2022 Fiscal Year Final Research Report

Elucidating the mechanisms to induce ameloblastoma and its trial for the clinical setting

Research Project

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Project/Area Number	20K09906
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 57020:Oral pathobiological science-related
Research Institution	Kyushu University
Principal Investigator	Fujii Shinsuke 九州大学, 歯学研究院, 講師 (60452786)
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)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	Arl4c / エナメル上皮腫 / BRAF V600E / Raf1
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.
Free Research Field	口腔病理学
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。