The Activation of &amp;#946;&lt;sub&gt;1&lt;/sub&gt;-integrin by Type I Collagen Coupling with the Hedgehog Pathway Promotes the Epithelial-Mesenchymal Transition in Pancreatic Cancer

Duan, Wanxing; Ma, Jiguang; Ma, Qingyong; Xu, Qinhong; Liu, Jing; Han, Liang; Li, Xuqi; Wang, Zheng; Wu, Zheng; Lv, Shifang; Ma, Zhenhua; Liu, Mouzhu; Wang, Fengfei; Wu, Erxi

doi:10.2174/1568009614666140402105101

Cited by 31 publications

(24 citation statements)

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“…Previous studies revealed that extracellular Gal-1 secreted by CAFs enhanced the invasiveness of GC cells by upregulating the expression of β1 integrin [22]. Similarly, higher expression of β1 integrin was also shown to induce EMT through the aberrant activation of the Hh pathway [28]. Therefore, we speculated that Gal-1 could activate the Hh pathway via binding to β1 integrin.…”

Section: Resultsmentioning

confidence: 92%

Galectin-1 from cancer-associated fibroblasts induces epithelial–mesenchymal transition through β1 integrin-mediated upregulation of Gli1 in gastric cancer

Yan¹,

Tang²,

Xiong³

et al. 2016

J Exp Clin Cancer Res

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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.

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Section: Resultsmentioning

confidence: 92%

Galectin-1 from cancer-associated fibroblasts induces epithelial–mesenchymal transition through β1 integrin-mediated upregulation of Gli1 in gastric cancer

Yan¹,

Tang²,

Xiong³

et al. 2016

J Exp Clin Cancer Res

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“…The main conduits of EMT‐related collagen effects are integrins as shown in melanoma and pancreatic cancer cells (Girotti et al, ; Duan et al, ). Thus, Duan et al () specify that the collagen I‐dependent promotion of the EMT phenotype in pancreatic cancer cells, including the overexpression of vimentin and N‐cadherin, the down‐regulation of E‐cadherin, as well as the enhanced proliferation and lower apoptotic rate, were mediated by β1‐integrin. Indeed, β1‐integrin down‐regulation abolished the repercussions prompted by collagen I and inactivated the FAK/Akt/ Erk axis; thus, efficiently blocking EMT.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, β1‐integrin down‐regulation abolished the repercussions prompted by collagen I and inactivated the FAK/Akt/ Erk axis; thus, efficiently blocking EMT. Interestingly, the above axis converges onto Gli‐1, a Hedgehog pathway protein, suggesting the existence of a cross‐talk between Hedgehog and β1‐integrin signaling (Duan et al, ).…”

Section: Discussionmentioning

confidence: 99%

Role of the extracellular matrix in cancer‐associated epithelial to mesenchymal transition phenomenon

Tzanakakis

Kavasi

Voudouri

et al. 2017

Developmental Dynamics

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The epithelial to mesenchymal transition (EMT) program is a crucial component in the processes of morphogenesis and embryonic development. The transition of epithelial to mesenchymal phenotype is associated with numerous structural and functional changes, including loss of cell polarity and tight cell-cell junctions, the acquisition of invasive abilities, and the expression of mesenchymal proteins. The switch between the two phenotypes is involved in human pathology and is crucial for cancer progression. Extracellular matrices (ECMs) are multi-component networks that surround cells in tissues. These networks are obligatory for cell survival, growth, and differentiation as well as tissue organization. Indeed, the ECM suprastructure, in addition to its supportive role, can process and deliver a plethora of signals to cells, which ultimately regulate their behavior. Importantly, the ECM derived signals are critically involved in the process of EMT during tumorigenesis. This review discusses the multilayer interaction between the ECM and the EMT process, focusing on contributions of discrete mediators, a strategy that may identify novel potential target molecules. Developmental Dynamics 247:368-381, 2018. V C 2017 Wiley Periodicals, Inc.

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“…For cell invasion assessment, Transwell chamber assays were performed using Transwell chambers (Millipore, USA) according to a protocol described previously [ 33 ]. In brief, cancer cells were serum-starved overnight and then pre-treated with GA for 24h.…”

Section: Methodsmentioning

confidence: 99%

Ginkgolic acid suppresses the development of pancreatic cancer by inhibiting pathways driving lipogenesis

Duan

Han

et al. 2015

Oncotarget

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Ginkgolic acid (GA) is a botanical drug extracted from the seed coat of Ginkgo biloba L. with a wide range of bioactive properties, including anti-tumor effect. However, whether GA has antitumor effect on pancreatic cancer cells and the underlying mechanisms have yet to be investigated. In this study, we show that GA suppressed the viability of cancer cells but has little toxicity on normal cells, e.g, HUVEC cells. Furthermore, treatment of GA resulted in impaired colony formation, migration, and invasion ability and increased apoptosis of cancer cells. In addition, GA inhibited the de novo lipogenesis of cancer cells through inducing activation of AMP-activated protein kinase (AMPK) signaling and downregulated the expression of key enzymes (e.g. acetyl-CoA carboxylase [ACC], fatty acid synthase [FASN]) involved in lipogenesis. Moreover, the in vivo experiment showed that GA reduced the expression of the key enzymes involved in lipogenesis and restrained the tumor growth. Taken together, our results suggest that GA may serve as a new candidate against tumor growth of pancreatic cancer partially through targeting pathway driving lipogenesis.

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The Activation of β<sub>1</sub>-integrin by Type I Collagen Coupling with the Hedgehog Pathway Promotes the Epithelial-Mesenchymal Transition in Pancreatic Cancer

Cited by 31 publications

References 0 publications

Galectin-1 from cancer-associated fibroblasts induces epithelial–mesenchymal transition through β1 integrin-mediated upregulation of Gli1 in gastric cancer

Galectin-1 from cancer-associated fibroblasts induces epithelial–mesenchymal transition through β1 integrin-mediated upregulation of Gli1 in gastric cancer

Role of the extracellular matrix in cancer‐associated epithelial to mesenchymal transition phenomenon

Ginkgolic acid suppresses the development of pancreatic cancer by inhibiting pathways driving lipogenesis

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