RAF1–MEK/ERK pathway‐dependent ARL4C expression promotes ameloblastoma cell proliferation and osteoclast formation

Ameloblastoma is an odontogenic neoplasm characterized by slow intraosseous growth with progressive jaw resorption. Recent reports have revealed that ameloblastoma harbours an oncogenic BRAFV600E mutation with mitogen‐activated protein kinase (MAPK) pathway activation and described cases of amelobla...

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Published in:	The Journal of pathology Vol. 256; no. 1; pp. 119 - 133
Main Authors:	Fujii, Shinsuke, Ishibashi, Takuma, Kokura, Megumi, Fujimoto, Tatsufumi, Matsumoto, Shinji, Shidara, Satsuki, Kurppa, Kari J, Pape, Judith, Caton, Javier, Morgan, Peter R, Heikinheimo, Kristiina, Kikuchi, Akira, Jimi, Eijiro, Kiyoshima, Tamotsu
Format:	Journal Article
Language:	English
Published:	Chichester, UK John Wiley & Sons, Ltd 01-01-2022 Wiley Subscription Services, Inc
Subjects:	ADP-Ribosylation Factors - metabolism Ameloblastoma Ameloblastoma - genetics Ameloblastoma - metabolism ARL4C Bone marrow Bone resorption BRAFV600E Catenin Cell growth Cell proliferation Cell Proliferation - genetics Cell Proliferation - physiology Cell Transformation, Neoplastic - genetics Extracellular signal-regulated kinase Extracellular Signal-Regulated MAP Kinases - metabolism Female Gene Expression Regulation, Neoplastic - genetics Humans Jaw Kinases Male MAP kinase MAP Kinase Signaling System - physiology Metabolic pathways Mitogen-Activated Protein Kinase Kinases - metabolism Morphogenesis Mutation Neoplasia Osteoblasts osteoclast formation Osteoclasts - metabolism Osteoclasts - pathology proliferation Protein kinase Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Raf protein RAF1 Ribosylation Signal transduction siRNA TRANCE protein Tumorigenesis Tumors Wnt protein Wnt Signaling Pathway - genetics ARL4C BRAFV600E osteoclast formation proliferation RAF1 ameloblastoma
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Summary:	Ameloblastoma is an odontogenic neoplasm characterized by slow intraosseous growth with progressive jaw resorption. Recent reports have revealed that ameloblastoma harbours an oncogenic BRAFV600E mutation with mitogen‐activated protein kinase (MAPK) pathway activation and described cases of ameloblastoma harbouring a BRAFV600E mutation in which patients were successfully treated with a BRAF inhibitor. Therefore, the MAPK pathway may be involved in the development of ameloblastoma; however, the precise mechanism by which it induces ameloblastoma is unclear. The expression of ADP‐ribosylation factor (ARF)‐like 4c (ARL4C), induced by a combination of the EGF–MAPK pathway and Wnt/β‐catenin signalling, has been shown to induce epithelial morphogenesis. It was also reported that the overexpression of ARL4C, due to alterations in the EGF/RAS–MAPK pathway and Wnt/β‐catenin signalling, promotes tumourigenesis. However, the roles of ARL4C in ameloblastoma are unknown. We investigated the involvement of ARL4C in the development of ameloblastoma. In immunohistochemical analyses of tissue specimens obtained from 38 ameloblastoma patients, ARL4C was hardly detected in non‐tumour regions but tumours frequently showed strong expression of ARL4C, along with the expression of both BRAFV600E and RAF1 (also known as C‐RAF). Loss‐of‐function experiments using inhibitors or siRNAs revealed that ARL4C elevation depended on the RAF1–MEK/ERK pathway in ameloblastoma cells. It was also shown that the RAF1–ARL4C and BRAFV600E–MEK/ERK pathways promoted cell proliferation independently. ARL4C‐depleted tumour cells (generated by knockdown or knockout) 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 through the increased RANKL expression of mouse bone marrow cells and/or primary osteoblasts. These results suggest that the RAF1–MEK/ERK–ARL4C axis, which may function in cooperation with the BRAFV600E–MEK/ERK pathway, promotes ameloblastoma development. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Bibliography:	These authors contributed equally to this work as second authors. No conflicts of interest were declared. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-3417 1096-9896
DOI:	10.1002/path.5814