Roles of Signaling Pathways in the Epithelial-Mesenchymal Transition in Cancer

Liu, Xia; Yun, Fen; Shi, Lin; Li, Zhehai; Luo, Nianrong; Jia, Yong

doi:10.7314/apjcp.2015.16.15.6201

Cited by 78 publications

(69 citation statements)

References 53 publications

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“…Migration and invasion are two basic features of malignant tumor cells. EMT is an important mechanism in tumor invasion and metastasis in which the adhesion protein E-cadherin plays a central role [8, 12]. Gal-1 was reported to induce EMT in hepatocellular carcinoma [11], but no data on GC has been provided to-date.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

“…Major signaling pathways involved in EMT include the TGF-β, Wnt, Notch, and Hedgehog (Hh) pathways [12]. In GC, tumorigenicity and EMT are regulated through activation of glioma-associated oncogene 1 (Gli1), a key member of the Hh signaling pathway [13–15].…”

Section: Introductionmentioning

confidence: 99%

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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“…TGFβ1–Smad3 signaling pathway plays an important role in the process of cell differentiation, and it is very important for the process of embryonic stem cells to epithelial cells and mesenchymal cells . On the other hand, epidermal renewal is performed by the stem cells of the epidermal basement membrane.…”

Section: Discussionmentioning

confidence: 99%

TGFβ1‐Smad3‐Jagged1‐Notch1–Slug signaling pathway takes part in tumorigenesis and progress of tongue squamous cell carcinoma

Zhang

Liang

Liu

et al. 2016

J Oral Pathology Medicine

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The key protein expression in TGFβ1-Smad3-Jagged1-Notch1-Slug signaling pathway significantly correlated with the clinicopathological features of TSCC patients. It's potential as a biomarker and a novel therapeutic target for TSCC patients at risk of metastasis. It may play an irreplaceable role in TSCC progression which may attribute to promoting EMT which enhances cell migration, invasion and metastasis.

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“…However, the molecular mechanisms underlying the development of metastatic breast cancer remain unclear, and defining such mechanisms is of paramount importance. It is well known that activation of various signaling pathways promotes the epithelial-to-mesenchymal transition (EMT) and development of a metastatic phenotype in breast cancer cells (4). Human epidermal growth factor receptor 2 (Her2 or ErbB2) is a type I transmembrane receptor tyrosine kinase that belongs to the epidermal growth factor receptor (Egfr) family (5).…”

Section: Introductionmentioning

confidence: 99%

Melatonin Represses Metastasis inHer2-Postive Human Breast Cancer Cells by Suppressing RSK2 Expression

Mao

Summers

Xiang

et al. 2016

Molecular Cancer Research

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The importance of the circadian/melatonin signal in suppressing the metastatic progression of breast and other cancers has been reported by numerous laboratories including our own. Currently, the mechanisms underlying the anti-metastatic actions of melatonin have not been well established. In the present study, the anti-metastatic actions of melatonin were evaluated and compared on the ERα-negative, Her2-positive SKBR-3 breast tumor cell line and ERα-positive MCF-7 cells overexpressing a constitutively active HER2.1 construct (MCF-7Her2.1 cells). Activation of Her2 is reported to induce the expression and/or phosphorylation-dependent activation of numerous kinases and transcription factors that drive drug resistance and metastasis in breast cancer. A key signaling node activated by the Her2/Mapk/Erk pathway is Rsk2, which has been shown to induce numerous signaling pathways associated with the development of epithelial-to-mesenchymal transition (EMT) and metastasis including: Creb, Stat3, cSrc, Fak, Pax, Fascin, and actin polymerization. The data demonstrate that melatonin (both endogenous and exogenous) significantly represses this invasive/metastatic phenotype through a mechanism that involves the suppression of EMT, either by promoting mesenchymal-to-epithelial transition (MET), and/or by inhibiting key signaling pathways involved in later stages of metastasis. These data, combined with our earlier in vitro studies, support the concept that maintenance of elevated and extended duration of nocturnal melatonin levels plays a critical role in repressing the metastatic progression of breast cancer.

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Roles of Signaling Pathways in the Epithelial-Mesenchymal Transition in Cancer

Cited by 78 publications

References 53 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

TGFβ1‐Smad3‐Jagged1‐Notch1–Slug signaling pathway takes part in tumorigenesis and progress of tongue squamous cell carcinoma

Melatonin Represses Metastasis inHer2-Postive Human Breast Cancer Cells by Suppressing RSK2 Expression

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