Elucidating the mechanisms to induce ameloblastoma and its trial for the clinical setting
| Project/Area Number |
20K09906
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 57020:Oral pathobiological science-related
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
清島 保 九州大学, 歯学研究院, 教授 (20264054)
自見 英治郎 九州大学, 歯学研究院, 教授 (40276598)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | Arl4c / エナメル上皮腫 / BRAF V600E / Raf1 / 破骨細胞 / ARL4C / BRAFV600E |
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| Outline of Research at the Start |
「エナメル上皮腫におけるArl4cの機能解析とその臨床応用」を目指し、以下の2点を明らかにすることを計画している。
①エナメル上皮腫の腫瘍形成・破骨細胞誘導におけるArl4cの機能の解明
②モデル動物を用いたArl4cを標的とするエナメル上皮腫の抗腫瘍効果の解析
申請者らが同定した新規がん関連遺伝子Arl4cのエナメル上皮腫における機能解析を行い、Arl4cを分子標的とした新規治療法の開発を目指す点が本研究の概要である。
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| Outline of Final Research Achievements |
Ameloblastoma is an odontogenic neoplasm characterized by slow intraosseous growth with progressive jaw resorption. Recent reports revealed that ameloblastoma harbors an oncogenic BRAF V600E mutation with MAPK pathway activation. However, the precise mechanism by which MAPK pathway induces ameloblastoma is unclear. In immunohistochemical analyses of tissue specimens obtained from ameloblastoma patients, ARL4C was frequently expressed with both BRAF V600E and RAF1. ARL4C-depleted tumour cells exhibited decreased proliferation and migration capabilities. Finally, when ameloblastoma cells were co-cultured with mouse bone marrow cells and primary osteoblasts, ameloblastoma cells induced osteoclast formation. ARL4C elevation in ameloblastoma further promoted its formation capabilities. These results suggest that the RAF1-MEK/ERK-ARL4C axis, which may function in cooperation with the BRAF V600E-MEK/ERK pathway, promotes ameloblastoma development.
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| Academic Significance and Societal Importance of the Research Achievements |
エナメル上皮腫は口腔特有の良性腫瘍であるが、臨床的には良性腫瘍の範疇をこえるような病態を呈することがある。本研究において、エナメル上皮腫では、少なくとも2種類のシグナル伝達が活性化していることを見出した。本研究結果より、臨床の病態に関連するエナメル上皮種の新たな病因論が明らかになったと考えられた。BRAF V600E阻害剤はすでに皮膚癌に応用されており、エナメル上皮腫にも適応されつつある。より効果的な治療効果をもたらすためには、RAF1阻害剤の併用が望まれる。本研究成果はエナメル上皮腫の新たな診断方法や予後の判定法の確立および治療への応用に発展できると考えられる。
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Report
(4 results)
Research Products
(29 results)
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[Journal Article] The Semaphorin 3A-AKT axis-mediated cell proliferation in salivary gland morphogenesis and adenoid cystic carcinoma pathogenesis.2022
Author(s)
Fujii S, Fujimoto T, Hasegawa K, Nagano R, Ishibashi T, Kurppa KJ, Mikami Y, Kokura M, Tajiri Y, Kibe T, Wada H, Wada N, Kishida S, Higuchi Y, Kiyoshima T.
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Journal Title
Pathol Res Pract.
Volume: 236
Pages: 153991-153991
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] RAF1-MEK/ERK pathway-dependent ARL4C expression promotes ameloblastoma cell proliferation and osteoclast formation.2021
Author(s)
Fujii S, Ishibashi T, Kokura M, Fujimoto T, Matsumoto S, Shidara S, Kurppa KJ, Pape J, Caton J, Morgan PR, Heikinheimo K, Kikuchi A, Jimi E, Kiyoshima T.
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Journal Title
J Pathol.
Volume: 256(1)
Issue: 1
Pages: 119-133
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] RAF1-MEK/ERK pathway-dependent ARL4C expression promotes ameloblastoma cell proliferation and osteoclast formation2022
Author(s)
Shinsuke Fujii, Takuma Ishibashi, Megumi Kokura, Tatsufumi Fujimoto, Shinji Matsumoto, Satsuki Shidara, Kari J Kurppa, Judith Pape, Javier Caton, Peter R Morgan, Kristiina Heikinheimo, Akira Kikuchi, Eijiro Jimi, Tamotsu Kiyoshima
Organizer
TMD 2022 14th Tooth Morphogenesis and Differentitaton
Related Report
Int'l Joint Research
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