EphA2 promotes epithelial–mesenchymal transition through the Wnt/β-catenin pathway in gastric cancer cells

Huang, Jin; Xiao, Desheng; Li, Guanghui; Ma, Junliang; Chen, P.; Yuan, Wenhui; Hou, Futao; Ge, Jie; Zhong, Meizuo; Tang, Yurong; Xia, Xuefeng; Chen, Z.

doi:10.1038/onc.2013.238

Cited by 176 publications

(161 citation statements)

References 32 publications

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“…Aberrant Wnt/β‐catenin signaling is known to play an important role in the initiation and maintenance of GC (Hidaka et al ., 2013; Ju et al ., 2014). While Wnt signaling is activated, β‐catenin is stabilized and accumulates in the cytoplasm and then migrates to the nucleus where it binds to the T‐cell factor/lymphoid enhancer‐binding factor (TCF/LEF) to promote transcription of various target genes, inducing those related to EMT (Clevers, 2006; Clevers and Nusse, 2012; Huang et al ., 2014). In the present study, we found that DDAH1 overexpression significantly decreased the level of β‐catenin, whereas its knockdown produced the opposite effect.…”

Section: Discussionmentioning

confidence: 99%

DDAH1 mediates gastric cancer cell invasion and metastasis via Wnt/β‐catenin signaling pathway

et al. 2017

Molecular Oncology

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Gastric cancer (GC) represents the fourth most common malignant neoplasm and the second leading cause of cancer death. Despite therapeutic advances in recent decades, the clinical outcome remains dismal owing to the fact that most patients with GC show advanced disease at diagnosis and current chemotherapy only confers a modest survival advantage. Identification of key molecular signaling pathways involved in gastric carcinogenesis and progression would aid in early diagnosis and provide a rational design for targeted therapies in selected patients with advanced GC, to improve their outcome. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the main enzyme that can degrade asymmetric dimethylarginine, an endogenous nitric oxide synthase (NOS) inhibitor. Increased DDAH1 expression and NO production have been linked to multiple pathological conditions including cancer. However, the prognostic significance of DDAH1 in patients with GC and its function in GC progression remain undefined. In this study, we found that downregulation of DDAH1 was frequently detected in GC tissues and strongly correlated with more aggressive phenotypes and poor prognosis. Functional assays confirmed that forced expression of DDAH1 in the GC cells suppressed cell migration and invasion in vitro, as well as metastatic potential in vivo. DDAH1 overexpression inhibited the epithelial–mesenchymal transition process by increasing β‐catenin degradation through the attenuation of Wnt/GSK‐3β signaling. In contrast, knockdown of DDAH1 produced the opposite effect. These findings suggest that DDAH1 functions as a tumor suppressor in GC and may be exploited as a diagnostic and prognostic biomarker for GC.

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Section: Discussionmentioning

confidence: 99%

DDAH1 mediates gastric cancer cell invasion and metastasis via Wnt/β‐catenin signaling pathway

et al. 2017

Molecular Oncology

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“…On the other hand, nuclear b-catenin is correlated with an invasive phenotype in intestinal-type tumors [198] . This increase in tumor invasion is likely mediated by the upregulation of Wnt transcriptional targets, such as EphA2 (erythropoietin-producing hepatocellular) and membrane type 3 matrix metalloproteinase (MT3-MMP) genes [199,200] . Furthermore, evidence provided by Kim et al [201,202] suggests that TC1 (C8orf4), which is upregulated in high-grade gastric cancers, coordinates the upregulation of Wnt/b-catenin target genes involved in the aggressive biological behavior and poor clinical outcome observed in advanced gastric cancer [202,203] .…”

Section: Wnt/b-catenin Signaling and Metastatic Potential In Gastric mentioning

confidence: 99%

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

Chiurillo

2015

WJEM

254

214

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Gastric cancer remains one of the most common cancers worldwide and one of the leading cause for cancerrelated deaths. Gastric adenocarcinoma is a multifactorial disease that is genetically, cytologically and architecturally more heterogeneous than other gastrointestinal carcinomas. The identification of specific membrane, intracellular, and extracellular components of the Wnt pathway has revealed potential targets for gastric cancer therapy. High-throughput "omics" approaches will help in the search for Wnt pathway antagonist in the near future.

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“…Expression of EphA1 and EphA2 is associated with poor prognosis in gastric cancer. 115,116 Increased EphA1 expression significantly correlated with increased tumor grade and lymph node metastasis and decreased cumulative survival in gastric carcinomas. Ephrin-A1 mRNA transcripts independently predicted poor prognosis in colorectal cancer patients and knockdown of this ligand inhibited proliferation and migration of colon carcinoma cell lines.…”

Section: Eph Receptor and Ephrin Signaling In Gastrointestinal Diseasementioning

confidence: 99%

Eph receptor and ephrin function in breast, gut, and skin epithelia

White¹,

Getsios

2014

Cell Adhesion & Migration

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Abbreviations: ADAM, a disintegrin and metalloprotease; Apc, adenomatous polyposis coli; Eph, erythropoietin-producing hepatocellular; ER, estrogen receptor; Erk, extracellular signal-regulated kinase; GEF, guanine nucleotide exchange factor; GPI, glycosylphosphatidylinositol; HER2, human epidermal growth factor receptor 2; HGF, hepatocyte growth factor; IBD, inflammatory bowel disease; KLF, Kr€ uppel-like factor; MAPK, mitogen-activated protein kinase; MMTV-LTR, mouse mammary tumor virus-long terminal repeat; MT1-MMP, membrane-type 1 matrix metalloproteinase; PDZ, postsynaptic density protein 95, discs large 1, and zonula occludens-1; PTP, protein tyrosine phosphatase; RTK, receptor tyrosine kinase; SH2, Src homology 2; SHIP2, SH2 inositol phosphatase 2; SLAP, Src-like adaptor protein; TCF, T-cell specific transcription factor; TEB, terminal end bud; TNFa, tumor necrosis factor a:Epithelial cells are tightly coupled together through specialized intercellular junctions, including adherens junctions, desmosomes, tight junctions, and gap junctions. A growing body of evidence suggests epithelial cells also directly exchange information at cell-cell contacts via the Eph family of receptor tyrosine kinases and their membrane-associated ephrin ligands. Ligand-dependent and -independent signaling via Eph receptors as well as reverse signaling through ephrins impact epithelial tissue homeostasis by organizing stem cell compartments and regulating cell proliferation, migration, adhesion, differentiation, and survival. This review focuses on breast, gut, and skin epithelia as representative examples for how Eph receptors and ephrins modulate diverse epithelial cell responses in a context-dependent manner. Abnormal Eph receptor and ephrin signaling is implicated in a variety of epithelial diseases raising the intriguing possibility that this cellcell communication pathway can be therapeutically harnessed to normalize epithelial function in pathological settings like cancer or chronic inflammation.

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EphA2 promotes epithelial–mesenchymal transition through the Wnt/β-catenin pathway in gastric cancer cells

Cited by 176 publications

References 32 publications

DDAH1 mediates gastric cancer cell invasion and metastasis via Wnt/β‐catenin signaling pathway

DDAH1 mediates gastric cancer cell invasion and metastasis via Wnt/β‐catenin signaling pathway

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

Eph receptor and ephrin function in breast, gut, and skin epithelia

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