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Affiliation |
Faculty of Medicine School of Medicine Oncopathology and morphopathology |
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Associate Professor |
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FUKUSHIMA Tsuyoshi
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Degree 【 display / non-display 】
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Doctor of Philosophy in Medicine ( 2007.7 University of Miyazaki )
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学士（医学） ( 1996.3 宮崎医科大学 )
Research Areas 【 display / non-display 】
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Life Science / Experimental pathology
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Life Science / Neurosurgery
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Life Science / Human pathology
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Life Science / Molecular biology
Papers 【 display / non-display 】
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Silencing of insulin-like growth factor binding protein-2 (IGFBP-2) in human glioblastoma cells reduces both invasiveness and expression of progression-associated gene CD24. Reviewed International journal
Fukushima, T., Tezuka, T., Shimomura, T., Nakano, S., Kataoka, H.
The Journal of Biological Chemistry 282 ( 25 ) 18634 - 18644 2007.6
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)
Glioblastoma multiforme (GBM) is a malignant brain tumor characterized by rapid growth and extensive invasiveness. Overexpression of insulin-like growth factor-binding protein-2 (IGFBP-2) has been reported in GBM. However, it remains to be determined how IGFBP-2 is involved in the progression of GBM. We utilized short hairpin-RNA (shRNA) expression retroviral vectors to inactivate the IGFBP-2 gene permanently in two human GBM cell lines, U251 and YKG-1. The stable knockdown of IGFBP-2 resulted in decreased invasiveness, decreased saturation density of the cells in vitro, and decreased tumorigenicity in nude mice. Transcriptional profiling of both lines revealed several genes that were significantly down-regulated by inactivation of IGFBP-2. One such gene was CD24, which has been implicated in progression of various cancers. Indeed, CD24 was expressed in most GBM cases and the inactivation of CD24 in GBM cells suppressed cellular invasiveness, as was the case for IGFBP-2. Forced overexpression of CD24 led to increased invasiveness of both IGFBP-2-inactivated GBM cell lines and also A172, a human GBM cell line with low endogenous CD24. Further supporting the inter-relationship between IGFBP-2 and CD24, knockdown of IGFBP-2 suppressed the CD24 promoter activity. Moreover, both CD24 promoter activity and in vitro invasiveness were restored in knockdown cells by transfection with an IGFBP-2 expression plasmid. These results indicate that CD24 is modulated by IGFBP-2 and contributes to IGFBP-2-enhanced invasiveness of GBM cells.
Other Link： http://www.jbc.org/content/282/25/18634.long
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Hepatocyte growth factor activator inhibitor type 1 regulates epithelial to mesenchymal transition through membrane-bound serine proteinases. Reviewed International journal
Haixia Cheng, Tsuyoshi Fukushima, Nobuyasu Takahashi, Hiroyuki Tanaka and Hiroaki Kataoka
Cancer Research 69 ( 5 ) 1828 - 1835 2009.3
Language：English Publishing type：Research paper (scientific journal)
Hepatocyte growth factor activator inhibitor-1 (HAI-1), encoded by the serine protease inhibitor Kunitz type 1 (SPINT1) gene, is a membrane-associated proteinase inhibitor that potently inhibits a variety of serine proteinases, including those that are membrane bound. Although HAI-1/SPINT1 is widely expressed by epithelial cells and cancer cells, its functional role is still unclear, particularly in cancer. Here, we show that stable knockdown of HAI-1/SPINT1 in the human pancreatic cancer cell line SUIT-2 induces an elongated spindle-like morphology associated with accelerated invasion, thereby mimicking an epithelial to mesenchymal transition (EMT). We found that HAI-1/SPINT1 knockdown significantly reduced the expression of E-cadherin and was accompanied by up-regulation of Smad-interacting protein 1 (SIP1), an E-cadherin transcriptional repressor. In addition, matrix metalloproteinase-9 (MMP-9) was up-regulated. Similar results were obtained in the HLC-1 lung carcinoma cell line. Moreover, a metastatic variant of SUIT-2 (S2-CP8) that showed loss of E-cadherin expression also showed a significantly reduced level of HAI-1/SPINT1. Engineered overexpression of HAI-1/SPINT1 in S2-CP8 resulted in reversion of E-cadherin expression and SIP1 down-regulation, which accompanied reestablishment of epithelial morphology in culture. The EMT caused by HAI-1/SPINT1 knockdown seemed to be mediated, at least partly, by membrane-bound serine proteinases, matriptase/ST14 and TMPRSS4, as knockdown of matriptase/ST14 or TMPRSS4 in HAI-1/SPINT1 knockdown SUIT-2 cells and HLC-1 cells resulted in reversion of SIP1 and/or MMP-9 expression levels. We suggest that interactions between HAI-1/SPINT1 and membrane-bound serine proteinases contribute to transcriptional and functional changes involved in EMT in certain carcinoma cells.
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Antitumor effect of dehydroxymethylepoxyquinomicin, a small molecule inhibitor of nuclear factor-κB, on glioblastoma. Reviewed International journal
Fukushima T, Kawaguchi M, Yorita K, Tanaka H, Takeshima H, Umezawa K, Kataoka H
Neuro-oncology 14 ( 1 ) 19 - 28 2012.1
Language：English Publishing type：Research paper (scientific journal)
Glioblastoma is the most malignant type of brain tumor. Despite recent advances in therapeutic modalities, the prognosis of glioblastoma remains very poor. Recent studies have indicated that RelA/nuclear factor (NF)-κB is consistently activated in human glioblastoma. In this study, we searched for a new treatment modality for glioblastoma, by examining the effects of dehydroxymethylepoxyquinomicin (DHMEQ), a unique small molecule inhibitor of NF-κB. Addition of DHMEQ to cultured human glioblastoma cells inhibited the nuclear translocation of RelA. It also reduced the growth rate of human glioblastoma cells significantly in 6 cell lines and modestly in 3 among 10 cell lines examined. Then, we performed further analyses using 3 sensitive cell lines (U87, U251, and YKG-1). The growth retardation was accompanied by G2/M arrest in vitro. Increased apoptosis was observed in U87 and YKG-1, but not U251 cells after DHMEQ treatment. Then, we tested the efficacy of DHMEQ in chemoprevention through the use of a nude mouse model. Subcutaneous tumors formed by U87 or U251 cells were reduced by ∼40% in size by intraperitoneal administration of DHMEQ started immediately after implantation of the cells. DHMEQ treatment achieved statistically significant improvements in survival curves of mice intracranially implanted with U87 or U251 cells. Histological analysis revealed increased areas of necrosis, increased numbers of collapsed microvessels, decreased nuclear immunoreactivity of RelA, and decreased immunoreactivity of urokinase-type plasminogen activator in the DHMEQ-treated U87 tumor tissues. These results suggest that the targeting of NF-κB by DHMEQ may serve as a promising treatment modality in glioblastoma.
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Hepatocyte growth factor activator inhibitor type 1 suppresses metastatic pulmonary colonization of pancreatic carcinoma cells. Reviewed International journal
Fukushima T, Kawaguchi M, Yamasaki M, Tanaka H, Yorita K, Kataoka H.
Cancer Science 102 ( 2 ) 407 - 413 2011.2
Language：English Publishing type：Research paper (scientific journal)
Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a transmembrane protease inhibitor that regulates the activities of membrane-bound and extracellular serine proteases. HAI-1 has two Kunitz-type inhibitor domains with the N-terminal Kunitz domain (KD1) responsible for inhibiting known target proteases. Previously, we reported that knockdown of HAI-1 in the human pancreatic carcinoma cell line SUIT-2 resulted in epithelial to mesenchymal transition. To evaluate the role of HAI-1 in metastasis, we examined the metastatic capability of SUIT-2 cells that did or did not stably express HAI-1 short-hairpin RNA in an experimental pulmonary metastasis assay using nude mice. The extent of pulmonary metastasis was verified by histological examination and direct measurement of human cytokeratin 19 mRNA levels. One week after injecting SUIT-2 cells into mouse tail veins, apparent metastatic colonization was observed in 36% (4/11) of mice injected with HAI-1-knockdown SUIT-2, whereas none (0/11) of the control mice were positive for metastasis. After 2 weeks the metastasis positive ratios were 80% (4/5) and 40% (2/5), and after 4 weeks the ratios were 82% (9/11) and 45% (5/11) for HAI-1-knockdown and control SUIT-2 cells, respectively. Thus, loss of HAI-1 promoted pulmonary metastasis. Co-injection of recombinant KD1 abolished metastasis produced by HAI-1-knockdown SUIT-2 cells after 1 week. Moreover, recombinant KD1 restored E-cadherin levels in HAI-1 knockdown SUIT-2 cells and reduced their invasiveness in vitro. These data indicate that HAI-1 regulates pulmonary metastasis of SUIT-2, and KD1 may have therapeutic application for inhibiting metastatic cancer cell spreading.
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Adrenomedullin alleviates mucosal injury in experimental colitis and increases claudin-4 expression in the colonic epithelium Reviewed International journal
Kawaguchi M., Kataoka H., Kiwaki T., Weiting L., Nagata S., Kitamura K., Fukushima T.
FEBS Open Bio 13 ( 4 ) 713 - 723 2023.4
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：FEBS Open Bio
Adrenomedullin (AM) is a peptide with pleiotropic physiological functions that attenuates intestinal mucosal inflammation. However, the mechanism underpinning mucosal protection by AM is not fully understood, and its effect on intestinal epithelial cells remains unclear. Here, we investigated the effects of AM on junctional molecules in primary-cultured murine intestinal epithelial cells and discovered that AM upregulates claudin-4 expression. In a mouse model of dextran sulfate sodium-induced colitis, AM administration also enhanced claudin-4 expression and accelerated mucosal regeneration. Furthermore, AM reversed TNFα-mediated downregulation of claudin-4 and loss of cell–cell adhesion of the HCT116 human intestinal epithelial cell line in vitro. These results indicate that AM may enhance intestinal epithelial integrity by upregulating claudin-4 expression.
Books 【 display / non-display 】
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Tsuyoshi Fukushima（ Role： Joint editor , Chapter 5; Alkylatýng Agents and Treatment of Gliomas (pp. 145-171) ）
Nova Science Publishers, Inc. 2013.7
Language：English Book type：Scholarly book
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Tsuyoshi Fukushima and Hiroaki Kataoka（ Role： Joint editor , Chapter 19: Insulin-Like Growth Factor Binding Protein-2: A Possible Regulator of Invasive Growth in Glioblastoma. (pp.395-410)）
InTech 2011.9
Language：English Book type：Scholarly book
MISC 【 display / non-display 】
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Hepatocyte growth factor activator; a proteinase linking tissue injury with repair Reviewed
Tsuyoshi Fukushima, Shuichiro Uchiyama, Hiroyuki Tanaka, Hiroaki Kataoka
International Journal of Molecular Sciences 19 ( 11 ) 3435 - 3435 2018.11
Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal) Publisher：Molecular Diversity Preservation International, Multidisciplinary Digital Publishing Institute
Hepatocyte growth factor (HGF) promotes pleiotropic signaling through its specific receptor tyrosine kinase, MET. As such, it has important roles in the regeneration of injured tissues. Since HGF is produced mainly by mesenchymal cells and MET is expressed in most epithelial, endothelial and somatic stem cells, HGF functions as a typical paracrine growth factor. HGF is secreted as an inactive precursor (proHGF) and requires proteolytic activation to initiate HGF-induced MET signaling. HGF activator (HGFAC) is a serum activator of proHGF and produces robust HGF activities in injured tissues. HGFAC is a coagulation factor XII-like serine endopeptidase that circulates in the plasma as a zymogen (proHGFAC). Thrombin, kallikrein-related peptidase (KLK)-4 or KLK-5 efficiently activates proHGFAC. The activated HGFAC cleaves proHGF at Arg494-Val495, resulting in the formation of the active disulfide-linked heterodimer HGF. Macrophage stimulating protein, a ligand of RON, is also activated by HGFAC in vivo. Although HGFAC functions primarily at the site of damaged tissue, a recent report has suggested that activated HGFAC relays a signal to stem cells in non-injured tissues via proHGF activation in the stem cell niche. This review focuses on current knowledge regarding HGFAC-mediated proHGF activation and its roles in tissue regeneration and repair.
DOI： 10.3390/ijms19113435
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Alkylating agents and treatment of gliomas Reviewed
Fukushima T.
Alkylating Agents as Environmental Carcinogen and Chemotherapy Agents 145 - 170 2013.1
Language：English Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media) Publisher：Nova Science Pub Inc
Nitrosoureas have been commonly used for the treatment of malignant gliomas since the 1970s. However, the prognosis of patients with malignant gliomas remains extremely poor despite the fact that multidisciplinary approaches involving surgery, chemotherapy, and radiotherapy have been used for several decades. Recently, the novel alkylating agent temozolomide (TMZ) was shown to improve the survival of patients with malignant gliomas (including glioblastomas) in many clinical studies and has become one of the standard modalities for treatment of newly diagnosed and recurrent malignant gliomas. Temozolomide is a prodrug that can be orally administered and is hydrolytically processed in the blood to yield the methyldiazonium cation, which has DNA methylating activity. Patients can receive ambulatory treatment with TMZ because of its oral administration route and minimal side effects. The expression level of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is the most important factor for a favorable outcome in patients treated with TMZ as well as those treated with nitrosoureas, and the epigenetic silencing of MGMT is the strongest predictive marker. The treatment course for patients with tumors lacking MGMT promoter methylation is unknown, and recurrence is unavoidable even in patients with TMZ-sensitive glioblastoma. While TMZ has provided a significant survival benefit, innovative modalities that can be combined with TMZ and radiotherapy are still required. In this chapter, we review the history and chemistry of alkylating agents for the treatment of malignant gliomas. In particular, we focus on TMZ and its effects on tumor cells. Furthermore, chemoresistance to TMZ and current chemotherapies used for the treatment of malignant gliomas are discussed.
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Anti-Glioma Therapy with Temozolomide and Status of the DNA-Repair Gene MGMT Reviewed
Fukushima T, Takeshima H, Kataoka H.
Anticancer Research 29 ( 11 ) 4845 - 4854 2009.11
Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal) Publisher：Athens, Greece : Hellenic Anticancer Institute
The prognosis of patients with glioblastoma is extremely poor despite multimodal treatments including surgery, chemotherapy and radiotherapy. Recently, the alkylating agent, temozolomide (TMZ) has been shown to improve survival in patients with malignant gliomas, including those with glioblastoma in some clinical studies, and has become one of the standard modalities for treatment of newly diagnosed and recurrent malignant gliomas. The epigenetic silencing of the DNA repair enzyme O(6)-methylguanine-DNA-methyltransferase (MGMT) is the strongest predictive marker for favorable outcome in patients treated with TMZ. However, it remains to be determined how patients with tumors lacking MGMT promoter methylation should be treated. Moreover, even patients with TMZ-sensitive glioblastoma cannot avoid eventual recurrence. In this article, we review the mechanism of the effect of TMZ on tumor cells and resistance to TMZ, and provide an overview of the current management and trials for patients with glioblastoma.
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Roles of insulin-like growth factor binding protein-2 (IGFBP-2) in glioblastoma. Reviewed
Tsuyoshi Fukushima, Hiroaki Kataoka
Anticancer Research 27 ( 6A ) 3685 - 3692 2007.11
Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal) Publisher：J.G. Delinassios, Anticancer Research
Insulin-like growth factor binding protein-2 (IGFBP-2) is reported to be a modulator of the action of insulin-like growth factors (IGFs), whereas IGF-independent effects of IGFBP-2 on cellular proliferation, apoptosis, and mobility have been revealed not only during the embryonic state but also in the pathological state of cancer. As well as other types of carcinomas, overexpression of IGFBP-2 has been reported in glioblastoma multiforme (GBM), the most malignant brain tumor characterized by rapid growth, extensive invasiveness, and angiogenesis. However, it remains unclear how IGFBP-2 is involved in the malignant features of GBM. This review outlines the IGF-dependent and -independent functions of IGFBP-2 and focuses on the roles of IGFBP-2 in the progression of GBM.
Presentations 【 display / non-display 】
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A case of brain tumor accompanied by systemic metastasis with bone marrow carcinomatosis
Fukushima T, Saito K, Horinouchi S, Kawaguchi M, Kataoka H
The 31st Annual Meeting of the Japanese Association for Metastasis Research 2023.7.8
Event date： 2023.7.7 - 2023.7.8
Language：Japanese Presentation type：Symposium, workshop panel (public)
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Exploratory research for novel functional genes in glioblastoma Invited
Tsuyoshi Fukushima
The 39th Annual Meeting of Japan Human Cell Society 2021.10.31
Event date： 2021.10.30 - 2021.10.31
Language：Japanese Presentation type：Oral presentation (invited, special)
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Roles of membrane-bound serine protease inhibitor, HAI-1, in invasion and metastasis of cancers Invited International conference
Fukushima T
14th International Biennial Congress of the Metastasis Research Society (MRS 2012) (Brisbaene, QL, Australia) 2012.9.5 the Metastasis Research Society
Event date： 2012.9.2 - 2012.9.5
Language：English Presentation type：Symposium, workshop panel (nominated)
Venue：Brisbaene, QL, Australia
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Roles of membrane-bound serine protease inhibitor, HAI-1, in invasion and metastasis of cancers Invited
Tsuyoshi Fukushima
21st Annual meeting of the Japanese Association for Metastasis research 2012.7.13
Event date： 2012.7.12 - 2012.7.13
Language：Japanese Presentation type：Symposium, workshop panel (nominated)
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Silencing of CD24 affects some progression-associated genes in human glioblastoma cells. International conference
Tsuyoshi Fukushima, Makiko Kawaguchi, Nobuyasu Takahashi, Hiroyuki Tanaka, Hiroshi Itoh, Hiroaki Kataoka
2008.4.13
Event date： 2008.4.12 - 2008.4.16
Language：English Presentation type：Poster presentation
Country：United States
Awards 【 display / non-display 】
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第31回日本ヒト細胞学会学術集会ポスター発表賞
2013.8 日本ヒト細胞学会
福島剛
Award type：Award from Japanese society, conference, symposium, etc. Country：Japan
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日本がん転移学会研究奨励賞
2012.7 日本がん転移学会
福島剛
Award type：Award from Japanese society, conference, symposium, etc. Country：Japan
Grant-in-Aid for Scientific Research 【 display / non-display 】
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Multifaceted approach for understanding of malignant phenotype of glioblastoma
Grant number：17K08764 2017.04
Grant-in-Aid for Scientific Research Grant-in-Aid for Scientific Research(C)
Authorship：Principal investigator
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膠芽腫の悪性形質の鍵となる遺伝子の探索
Grant number：24590486 2012.04 - 2015.03
科学研究費補助金 基盤研究(C)
Authorship：Principal investigator
本研究は、膠芽腫での高発現が報告されているが、その意義や機能が未だよくわかっていない遺伝子を解析し、その下流または上流のシグナル伝達に関わる新規機能遺伝子を探索して、膠芽腫の新規治療標的を見出そうとするものである。これまでの研究成果をもとに、本研究は膠芽腫におけるIGFBP-2 と CD24 の役割および、悪性形質を制御する作用機序を解明し、そこに関わるシグナル伝達分子が治療標的になりうるかを検討する。同時に、IGFBP-2 と CD24 を足がかりにしてcDNA マイクロアレイを用いた網羅的解析を行い、IGFBP-2、CD24 の上流、下流で膠芽腫の悪性形質に関わっている新たな機能分子を探索する。
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膠芽腫の新規治療標的探索
Grant number：22790384 2010.04 - 2012.03
科学研究費補助金 若手研究(B)
Authorship：Principal investigator
膠芽腫（Glioblastoma）は、極めて予後不良の悪性脳腫瘍であり、最もブレークスルーが待望されている難治性癌の一つである。本研究は膠芽腫の悪性形質を左右する新たな機能遺伝子およびシグナル伝達を探索し、新規治療標的を見出すことを目的とする。既存の知見にとらわれない新たな発見を得るため、網羅的解析と機能解析の両面からアプローチする。申請者がこれまでの研究で明らかしてきた IGFBP-2 と CD24 の膠芽腫の悪性形質への関与の知見をもとに、IGFBP-2 および CD24 が膠芽腫の悪性形質を制御している機序を解析するとともに、さらに、未だ同定されていない新規機能遺伝子を探索し、新たな治療標的を見出すことが本研究の目的である。
Reverse genetics 的アプローチとして、安定的ノックダウンの系を用いて、IGFBP-2 と CD24 が膠芽腫の浸潤性増殖を促進する機序と、そこに関与する因子を解析し、悪性形質に関与していて治療標的となりうる候補遺伝子を絞り込んでいく。Forward genetics 的アプローチとして、IGFBP-2 を制御している未知の遺伝子を網羅的に探索するために、IGFBP-2 のプロモーターとランダムアンチセンスライブラリーを用いた expression cloning 法を試みる。この方法によって、既知のシグナル伝達からは予想出来ない新たな機能遺伝子が渉猟されることが期待される。IGFBP-2 を制御して膠芽腫の悪性形質を左右している遺伝子を数個絞り込んで、それらの遺伝子の発現と悪性形質の関係を解析するまでを本研究期間中の目標としたい。 -
Exploratory analysis for functional genes which regulate the malignant features of glioblastoma
Grant number：20790307 2008.04 - 2010.03
Grant-in-Aid for Scientific Research Grant-in-Aid for Young Scientists(B)
Authorship：Principal investigator
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膠芽腫の浸潤性増殖における新規機能遺伝子の探索
Grant number：19890168 2007.10 - 2008.03
科学研究費補助金 若手研究(スタートアップ)
Authorship：Principal investigator
著明な浸潤性増殖と血管新生を特徴とする悪性脳腫瘍である膠芽腫について、新規機能遺伝子を同定することを目的とする。これまで解析してきたIGFBP-2 と CD24 が膠芽腫の浸潤性増殖を促進する機序と、そこに関与する因子を解析し、膠芽腫の悪性形質を制御するための分子標的を探索したい。また、IGFBP-2 および CD24 の発現が薬剤耐性や放射線治療耐性へ関与する可能性を検討し、現在用いられている治療の補助療法の標的となり得ないか検討する。さらに、cDNA マイクロアレイによって渉猟されたIGFBP-2と連動して変動する CD24 以外の遺伝子について、ノックダウンを行って同様に解析し、悪性形質に関与し、治療標的となりうる候補遺伝子を絞り込んでいく。
Available Technology 【 display / non-display 】
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膠芽腫における新規機能遺伝子の探索
難治性がんの浸潤、転移機構の解明
腫瘍周囲微小環境におけるプロテアーゼ活性調節機構の解明Home Page： 宮崎大学医学部 病理学講座 腫瘍・再生病態学分野
Related fields where technical consultation is available：培養細胞への遺伝子導入
マウスへの培養細胞脳内移植Message：病理学は、外科病理診断を行う実践的診療部門であると共に、形態を足がかりにして病気の本質を解明する基礎医学であり、膠芽腫を初めとする難治性癌の研究に適した分野であると思います。新規治療に繋がる発見を目標に研究を進めていきます。