Immunohistochemical demonstration of EphA2 processing by MT1-MMP in invasive cutaneous squamous cell carcinoma

Tatsukawa, Ryoko; Koga, Kaori; Aoki, Mikiko; Koshikawa, Naohiko; Imafuku, Shinichi; Nakayama, Juichiro; Nabeshima, Kazuki

doi:10.1007/s00428-016-1934-9

Cited by 8 publications

(9 citation statements)

References 36 publications

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“…In situ PLA was used to assess protein-protein interactions. Cells grown on 8-well culture slides (Nunc Lab-Tek chamber Slide System, ThermoFisher scientific), were immediately fixed and subjected to in situ PLA using the Duolink detection kit (Sigma-Aldrich, St. Louis, MO) according to the manufacturer’s instructions and described previously [22]. After blocking, slides were incubated with mouse anti-Emmprin (1:100; R&D) or rabbit anti-CD73 (1:100; GeneTex, Irvine, CA) primary antibodies.…”

Section: Methodsmentioning

confidence: 99%

CD73 complexes with emmprin to regulate MMP-2 production from co-cultured sarcoma cells and fibroblasts

et al. 2019

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Background Interaction between cancer cells and fibroblasts mediated by extracellular matrix metalloproteinase inducer (emmprin, CD147) is important in the invasion and proliferation of cancer cells. However, the exact mechanism of emmprin mediated stimulation of matrix metalloprotease-2 (MMP-2) production from fibroblasts has not been elucidated. Our previous studies using an inhibitory peptide against emmprin suggested the presence of a molecule on the cell membrane which forms a complex with emmprin. Here we show that CD73 expressed on fibroblasts interacts with emmprin and is a required factor for MMP-2 production in co-cultures of sarcoma cells with fibroblasts. Methods CD73 along with CD99 was identified by mass spectrometry analysis as an emmprin interacting molecule from a co-culture of cancer cells (epithelioid sarcoma cell line FU-EPS-1) and fibroblasts (immortalized fibroblasts cell line ST353i). MMP-2 production was measured by immunoblot and ELISA. The formation of complexes of CD73 with emmprin was confirmed by immunoprecipitation, and their co-localization in tumor cells and fibroblasts was shown by fluorescent immunostaining and proximity ligation assays. Results Stimulated MMP-2 production in co-culture of cancer cells and fibroblasts was completely suppressed by siRNA knockdown of CD73, but not by CD99 knockdown. MMP-2 production was not suppressed by CD73-specific enzyme inhibitor (APCP). However, MMP-2 production was decreased by CD73 neutralizing antibodies, suggesting that CD73-mediated suppression of MMP-2 production is non-enzymatic. In human epithelioid sarcoma tissues, emmprin was immunohistochemically detected to be mainly expressed in tumor cells, and CD73 was expressed in fibroblasts and tumor cells: emmprin and CD73 were co-localized predominantly on tumor cells. Conclusion This study provides a novel insight into the role of CD73 in emmprin-mediated regulation of MMP-2 production.

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Section: Methodsmentioning

confidence: 99%

CD73 complexes with emmprin to regulate MMP-2 production from co-cultured sarcoma cells and fibroblasts

et al. 2019

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“…48) Moreover, in human invasive cutaneous squamous cell carcinoma tissue, EphA2 was also reported to be processed by MT1-MMP, and cleaved EphA2 was positively related to lymph node metastasis. 59) Therefore, the noncanonical pathway of EphA2 appears to play pivotal functions in MT1-MMP-expressing human tumor microenvironments.…”

Section: Cell Motility and Cell Morphologymentioning

confidence: 99%

Emerging and Diverse Functions of the EphA2 Noncanonical Pathway in Cancer Progression

Zhou

Sakurai

2017

Biological & Pharmaceutical Bulletin

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Erythropoietin-producing hepatocellular receptor A2 (EphA2) receptor tyrosine kinase controls multiple physiological processes to maintain homeostasis in normal cells. In many types of solid tumors, it has been reported that EphA2 is overexpressed and plays a critical role in oncogenic signaling. However, in recent years, the opposing functions of EphA2 have been explained by the canonical and noncanonical signaling pathways. Ligand-and tyrosine kinase-dependent EphA2 activation (the canonical pathway) inhibits cancer cell proliferation and motility. In contrast, ligand-and tyrosine kinase-independent EphA2 signaling (the noncanonical pathway) promotes tumor survival and metastasis and controls acquired drug resistance and maintenance of cancer stem cell-like properties. Evidence has accumulated showing that the EphA2 noncanonical pathway is mainly regulated by inflammatory cytokines and growth factors via phosphorylation at Ser-897 in the intracellular C-tail region via some serine/threonine kinases, including p90 ribosomal S6 kinase. In this review, we focus on the regulation of Ser-897 phosphorylation and its functional importance in tumor malignancy and discuss future therapeutic targeting.

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“…Usually, EphA2 is expressed at low levels in normal epithelial cells [ 6 ], whereas high levels of EphA2 have been observed in many solid tumors. Growing evidence indicate that EphA2 plays an important role in cellular transformation, primary tumor initiation, progression, and angiogenesis, and tumor invasion [ 7 – 9 ].…”

Section: Introductionmentioning

confidence: 99%

miR-302b inhibits tumorigenesis by targeting EphA2 via Wnt/ β-catenin/EMT signaling cascade in gastric cancer

Huang¹,

He²,

McLeod³

et al. 2017

BMC Cancer

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BackgroundEphA2 is a crucial oncogene in gastric cancer (GC) development and metastasis, this study aims to identify microRNAs that target it and serve as key regulators of gastric carcinogenesis.MethodsWe identified several potential microRNAs targeting EphA2 by bioinformatics websites and then analyzed the role of miR-302b in modulating EphA2 in vitro and in vivo of GC, and it’s mechanism.ResultsOur analysis identified miR-302b, a novel regulator of EphA2, as one of the most significantly downregulated microRNA (miRNA) in GC tissues. Overexpression of miR-302b impaired GC cell migratory and invasive properties robustly and suppressed cell proliferation by arresting cells at G0–G1 phase in vitro. miR-302b exhibited anti-tumor activity by reversing EphA2 regulation, which relayed a signaling transduction cascade that attenuated the functions of N-cadherin, β-catenin, and Snail (markers of Wnt/β-catenin and epithelial-mesenchymal transition, EMT). This modulation of EphA2 also had distinct effects on cell proliferation and migration in GC in vivo.ConclusionsmiR-302b serves as a critical suppressor of GC cell tumorigenesis and metastasis by targeting the EphA2/Wnt/β-catenin/EMT pathway.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3875-3) contains supplementary material, which is available to authorized users.

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Immunohistochemical demonstration of EphA2 processing by MT1-MMP in invasive cutaneous squamous cell carcinoma

Cited by 8 publications

References 36 publications

CD73 complexes with emmprin to regulate MMP-2 production from co-cultured sarcoma cells and fibroblasts

CD73 complexes with emmprin to regulate MMP-2 production from co-cultured sarcoma cells and fibroblasts

Emerging and Diverse Functions of the EphA2 Noncanonical Pathway in Cancer Progression

miR-302b inhibits tumorigenesis by targeting EphA2 via Wnt/ β-catenin/EMT signaling cascade in gastric cancer

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