| 1. |
Shinsuke Fujii, Kana Hasegawa, Takashi Maehara, Kari J Kurppa, Kristiina Heikinheimo, Kristy A. Warner, Satoshi Maruyama, Yudai Tajiri, Jacques E. Nör, Jun-ichi Tanuma, Shintaro Kawano, Tamotsu Kiyoshima, Wnt/β-catenin-C-kit axis may play a role in adenoid cystic carcinoma prognostication, Pathology - Research and Practice, 10.1016/j.prp.2024.155148, 155148-155148, 2024.01. |
| 2. |
Thinh Thi Kim Truong, Shinsuke Fujii, Ryoko Nagano, Kana Hasegawa, Megumi Kokura, Yuta Chiba, Keigo Yoshizaki, Satoshi Fukumoto, Tamotsu Kiyoshima, Arl4c is involved in tooth germ development through osteoblastic/ameloblastic differentiation., Biochemical and biophysical research communications, 10.1016/j.bbrc.2023.09.014, 679, 167-174, 2023.09, Murine tooth germ development proceeds in continuous sequential steps with reciprocal interactions between the odontogenic epithelium and the adjacent mesenchyme, and several growth factor signaling pathways 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, and is thereby involved in epithelial morphogenesis and tumorigenesis. In contrast, the other functions of Arl4c (in addition to cellular growth) are largely unknown. Although we recently demonstrated the involvement of the upregulated expression of Arl4c in the proliferation of ameloblastomas, which have the same origin as odontogenic epithelium, its effect on tooth germ development remains unclear. In the present study, single-cell RNA sequencing (scRNA-seq) analysis revealed that the expression of Arl4c, among 17 members of the Arf-family, was specifically detected in odontogenic epithelial cells, such as those of the stratum intermedium, stellate reticulum and outer enamel epithelium, of postnatal day 1 (P1) mouse molars. scRNA-seq analysis also demonstrated the higher expression of Arl4c in non-ameloblast and inner enamel epithelium, which include immature cells, of P7 mouse incisors. In the mouse tooth germ rudiment culture, treatment with SecinH3 (an inhibitor of the ARNO/Arf6 pathway) reduced the size, width and cusp height of the tooth germ and the thickness of the 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 the expression of Arl4c was involved in cell proliferation and osteoblastic cytodifferentiation in odontogenic epithelial cells. Finally, RNA-seq analysis with a gene set enrichment analysis (GSEA) and Gene Ontology (GO) analysis showed that osteoblastic differentiation-related gene sets 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/ameloblastic differentiation.. |
| 3. |
Shinsuke Fujii, Tamotsu Kiyoshima, The role of Wnt, ARL4C, and Sema3A in developmental process and disease pathogenesis., Pathology international, 10.1111/pin.13325, 73, 6, 217-233, 2023.06, Various types of tumors, including malignant and benign ones, occur in the oral cavity. These arise from the mucosal epithelium, odontogenic epithelium, and salivary gland. To date, few major driver events in oral tumors have been identified. Accordingly, molecular targets in anti-tumor therapy for oral tumors are lacking. We focused on elucidating the function of aberrantly activated signal transduction related to oral tumor formation, especially in oral squamous cell carcinoma, ameloblastoma, and adenoid cystic carcinoma, which are raised as common oral tumors. Wnt/β-catenin-dependent pathway is involved in the developmental process, organ homeostasis and disease pathogenesis through regulating various cellular functions by enhancing transcriptional activity. Recently, we identified ADP-ribosylation factor (ARF)-like 4c (ARL4C) and Semaphorin 3A (Sema3A), the expression of which is regulated by Wnt/β-catenin-dependent pathway, and characterized their functions in the developmental process and tumor formation. This review highlights the recent advances in understanding the roles of Wnt/β-catenin-dependent pathway, ARL4C and Sema3A, as determined by pathological and experimental studies.. |
| 4. |
Dania Zuhier Ragheb Alkhatib, Thinh Thi Kim Truong, Shinsuke Fujii, Kana Hasegawa, Ryoko Nagano, Yudai Tajiri, Tamotsu Kiyoshima, Stepwise activation of p63 and the MEK/ERK pathway induces the expression of ARL4C to promote oral squamous cell carcinoma cell proliferation., Pathology, research and practice, 10.1016/j.prp.2023.154493, 246, 154493-154493, 2023.06, Carcinogenesis is a multistep process wherein cells accumulate multiple genetic alterations and 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 a preneoplastic lesion/benign tumor to cancer. Histologically, oral squamous cell carcinoma (OSCC) progresses in multiple ordered steps that begin with mucosal epithelial cell hyperplasia, which is followed by dysplasia, carcinoma in situ and invasive carcinoma. It is therefore hypothesized that genetic alteration-mediated multistep carcinogenesis would be involved in the development of OSCC; however, the detailed molecular mechanisms are unknown. We clarified the comprehensive gene expression patterns and carried out an enrichment analysis using DNA microarray data from a pathological specimen of OSCC (including a non-tumor region, carcinoma in situ lesion and invasive carcinoma lesion). The expression of numerous genes and signal activation were altered in the development of OSCC. Among these, the p63 expression was increased and the MEK/ERK-MAPK pathway was activated in carcinoma in situ lesion and in invasive carcinoma lesion. Immunohistochemical analyses revealed that p63 was initially upregulated in carcinoma in situ 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 the 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 frequently merged in invasive carcinoma lesions. Loss-of-function experiments using inhibitors and siRNAs revealed that p63 and MEK/ERK-MAPK cooperatively induce the expression of ARL4C and cell growth in OSCC cells. These results suggest that the stepwise activation of p63 and MEK/ERK-MAPK contributes to OSCC tumor cell growth through regulation of ARL4C expression.. |
| 5. |
Nagano, Ryoko; Fujii, Shinsuke; Hasegawa, Kana; Maeda, Hidefumi; Kiyoshima, Tamotsu, Wnt signaling promotes tooth germ development through YAP1-TGF- βsignaling, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 10.1016/j.bbrc.2022.09.012, 630, 64-70, 2022.11. |
| 6. |
Yurie Mikami, Shinsuke Fujii, Kenichi Kouhashi, Yuichi Yamada, Masafumi Moriyama, Shintarou Kawano, Seiji Nakamura, Yoshinao Oda, Tamotsu Kiyoshima, Low grade myofibroblastic sarcoma arising in the tip of the tongue with intravascular invasion
A case report, Oncology Letters, 10.3892/ol.2018.9115, 16, 3, 3889-3894, 2018.09. |
| 7. |
Mikami Yurie, Fujii Shinsuke, Kengo Nagata, Hiroko Wada, Kana Hasegawa, Misaki Abe, Reiko U. Yoshimoto, Shintaro Kawano, Seiji Nakamura, Tamotsu Kiyoshima, GLI-mediated Keratin 17 expression promotes tumor cell growth through the anti-apoptotic function in oral squamous cell carcinomas., J Cancer Res Clin Oncol, 10.1007/s00432-017-2398-2, 143, 8, 1381-1393, 2017.03. |
| 8. |
Fujii S, Shinjo K, Matsumoto S, Harada T, Nojima S, Sato S, Usami Y, Toyosawa S, Morii E, Kondo Y, Kikuchi A, Epigenetic upregulation of ARL4C, due to DNA hypomethylation in the 3’-untranslated region, promotes tumorigenesis of lung squamous cell carcinoma, Oncotarget, doi: 10.18632/oncotarget.13147., 6, 49, 81571-81587, 2016.10. |
| 9. |
Fujii S, Maeda H, Wada N, Tomokiyo A, Saito M, Akamine A, Investigating a clonal human periodontal ligament progenitor/stem cell line in vitro and in vivo., J Cell Physiol, 215(3):743-749, 2008.03. |
| 10. |
Shinsuke Fujii., Hidefumi Maeda., Naohisa Wada., Yoshio Kano., Akifumi Akamine. , Establishing and characterizing human periodontal ligament fibroblasts immortalized by SV40T-antigen and hTERT gene transfer., Cell and tissue research, 324巻 117-125頁, 2006.01. |
