A1 Refereed original research article in a scientific journal

Wnt/β-catenin-YAP axis in the pathogenesis of primary intraosseous carcinoma NOS, deriving from odontogenic keratocyst




AuthorsNakako, Yusuke; Hasegawa, Kana; Fujii, Shinsuke; Kami, Yukiko; Sakamoto, Taiki; Sakamoto, Mizuki; Moriyama, Masafumi; Kurppa, Kari J.; Heikinheimo, Kristiina; Yoshiura, Kazunori; Kawano, Shintaro; Kiyoshima, Tamotsu

PublisherElsevier

Publication year2024

JournalPathology - Research and Practice

Journal name in sourcePathology, research and practice

Journal acronymPathol Res Pract

Article number155420

Volume260

ISSN0344-0338

eISSN1618-0631

DOIhttps://doi.org/10.1016/j.prp.2024.155420

Web address https://doi.org/10.1016/j.prp.2024.155420

Self-archived copy’s web addresshttps://research.utu.fi/converis/portal/detail/Publication/456965712


Abstract
Odontogenic tumors (OGTs), which originate from cells of odontogenic apparatus and their remnants, are rare entities. Primary intraosseous carcinoma NOS (PIOC), is one of the OGTs, but it is even rarer and has a worse prognosis. The precise characteristics of PIOC, especially in immunohistochemical features and its pathogenesis, remain unclear. We characterized a case of PIOC arising from the left mandible, in which histopathological findings showed a transition from the odontogenic keratocyst to the carcinoma. Remarkably, the tumor lesion of this PIOC prominently exhibits malignant attributes, including invasive growth of carcinoma cell infiltration into the bone tissue, an elevated Ki-67 index, and lower signal for CK13 and higher signal for CK17 compared with the non-tumor region, histopathologically and immunohistopathologically. Further immunohistochemical analyses demonstrated increased expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C) (accompanying expression of β-catenin in the nucleus) and yes-associated protein (YAP) in the tumor lesion. On the other hand, YAP was expressed and the expression of ARL4C was hardly detected in the non-tumor region. In addition, quantitative RT-PCR analysis using RNAs and dot blot analysis using genomic DNA showed the activation of Wnt/β-catenin signaling and epigenetic alterations, such as an increase of 5mC levels and a decrease of 5hmC levels, in the tumor lesion. A DNA microarray and a gene set enrichment analysis demonstrated that various types of intracellular signaling would be activated and several kinds of cellular functions would be altered in the pathogenesis of PIOC. Experiments with the GSK-3 inhibitor revealed that β-catenin pathway increased not only mRNA levels of ankyrin repeat domain1 (ANKRD1) but also protein levels of YAP and transcriptional co-activator with PDZ-binding motif (TAZ) in oral squamous cell carcinoma cell lines. These results suggested that further activation of YAP signaling by Wnt/β-catenin signaling may be associated with the pathogenesis of PIOC deriving from odontogenic keratocyst in which YAP signaling is activated.

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Funding information in the publication
This work was supported by JSPS KAKENHI Grants to S.F. (2023–2025) (JP22KK0262), (2024–2027)(JP24Ko2615), K.H. (2021–2023) (JP21K09843), and T.K. (2023–2026) (JP23H03102), and Takeda Science Foundation, The Shinnihon Foundation of Advanced Medical Treatment Research, The Mochida Memorial Foundation for Medical and Pharmaceutical Research, TERUMO LIFE SCIENCE FOUNDATION and The Ube Industries Foundation to S.F., Takeda Science Foundation and Fukuoka Public Health Promotion Organization Cancer Research Fund and Kaibara Morikazu Medical Science Promotion Foundation to K.H., and Maritza and Reino Salonen Foundation to K.H.


Last updated on 2025-13-02 at 09:50