, Salvati, Po, Besharat, Capalbo, C., De Smaele, Di Marcotullio, Canettieri, Eramo, A., Tartaglia, M., Ferretti, Screpanti, Vacca, ... Tartaglia, A. M. (2017). Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma. Oncogene, 36, 4641-4652.