BackgroundGastric cancer (GC) is characterized by the excessive deposition of extracellular matrix, which is thought to contribute to this tumor’s malignant behavior. Epithelial-mesenchymal transition (EMT) is regarded as a crucial contributing factor to cancer progression. Galectin-1 (Gal-1), a β-galactoside-binding protein abundantly expressed in activated cancer-associated fibroblasts (CAFs), has been reported to be involved in GC progression and metastasis by binding to β1 integrin, which, in turn, can bind to matrix proteins and activate intracellular cascades that mediate EMT. Increasing evidence suggests that abnormal activation of the hedgehog (Hh) signaling pathway enhances GC cell migration and invasion. The purpose of our study is to explore the role of Gal-1 in the GC progression and metastasis as well as the regulatory mechanism.MethodsWe hypothesized that Gal-1 binding to β1 integrin would lead to paracrine signaling between CAFs and GC cells, mediating EMT by upregulating Gli1. Invasion and metastasis effects of the Gal-1 and Gli1 were evaluated using wound healing and invasion assay following transfection with mimics. Additionally, to facilitate the delineation of the role of the Hh signaling in GC, we monitored the expression level of associated proteins. We also evaluated the effects of β1 integrin on these processes. Furthermore, Gal-1 and Gli1 expression in GC patient samples were examined by immunohistochemistry and western blot to determine the correlation between their expression and clinicopathologic characteristics. The Kaplan-Meier method and Cox proportional hazards model were used to analyze the relationship of expression with clinical outcomes.ResultsGal-1 was found to induce EMT, GC cell migration and invasion. Further data showed that Gal-1 up-regulated Gli1 expression. β1 integrin was responsible for Gal-1-induced Gli1 expression and EMT. In clinical GC tissue, it confirmed a positive relationship between Gal-1 and Gli1 expression. Importantly, their high expression is correlated to poor prognosis.ConclusionGal-1 from CAFs binds to a carbohydrate structure in β1 integrin and plays an important role in the development of GC by inducing GC metastasis and EMT through targeting Gli1. This study highlights the potential therapeutic value of Gal-1 for suppression of GC metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0449-1) contains supplementary material, which is available to authorized users.
Galectin-1 (Gal-1) has been reported to be an independent prognostic indicator of poor survival in gastric cancer and overexpression of Gal-1 enhances the invasiveness of gastric cancer cells. However, the downstream mechanisms by which Gal-1 promotes invasion remains unclear. Moreover, the function of Gal-1 in the epithelial-mesenchymal transition (EMT) in gastric cancer has not yet been elucidated. In this study, we observed Gal-1 expression was upregulated and positively associated with metastasis and EMT markers in 162 human gastric cancer tissue specimens. In vitro studies showed Gal-1 induced invasion, the EMT phenotype and activated the non-canonical hedgehog (Hh) pathway in gastric cancer cell lines. Furthermore, our data revealed that Gal-1 modulated the non-canonical Hh pathway by increasing the transcription of glioma-associated oncogene-1 (Gli-1) via a Smoothened (SMO)-independent manner, and that upregulation of Gal-1 was strongly associated with gastric cancer metastasis. We conclude that Gal-1 promotes invasion and the EMT in gastric cancer cells via activation of the non-canonical Hh pathway, suggesting Gal-1 could represent a promising therapeutic target for the prevention and treatment of gastric cancer metastasis.
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