title: WISP-1 promotes VEGF-C-dependent lymphangiogenesis by inhibiting miR-300 in human oral squamous cell carcinoma cells.
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.
authors.affiliation: Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Ching-Chia
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Po-Chun
authors.initials: PC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Ming-Yu
authors.initials: MY
authors.lastname: Lein
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Ching-Wen
authors.initials: CW
authors.lastname: Tsao
authors.affiliation: Sing Wang Animal Hospital, Taichung, Taiwan.
authors.forename: Chiu-Chen
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
authors.forename: Shih-Wei
authors.initials: SW
authors.lastname: Wang
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.|Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
authors.affiliation: Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Kwong-Chung
authors.initials: KC
authors.lastname: Tung
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D015153:Blotting, Western; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D017077:Culture Media, Conditioned / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D042583:Lymphangiogenesis / Q000187:drug effects / Q000235:genetics*; D042601:Lymphatic Vessels / Q000187:drug effects / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics* / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D020413:3' Untranslated Regions; D055511:CCN Intercellular Signaling Proteins; D017077:Culture Media, Conditioned; D039302:Integrin alphaVbeta3; D035683:MicroRNAs; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D042582:Vascular Endothelial Growth Factor C; D000099200:Scaffold Protein ILK; C116396:CCN4 protein, human; C000596512:MIRN300 microRNA, human
keywords: OSCC; VEGF-C; WISP-1; lymphangiogenesis; miR-300
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