Gli1 mediates lung cancer cell proliferation and Sonic Hedgehog-dependent mesenchymal cell activation

• Published in: PloS one 2013-05, Vol.8 (5), p.e63226-e63226
• Main Authors: Bermudez, Olga, Hennen, Elisabeth, Koch, Ina, Lindner, Michael, Eickelberg, Oliver
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Angiogenesis; Animals; Biology; Breast cancer; Cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell activation; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Collagen; Collagen - metabolism; Crosstalk; Cyclin D - metabolism; Cyclin D1; Cyclin D2; Development and progression; DNA binding proteins; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Gene expression; Hedgehog protein; Hedgehog Proteins - antagonists & inhibitors; Hedgehog Proteins - metabolism; Humans; Leukemia; Ligands; Lung cancer; Lung carcinoma; Lung diseases; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical prognosis; Medicine; Mesenchyme; Mesoderm - pathology; Metastases; Metastasis; Mice; Morphogenesis; Neoplasm Invasiveness; Non-small cell lung cancer; Non-small cell lung carcinoma; Proteins; Pulmonary fibrosis; Signal Transduction - drug effects; Signaling; Squamous cell carcinoma; Stem cells; Stromal cells; Studies; Thoracic surgery; Transcription factors; Transcription Factors - metabolism; Veratrum Alkaloids - pharmacology; Zinc Finger Protein GLI1
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0063226

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.