GLI2 but not GLI1/GLI3 plays a central role in the induction of malignant phenotype of gallbladder cancer

Abstract

We previously reported that Hedgehog (Hh) signal was enhanced in gallbladder cancer (GBC) and was involved in the induction of malignant phenotype of GBC. In recent years, therapeutics that target Hh signaling have focused on molecules downstream of smoothened (SMO). The three transcription factors in the Hh signal pathway, glioma-associated oncogene homolog 1 (GLI1), GLI2, and GLI3, function downstream of SMO, but their biological role in GBC remains unclear. In the present study, the biological significance of GLI1, GLI2, and GLI3 were analyzed with the aim of developing novel treatments for GBC. It was revealed that GLI2, but not GLI1 or GLI3, was involved in the cell cycle-mediated proliferative capacity in GBC and that GLI2, but not GLI1 or GLI3, was involved in the enhanced invasive capacity through epithelial-mesenchymal transition. Further analyses revealed that GLI2 may function in mediating gemcitabine sensitivity and that GLI2 was involved in the promotion of fibrosis in a mouse xenograft model. Immunohistochemical staining of 66 surgically resected GBC tissues revealed that GLI2-high expression patients had fewer numbers of CD3 + and CD8 + tumor-infiltrating lymphocytes (TILs) and increased programmed cell death ligand 1 (PD-L1) expression in cancer cells. These results suggest that GLI2, but not GLI1 or GLI3, is involved in proliferation, invasion, fibrosis, PD-L1 expression, and TILs in GBC and could be a novel therapeutic target. The results of this study provide a significant contribution to the development of a new treatment for refractory GBC, which has few therapeutic options.

FOXP3 Isoforms Expression in Cervical Cancer: Evidence about the Cancer-Related Properties of FOXP3Δ2Δ7 in Keratinocytes

“…Other gene upregulated was GLI2, it has been identified as a potent oncogene that mediates the hedgehog signaling pathway [69][70][71]; in CC it was shown that its subexpression inhibited the growth and migration of cell lines derived from cancer, and it was also associated as a poor prognostic marker based on TCGA data [72].…”

Update on Chemoresistance Mechanisms to First-Line Chemotherapy for Gallbladder Cancer and Potential Reversal Strategies

“… 23 Other studies have confirmed that GLI2, a transcription factor in the Hedgehog (Hh) signaling pathway, promotes cell invasion by activating GBC cell EMT, increasing cancer cell sensitivity to GEM. 28 Noncoding genes can also affect GBC-mediated drug resistance properties by altering cell invasiveness. For example, researchers from Zhongshan Hospital of Fudan University found that lncRNA-RP11-147L13.8 overexpression inhibited GBC cell migration and invasion and increased GBC cell sensitivity to GEM.…”

“… 29 However, inhibition of GLI2 in the Hh signaling pathway reduces GBC sensitivity to GEM. 28 Targeted inhibition of the EGFR/HER2 pathway can also enhance the antiproliferative effect of GEM in the biliary tract and GBC. 81 Interestingly, GBC cells show increased sensitivity to GEM after inhibition of Hippo-Yes-associated protein 1 (YAP1) signaling.…”

“…A research team from Fudan University Shanghai Cancer Center found that MBD1 promotes the malignant behaviors, including invasion, proliferation and migration, and EMT, of GBC cells and induces chemoresistance to GEM 23. Other studies have confirmed that GLI2, a transcription factor in the Hedgehog (Hh) signaling pathway, promotes cell invasion by activating GBC cell EMT, increasing cancer cell sensitivity to GEM 28. Noncoding genes can also affect GBC-mediated drug resistance properties by altering cell invasiveness.…”

“…UCP2 knockdown inhibits the NF-κB/β-catenin axis in GBC, and treatment with a UCP2 inhibitor increases GEM sensitivity in animal xenograft models 29. However, inhibition of GLI2 in the Hh signaling pathway reduces GBC sensitivity to GEM 28. Targeted inhibition of the EGFR/HER2 pathway can also enhance the antiproliferative effect of GEM in the biliary tract and GBC 81.…”