Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma

• Subarnbhesaj, Ajiravudh

• Miyauchi, Mutsumi

• Chanbora, Chea

• Mikuriya, Aki

• Nguyen, Phuong Thao

• Furusho, Hisako

• Ayuningtyas, Nurina Febriyanti

• Fujita, Minoru

• Toratani, Shigeaki

• Takechi, Masaaki

• Niida, Shumpei

• Takata, Takashi

• Sakamuri V. Reddy

  editor

抄録

Background: Vascular endothelial growth factor (VEGF) is a highly specific signaling protein for vascular endothelial cells that plays a critical role in tumor growth and invasion through angiogenesis, and may contribute to cell migration and activation of pre-osteoclasts, osteoclasts and some tumor cells. Objectives: We aimed to clarify the detailed roles of VEGF-Flt-1 signaling in bone invasion of oral squamous cell carcinoma (OSCC) cells. Results: Forty-two (42) of 54 cases with gingival SCC (77.8%) strongly expressed VEGF, and had a significantly increased number of Flt-1+ osteoclasts (p<0.01) and more aggressive bone invasion (p<0.05). PlGF, a ligand of Flt-1, induced osteoclastogenesis in single culture of bone marrow cells (BMCs), and inhibition of Flt-1-signaling by VEGF tyrosine kinase inhibitor and It’s down stream (Akt and ERK1/2) inhibitos reduced osteoclastogenesis in PlGF-stimulated BMCs (p<0.01). In molecular level, PlGF stimulation significantly upregulated RANKL expression in Flt-1-expressing HSC2 cells via phosphorylation of Akt and ERK1/2. In the co-culture of VEGF-producing HSC2 cells and BMCs, number of TRAP-positive osteoclasts markedly increased (p<0.01). The osteoclastogenesis was significantly inhibited by RANKL-neutralizing antibody (p<0.01) as well as by VEGF tyrosine kinase inhibitor (p<0.01) and it’s downstream (Akt and ERK1/2) inhibitors (p<0.01, p<0.05, respectively). Conclusion: VEGF-Flt-1 signaling induces osteoclastogenesis in OSCC through two possible ways: 1) VEGF produced from OSCC cells can directly stimulate the Flt-1 pathway in preosteoclasts to induce migration to future bone resorbing area and differentiation into osteoclasts, and 2) VEGF-Flt-1 signaling upregulates RANKL expression in OSCC cells, which indirectly leads to osteoclast differentiation. Therefore, blocking of the VEGF-Flt-1 signaling may help inhibit bone invasion of OSCC.

収録刊行物

• PLoS ONE

  PLoS ONE 12 (11), e0187092-, 2017-11-17

  Public Library of Science

キーワード

• Multidisciplinary

詳細情報

• CRID: 1050014791007683200
• NII論文ID: 120006799373
• DOI: 10.1371/journal.pone.0187092
• ISSN: 19326203
• Web Site: http://ir.lib.hiroshima-u.ac.jp/00048681
• Web Site: http://dx.plos.org/10.1371/journal.pone.0187092
• 本文言語コード: en
• 資料種別: journal article
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