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Development of oral cancer therapy using exosome-derived miRNAs that regulate HBp17/FGFBP

Research Project

Project/Area Number 19K10332
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 57060:Surgical dentistry-related
Research InstitutionHiroshima University

Principal Investigator

Shintani Tomoaki  広島大学, 病院(歯), 講師 (90403518)

Co-Investigator(Kenkyū-buntansha) 岡本 哲治  東亜大学, その他の研究科, 教授 (00169153)
林堂 安貴  広島大学, 病院(歯), 講師 (70243251)
Project Period (FY) 2019-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords微小環境 / 血管新生 / エクソソーム / 活性化ビタミンD3 / NF kappa b / micro RNA / MicroRNA / miR-6887-5p / HBp17/FGFBP-1 / microRNA
Outline of Research at the Start

活性型ビタミンD3の異性体であるED-71が、転写因子NF-κBシグナル伝達経路を抑制することにより,扁平上皮癌(SCC)/細胞口腔扁平上皮癌(OSCC)細胞のHBp17/FGFBP 発現が抑制された。さらに、in vitroおよびin vivoにおけるSCC/OSCC細胞の増殖抑制効果が認められた。
ED-71添加群および非添加群のA431細胞の培養上清より、exosomeを分離した。miRNAマイクロアレイ法を用いて、exosomal miRNAs発現の網羅的解析を行った結果、ED-71により発現量が2倍以上増加する12種類のexosomal miRNAsを同定した。

Outline of Final Research Achievements

We have previously reported that Eldecalcitol (ED-71), an analog of 1α,25(OH)2D3, downregulated the expression of HBp17/FGFBP-1 and inhibited the proliferation of squamous cell carcinoma (SCC) cells in vitro and in vivo through NF-κb inhibition. To explore the possibility of microRNA (miRNA) control of HBp17/FGFBP-1, we analyzed exosomal miRNAs from medium conditioned by A431 cells treated with ED-71. Microarray analysis revealed that 12 exosomal miRNAs were upregulated in ED-71-treated A431 cells. MiR-6887-5p was identified to have a predicted mRNA target matching the 3'-UTR of HBp17/FGFBP-1. The 3'-UTR of HBp17/FGFBP-1 was confirmed to be a direct target of miR-6887-5p in SCC/OSCC cells, as assessed with a luciferase reporter assay. Functional assessment revealed that overexpression of miR-6887-5p in SCC/OSCC cells inhibited cell proliferation and colony formation in vitro, and inhibited tumor growth in vivo compared with control.

Academic Significance and Societal Importance of the Research Achievements

我々は、ED-71がSCC/OSCC細胞のエクソソームmiR-6887-5pを刺激すること、そしてmiR-6887-5pがHBp17/FGFBP-1を直接標的とすることにより、in vitroおよびin vivoでの腫瘍増殖、SCC/OSCC細胞のコロニー形成を抑制することを報告した。我々の知見は、エクソソームmiR-6887-5pが、1α,25(OH)2D3およびそのアナログの高カルシウム血症効果を回避しつつ、HBp17/FGFBP-1を標的とするSCC腫瘍の治療薬となることを示唆している。

Report

(6 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report

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Published: 2019-04-18   Modified: 2025-01-30  

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