Gli promotes epithelial-mesenchymal transition in human lung adenocarcinomas

Abstract

Adenocarcinoma is the most common type of lung cancer. Epithelial-mesenchymal transition (EMT) is required for tumor invasion/metastasis and the components that control this process are potential therapeutic targets. This study we examined the role of Gli in lung adenocarcinoma and whether its activation regulates metastasis through EMT in lung adenocarcinoma. We found that tumors with high Gli expression had significantly lower E-Cadherin expression in two independent cohorts of patients with lung adenocarcinoma that we studied. In vitro up-regulation of SHh resulted in increased cell migration while small molecule inhibitors of Smo or Gli significantly reduced cell mobility both in a wound healing assay and in a 3D cell invasion assay. Inhibition of Gli in vivo decreased tumor growth and induced an increase in E-Cadherin expression. Our results indicate that Gli may be critical for lung adenocarcinoma metastasis and that a novel Gli inhibitor shows promise as a therapeutic agent by preventing cell migration and invasion in vitro and significantly reducing tumor growth and increasing E-Cadherin expression in vivo.

Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

“…Hh pathway was identified from the screen as one of the pathways [ 116 ]. Moreover, Shh pathway is associated with EMT, with a correlation between Gli, E-cadherin, and vimentin expressions in IHC [ 63 , 117 ]. NSCLC cells that acquired an EMT phenotype under TGF-β exposure are resistant to cisplatin, but inhibition of Shh pathway is able to sensitize the cells to cisplatin and decrease the expression of CSC phenotype [ 115 ].…”

“…The main resistance mechanism is the acquisition of T790M mutation, but EMT has also been described as a major factor of secondary progression with EGFR TKI [ 125 ]. Shh pathway is closely associated with EMT [ 63 , 117 ]. Moreover, Shh pathway is associated with presence of EGFR mutations in lung adenocarcinoma [ 126 ].…”

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

“…There are three GLI proteins in mammalian cells that act in a specific manner to regulate tissue patterning, cell proliferation and survival via positive and negative feedback mechanisms depending on the context and cell-type ( 22 , 23 ). GLI proteins can act as activators or repressors, depending on the ratio of said proteins ( 24 ). GLI1 is a transcriptional activator.…”

“…In cancer, SHH deregulated activation was first described in nevoid basal cell carcinoma syndrome, where the inherited loss-of-function mutations of the PTCH1 gene was associated with tumour development ( 29 , 30 ). Abnormal Shh signalling is now associated with the progression and maintenance of several malignant tumours, e.g., glioblastomas, lung cancer, prostate cancer and gastric cancer ( 24 , 31 - 34 ). Additionally, it can participate in tumour development via somatic mutations in upstream pathway proteins (SMO and PTC1), overexpression of GLI transcription factors or in a ligand-dependent manner ( 25 ).…”

Cross-talk between Human Papillomavirus Oncoproteins and Hedgehog Signaling Synergistically Promotes Stemness in Cervical Cancer Cells

“…The hedgehog (Hh)/GLI signaling, which is a highly conserved pathway that regulates patterning and progenitor cell fate in normal animal development, has been implicated in promoting stemness, chemoresistance 11 12 13 and metastasis 14 15 16 17 . The key events in activation of GLI signaling are binding of ligand Ihh, Shh to its receptor Patch, which relieves its inhibition on another receptor Smo.…”