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Affiliation |
Faculty of Medicine School of Medicine Department of Medicine of Sensory and Motor Organs, Oral and Maxillofacial Surgery |
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YAMASHITA Yoshihiro
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Research Areas 【 display / non-display 】
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Life Science / Surgical dentistry
Papers 【 display / non-display 】
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Izumi A., Yamamoto K., Kawaguchi M., Yamashita F., Fukushima T., Kiwaki T., Tanaka H., Yamashita Y., Kataoka H.
Cancer Science 113 ( 6 ) 2179 - 2193 2022.6
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Cancer Science
Hepatocyte growth factor (HGF) activator inhibitor type-1 (HAI-1), encoded by the SPINT1 gene, is a transmembrane protease inhibitor that regulates membrane-anchored serine proteases, particularly matriptase. Here, we explored the role of HAI-1 in tongue squamous cell carcinoma (TSCC) cells. An immunohistochemical study of HAI-1 in surgically resected TSCC revealed the cell surface immunoreactivity of HAI-1 in the main portion of the tumor. The immunoreactivity decreased in the infiltrative front, and this decrease correlated with enhanced lymphatic invasion as judged by podoplanin immunostaining. In vitro homozygous deletion of SPINT1 (HAI-1KO) in TSCC cell lines (HSC3 and SAS) suppressed the cell growth rate but significantly enhanced invasion in vitro. The loss of HAI-1 resulted in enhanced pericellular activities of proteases, such as matriptase and urokinase-type plasminogen activator, which induced activation of HGF/MET signaling in the co-culture with pro-HGF-expressing fibroblasts and plasminogen-dependent plasmin generation, respectively. The enhanced plasminogen-dependent plasmin generation was abrogated partly by matriptase silencing. Culture supernatants of HAI-1KO cells had enhanced potency for converting the proform of vascular endothelial growth factor-C (VEGF-C), a lymphangiogenesis factor, into the mature form in a plasminogen-dependent manner. Furthermore, HGF significantly stimulated VEGF-C expression in TSCC cells. Orthotopic xenotransplantation into nude mouse tongue revealed enhanced lymphatic invasion of HAI-1KO TSCC cells compared to control cells. Our results suggest that HAI-1 insufficiency leads to dysregulated pericellular protease activity, which eventually orchestrates robust activation of protease-dependent growth factors, such as HGF and VEGF-C, in a tumor microenvironment to contribute to TSCC progression.
DOI： 10.1111/cas.15346
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Yamaguma Y., Sugita N., Choijookhuu N., Yano K., Lee D., Ikenoue M., Fidya , Shirouzu S., Ishizuka T., Tanaka M., Yamashita Y., Chosa E., Taniguchi N., Hishikawa Y.
Histochemistry and Cell Biology 157 ( 3 ) 359 - 369 2022.3
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Histochemistry and Cell Biology
High-mobility group box 2 (HMGB2) is a chromatin-associated protein that is an important regulator of gene transcription, recombination, and repair processes. The functional importance of HMGB2 has been reported in various organs, including the testis, heart, and cartilage. However, its role in the ovary is largely unknown. In this study, ovary tissues from wild-type (WT) and HMGB2-knock-out (KO) mice were examined by histopathological staining and immunohistochemistry. The ovary size and weight were significantly lower in HMGB2-KO mice than in age-matched WT littermates. Histopathological analysis revealed ovarian atrophy and progressive fibrosis in 10-month-old HMGB2-KO mouse ovaries. Compared to age-matched WT mice, the numbers of oocytes and developing follicles were significantly decreased at 2 months of age and were completely depleted at 10 months of age in HMGB2-KO mice. Immunohistochemistry revealed the expression of HMGB2 in the granulosa cells of developing follicles, oocytes, some corpora lutea, and stromal cells. Importantly, HMGB2-positive cells were co-localized with estrogen receptor beta (ERβ), but not ERα. Estrogen response element-binding activity was demonstrated by southwestern histochemistry, and it was decreased in HMGB2-KO mouse ovaries. Cell proliferation activity was also decreased in HMGB2-KO mouse ovaries in parallel with the decreased folliculogenesis. These results indicated that the depletion of HMGB2 induced ovarian atrophy that was characterized by a decreased ovarian size and weight, progressive fibrosis, as well as decreased oocytes and folliculogenesis. In conclusion, we demonstrated the crucial role of HMGB2 in mouse ovarian folliculogenesis through ERβ expression.
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Role of Mel1/Prdm16 in bone differentiation and morphology
Kaneda-Nakashima K., Igawa K., Suwanruengsri M., Naoyuki F., Ichikawa T., Funamoto T., Kurogi S., Sekimoto T., Yamashita Y., Chosa E., Yamaguchi R., Morishita K.
Experimental Cell Research 410 ( 2 ) 112969 2022.1
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Experimental Cell Research
MEL1 (MDS1/EVI1-like gene 1/PRDM16), a zinc finger protein, is located near the chromosomal breakpoint at 1p36 in human acute myeloid leukemia (AML) cells with the t (1; 3) (p36; q21) translocation. Mel1/Prdm16 is not only a causative gene of leukemia, but also has multiple regulatory functions, such as the regulation of fat metabolism. To investigate the function of Mel1/Prdm16, we generated Mel1/Prdm16-deficient mice, but homozygous deficiency (Mel1/Prdm16−/−) was embryonic lethal at E 11.5. Heterozygous mice showed abnormal cartilage and bone formation in the postnatal skull and long bones, suggesting that Mel1/Prdm16 expression plays an important role in bone development. In osteoblast and chondrocyte cell lines, Mel1/Prdm16 promotes the differentiation of chondrocytes and regulates the differentiation of osteoblasts. Transient repression of the master regulator Runx2 is required for chondrocyte differentiation at an early stage of differentiation. However, in Mel1/Prdm16-suppressed ATDC5 cells, the initial suppression of Runx2 was lacking and its expression was upregulated at the beginning of differentiation, suggesting that chondrogenic differentiation is suppressed in Mel1/Prdm16+/− mesenchymal progenitor cells because Runx2 expression is upregulated during the early stage of differentiation. Thus, the Mel1/Prdm16 gene may be involved in the early repression of Runx2 expression during osteochondral differentiation and promote chondrogenic differentiation.
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Decreased prostasin expression is associated with aggressiveness of oral squamous cell carcinoma
Yamamoto K., Yamashita F., Kawaguchi M., Izumi A., Kiwaki T., Kataoka H., Kaneuji T., Yamashita Y., Fukushima T.
Human Cell 34 ( 5 ) 1434 - 1445 2021.9
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Human Cell
Prostasin is a glycosylphosphatidylinositol-anchored serine protease widely expressed in epithelial cells, with crucial epidermal barrier functions. Evidence has suggested prostasin may have served as a tumor suppressor in various cancers, but its role in oral squamous cell carcinoma (OSCC) remains unclear. Thus, herein, we conducted an immunohistochemical prostasin study in 119 resected OSCC cases. Prostasin expression was decreased in 63% (75/119) of cases. OSCC with decreased prostasin immunoreactivity (low prostasin cases) tended to show a higher histological grade (p = 0.0088) and a more infiltrative cancer cell morphology (p = 0.0024). We then explored the role of prostasin in the OSCC cell lines: SAS and HSC-4. SAS did not express detectable prostasin levels, whereas HSC-4 expressed low but distinct levels. Prostasin overexpression suppressed the proliferation and migration of both OSCC lines in vitro. Conversely, prostasin silencing significantly enhanced growth rates of HSC-4. Finally, we analyzed the impact of prostasin expression on the prognosis of patients with OSCC; decreased expression tended to correlate with shorter overall survival (p = 0.0291) after resection. This trend was supported by our analyses using a public database (Kaplan–Meier plotter) of head and neck squamous cell carcinomas. In conclusion, we showed decreased prostasin expression was associated with aggressive features and a poorer prognosis of OSCC.
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Nasu J., Uto T., Fukaya T., Takagi H., Fukui T., Miyanaga N., Nishikawa Y., Yamasaki S., Yamashita Y., Sato K.
International Immunology 32 ( 10 ) 673 - 682 2021
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：International Immunology
C-type lectin receptors (CLRs), pattern recognition receptors (PRRs) with a characteristic carbohydrate recognition domain (CRD) in the extracellular portion, mediate crucial cellular functions upon recognition of glycosylated pathogens and self-glycoproteins. CLEC4A is the only classical CLR that possesses an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM), which possibly transduces negative signals. However, how CLEC4A exerts cellular inhibition remains unclear. Here, we report that the self-interaction of CLEC4A through the CRD is required for the ITIM-mediated suppressive function in conventional dendritic cells (cDCs). Human type 2 cDCs (cDC2) and monocytes display a higher expression of CLEC4A than cDC1 and plasmacytoid DCs (pDCs) as well as B cells. The extracellular portion of CLEC4A specifically binds to a murine cDC cell line expressing CLEC4A, while its extracellular portion lacking the N-glycosylation site or the EPS motif within the CRD reduces their association. Furthermore, the deletion of the EPS motif within the CRD or ITIM in CLEC4A almost completely impairs its suppressive effect on the activation of the murine cDC cell line, whereas the absence of the N-glycosylation site within the CRD exhibits partial inhibition on their activation. On the other hand, antagonistic monoclonal antibody (mAb) to CLEC4A, which inhibits the self-interaction of CLEC4A and its downstream signaling in murine transfectants, enhances the activation of monocytes and monocyte-derived immature DCs upon stimulation with a Toll-like receptor (TLR) ligand. Thus, our findings suggest a pivotal role of the CRD in self-interaction of CLEC4A to elicit the ITIM-mediated inhibitory signal for the control of the function of cDCs.
Books 【 display / non-display 】
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知っておきたい顎・歯・口腔の画像診断
近藤雄大、中村友梨、山下善弘（ Role： Joint author）
株式会社学研メデイカル秀潤社 2017.8
Language：Japanese Book type：Scholarly book
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ガイドライン外来診療 2017
有村慶一、近藤雄大、山下善弘（ Role： Joint author）
日経メディカル開発 2017.2
Language：Japanese Book type：General book, introductory book for general audience
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みやざきの医療
近藤雄大、山下善弘（ Role： Joint author）
朝日新聞 2017.1
Language：Japanese
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Clinical applications of robotic image-guided fractionated stereotactic radiotherapy for recurrent oral squamous cell carcinoma patients who cannot undergo surgery in Oral Cancer: Symptoms, Management and Risk Factors; Nova Science Publishers
Yamashita Y., Yamamoto N., Tanaka T., Oda M., Miyamoto I., Yoshiga D., Nogami S., Kito S., Wakasugi-Sato N., Matsumoto-Takeda S., Ishikawa A., Matsuo K., Koga H., Ozeki S., Takahashi T., Morimoto Y.（ Role： Joint author）
Nova Science Publishers 2013.12
Language：English Book type：Scholarly book
MISC 【 display / non-display 】
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Yamaguma Y., Kaneuji T., Shirouzu S., Fukui T., Nakamura Y., Hirayama B., Kiyomiya H., Nagata J., Yamashita Y.
Oral Oncology 127 105817 2022.4
Language：Japanese Publishing type：Rapid communication, short report, research note, etc. (scientific journal) Publisher：Oral Oncology
Although Mohs paste can control bleeding, exudates, and odors from tumors, there have been no reports of the combination of Mohs paste with other treatments, such as chemotherapy, in oral cancer. Here, we report the combination of Mohs paste and chemotherapy for a case of metastatic oral cancer to the precordium skin and bilateral axillary lymph nodes. The tumors almost completely disappeared after the treatment. Combination therapy of Mohs paste and chemotherapy appears to have a better antitumor effect than Mohs paste alone.
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Fukui T., Fukaya T., Uto T., Takagi H., Nasu J., Miyanaga N., Nishikawa Y., Koseki H., Choijookhuu N., Hishikawa Y., Yamashita Y., Sato K.
Scientific Reports 10 ( 1 ) 16375 2020.12
Language：Japanese Publishing type：Rapid communication, short report, research note, etc. (scientific journal) Publisher：Scientific Reports
This Article contains errors in the Methods section, under the subheading ‘Generation of Cd103-/- mice’, “The linearized targeting construct was introduced by electroporation into C57BL/6-derived JN/2 recombinant embryonic stem cell (ESC) and neomycin-resistant clones were first screened for homologous recombination by PCR utilizing a pair of the following oligonucleotides: Primer 1 (5'-ATA TGT AGT GTC TGG TCA GGA TAA TAG TTG-3') and Primer 2 (5'-ATA ACC TCC TCT CCT ATG GTA CCT AAA C-3').” should read: “The linearized targeting construct was introduced by electroporation into C57BL/6-derived JN/2 recombinant embryonic stem cell (ESC) and neomycin-resistant clones were first screened for homologous recombination by PCR utilizing a pair of the following oligonucleotides: Primer 1 (5'-ATA TGT AGT GTC TGG TCA GGA TAA TAG TTG-3') and Primer 3 (5'-ATA ACC TCC TCT CCT ATG GTA CCT AAA C-3').” “Transmission of the targeted allele was confirmed by PCR with Primer 1 and Primer 3 (5'-CTT TAT ATT TCA TTT TTG CTC AGG CTT C-3'). The mutant mice were cross-mated for more than nine generations with B6.FLIP mice to excise the flanked FRT sites by Flp-recombinase, and 8- to 12-week-old Cd103+/+ littermates were used as WT mice. Then, Cd103+/- littermates were crossed to obtain homozygotes, and transmission of the targeted allele was confirmed by PCR with Primer 1 and Primer 3.” should read: “Transmission of the targeted allele was confirmed by PCR with Primer 1 and Primer 2 (5'-CTT TAT ATT TCA TTT TTG CTC AGG CTT C-3'). The mutant mice were cross-mated for more than nine generations with B6.FLIP mice to excise the flanked FRT sites by Flp-recombinase, and 8- to 12-week-old Cd103+/+ littermates were used as WT mice. Then, Cd103+/- littermates were crossed to obtain homozygotes, and transmission of the targeted allele was confirmed by PCR with Primer 1 and Primer 2”.
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A case of mucositis due to the allergy to self-curing resion. Oral Science International,
Hashimoto K*., Naganuma K., Yamashita Y., Ikebe T., Ozeki S
Oral Science International 11 37 - 39 2014.1
Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal) Publisher：ELSEVIER
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A case of mucositis due to the allergy to self-curing resion.
Hashimoto K*., Naganuma K., Yamashita Y., Ikebe T., Ozeki S.
Oral Science International 11 37 - 39 2014.1
Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal) Publisher：Elisevier
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A case of mucositis due to the allergy to self-curing resion. Oral Science International,
Hashimoto K*., Naganuma K., Yamashita Y., Ikebe T., Ozeki S
Oral Science International 11 37 - 39 2014.1
Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal) Publisher：ELSEVIER
Presentations 【 display / non-display 】
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口腔内に初発症状を呈した特発性血小板減少性紫斑病の１例
髙森晃一，長井健太郎，酒井博史，迫田隅男，山下善弘
第26回（一社）日本有病者歯科医療学会 総会・学術大会
Event date： 2017.3.4 - 2017.3.5
Language：Japanese Presentation type：Poster presentation
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β-TCPを用いた血管柄付骨組織再生に関する実験的研究
山本晃士、近藤雄大、金氏毅、末廣雄作、山口良二、片岡寛章、橋本憲一郎、池邉哲郎、山下善弘
第35回 日本口腔腫瘍学会総会
Event date： 2017.1.26 - 2017.1.28
Language：Japanese Presentation type：Poster presentation
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NDRG2発現と4NQO 投与による OSCC 発癌・転移機構の関連性の検討
田村知丈1 共同演者 市川朝永2、近藤雄大1、田川友梨1、山本晃士1、中畑新吾2、森下和広2、山下善弘1
第35回 日本口腔科学会学術集会
Event date： 2017.1.26 - 2017.1.27
Language：Japanese Presentation type：Poster presentation
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Clinical and histopathological evaluation of malignant transformation in oral leukoplakia in our department Invited International conference
Yohei Uemura, Takashi Baba, Yuudai Kondo, Yoshihiro Yamashita
The Third Myanmar-Japan Symposium
Event date： 2016.12.3 - 2016.12.4
Language：English Presentation type：Oral presentation (general)
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エナメル上皮手術後の狭小な下顎骨に対して、骨延長術を併用して治療を行った１例
末廣雄作、近藤雄大、金氏毅、田中純一郎、福井丈仁、野海健太、長井健太郎、山下善弘
第61回日本口腔外科学会総会・学術大会
Event date： 2016.11.26
Language：Japanese Presentation type：Oral presentation (general)
Grant-in-Aid for Scientific Research 【 display / non-display 】
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口腔扁平上皮癌におけるリンパ節転移の新規遺伝子診断アルゴリズムの確立
Grant number：21K10119 2021.04 - 2026.03
独立行政法人日本学術振興会 科学研究費補助金 基盤研究(C)
Authorship：Principal investigator
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人工呼吸器管理患者における高感度濁度計の口腔清潔度評価としての有用性の検討
2015.04 - 2017.04
科学研究費補助金 基盤研究(C)
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人工骨補填材を用いた生体内での血管柄付骨組織再生に関する実験的研究
2011.04 - 2016.03
科学研究費補助金 基盤研究(C)
Authorship：Principal investigator
人工骨補填材を用いた生体内での血管柄付骨組織再生に関する実験的研究
Available Technology 【 display / non-display 】
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腔癌における発癌・転移・浸潤関連因子に関する基礎研究・応用研究
腔外科疾患における新しい治療法・診断法の開発
腔機能・口腔内細菌と全身疾患との関連性の解明Related fields where technical consultation is available：口腔癌、口腔機能、口腔内細菌、口腔と全身疾患との関連、低侵襲手術（内視鏡 顕微鏡等）
Message：共同研究が可能なテーマ：口腔癌の基礎・応用研究、口腔機能・口腔内細菌の分析、口腔と全身疾患との関連性の解明、低侵襲手術（内視鏡 顕微鏡等）の技術開発