Abstract
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.
Highlights
Gastric cancer (GC) is characterized by the excessive deposition of extracellular matrix, which is thought to contribute to this tumor’s malignant behavior
cancer-associated fibroblasts (CAFs)-derived Gal-1 induces Epithelial-mesenchymal transition (EMT) in GC cells via activation of the Hh pathway A previous study from our group described the isolation of CAFs and normal gastric fibroblasts (NGFs), and the preparation of recombinant lentiviruses to downregulate Gal-1 expression in CAFs (Down) or overexpress Gal-1 in CAFs (Over) [6]
We confirmed that Gal-1 was strongly expressed in fibroblasts in the stroma of the GC lesion from which CAFs was isolated
Summary
Gastric cancer (GC) is characterized by the excessive deposition of extracellular matrix, which is thought to contribute to this tumor’s malignant behavior. The development of gastric cancer (GC) is a complex, multi-step process associated with an enormous number of genetic alterations, upregulation of cancer-causing genes, downregulation of tumor-suppressor genes, and the acquisition of metastatic ability [1]. During the process of metastasis and invasion, tumor cells are able to induce a series of changes characterized by diffusible growth factors and cytokines, components of the extracellular matrix, fibroblasts, and myofibroblasts ( called cancer-associated fibroblasts [CAFs]), comprising the tumor microenvironment [4]. A large number of studies have shown that epithelial-mesenchymal transition (EMT) plays a critical role in cancer cell invasion and metastasis, and leads to downregulation of epithelial-associated markers such as E-cadherin and upregulation of mesenchymal markers such as vimentin [7]. As a result of EMT, tumor cells acquire metastatic and invasive properties, exhibit characteristics that resemble embryonic mesenchymal cells, and have an enhanced ability to penetrate the surrounding stroma to initiate the formation of new neoplastic foci [8]
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