Sonic Hedgehog/Gli1 Signaling Pathway Regulates Cell Migration and Invasion via Induction of Epithelial-to-mesenchymal Transition in Gastric Cancer

Abstract

Background:The aberrant activation of the Sonic hedgehog (Shh) signaling pathway is involved in progression of several types of cancer, including gastric cancer (GC). However, it remains uncertain whether it also plays a critical role in promoting cancer initiation and progression by inducing epithelial-to-mesenchymal transition (EMT) in GC. Thus, the aim of the present study was to determine whether the Shh pathway is involved in GC, and to investigate the function of the Shh pathway in the induction of EMT in GC. Materials and methods: The expression levels of Shh pathway members and EMT markers were examined in GC tissues by immunohistochemistry. The association between these factors and patient clinicopathological characteristics was analyzed. In addition, Gli-antagonist 61 (GANT61) was used to block Shh/Gli1 pathway activity, and recombinant Shh proteins (N-Shh) were used to activate the Shh pathway in GC cells. Wound healing and Transwell invasion and migration assays were performed to assess the effects of the Shh pathway on the migration and invasion of GC cells in vitro. Furthermore, western blot analysis was used to examine the changes in protein expression. Results: The results demonstrated that these Shh/Gli1 pathway members were upregulated in GC tissues, and that Gli1 upregulation was associated with tumor progression and a poor prognosis. Gli1 expression was negatively associated with E-cadherin (E-Cad) expression, and positively with Vimentin (VIM) expression in GC specimens. Further analysis revealed that when the Shh/Gli1 pathway was activated, the migratory and invasive abilities of GC cells were enhanced, and the expression levels of Gli1 and VIM were increased, while E-Cad expression was decreased. Opposite results were observed when the Shh/Gli1 pathway was blocked by GANT61. Conclusions: The present study indicated that the Shh/Gli1 pathway exhibits an abnormal activation pattern in GC with possible predictive and prognostic significance. The Shh/Gli1 pathway may promote the migratory and invasive potential of GC cells by inducing EMT. The Shh/Gli1 pathway can thus be considered as a potential therapeutic target for GC.

Silencing of Histone Deacetylase 6 Decreases Cellular Malignancy and Contributes to Primary Cilium Restoration, Epithelial-to-Mesenchymal Transition Reversion, and Autophagy Inhibition in Glioblastoma Cell Lines

“…Our results corroborate those of Yang et al [64] in the sense that Shh inhibition was produced after HDAC6 silencing, as they demonstrated that HDAC6 was upregulated in glioma stem cells compared to non-stem tumor cells, and that HDAC6 inhibition downregulated Gli1, Ptch1, and Ptch2 expression and activity in glioma stem cells. A decrease in the Shh pathway decreases cell migration and reverses EMT in lung cancer [65] and gastric cancer [47]. We have also demonstrated these effects after HDAC6 silencing in glioblastoma.…”

“…Although we detected overexpression of Gli1 in the three tumor cell lines, by means of the luciferase assay, we observed that this pathway was only active in the U87MG line. This result contrasts with the fact that the Shh pathway promotes EMT [47], as it is precisely the U87MG line, the most epithelial of the three glioblastoma cell lines, that presents an active Shh pathway. However, T98G cells have been shown to be activated with recombinant Shh treatment but not inhibited after GANT61 treatment [48], which we believe reinforces our results.…”

Dual activation of Hedgehog and Wnt/β-catenin signaling pathway caused by downregulation of SUFU targeted by miRNA-150 in human gastric cancer

“…Wnt signaling is constitutively active in 30% of GC cases [ 7 ], and Hh signaling is aberrantly active in GC [ 18 ]. These findings implicate the importance of both pathways in gastric tumorigenesis and progression.…”

“…Hh signaling inhibition leads to the increased expression of E-cad and decreased expression of VIM, whereas Hh signaling activation has the opposite effects. Overall, these results indicate that Hh signaling activation induces EMT, which in turn enhances GC progression and metastasis [ 18 ]. In this study, we found that cells transfected with miRNA-150 mimics exhibited increased activation of the Hh signaling pathway and promotion of EMT, whereas cells transfected with miRNA-150 inhibitors displayed suppression of Hh signaling and inhibition of EMT.…”

Analysis of Collagen type X alpha 1 (COL10A1) expression and prognostic significance in gastric cancer based on bioinformatics

“…Regulation of actin cytoskeleton is correlated with migration and invasion of cancer [ 29 ], kinesin superfamily protein 2A, a key protein in this signaling pathway, playing the role of oncogenes in a variety of cancers [ 30–32 ]. The Hedgehog signaling processes play a significant part in the development of chronic gastritis to GC [ 33 ]; it also promotes the growth of GC cells [ 34 ] and improves the ability of migration and invasion [ 35 ]. The CAM pathway is related to tumor angiogenesis, invasion and metastasis [ 36 ].…”