Gli1 mediates lung cancer cell proliferation and sonic hedgehog-dependent mesenchymal cell activation.

Non-Small-Cell-Lung-Cancer (NSCLC) represents approximately 85% of
all lung cancers and remains poorly understood. While signaling
pathways operative during organ development, including Sonic
Hedgehog (Shh) and associated Gli transcription factors (Gli1-3),
have recently been found to be reactivated in NSCLC, their
functional role remains unclear. Here, we hypothesized that
Shh/Gli1-3 could mediate NSCLC autonomous proliferation and
epithelial/stromal signaling in the tumoral tissue. In this
context, we have investigated the activity of Shh/Gli1-3 signaling
in NSCLC in both, cancer and stromal cells. We report here that
inhibition of Shh signaling induces a significant decrease in the
proliferation of NSCLC cells. This effect is mediated by Gli1 and
Gli2, but not Gli3, through regulation of cyclin D1 and cyclin D2
expression. While exogenous Shh was unable to induce signaling in
either A549 lung adenocarcinoma or H520 lung squamous carcinoma
cells, both cells were found to secrete Shh ligand, which induced
fibroblast proliferation, survival, migration, invasion, and
collagen synthesis. Furthermore, Shh secreted by NSCLC mediates the
production of proangiogenic and metastatic factors in lung
fibroblasts. Our results thus provide evidence that Shh plays an
important role in mediating epithelial/mesenchymal crosstalk in
NSCLC. While autonomous Gli activity controls NSCLC proliferation,
increased Shh expression by NSCLC is associated with fibroblast
activation in tumor-associated stroma. Our study highlights the
relevance of studying stromal-associated cells in the context of
NSCLC regarding new prognosis and therapeutic options.