Kyushu University [Tamotsu Kiyoshima (Professor) Faculty of Dental Science, Department of Dental Science]

Department of Dental Science
Graduate School of Dental Science

Department of Dentistry
School of Dentistry

092-642-6328

092-642-6329

D.D.S., Ph.D.

No

Morphological Oral Biology, Oral pathology

02years01months

1.Regeneration of the tooth
Three approaches as follows is aimed at the regeneration of the tooth.
1) Elucidation of the mechanism in the odontogenesis
2) Analysis the tissue-specific mechanism in aging process
3) Isolation and identification of the tissue-specific stem cells

2.Analysis of differences between oral cancers through cellular and molecular biological approaches
This research is aimed at the development of the new gene therapy method for oral cancer using the gene considered to relate to the profiles of oral cancers.

(Undergraduate School)
Oral pathology: (Lecture) The generalities and the particulars
(Exercise) The explanation of the pathological specimens meeting each unit of a lecture, and the instruction of the observation under a microscope
Outline of the dental and medical science: Introduction of the dental science
Comprehensive dental science
Research exposure: For 3rd and sixth grades

Inspection and exercise are performed to the student who expects experience of research activities in the spring and/or summer vacations, within limited condition that is fully taken the safe side into consideration.

(Graduate School)
The graduate students will study a part of above-mentioned research and write papers on it under instruction to be a "researcher" in the future. Moreover, they will be involved also in autopsy or pathological diagnosis of the oral disease from the department of medical examination so as to understand the fundamentals of pathology.

Research Interests

Molecular and genetic investigation on the development and regeneration of the tooth
keyword : regeneration of the tooth, tooth development, odontogenesis, epithelial-mesenchymal interaction
2000.01Vertebrate organs are typically composed of epithelial and mesenchymal tissues. Signaling between these tissues governs many aspects of odontogenesis, from the initiation of organ development to the terminal differentiation of organ specific cell types. As well as many other embryonic organs, the development and differentiation of the tooth germ depends on such inductive interactions. We previously demonstrated that odontogenesis occurs between embryonic day 10.5 (E10.5) and E12. Based on the histological findings, we performed cDNA subtraction between the E10.5 and E12 mandibles to detect any differentially expressed genes which might be involved in the initiation of odontogenesis. By sequencing, homology search and semi-quantitative RT-PCR, we found about twenty differentially expressed genes in the course of the early developmental stage of the mouse mandible. These genes are functionally related to protein transport, signal transduction, transcription, translation and molecular chaperon activity. To elucidation of the mechanism in the odontogenesis, we are going to characterize these functions with in situ hybridization analyses, analyses of protein interactions (yeast two-hybrid system and reporter assay) and so on. Taken together with data of analysis the tissue-specific mechanism in aging process and isolation/identification of the tissue-specific stem cells, development of method for tooth regeneration is undertaken..
Age-dependent change of the periodontal tissue
keyword : tooth regeneration, periodontal tissue, aging, cell scenesence, protein interaction
2000.01.
Analysis of differentially expressing genes among oral squamous cell carcinomas and gene-associated functions
keyword : oral carcinoma, invasion, metastasis, transcriptional regulation, Protein-Protein Interaction
2000.01We previously established a human carcinoma cell line, MISK81-5 from a metastatic lymph node of oral squamous cell carcinoma. The sMISK was derived from MISK81-5 as a subpopulation having higher tumorigenicity. The analysis of differences between characteristics of the MISK81-5 cell line and its subpopulation, sMISK will be useful for studying the biological behavior of oral squamous cell carcinoma (OSCC). We then performed cDNA subtraction between these cells to detect differentially expressed genes, some of which might be involved in the biological behavior of OSCC. By sequencing, homology search and semi-quantitative RT-PCR, we found differentially expressed genes. These genes are functionally involved in signal transduction, transcription, translation and chromatin reorganization. Compared with those genes expressed in other OSCC and gastric carcinoma cell lines and keratinocytes, expressing pattern in some of these genes was interesting. To characterize the mechanism of carcinogenesis utilized by recombinant proteins based on these genes, we are going to analyze the ability of the proteins to effect on the physical profiles of the OSCC, identify the putative proteins to interact with recombinant proteins, and characterize their promoters with mutational analysis. This research is aimed at the identification of the target genes for the development of the new gene therapy method for oral cancer..

Academic Activities

Reports

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1.

Shinsuke Fujii, Tamotsu Kiyoshima , The role of Wnt, ARL4C, and Sema3A in developmental process and disease pathogenesis, Pathology international., 10.1111/pin.13325, 2023.04, 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..

Papers

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1.	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..
2.	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..
3.	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, 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..
4.	S Kawano, T Hattori, Y Mikami, T Chikui, T Kawazu, T Sakamoto, Y Maruse, S Tanaka, E Hamada, M Hiwatashi, Y Shiraishi, K Oobu, T Kiyoshima, S Nakamura, Prediction of nodal metastasis based on intraoral sonographic findings of the primary lesion in early-stage tongue cancer, International journal of oral and maxillofacial surgery., 10.1016/j.ijom.2022.08.021, 52, 5, 515-523, 2023.05, The aim of this study was to clarify the correlation between imaging findings obtained using intraoral ultrasonography (US) and pathological findings of tongue cancers, and to examine the predictive value of intraoral US findings with respect to occult nodal metastasis. This was a retrospective study based on the medical records of 123 patients with T1-2N0 tongue cancer. The depth of invasion (DOI) on intraoral US was positively correlated with the pathological invasion depth (PID) (ρ = 0.7080, P
5.	RYOKO NAGANO, SHINSUKE FUJII, KANA HASEGAWA, HIDEFUMI MAEDA, TAMOTSU KIYOSHIMA., Wnt signaling promotes tooth germ development through YAP1-TGF-β signaling, Biochemical and biophysical research communications., 10.1016/j.bbrc.2022.09.012, 630, 64-70, 2022.09, Tooth germ development involves continuous and sequential steps with reciprocal interactions between odontogenic epithelium and the adjacent mesenchyme. Several growth factors, including Wnt, are essential for tooth germ development. Molecular mechanisms underlying Wnt/β-catenin-regulated tooth germ development are poorly understood. In tooth germ rudiments culture, we recently demonstrated that Semaphorin 3A (Sema3A), an axonal guidance factor, stimulation reversed Wnt/β-catenin signaling-dependent decreased cell proliferation but did not completely rescue the morphological anomalies of tooth germ, suggesting that an uncharacterized signaling pathway may be essential in Wnt/β-catenin signaling-dependent tooth germ development. Herein, an enrichment analysis using DNA microarray data, which was obtained in our previous research, revealed that Wnt/β-catenin signaling negatively regulates YAP1 and/or TGF-β signalings. In odontogenic epithelial cells and tooth germ rudiments, Wnt/β-catenin signaling activation reduced YAP1 expression, thereby suppressing YAP1 and TGF-β signalings sequentially. Additionally, YAP1 signaling induced TGF-β2 expression to promote TGF-β signaling in the cells. Finally, Wnt/β-catenin signaling-dependent disorganized tooth germ development, in which YAP1 signaling was suppressed, was reversed by TGF-β stimulation. These results suggest that Wnt/β-catenin signaling contributes to the tooth germ development through YAP1-TGF-β signaling..
6.	RYOKO NAGANO, SHINSUKE FUJII, HIROKO WADA, MAYU MATSUMURA-KAWASHIMA, YURIE MIKAMI, MASAFUMI MORIYAMA, TORU CHIKUI, KAZUNORI YOSHIURA, SEIJI NAKAMURA, TAMOTSU KIYOSHIMA., Lipomatous mixed tumor of the skin with cystic formation affecting the upper lip: a case report, Experimental and Therapeutic Medicine, 10.3892/etm.2022.11600, 24, 5, 664, 2022.09, [URL], Mixed tumor of the skin (MTS) is a rare neoplasm derived from the sweat glands with a reported frequency of 0.01-0.098% among all primary skin tumors. MTS often occurs in the head and neck region and is characterized by a mixture of epithelial, myoepithelial and stromal components. MTS also shows various morphological patterns, thus the presence of variants with rare components and its rarity make the clinical diagnosis even more difficult. A 47-year-old man was referred due to a painless, slowly growing, exophytic swelling intracutaneous mass of the upper lip. Magnetic resonance imaging revealed that the mass was a solid tumor with a fatty component in the proximal portion, while the distal portion was cystic and possibly contained highly viscous fluid. The mass was located between the skin and the orbicularis oris muscle in the upper lip. Excisional biopsy was performed and the lesion showed two intriguing features: A tumor with extensive lipomatous stroma and some large cysts. It was histopathologically diagnosed as lipomatous MTS with cystic formation in the upper lip. No evident signs of recurrence were observed during follow-up. The present report describes this case and includes a brief literature review of reported cases in the lip, since MTS can be confused with various skin lesions in clinical settings due to this rarity. Recognition by clinicians of different variants of MTSs, including the present case, is important for preventing erroneous diagnosis and treatment..
7.	Shinsuke Fujii, Tatsufumi Fujimoto, Kana Hasegawa, Ryoko Nagano, Takuma Ishibashi, Kari J.Kurppa, Yurie Mikami, Megumi Kokura, Yudai Tajiri, Toshiro Kibe, Hiroko Wada, Naohisa Wada, Shosei Kishida, Yoshinori Higuchi, Tamotsu Kiyoshima., The Semaphorin 3A-AKT axis-mediated cell proliferation in salivary gland morphogenesis and adenoid cystic carcinoma pathogenesis, Pathology - Research and Practice, 10.1016/j.prp.2022.153991, in press, 2022.08, We recently demonstrated that Semaphorin 3 A (Sema3A), the expression of which is negatively regulated by Wnt/β-catenin signaling, promotes odontogenic epithelial cell proliferation, suggesting the involvement of Sema3A in tooth germ development. Salivary glands have a similar developmental process to tooth germ development, in which reciprocal interactions between the oral epithelium and adjacent mesenchyme proceeds via stimulation with several growth factors; however, the role of Sema3A in the development of salivary glands is unknown. There may thus be a common mechanism between epithelial morphogenesis and pathogenesis; however, the role of Sema3A in salivary gland tumors is also unclear. The current study investigated the involvement of Sema3A in submandibular gland (SMG) development and its expression in adenoid cystic carcinoma (ACC) specimens. Quantitative RT-PCR and immunohistochemical analyses revealed that Sema3A was expressed both in epithelium and in mesenchyme in the initial developmental stages of SMG and their expressions were decreased during the developmental processes. Loss-of-function experiments using an inhibitor revealed that Sema3A was required for AKT activation-mediated cellular growth and formation of cleft and bud in SMG rudiment culture. In addition, Wnt/β-catenin signaling decreased the Sema3A expression in the rudiment culture. ACC arising from salivary glands frequently exhibits malignant potential. Immunohistochemical analyses of tissue specimens obtained from 10 ACC patients showed that Sema3A was hardly observed in non-tumor regions but was strongly expressed in tumor lesions, especially in myoepithelial neoplastic cells, at high frequencies where phosphorylated AKT expression was frequently detected. These results suggest that the Sema3A-AKT axis promotes cell growth, thereby contributing to morphogenesis and pathogenesis, at least in ACC, of salivary glands..
8.	Kana Hasegawa, Shinsuke Fujii, Kari J Kurppa, Takashi Maehara, Kazunari Oobu, Seiji Nakamura, Tamotsu Kiyoshima, Clear cell squamous cell carcinoma of the tongue exhibits characteristics as an undifferentiated squamous cell carcinoma, Pathology - Research and Practice, 10.1016/j.prp.2022.153909, 235, 153909, 2022.04, [URL], Clear cell squamous cell carcinoma (CCSCC), where cells show abundant clear cytoplasm, is a variant of squamous cell carcinoma (SCC) and a rare entity in the oral cavity. The characteristics of CCSCC, especially in immunohistochemical features, remain unclear. We characterized a case of CCSCC arising from the oral mucosal epithelium of tongue, where the clear cell lesion accounted for a predominant portion of the tumor. This CCSCC, which was partially surrounded by conventional SCC, exhibited cellular atypia immunohistopathologically and histopathologically with a high Ki-67 index, increased number of mitotic figures and enlarged nuclei. Intravascular invasion of the carcinoma cells was also observed. Furthermore, the CCSCC recurred and metastasized to the cervical lymph nodes and both lungs three months after resection. Immunohistochemical analyses demonstrated decreased expression of p40 (an isoform of SCC marker p63), ADP-ribosylation factor (ARF)-like 4c (ARL4C), yes-associated protein (YAP) and 5-methylcytosine (5mC) in the CCSCC lesion compared with the surrounding SCC lesion, where the expression of ARL4C was upregulated compared with non-tumor region and YAP showed nuclear translocation. In addition, siRNA loss-of-function experiments revealed that p63 expression was required for ARL4C expression and DNA methylation was induced by p63 and YAP/transcriptional co-activator with PDZ-binding motif (TAZ) signaling in oral SCC cell lines. These results suggest that CCSCC, in which several markers of SCC-associated intracellular signaling pathways are downregulated, together with evidence of altered epigenetic regulation, is characterized as an undifferentiated SCC variant..
9.	Shinsuke Fujii, Takuma Ishibashi, Megumi Kokura, Tatsufumi Fujimoto, Shinji Matsumoto, Satsuki Shidara, Kari J Kurppa, Judith Pape, Javier Caton, Peter R Morgan, Kristiina Heikinheimo, Akira Kikuchi, Eijiro Jimi, Tamotsu Kiyoshima, RAF1-MEK/ERK pathway-dependent ARL4C expression promotes ameloblastoma cell proliferation and osteoclast formation, J Pathol., 10.1002/path.5814, 256, 1, 119-133, 2022.01, Ameloblastoma is an odontogenic neoplasm characterized by slow intraosseous growth with progressive jaw resorption. Recent reports have revealed that ameloblastoma harbours an oncogenic BRAF V600E mutation with mitogen-activated protein kinase (MAPK) pathway activation and described cases of ameloblastoma harbouring a BRAF V600E 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 tumorigenesis. 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 BRAF V600E 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 BRAF V600E-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 BRAF V600E-MEK/ERK pathway, promotes ameloblastoma development..
10.	Kana Hasegawa, Shinsuke Fujii, Shinji Matsumoto, Yudai Tajiri, Akira Kikuchi, Tamotsu Kiyoshima, YAP signaling induces PIEZO1 to promote oral squamous cell carcinoma cell proliferation, J Pathol, 10.1002/path.5553, 253, 1, 80-93, 2021.01, Most cancer cells are exposed to altered extracellular environments, such as an increase in extracellular matrix (ECM) stiffness and soluble signals consisting of growth factors and cytokines. It is therefore conceivable that changes in tumor extracellular environments affect tumor cell behavior. The Hippo pathway reportedly responds to the extracellular environment and regulates the nuclear localization of the transcription co-activator, yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ). Inactivation of the Hippo pathway with nuclear translocation of YAP/TAZ stimulates cell proliferation. Its pathway also regulates gene expression, but the precise molecule(s) meditating the cell-proliferating effect of YAP signaling on oral squamous cell carcinoma (OSCC) is unclear. First, we examined the effects of YAP signaling on OSCC tumorigenesis. Loss-of-function experiments using siRNA or an inhibitor, and immunohistochemical analyses of tissue specimens obtained from OSCC patients demonstrated that YAP signaling was involved in OSCC cell proliferation. Second, we identified Piezo-type mechanosensitive ion channel component 1 (PIEZO1), a Ca2+ channel, as a transcriptional target of YAP signaling and showed that elevated PIEZO1 was required for PIEZO1 agonist-dependent Ca2+ entry and cell proliferation in OSCC cells. Experiments using three-dimensional and suspension culture revealed that PIEZO1 was involved in OSCC cellular growth. Finally, YAP overexpression in the nucleus and/or cytoplasm was immunohistochemically detected in tumor lesions with frequent expression of both PIEZO1 and Ki-67, but not in non-tumor regions of OSCC specimens. These results suggest that the YAP/PIEZO1 axis promotes OSCC cell growth. .
11.	Shinsuke Fujii, Yudai Tajiri, Kana Hasegawa, Shinji Matsumoto, Reiko U. Yoshimoto, Hiroko Wada, Shosei Kishida, Mizuho A. Kido, Hiromasa Yoshikawa, Satoru Ozeki, Tamotsu Kiyoshima, The TRPV4-AKT axis promotes oral squamous cell carcinoma cell proliferation via CaMKII activation., Laboratory Investigation, 10.1038/s41374-019-0357-z., 100, 2, 311-323, 2020.02, Most human malignant tumor cells arise from epithelial tissues, which show distinctive characteristics, such as polarization, cell-to-cell contact between neighboring cells, and anchoring to a basement membrane. When tumor cells invaginate into the stroma, the cells are exposed to extracellular environments, including the extracellular matrix (ECM). Increased ECM stiffness has been reported to promote cellular biological activities, such as excessive cellular growth and enhanced migration capability. Therefore, tumorous ECM stiffness is not only an important clinical tumor feature but also plays a pivotal role in tumor cell behavior. Transient receptor potential vanilloid 4 (TRPV4), a Ca2+-permeable nonselective cation channel, has been reported to be mechano-sensitive and to regulate tumorigenesis, but the underlying molecular mechanism in tumorigenesis remains unclear. The function of TRPV4 in oral squamous cell carcinoma (OSCC) is also unknown. The current study was conducted to investigate whether or not TRPV4 might be involved in OSCC tumorigenesis. TRPV4 mRNA levels were elevated in OSCC cell lines compared with normal oral epithelial cells, and its expression was required for TRPV4 agonist-dependent Ca2+ entry. TRPV4-depleted tumor cells exhibited decreased proliferation capabilities in three-dimensional culture but not in a low-attachment plastic dish. A xenograft tumor model demonstrated that TRPV4 expression was involved in cancer cell proliferation in vivo. Furthermore, loss-of-function experiments using siRNA or an inhibitor revealed that the TRPV4 expression was required for CaMKII-mediated AKT activation. Immunohistochemical analyses of tissue specimens obtained from 36 OSCC patients showed that TRPV4 was weakly observed in non-tumor regions but was strongly expressed in tumor lesions at high frequencies where phosphorylated AKT expression was frequently detected. These results suggest that the TRPV4/CaMKII/AKT axis, which might be activated by extracellular environments, promotes OSCC tumor cell growth..
12.	Shinsuke Fujii, Kengo Nagata, Shinji Matsumoto, Ken-ichi Kohashi, Akira Kikuchi, Yoshinao Oda, Tamotsu Kiyoshima, Naohisa Wada, Wnt/β-catenin signaling, which is activated in odontomas, reduces Sema3A expression to regulate odontogenic epithelial cell proliferation and tooth germ development., Scientific Reports., 10.1038/s41598-019-39686-1, 9, 2019.03, Odontomas, developmental anomalies of tooth germ, frequently occur in familial adenomatous polyposis patients with activated Wnt/β-catenin signaling. However, roles of Wnt/β-catenin signaling in odontomas or odontogenic cells are unclear. Herein, we investigated β-catenin expression in odontomas and functions of Wnt/β-catenin signaling in tooth germ development. β-catenin frequently accumulated in nucleus and/or cellular cytoplasm of odontogenic epithelial cells in human odontoma specimens, immunohistochemically. Wnt/β-catenin signaling inhibited odontogenic epithelial cell proliferation in both cell line and tooth germ development, while inducing immature epithelial bud formation. We identified Semaphorin 3A (Sema3A) as a downstream molecule of Wnt/β-catenin signaling and showed that Wnt/β-catenin signaling-dependent reduction of Sema3A expression resulted in suppressed odontogenic epithelial cell proliferation. Sema3A expression is required in appropriate epithelial budding morphogenesis. These results suggest that Wnt/β-catenin signaling negatively regulates odontogenic epithelial cell proliferation and tooth germ development through decreased-Sema3A expression, and aberrant activation of Wnt/β-catenin signaling may associate with odontoma formation..
13.	Yurie Mikami, Shinsuke Fujii, Ken-Ichi Kohashi, Yuichi Yamada, Masafumi Moriyama, Shintaro 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, Low-grade myofibroblastic sarcoma (LGMS) is a rare intermediate tumor, which rarely metastasizes and has myofibroblastic differentiation in various sites. It is particularly associated with the tongue in the head and neck region. The lack of any pathological features means it is difficult to make a conclusive diagnosis of LGMS. The immunohistochemical features and genomic rearrangements, including SS18-SSXs and MYH9-USP6s and the genetic mutations of cancer-associated genes, including APC, CTNNB1, EGFR, KRAS, PIK3CA and p53 were examined in a case of LGMS arising in the tip of the tongue. Immunohistochemically, the tumor cells were positive for alpha-smooth muscle actin and vimentin, as in previous reports. They demonstrated neither genomic rearrangements nor point mutations of cancer-associated genes. Although several tumor cells demonstrated intravascular invasion, the MIB-l labeling index of the cells was the same as the original lesion. To the best of our knowledge, this is the first case report of LGMS arising in the tip of the tongue with intravascular invasion..
14.	Yurie Mikami, Shinsuke　Fujii, 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, [URL], PURPOSE:Keratin 17 (KRT17) has been suggested as a potential diagnostic marker of squamous cell carcinoma including oral squamous cell carcinoma (OSCC). The current study was conducted to clarify the function of KRT17 and its expression mechanism in OSCC.METHODS:Immunohistochemical analyses were carried out to examine the expression of KRT17, GLI family zinc finger (GLI)-1, GLI-2, or cleaved caspase-3 in OSCCs. The expression of KRT17, GLI-1, or GLI-2 was investigated among OSCC cell lines, and the effects of loss-of-function of KRT17 or GLI, using siRNA or inhibitor, on the cell growth of the OSCC cell line HSC-2 particularly with respect to apoptosis were examined.RESULTS:Immunohistochemical analyses of tissue specimens obtained from 78 OSCC patients revealed that KRT17 was not observed in non-tumor regions but was strongly expressed at high frequencies in tumor regions. Knockdown of KRT17 increased the number of cleaved caspase-3-positive cells, leading to the reduction of cell number. Loss-of-function of GLI-1 or GLI-2 also increased the cell numbers of apoptotic cells positive for staining of Annexin-V and propidium iodide (PI) and the terminal deoxynucleotidyl transferase dUTP-biotin nick-end labeling (TUNEL) method, and induced DNA fragmentation. This inhibitory effect on cell growth was partially rescued by exogenous KRT17 expression. In the KRT17-positive regions in OSCCs, GLI-1 or GLI-2 was frequently detected, and the number of cells with cleaved caspase-3 positive was decreased.CONCLUSIONS:KRT17 promotes tumor cell growth, at least partially, through its anti-apoptotic effect as a result of the KRT17 overexpression by GLIs in OSCC..
15.	Kana Hasegawa, Hiroko Wada, Kengo Nagata, Hiroaki Fujiwara, Naohisa Wada, Hirotaka Someya, Yurie Mikami, Hidetaka Sakai, Tamotsu Kiyoshima, Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) expression and possible function in mouse tooth germ development, Int. J. Mol. Med., 10.1007/s10735-016-9680-5, 47, 4, 375-387, 2016.08.
16.	Hirotaka Someya, Fujiwara Hiroaki, Kengo Nagata, Hiroko Wada, Kana Hasegawa, Yurie Mikami, Akiko Jinno, Hidetaka Sakai, Kiyoshi Koyano, Tamotsu Kiyoshima, Thymosin beta 4 is associated with RUNX2 expression via the Smad and Akt signaling pathways in mouse dental epithelial cells., Int. J. Mol. Med., doi: 10.3892/ijmm.2015.2118., 35, 5, 1169-1178, 2015.05.
17.	Makiko Kihara, Tamotsu Kiyoshima, Kengo Nagata, Hiroko Wada, Fujiwara Hiroaki, Kana Hasegawa, Hirotaka Someya, Ichiro Takahashi, Hidetaka Sakai, Itm2a expression in the developing mouse first lower molar, and the subcellular localization of itm2a in mouse dental epithelial cells., PLoS One., doi: 10.1371/journal.pone.0103928., 9, 7, e103928, 2014.07.
18.	Tamotsu Kiyoshima, Fujiwara Hiroaki, Kengo Nagata, Hiroko Wada, Yukiko Okuma, Maho Shiotsuka, Makiko Kihara, Kana Hasegawa, Hirotaka Someya, Hidetaka Sakai, Induction of dental epithelial cell differentiation marker gene expression in non-odontogenic human keratinocytes by transfection with thymosin beta 4., Stem Cell Research, doi: 10.1016/j.scr.2013.11.006., 12, 1, 309-322, 2014.01.
19.	Maho Shiotsuka, Hiroko Wada, Tamotsu Kiyoshima, Kengo Nagata, Fujiwara Hiroaki, Makiko Kihara, Kana Hasegawa, Hirotaka Someya, Ichiro Takahashi, Hidetaka Sakai, The expression and function of thymosin beta 10 in tooth germ development., Int J Dev Biol, doi: 10.1387/ijdb.120240hs., 57, 11-12, 873-883, 2013.12.
20.	Tamotsu Kiyoshima, Hisato Yoshida, Hiroko Wada, Kengo Nagata, Fujiwara Hiroaki, Makiko Kihara, Kana Hasegawa, Hirotaka Someya, Hidetaka Sakai, Chemoresistance to Concanamycin A1 in Human Oral Squamous Cell Carcinoma Is Attenuated by an HDAC Inhibitor Partly via Suppression of Bcl-2 Expression, PLOS ONE, 10.1371/journal.pone.0080998, 8, 11, 2013.11.
21.	Tamotsu Kiyoshima, Kengo Nagata, Hiroko Wada, Fujiwara Hiroaki, Maho Shiotsuka, Makiko Kihara, Kana Hasegawa, Hirotaka Someya, Hidetaka Sakai, Immunohistochemical Expression of Thymosin β4 in Ameloblastomas and Odontomas., Histol. Histopathol., doi: 10.3892/ijo.2012.1594., 28, 6, 775-786, 2013.06.
22.	Yukiko Okuma, Tamotsu Kiyoshima, Ieyoshi Kobayashi, Kengo Nagata, Hiroko Wada, Fujiwara Hiroaki, Haruyoshi Yamaza, Kazuaki Nonaka, Hidetaka Sakai, Multiple functional involvement of Thymosin beta-4 in tooth germ development, HISTOCHEMISTRY AND CELL BIOLOGY, 10.1007/s00418-012-1033-1, 139, 2, 355-370, 2013.02.
23.	Tamotsu Kiyoshima, Norio Enoki, Ieyoshi Kobayashi, Takako Sakai, Kengo Nagata, Hiroko Wada, Fujiwara Hiroaki, 大隈由紀子, Hidetaka Sakai, Oxidative stress caused by a low concentration of hydrogen peroxide induces senescence-like changes in mouse gingival fibroblasts., Int. J. Mol. Med., doi: 10.3892/ijmm.2012.1102., 30, 5, 1007-1012, 2012.11.
24.	Lutfun Naher, Tamotsu Kiyoshima, Ieyoshi Kobayashi, Hiroko Wada, Kengo Nagata, Fujiwara Hiroaki, 大隈由紀子, Satoru Ozeki, Seiji Nakamura, Hidetaka Sakai, STAT3 signal transduction through interleukin-22 in oral squamous cell carcinoma., Int. J. Oncol., doi: 10.3892/ijo.2012.1594., 41, 5, 1577-1586, 2012.11.
25.	Takahashi KF, Kiyoshima T, Kobayashi I, Xie M, Yamaza H, Fujiwara H, Ookuma Y, Nagata K, Wada H, Sakai T, Terada Y, Sakai H., Protogenin, a new member of the immunoglobulin superfamily, is implicated in the development of the mouse lower first molar., BMC Dev Biol., 10:115-129, 2010.11.
26.	Hideaki Fukuzawa, Tamotsu Kiyoshima, Ieyoshi Kobayashi, Satoru Ozeki, Hidetaka Sakai, Transcription promoter activity of the human S100A7 gene in oral squamous cell carcinoma cell lines., Biochem, Biophys.Acta, 1759: 171-176,, 2006.04.
27.	Ken-ichiro Hashimoto, Tamotsu Kiyoshima, Kou Matsuo, Satoru Ozeki, Hidetaka Sakai, Effect of SCCA1 and SCCA2 on the suppression of TNF-a-induced cell death by impeding the release of mitochondrial cytochrome c in oral squamous cell carcinoma cell line., Tumor Biol., 10.1159/000086949, 26, 4, 165-172, 26:165-172, 2005.07.
28.	Ogasawara T, Yoshimine Y, Kiyoshima T, Kobayashi I, Matsuo K, Akamine A, Sakai H, In situ expression of RANKL, RANK, osteoprotegerin and cytokines in osteoclasts of rat periodontal tissue., J Periodontal Res., 10.1111/j.1600-0765.2004.00699.x, 39, 1, 42-49, Vol.39, pp.42-9., 2004.01.
29.	Kiyoshima T, Yamauchi M, Wong C, Jheon A, Ganss B, Sodek J., An L1 element disrupts human bone sialoprotein promoter: lack of tissue-specific regulation by distalless5 (Dlx5) and runt homeodomain protein2 (Runx2)/core binding factor a1 (Cbfa1) elements., Gene, Vol.299, pp.205-17., 2002.10.
30.	Okamura K, Kiyoshima T, Shima K, Kobayashi I, Matsuo K, Ishibashi H, Komatsu S, Rasul AM, Sakai H., Immunohistochemical expression of CA19-9 and CA125 in mucoepidermoid and adenoid cystic carcinomas of the salivary gland., Oral Oncol., 10.1016/S1368-8375(01)00049-5, 38, 3, 244-250, Vol.38, pp.244-50., 2002.04.
31.	Wada H, Kobayashi I, Yamaza H, Matsuo K, Kiyoshima T, Akhtar M, Sakai T, Koyano K, Sakai H., In situ expression of heat shock proteins, Hsc73, Hsj2 and Hsp86 in the developing tooth germ of mouse lower first molar., Histochem J., 10.1023/A:1020930228303, 34, 3-4, 105-109, Vol.34, pp.105-9., 2002.03.
32.	Yamaza H, Matsuo K, Kobayashi I, Wada H, Kiyoshima T, Akhtar M, Ishibashi Y, Sakai T, Akamine A, Sakai H., Expression of Set-alpha during morphogenesis of mouse lower first molar, Histochem J., 10.1023/A:1014491111628, 33, 8, 437-441, Vol.33,pp.437-41, 2001.08.
33.	Kiyoshima T, Shima K, Kobayashi I, Matsuo K, Okamura K, Komatsu S, Rasul AM, Sakai H., Expression of p53 tumor suppressor gene in adenoid cystic and mucoepidermoid carcinomas of the salivary glands, Oral Oncol., 10.1016/S1368-8375(00)00083-X, 37, 3, 315-322, Vol.37,pp.315-22, 2001.04.
34.	Shigemura N, Kiyoshima T, Sakai T, Matsuo K, Momoi T, Yamaza H, Kobayashi I, Wada H, Akamine A, Sakai H., Localization of activated caspase-3-positive and apoptotic cells in the developing tooth germ of the mouse lower first molar, Histochem J., 10.1023/A:1017900305661, 33, 5, 253-258, Vol.33,pp.253-8, 2001.03.
35.	Yamaza H, Matsuo K, Kiyoshima T, Shigemura N, Kobayashi I, Wada H, Akamime A, Sakai H., Detection of differentially expressed genes in the early developmental stage of the mouse mandible, Int J Dev Biol., 45, 4, 675-680, Vol.45,pp.675-80, 2001.01.
36.	Shima K, Kobayashi I, Saito I, Kiyoshima T, Matsuo K, Ozeki S, Ohishi M, Sakai H., Incidence of human papillomavirus 16 and 18 infection and p53 mutation in patients with oral squamous cell carcinoma in Japan, Br J Oral Maxillofac Surg., Vol.38,pp.445-50, 2000.10.
37.	Li C.Y., Shirasuna K., Ishibashi H., Nakayama H. and Kiyoshima T., Epithelial-myoepithelial carcinoma arising in pleomorphic adenoma of the palate., Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod., 10.1067/moe.2000.108099, 90, 4, 460-465, 2000.10.
38.	Sakai T, Kiyoshima T, Kobayashi I, Moroi R, Ibuki T, Nagadome M, Terada Y, Sakai H., Age-dependent changes in the distribution of BrdU- and TUNEL-positive cells in the murine gingival tissue, J Periodontol., 10.1902/jop.1999.70.9.973, 70, 9, 973-981, Vol.70,pp.973-81, 1999.09.
39.	Kobayashi I, Shima K, Saito I, Kiyoshima T, Matsuo K, Ozeki S, Ohishi M, Sakai H., Prevalence of Epstein-Barr virus in oral squamous cell carcinoma, J Pathol., 10.1002/(SICI)1096-9896(199909)189:13.0.CO;2-4, 189, 1, 34-39, Vol.189,pp.34-9, 1999.09.
40.	Shigemura N, Kiyoshima T, Kobayashi I, Matsuo K, Yamaza H, Akamine A, Sakai H., The distribution of BrdU- and TUNEL-positive cells during odontogenesis in mouse lower first molars, Histochem J., 10.1023/A:1003796023992, 31, 6, 367-377, Vol.31,pp.367-77, 1999.07.
41.	Kobayashi I., Kiyoshima T., Ozeki S., Shima K., Shigemura N., Matsuo K. and Sakai H., Immunohistochemical and ultrastructural study of a papillary cystadenocarcinoma arising from the sublingual gland., J. Oral Pathol. Med., 28, 6, 282-286, 1999.07.
42.	Kiyoshima T., Kobayashi, I., Matsuo K., Ishibashi Y., Miyoshi A., Akashi Y. and Sakai H., Immunohistochemical localization of laminin, collagen type IV and heparan sulfate proteoglycan in human colorectal adenocarcinoma: correlation with local invasive pattern and lymph node metastasis, Acta Histochemica et Cytochemica, 31, 1, 39-47, Vol.31,pp.39-47, 1998.01.
43.	Kazuhiko Okamura, Ieyoshi Kobayashi, Kou Matsuo, Tamotsu Kiyoshima, Kenji Yamamoto, Akira Miyoshi, Hidetaka Sakai, Immunohistochemical localization of cathepsin D, proliferating cell nuclear antigen and epidermal growth factor receptor in human breast carcinoma analysed by computer image analyser: correlation with histological grade and metastatic behaviour, HISTOPATHOLOGY, 31, 6, 540-548, 1997.12.
44.	Kobayashi I., Matsuo K., Kiyoshima T., Shinohara M. and Sakai H., Salivary Duct Carcinoma with Sebaceous Cell Differentiation arising from Parotid Gland: Histological, Immunohistochemical and Ultrastructural Analyses of a Case., Oral Med. Pathol., 2, 89-93, 1997.03.
45.	Okamura K., Kobayashi I., Matsuo K., Kiyoshima T., Yamamoto K., Miyoshi A. and Sakai H., Immunohistochemical localization of cathepsin D, proliferating cell nuclear antigen and epidermal growth factor receptor in human breast carcinoma analyzed by computor image analyzer: correlation with the histological grade and the metastatic activity of carcinoma., Histopathology, 31, 540-548, 1997.03.
46.	Kou Matsuo, Ieyoshi Kobayashi, Takayuki TSUKUBA, Tamotsu Kiyoshima, Yukiko Ishibashi, Akira Miyoshi, Kenji Yamamoto, Hidetaka Sakai, Immunohistochemical localization of cathepsins D and E in human gastric cancer: A possible correlation with local invasive and metastatic activities of carcinoma cells, HUMAN PATHOLOGY, 27, 2, 184-190, 1996.02.

Presentations

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1.	Kana Hasegawa, Shinsuke Fujii, Tamotsu Kiyoshima, YAP-PIEZO1 axis promotes cell proliferation of oral squamous cell carcinoma, Kyudai Oral Bioscience & OBT Research Center 5th Joint International Symposium 2021, 2021.11.
2.	＃Tatsufumi Fujimoto, ＠Shinsuke Fujii,　＠Tamotsu Kiyoshima, Sema3A-AKT Axis In Salivary Gland And Adenoid Cystic Carcinoma Developments, 第68回JADR学術大会, 2020.11.
3.	Misaki Abe, Hiroko Wada, Tamotsu Kiyoshima, Expression and function of Piezo1 and Piezo2 in tooth germ development, Kyudai Oral Bioscience 2018, 2018.02.
4.	Hiroko Wada, Kana Hasegawa, Kengo Nagata, Naohisa Wada, Yurie Mikami, Hidetaka Sakai, Tamotsu Kiyoshima, The expression pattern of the FRG1 in the mouse developing tooth germ., The 95th General Session & Exhibition of the IADR, 2017.03.
5.	Hiroko Wada, Aki Kinjo, Yurie Mikami, Tuyoshi Sugiura, Tamotsu Kiyoshima, Mandibular tumor, The 27th Annual Meeting of the Japanese Society of Oral Pathology, 2016.08.
6.	Reiko U. Yoshimoto, Reona Aijima, Yasuyoshi Ohsaki, Zhang J.Q., Cao A.L., Tamotsu Kiyoshima, Kido M.A., Temperature changes effect on intercellular adhesion of oral epithelial cells., The 15th International Symposium on Molecular and Neural Mechanism of Taste and Olfactory Perception., 2016.06.
7.	吉田寿人, Ying Wang, 清島保, 坂井英隆, Analysis of the Anti-tumor Effects of V-ATPase inhibitor, Concanamycin A1, on Oral Squamous Cell Carcinoma, 103rd USCAP (United States & Canadian Academy of Pathology) Annual Meeting, 2014.03.
8.	木原槇子, 清島保, 永田健吾, 和田裕子, 藤原弘明, 長谷川佳那, 染矢祐孝, 髙橋一郎, 坂井英隆, Itm2a Expression during the Tooth Germ Development, Kyudai Oral Bioscience (KOB), 2014.02.
9.	Pathological study of biopsied minor salivary glands in IgG4-related sclerosing disease. -Report of a case- .
10.	Transcriptional Regulation of S100A7 in Oral Squamous Cell Carcinoma.

Membership in Academic Society

Japanese Dental Education Association
Japanese Stomatological Society
The Japanese Society of Conservative Dentistry
Japanese Society of Pediatric Oral and Maxillofacial Surgery
The Japanese Society of Pathology
The Japanese Society for Oral Pathology
Japanese Cancer Association
Japanese Society for Oral Tumors
Japanese Society of Oral and Maxillofacial Surgeon
Japanese Association for Oral Biology
The Japanese Society for the Temporomandibular Joint

Awards

The Jeremy Jass Prize for Research Excellence in Pathology:
Each year, The Journal of Pathology awards the Jeremy Jass Prize for Research Excellence in Pathology to the authors of the paper published in the preceding year that is considered best by the Editorial Team of the Journal.

Educational Activities

Pathology/Oral pathology: (Lecture/Exercise) The explanation of the typical pathological specimens based on the lecture, and the instruction of the observation under a microscope
Comprehensive dental science
Research exposure: For fourth and sixth grades, the instruction and the exercise of the molecular biological examination concerning the above-mentioned research as well as pathological diagnosis.

The graduate students will study a part of above-mentioned research and write papers on it under instruction to be a "researcher" in the future. Moreover, they will be involved also in autopsy or pathological diagnosis of the oral disease from the department of medical examination so as to understand the fundamentals of pathology.

Other Educational Activities

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Professional and Outreach Activities

I work as a members in the dental educational course of JICA in Faculty of Dental Science, Kyushu University, and have the class for the oral pathology and recent data associated with the oral diseases according to the course curriculum ..

https://kyushu-u.elsevierpure.com/en/persons/tamotsu-kiyoshima Reseacher Profiling Tool Kyushu University Pure

https://kyushu-u.elsevierpure.com/en/persons/tamotsu-kiyoshima
　Reseacher Profiling Tool　Kyushu University Pure