鹿児島大学 · 医歯学域医学系 · 教授

研究キーワードameloblastoma・oral tumor biology・ameloblastoma-osteoblast signaling・ferroptosis・Semaphorin 3A・oral squamous cell carcinoma

研究分野医化学一般・外科系歯学・機能生物化学・環境生理学(含体力医学・栄養生理学)・病態医化学・脳神経外科学・内科学一般(含心身医学)・内科系臨床医学

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• 野中 美希, 柿木 亮, 岸田 昭世, 大島 佳織, 後藤 元秀, 上園 保仁, 上野 進 . がん悪液質モデルマウスに出現する心機能障害と自発運動負荷がもたらす治療的効果 . 日本毒性学会学術年会49.1 ( 0 ) P-154 2022年 詳細を見2022 · 記述言語： 日本語 出版者・発行元： 日本毒性学会 <p>【目的】がん悪液質は心機能障害を伴うことが報告されているが、ヒトの臨床像を反映する適切なモデル動物が少ないため、がん悪液質と心機能との関連は未だ不明な点が多い。我々はヒト胃がん細胞株85As2を移植したマウスが、ヒト悪液質と類似した症状を示すモデルになることを見出している。本研究では同モデルを用い、心機能障害の分子メカニズムとともに自発運動（回し車）による治療効果についても検討を行った。</p><p>【方法】85As2細胞を8週齢の雄性BALB/cヌードマウスの両腹皮下に移植し、移植後2週目より悪液質症状を呈するモデルを作製した。本研究では移植後2週目を前悪液質群、移植後8週目を悪液質群と定義し、同週齢対照群との比較から心機能を含む悪液質病態の評価、ならびにこれらに対する自発運動負荷の効果を検討した。</p><p> 【結果】同齢の対照群と比較し、前悪液質群ならびに悪液質群ではともに心重量が有意に減少し、特に悪液質群では減少が顕著であった。さらに左室駆出率（LVEF）についても前悪液質群、悪液質群で有意に減少していた。一方、マウスの心筋を用いてマイクロアレイ解析を行ったところ、心不全との関連性が報告されていないE3ユビキチンリガーゼに属する酵素 Xの遺伝子発現量が増加していた。また、回し車による自発運動負荷により、悪液質モデルの摂餌量と心重量の低下は抑制され、さらにはXの遺伝子発現量増加の抑制も認められ、LVEFも改善した。</p><p> 【結語】85As2細胞移植によるがん悪液質モデルマウスにおいて、自発運動負荷は悪液質症状のみならず心機能障害も改善することが明らかとなった。またマイクロアレイ解析で変動のあった酵素Xの遺伝子発現量は、心筋萎縮とともに増加し自発運動負荷により減少することから、がん悪液質に伴う心機能障害と関連があると考えられる。現在、酵素Xを介する経路についてさらに解析を進めている。</p> DOI： 10.14869/toxpt.49.1.0_p-154 CiNii Research
• Fujii S., Fujimoto T., Hasegawa K., Nagano R., Ishibashi T., Kurppa K.J., Mikami Y., Kokura M., Tajiri Y., Kibe T., Wada H., Wada N., Kishida S., Higuchi Y., Kiyoshima T. . The Semaphorin 3A-A2022 · 記述言語： 日本語 出版者・発行元： Pathology Research and Practice 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. DOI： 10.1016/j.prp.2022.153991 Scopus PubMed CiNii Research
• Chairani E., Fuchigami T., Koyama H., Ono Y., Iijima M., Kishida M., Kibe T., Nakamura N., Kishida S. . Intercellular signaling between ameloblastoma and osteoblasts . Biochemistry and2022 · 記述言語： 日本語 出版者・発行元： Biochemistry and Biophysics Reports Ameloblastoma is an odontogenic tumor located in the bone jaw with clinical characteristics of extensive bone resorption. It is a locally invasive tumor with a high recurrence rate despite adequate surgical removal. In bone disease, tumors and other cells including osteoblasts, osteoclasts, and osteocytes in the bone microenvironment contribute to the pathogenesis of tumor growth. However, the effect of osteoblasts on ameloblastoma cells is not well-understood, and there has been limited research on interactions between them. This study investigated interactions between ameloblastoma cells and osteoblasts using a human ameloblastoma cell line (AM-3 ameloblastoma cells) and a murine pre-osteoblast cell line (MC3T3-E1 cells). We treated each cell type with the conditioned medium by the other cell type. We analyzed the effect on cytokine production by MC3T3-E1 cells and the production of MMPs by AM-3 cells. Treatment with AM-3-conditioned medium induced inflammatory cytokine production of IL-6, MCP-1, and RANTES from MC3T3-E1 cells. The use of an IL-1 receptor antagonist suppressed the production of these inflammatory cytokines by MC3T3-E1 cells stimulated with AM-3-conditioned medium. The MC3T3-E1-conditioned medium triggered the expression of MMP-2 from AM-3 cells. Furthermore, we have shown that the proliferation and migration activity of AM-3 cells were accelerated by MC3T3-E1 conditioned media. In conclusion, these intercellular signalings between ameloblastoma cells and osteoblasts may play multiple roles in the pathogenesis of ameloblastoma. DOI： 10.1016/j.bbrep.2022.101233 Scopus PubMed CiNii Research
• Fuchigami T. . Molecular biological findings of ameloblastoma . Japanese Dental Science Review57 27 - 32 2021年11月 詳細を見る 記述言語： 日本語 出版者・2021 · 記述言語： 日本語 出版者・発行元： Japanese Dental Science Review Ameloblastoma is benign odontogenic tumours that mainly occur in the jawbone. This tumour induces aggressive invasion into the surrounding bone and has a high recurrence rate after surgery. Therefore, mandibular resection is performed in many patients with this tumour, causing aesthetic and functional problems. It is necessary to develop a novel treatment strategy for ameloblastoma, but there are currently no innovative treatments. Although our understanding of the molecular biological mechanisms of ameloblastoma is still insufficient, there have been many recent reports of new molecular biological findings on ameloblastoma. Therefore, bioactive factors that have potential for novel therapeutic methods, such as molecular targeted therapy, have been discovered in ameloblastoma. In this review, we summarize the molecular biological findings of ameloblastoma reported over several decades, focusing on factors involved in invasion into surrounding tissues and disease-specific gene mutations. We also mention the effect of the interaction between tumour cells and stromal components in ameloblastoma on tumour development. Scientific field of dental Science: Oral surgery, Odontogenic tumor, Ameloblastoma. DOI： 10.1016/j.jdsr.2020.12.003 Scopus PubMed

• Wntシグナル経路における受容体のエンドサイトーシスを解析する実験系の確立
• 低分子量G蛋白質Ralによる細胞内小胞輸送と細胞接着の制御機構
• Wnt(ウイント)シグナル伝達系を制御する新規蛋白質の同定
• デスアシルグレリン受容体を介した新しい食欲制御機構の解明

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