J Cancer 2020; 11(13):3932-3943. doi:10.7150/jca.42900

Research Paper

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

Bin Ke, Xiao-Na Wang, Ning Liu, Bin Li, Xue-Jun Wang, Ru-Peng Zhang, Han Liang

Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin, 300060, P.R. China

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Citation:
Ke B, Wang XN, Liu N, Li B, Wang XJ, Zhang RP, Liang H. Sonic Hedgehog/Gli1 Signaling Pathway Regulates Cell Migration and Invasion via Induction of Epithelial-to-mesenchymal Transition in Gastric Cancer. J Cancer 2020; 11(13):3932-3943. doi:10.7150/jca.42900. Available from https://www.jcancer.org/v11p3932.htm

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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.

Keywords: sonic hedgehog, epithelial-mesenchymal transition, gastric cancer, invasion, migration