Hedgehog signaling pathway is a potential therapeutic target for gallbladder cancer

Abstract

Gallbladder cancer (GBC) is a particularly deadly type of cancer with a 5-year survival rate of only 10%. New effective therapeutic strategies are greatly needed. Recently, we have shown that Hedgehog (Hh) signaling is reactivated in various types of cancer and is a potential therapeutic target. However, little is known about the biological significance of Hh signaling in human GBC. In this study, we determined whether Hh signaling could be a therapeutic target in GBC. The Hh transcription factor Gli1 was detected in the nucleus of GBC cells but not in the nucleus of normal gallbladder cells. The expression levels of Sonic Hh (Shh) and Smoothened (Smo) in human GBC specimens (n = 37) were higher than those in normal gallbladder tissue. The addition of exogenous Shh ligand augmented the anchor-dependent and anchor-independent proliferation and invasiveness of GBC cells in vitro. In contrast, inhibiting the effector Smo decreased the anchor-dependent and anchor-independent proliferation. Furthermore, the suppression of Smo decreased GBC cell invasiveness through the inhibition of MMP-2 and MMP-9 expression and inhibited the epithelial–mesenchymal transition. In a xenograft model, tumor volume in Smo siRNA-transfected GBC cells was significantly lower than in control tumors. These results suggest that Hh signaling is elevated in GBC and may be involved in the acquisition of malignant phenotypes, and that Hh signaling may be a potential therapeutic target for GBC.

Deguelin inhibits proliferation and migration of human pancreatic cancer cells in vitro targeting hedgehog pathway

“…Gli1 is an effective activator of protein kinase A and itself. Therefore, Gli1 localization within the nucleus is a biomarker of Hh activity (21). Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, play significant roles in tumor tissue remodeling, and are associated with a number of physiological or pathological processes.…”

Activation of sonic hedgehog signaling enhances cell migration and invasion by induction of matrix metalloproteinase-2 and -9 via the phosphoinositide-3 kinase/AKT signaling pathway in glioblastoma

“…Once SHH binds to its receptor Patched 1, the transmembrane protein Smoothened is released, causing the transport of the transcription factor glioma-associated oncogene (Gli) into the nucleus, where it regulates the transcription of target genes that control cell differentiation, survival and growth (5,6). Three Gli genes (Gli1, Gli2 and Gli3) have been identified in mammalian tissues, among which Gli1 is considered to be the only loyal marker of hedgehog pathway activity (8)(9)(10) studies have shown that the hedgehog pathway is associated with the migration and invasion of ovarian, pancreatic, esophageal and gastric carcinomas (6,(11)(12)(13). However, to date, the implication of the hedgehog pathway in the aggressiveness of GBM has not been elucidated.…”

“…It has been demonstrated that MMP-2 and MMP-9 are mostly associated with migration and invasion in multiple tumor types (14)(15)(16). Further studies have shown that the expression of MMP-2 and MMP-9 in several cancer types is mediated by numerous signaling pathways, which include the hedgehog signaling pathway, the wnt/β-catenin pathway, the phosphoinositide-3 kinase (PI3K)/AKT pathway and the mitogen-activated protein kinase (MAPK) pathway (10,17,18). It has been suggested that the hedgehog signaling pathway is cross-linked with other signaling pathways.…”

Targeting specific molecular pathways holds promise for advanced gallbladder cancer therapy

“…Overexpression 97% [56], 51.3% [57], 70% [58] Poor prognosis [56,58] [45]. 38.5% [109] Poor prognosis [109] Amplification 9% [45] HER2 (ERRB2) Mutation 9.8% [33] Early event [113] Overexpression 13.8% [110].…”