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ID 48681
本文ファイル
著者
Subarnbhesaj, Ajiravudh
Miyauchi, Mutsumi 大学院医歯薬保健学研究科(歯) 広大研究者総覧
Chanbora, Chea
Mikuriya, Aki
Nguyen, Phuong Thao
Furusho, Hisako 大学院医歯薬保健学研究科(歯) 広大研究者総覧
Ayuningtyas, Nurina Febriyanti
Fujita, Minoru 大学院医歯薬保健学研究科(歯)
Toratani, Shigeaki 大学院医歯薬保健学研究科(歯) 広大研究者総覧
Takechi, Masaaki 大学院医歯薬保健学研究科(歯) 広大研究者総覧
Niida, Shumpei
抄録(英)
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.
内容記述
This work was supported by Grants-in-Aid for scientific research (A) from the Ministry of Education, Science and Culture (#21249088 [T.T.]).
掲載誌名
PLoS ONE
12巻
11号
開始ページ
e0187092
出版年月日
2017-11-17
出版者
Public Library of Science
ISSN
1932-6203
出版者DOI
PubMedID
言語
英語
NII資源タイプ
学術雑誌論文
広大資料タイプ
学術雑誌論文
DCMIタイプ
text
フォーマット
application/pdf
著者版フラグ
publisher
権利情報
2017 Subarnbhesaj et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
関連情報URL
部局名
医歯薬保健学研究科