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医学部 医学科 病理学講座腫瘍・再生病態学分野 |
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助教 |
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論文 【 表示 ／ 非表示 】
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Izumi A, Yamamoto K, Kawaguchi M, Yamashita F, Fukushima T, Kiwaki T, Tanaka H, Yamashita Y, Kataoka H
Cancer science 2022年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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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Kiwaki T., Nagayasu M.A., Yamada N., Kodama Y., Umekita Y., Fukushima T., Kataoka H., Tanaka H.
Pathology International 72 ( 2 ) 144 - 146 2022年2月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Pathology International
DOI： 10.1111/pin.13189
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Yamashita F, Kaieda T, Shimomura T, Kawaguchi M, Lin CY, Johnson MD, Tanaka H, Kiwaki T, Fukushima T, Kataoka H
The FEBS journal 2022年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：FEBS Journal
Hepatocyte growth factor activator inhibitor-1 (HAI-1, also known as SPINT1) is an inhibitor of matriptase, a type-2 transmembrane protease widely expressed in epithelial cells. HAI-1 also functions as a chaperone to maintain the processing and localization of matriptase required for epithelial integrity. However, mechanisms underpinning the chaperone function remain to be elucidated. Here, we show that the first Kunitz domain (KD1) and the adjacent polycystic kidney disease (PKD) domain-like internal domain of HAI-1 are essential for the chaperone function. In HEK293T cells, which do not express endogenous HAI-1 or matriptase, forced matriptase overexpression was unsuccessful unless sufficient HAI-1 was co-expressed. Among mutant HAI-1 constructs, HAI-1 with inactivation mutation in KD1 (HAI-1mKD1) or HAI-1 lacking the PKD domain (HAI-1dPKD) was unable to support matriptase expression, and neither mutant formed a complex with activated matriptase. Matriptase did not localize to the cell surface when co-expressed with HAI-1dPKD. Moreover, HAI-1dPKD accumulated in the cytoplasm of HEK293T and HaCaT cells rather than localizing to the cell surface, presumably due to misfolding as judged by altered antibody recognition. On the other hand, activation-locked and activity-incompetent matriptase were stable and readily overexpressed and localized to the cell surface without HAI-1. Therefore, the observed matriptase instability was caused by its own catalytic activity in the absence of inhibitory HAI-1. The matriptase chaperone function of HAI-1 is thus mediated primarily by the inhibition of undesired intracellular matriptase activity, and the PKD domain is essential for the proper folding and trafficking of inhibitory HAI-1 and its chaperone function.
DOI： 10.1111/febs.16348
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An adult case of a retroperitoneal isolated enteric duplication cyst with the imaging changes over time. 査読あり
Inomata M, Kai K, Ikeda T, Ichihara A, Masuda R, Kiwaki T, Tanaka H, Kataoka H, Nanashima A
Surgical case reports 7 ( 1 ) 258 2021年12月
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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年9月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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.
MISC 【 表示 ／ 非表示 】
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Kiwaki T., Nagayasu M.A., Yamada N., Kodama Y., Umekita Y., Fukushima T., Kataoka H., Tanaka H.
Pathology International 72 ( 2 ) 144 - 146 2022年2月
記述言語：日本語 掲載種別：速報，短報，研究ノート等（学術雑誌） 出版者・発行元：Pathology International
DOI： 10.1111/pin.13189
講演・口頭発表等 【 表示 ／ 非表示 】
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ヒト HGF 導入 SCID マウスを用いた HGF-MET シグナル解析と阻害治療の開発 招待あり
木脇 拓道
第３８回日本ヒト細胞学会学術集会
開催年月日： 2020年8月22日 - 2020年8月23日
記述言語：日本語 会議種別：シンポジウム・ワークショップ パネル（指名）
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A synthetic small molecule inhibitor of pro-HGF activation, ZFH7116, suppresses the growth of SAS squamous cell carcinoma line in human HGF knock-in SCID mice: A pilot study 国際会議
Takumi Kiwaki, Makiko Kawaguchi, Koji Yamamoto, James W. Janetka, Hiroaki Kataoka
ASBMB Symposia: Serine Proteases in Pericellular Proteolysis and Signaling (Potomac, Md., USA) American Society for Biochemistry and Molecular Biology
開催年月日： 2019年9月12日 - 2019年9月15日
記述言語：英語 会議種別：ポスター発表
開催地：Potomac, Md., USA
受賞 【 表示 ／ 非表示 】
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2019年度日本病理学会九州沖縄支部優秀症例報告賞（若手病理医奨励賞）
2020年5月 日本病理学会九州・沖縄支部 A rare association between true thymic hyperplasia and thyroid follicular tumor: a case report
木脇 拓道
受賞区分：国内学会・会議・シンポジウム等の賞 受賞国：日本国
科研費（文科省・学振・厚労省）獲得実績 【 表示 ／ 非表示 】
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がん組織におけるHGF-METシグナル活性化機構の解明と、その阻害療法の開発
研究課題/領域番号：20K16175 2020年04月 - 2023年03月
科学研究費補助金 若手研究
担当区分：研究代表者
その他競争的資金獲得実績 【 表示 ／ 非表示 】
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がんの転移と細胞接着分子 L1CAM 発現との関連についての臨床病理学的検討
2020年08月 - 2021年03月
宮崎大学医学部附属病院 宮崎大学医学部附属病院2020年度臨床研究支援経費
資金種別：競争的資金
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ヒト固形がんにおける Patient derived xenograft (PDX) 株の樹立と，それを用いた HGF-MET シグナル標的治療の開発
2019年09月 - 2020年03月
宮崎大学医学部附属病院 宮崎大学医学部附属病院2019年度臨床研究支援経費
資金種別：競争的資金