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Wnt/β-catenin-YAP axis may be involved in primary intraosseous carcinoma, NOS, arising from odontogenic keratocyst

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 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 between the odontogenic keratocyst and the carcinoma. The tumorous lesion of this PIOC exhibited malignant potentials with an invasive growth of carcinoma cells 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 tumorous 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 tumorous lesion. A DNA microarray and gene ontology analysis demonstrated that numerous gene expression variations and signal activation, including Notch signaling, were altered in non-tumor and tumor lesions within this 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 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 development of PIOC arising from odontogenic keratocyst in which YAP signaling is activated.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253232 | GEO | 2024/01/26

REPOSITORIES: GEO

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Project description:Carcinogenesis is a multistep process in which cells accumulate multiple genetic alterations, as they progress to a more malignant phenotype. It has been proposed that sequential accumulation of gene abnormalities in specific genes drives the transition from non-tumorous epithelia through preneoplastic lesion/benign tumor to cancer. Histologically, progression to invasive oral squamous cell carcinoma (OSCC) follows multistep ordered series beginning with mucosal epithelial cell hyperplasia, followed by dysplasia, carcinoma in situ and invasive carcinoma. It is therefore speculated that genetic alterations-mediated multistep carcinogenesis would be involved in OSCC development, but their detailed molecular mechanisms are unknown. Herein, we clarified the comprehensive gene expression patterns and carried out an enrichment analysis using DNA microarray data obtained from an OSCC pathological specimen, which consists of non-tumor region, carcinoma in situ lesion and invasive carcinoma lesion. Numerous numbers of gene expression and signal activation were altered in the OSCC development. Of them, the expression of p63 was increased and MEK/ERK-MAPK pathway was activated in carcinoma in situ lesion as well as in invasive carcinoma lesion. Immunohistochemical analyses revealed that p63 was initially upregulated in carcinoma in situ lesions and ERK was sequentially activated in invasive carcinoma lesions in OSCC specimens. ADP-ribosylation factor (ARF)-like 4c (ARL4C), the expression of which is reportedly induced by p63 and/or MEK/ERK-MAPK pathway in OSCC cells, has been shown to promote tumorigenesis. Immunohistochemically, in OSCC specimens, ARL4C was more frequently detected in tumor lesions, especially in invasive carcinoma lesions than in carcinoma in situ lesions. Additionally, ARL4C and phosphorylated ERK were merged at high frequency in invasive carcinoma lesions. Loss-of-function experiments using inhibitors and siRNAs revealed that p63 and EGFR-MEK/ERK-MAPK cooperatively induce ARL4C expression in OSCC cells. These results suggest that the stepwise activation of p63 and EGFR-MEK/ERK-MAPK contributes to OSCC tumor cell growth though regulation of ARL4C expression.

Project description:Murine tooth germ development proceeds in continuous and sequential steps with reciprocal interactions between the odontogenic epithelium and the adjacent mesenchyme, and several growth factor signaling and their activation are required for tooth germ development. The expression of ADP-ribosylation factor (Arf)-like 4c (Arl4c) has been shown to induce cell proliferation, thereby involving in epithelial morphogenesis and tumorigenesis. However, other functions of Arl4c except for cellular growth are largely unknown. Although we recently demonstrated the involvement of the upregulated expression of Arl4c in cell proliferation of ameloblastoma, which has the same origin as odontogenic epithelium, its effect on tooth germ development remains unclear. Herein, single-cell RNA sequencing (scRNA-seq) analysis revealed that the expression of Arl4c, among 17 members of the Arf-family members, was specifically detected in odontogenic epithelial cells, such as stratum intermedium, stella reticulum and outer enamel epithelium, of postnatal day 1 (P1) mouse molar. In addition, scRNA-seq analysis showed higher expression of Arl4c in non-ameloblast and inner enamel epithelium, which include immature cells. In the mouse tooth germ rudiments culture, treatment with SecinH3 (an inhibitor of ARNO/Arf6 pathway) reduced the size, width and cusp height and the thickness of eosinophilic layer, which would involve the synthesis of dentin and enamel matrix organization. In addition, loss-of-function experiments using siRNAs and shRNA revealed that Arl4c expression was involved in cell proliferation and osteoblastic cytodifferentiation in odontogenic epithelial cells. Finally, RNA-seq analysis with gene set enrichment analyses (GSEA) and Gene Ontology (GO) analysis showed that osteoblastic differentiation-related gene set and/or GO terms were downregulated in shArl4c expressing odontogenic epithelial cells. These results suggest that the Arl4c-ARNO/Arf6 pathway axis contributes to tooth germ development through osteoblastic differentiation.

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Wnt/β-catenin-YAP axis may be involved in primary intraosseous carcinoma, NOS, arising from odontogenic keratocyst

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