Abstract
Oral squamous cell carcinoma (OSCC), which accounts for nearly 90% of head and neck cancers, is characterized by a poor prognosis and a low survival rate. Vascular endothelial growth factor-C (VEGF-C) has been implicated in lymphangiogenesis and is correlated with cancer metastasis. WNT1-inducible signaling pathway protein-1 (WISP)-1/CCN4 is an extracellular matrix-related protein that belongs to the CCN family and stimulates many biological functions. Our previous studies showed that WISP-1 plays an important role in OSCC migration and angiogenesis. However, the effect of WISP-1 on VEGF-C regulation and lymphangiogenesis in OSCC is poorly understood. Here, we showed a correlation between WISP-1 and VEGF-C in tissue specimens from patients with OSCC. To examine the lymphangiogenic effect of WISP-1, we used human lymphatic endothelial cells (LECs) to mimic lymphatic vessel formation. The results showed that conditioned media from WISP-1-treated OSCC cells promoted tube formation and cell migration in LECs. We also found that WISP-1-induced VEGF-C is mediated via the integrin αvβ3/integrin-linked kinase (ILK)/Akt signaling pathway. In addition, the expression of microRNA-300 (miR-300) was inhibited by WISP-1 via the integrin αvβ3/ILK/Akt cascade. Collectively, these results reveal the detailed mechanism by which WISP-1 promotes lymphangiogenesis via upregulation of VEGF-C expression in OSCC. Therefore, WISP-1 could serve as therapeutic target to prevent metastasis and lymphangiogenesis in OSCC.
Keywords:
OSCC; VEGF-C; WISP-1; lymphangiogenesis; miR-300.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions / genetics
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Blotting, Western
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CCN Intercellular Signaling Proteins / genetics*
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CCN Intercellular Signaling Proteins / metabolism
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CCN Intercellular Signaling Proteins / pharmacology
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Carcinoma, Squamous Cell / genetics*
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Cell Line
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Movement / genetics
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Culture Media, Conditioned / pharmacology
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Immunohistochemistry
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Integrin alphaVbeta3 / metabolism
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Lymphangiogenesis / drug effects
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Lymphangiogenesis / genetics*
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Lymphatic Vessels / drug effects
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Lymphatic Vessels / metabolism
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MicroRNAs / genetics*
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Mouth Neoplasms / genetics*
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Mouth Neoplasms / metabolism
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Mouth Neoplasms / pathology
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Vascular Endothelial Growth Factor C / genetics*
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Vascular Endothelial Growth Factor C / metabolism
Substances
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3' Untranslated Regions
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CCN Intercellular Signaling Proteins
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CCN4 protein, human
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Culture Media, Conditioned
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Integrin alphaVbeta3
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MIRN300 microRNA, human
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MicroRNAs
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Proto-Oncogene Proteins
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Vascular Endothelial Growth Factor C
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integrin-linked kinase
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt