Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention.

Toyokuni S

Free radical biology & medicine 2018.10

Molecular mechanisms of non-thermal plasma-induced effects in cancer cells.

Tanaka H, Mizuno M, Ishikawa K, Toyokuni S, Kajiyama H, Kikkawa F, Hori M

Biological chemistry 2018.10

A special issue of SFRR Asia: Cross talk between free radicals and mitochondria in health and disease.

Liu J, Toyokuni S, Surh YJ

Free radical research page： 1-51 2018.9

Plasma Biology for a Novel Cancer Treatment International journal

Toyokuni Shinya

JSAP Annual Meetings Extended Abstracts Vol. 2018.2 ( 0 ) page： 37 - 37 2018.9

動物モデルを用いたがん研究扁平上皮癌発症におけるHippo経路の役割(Animal models in cancer research Critical role of Hippo signaling pathway at the onset of squamous cell carcinomas)

鈴木聡, 西尾美希, 大森裕文, 藤庸子, 前濱朝彦, 青野ゆかり, 清野透, 田口健一, 益田宗幸, 豊國伸哉, 田代浩徳, 片渕秀隆

日本癌学会総会記事 Vol. 77回 page： 1110 - 1110 2018.9

アスベストが卵巣癌を起こす可能性についてクロシドライトは卵巣表層上皮におけるDNAの二本鎖切断を惹起する(Asbestos exposure as a possible cause of ovarian carcinogenesis)

本岡大社, 伊藤文哉, 田代浩徳, 片渕秀隆, 豊國伸哉

日本癌学会総会記事 Vol. 77回 page： 118 - 118 2018.9

Development of a novel monoclonal antibody against 4-hydroxy-2E,6Z-dodecadienal (4-HDDE)-protein adducts: Immunochemical application in quantitative and qualitative analyses of lipid peroxidation in vitro and ex vivo. International journal

Koji Uchida, Takahiro Shibata, Shinya Toyokuni, Bareket Daniel, Kamelija Zarkovic, Neven Zarkovic, Shlomo Sasson

Free radical biology & medicine Vol. 124 page： 12 - 20 2018.8

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Inc.

Non-enzymatic peroxidation of polyunsaturated fatty acids (PUFA) results in the formation of various α,β-unsaturated aldehydes, of which 4-hydroxyalkenals are abundant. The propensity of n-6 PUFA, such as linoleic acid, γ-linolenic acid and arachidonic acid, to undergo radical-induced peroxidation and generate 4-hydroxy-2E-nonenal (4-HNE) has been widely demonstrated. The ability of the latter to form covalent adducts with macromolecules and modify cellular functions has been linked to numerous pathological processes. Concomitantly, evidence has accumulated on specific signaling properties of low concentrations of 4-HNE that may induce hormetic and protective responses to peroxidation stress in cells. It has long been known that peroxidation of PUFA, and particularly arachidonic acid, also give rise to 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), which is more chemically reactive than 4-HNE. Few studies on 4-HDDE revealed its ability to avidly interact covalently with electronegative moieties in macromolecules and to its ability to selectively activate the transcriptional regulator Peroxisome Proliferator-Activated Receptor (PPAR)-β/δ. The research on 4-HDDE has been impeded due to the lack of available pure 4-HDDE and antibodies that recognize 4-HDDE-modified epitopes in proteins. The purpose of this study was to employ an established procedure to synthesize 4-HDDE and use it to create and characterize a monoclonal antibody against 4-HDDE-modified proteins and establish its application for ELISA and immunohistochemical analysis of cells and tissues and further expand lipid peroxidation research.

DOI： 10.1016/j.freeradbiomed.2018.05.079

Non-thermal plasma as a simple ferroptosis inducer in cancer cells: A possible role of ferritin International journal

Furuta Takahiro, Shi Lei, Toyokuni Shinya

PATHOLOGY INTERNATIONAL Vol. 68 ( 7 ) page： 442 - 443 2018.7

Administration of molecular hydrogen during pregnancy improves behavioral abnormalities of offspring in a maternal immune activation model Reviewed International journal

Kenji Imai, Tomomi Kotani, Hiroyuki Tsuda, Tomoko Nakano, Takafumi Ushida, Akira Iwase, Taku Nagai, Shinya Toyokuni, Akio Suzumura, Fumitaka Kikkawa

Scientific Reports Vol. 8 ( 1 ) page： 9221 2018.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Publishing Group

The aim of the present study was to investigate long-term outcomes of the offspring in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) model and the effect of maternal molecular hydrogen (H2) administration. We have previously demonstrated in the MIA mouse model that maternal administration of H2 attenuates oxidative damage and neuroinflammation, including induced pro-inflammatory cytokines and microglial activation, in the fetal brain. Short-term memory, sociability and social novelty, and sensorimotor gating were evaluated using the Y-maze, three-chamber, and prepulse inhibition (PPI) tests, respectively, at postnatal 3 or 4 weeks. The number of neurons and oligodendrocytes was also analyzed at postnatal 5 weeks by immunohistochemical analysis. Offspring of the LPS-exposed dams showed deficits in short-term memory and social interaction, following neuronal and oligodendrocytic loss in the amygdala and cortex. Maternal H2 administration markedly attenuated these LPS-induced abnormalities. Moreover, we evaluated the effect of H2 on LPS-induced astrocytic activation, both in vivo and in vitro. The number of activated astrocytes with hypertrophic morphology was increased in LPS-exposed offspring, but decreased in the offspring of H2-administered dams. In primary cultured astrocytes, LPS-induced pro-inflammatory cytokines were attenuated by H2 administration. Overall, these findings indicate that maternal H2 administration exerts neuroprotective effects and ameliorates MIA-induced neurodevelopmental deficits of offspring later in life.

DOI： 10.1038/s41598-018-27626-4

Acute fulminant invasive pulmonary aspergillosis in an immunocompetent host: An autopsy case report Reviewed International journal

Yuuki Ohara, Takahiko Ito, Makoto Ito, Kyoko Yamashita, Shinya Toyokuni

Medical Mycology Case Reports Vol. 20 page： 39 - 42 2018.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier B.V.

A 62-year-old previously healthy male who was a welder/smoker/drinker was admitted to Kani Tono Hospital for severe hypoxemia (Day 0). Initial physical and radiological examinations suggested an acute exacerbation of chronic obstructive pulmonary disease. However, respiratory failure developed rapidly, and he died on Day + 4. Aspergillus fumigatus was identified after his death, and he was diagnosed with invasive pulmonary aspergillosis. The clinical and pathological features are precisely described with pathogenetic considerations.

DOI： 10.1016/j.mmcr.2018.02.002

An autopsy case report: Differences in radiological images correlate with histology in Erdheim-Chester disease. Reviewed International journal

Yuuki Ohara, Seiichi Kato, Daisuke Yamashita, Akira Satou, Yoshie Shimoyama, Chie Hamaie, Motoki Sato, Nobutaro Ban, Koji Yamamoto, Takehiro Yamada, Hisashi Kawai, Koichi Ohshima, Shigeo Nakamura, Shinya Toyokuni

Pathology international Vol. 68 ( 6 ) page： 374 - 381 2018.6

Language：English Publishing type：Research paper (scientific journal)

p16 activation caused by oncogenic mutations may represent oncogene-induced senescence (OIS), a protective mechanism against oncogenic events. However, OIS can contribute to tumor development via tissue remodeling in some tumors. Erdheim-Chester disease (ECD), a rare non-Langerhans cell histiocytosis, is one such tumor. Its clinical and histological features vary, making it difficult to diagnose. Herein, we describe an autopsy of an ECD patient. The patient underwent radiological examinations, including 18 F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT), bone scintigraphy and CT. A biopsy from the lesion with the highest FDG accumulation confirmed the presence of foamy macrophages, a diagnostic clue for ECD. Based on this finding and the clinical features, ECD was diagnosed. However, the patient died from heart dysfunction. After the autopsy, each radiologically different site showed various histological findings regarding the morphology of macrophages, fibrosis, inflammation, and p16 expression. OIS-induced histological progression can cause certain changes observed in radiological images. In addition, in order to evaluate the increase in glucose metabolism, which can affect FDG accumulation, the expression of glucose transporter 1 and hexokinase II was also analyzed. Summarizing the radio-histological correlation can help further both the understanding and diagnosis of ECD.

DOI： 10.1111/pin.12663

タルクへの曝露は卵巣表層上皮細胞内の2価鉄イオンの増加に寄与し卵巣癌の発癌に関わる

本岡大社, 伊藤文哉, 田代浩徳, 片渕秀隆, 豊國伸哉

Biomedical Research on Trace Elements Vol. 29 ( 1 ) page： 71 - 71 2018.6

Ferroptosis in carcinogenesis and tumor biology International journal

Toyokuni Shinya

FREE RADICAL BIOLOGY AND MEDICINE Vol. 120 page： S19-S19 - S19 2018.5

Expression of P-REX2a is associated with poor prognosis in endometrial malignancies. International journal

Sho Takeshita, Yoriko Yamashita, Kosuke Shiomi, Nako Suzuki, Jun Yoshida, Aya Naiki-Ito, Shugo Suzuki, Shinya Akatsuka, Shinya Toyokuni, Takashi Takahashi, Shoko Mase, Atsushi Arakawa, Mayumi Sugiura-Ogasawara, Satoru Takahashi

Oncotarget Vol. 9 ( 37 ) page： 24778 - 24786 2018.5

Language：English Publishing type：Research paper (scientific journal)

P-REX2a is a PTEN inhibitor that also activates Rac 1. No associations with P-REX2a and human endometrial cancers have been reported to date. In this study, we immunohistochemically analyzed 155 uterine endometrial malignancies for P-REX2a expression. The P-REX2a-positive tumors displayed worse prognosis independent of PTEN expression. Then, we transduced either P-REX2a expression vector or short hairpin RNAs targeting P-REX2a into 2 uterine endometrioid carcinoma cell lines, OMC-2 and JHUEM-14. Ectopic expression of P-REX2a led to increased cell proliferation only in the PTEN-expressing OMC-2 cells but did not show any change in the PTEN-negative JHUEM-14 cells or the P-REX2a-knockdown cells. Induction of P-REX2a increased and knockdown of P-REX2a decreased cell migration in both cell lines. Then, we performed expression microarray analysis using these cells, and pathway analysis revealed that the expression of members of the GPCR downstream pathway displayed the most significant changes induced by the knockdown of P-REX2a. Immunohistochemical analysis revealed that Vav1, a member of the GPCR downstream pathway, was expressed in 139 of the 155 endometrial tumors, and the expression levels of Vav1 and P-REX2a showed a positive correlation (r = 0.44, p < 0.001). In conclusion, P-REX2a enhanced cell motility via the GPCR downstream pathway independently of PTEN leading to progression of uterine endometrioid malignancies and poor prognosis of the patients.

DOI： 10.18632/oncotarget.25349

Superiority of rat over murine model for studies on the evolution of cancer genome.

Akatsuka S, Li GH, Toyokuni S

Free radical research page： 1-5 2018.5

Effect of molecular hydrogen on uterine inflammation during preterm labour Reviewed International journal

Tomoko Nakano, Tomomi Kotani, Kenji Imai, Yukako Iitani, Takafumi Ushida, Hiroyuki Tsuda, Hua Li, Akira Iwase, Shinya Toyokuni, Fumitaka Kikkawa

Biomedical Reports Vol. 8 ( 5 ) page： 454 - 460 2018.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Spandidos Publications

Intrauterine inflammation causes preterm birth and is associated with complications in preterm neonates. Thus, strategies aimed at suppressing inflammation are expected to be effective for reducing the risk of preterm birth and associated complications. Our previous studies demonstrated that molecular hydrogen (H2), an anti-inflammatory agent, prevented inflammation-induced impairment in foetal brain and lung tissues in lipopolysaccharide (LPS)-induced rodent models. However, it remains unclear whether H2 is capable of inhibiting preterm labour. The aim of the current study was therefore to investigate the effect of H2 on inflammation-induced preterm labour. Pregnant ICR (CD-1) mice were divided into three groups: Control, LPS and H2 water (HW) + LPS. In the control and LPS groups, vehicle and LPS, respectively, were intraperitoneally injected on embryonic day 15.5. In the HW + LPS group, HW was administered 24 h prior to LPS injection. The time from LPS administration to parturition was compared between the LPS and HW + LPS groups. Maternal uterus was collected 6 h after LPS injection and the transcript levels of pro-inflammatory cytokines, contractile-associated proteins (CAPs), matrix metalloproteinase-3 (Mmp3) and endothelin-1 (Et1) were assessed by reverse transcription-quantitative polymerase chain reaction. The protein levels of cyclooxygenase-2 (Cox2) were also evaluated by immunohistochemistry. The time from LPS administration to parturition in the HW + LPS group was significantly increased compared with that in the LPS group (33.5±3.4 vs. 18.3±8.8 h, respectively, P=0.020). H2 administration also resulted in significantly higher progesterone levels compared with LPS treatment alone (P=0.002). The transcript levels of pro-inflammatory cytokines, CAPs, Mmp3 and Et1 in the uteri of the LPS group were significantly higher than those in the control group (all P&lt
0.05). In turn, all these levels with the exception of interleukin-8 and Mmp3 were significantly lower in the HW + LPS group compared with those in the LPS group (all P&lt
0.05). The protein levels of Cox2 in the LPS group were also significantly increased compared with those in the control (P&lt
0.001) and HW + LPS (P=0.003) groups. These results suggest that inflammation-induced changes in the uterus may be ameliorated through maternal H2 administration. Preventive H2 administration may therefore represent an effective strategy for the suppression of inflammation during preterm labour.

DOI： 10.3892/br.2018.1082

Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model Reviewed International journal

Yuuki Ohara, Shan Hwu Chew, Nobuaki Misawa, Shenqi Wang, Daiki Somiya, Kae Nakamura, Hiroaki Kajiyama, Fumitaka Kikkawa, Yuta Tsuyuki, Li Jiang, Kyoko Yamashita, Yoshitaka Sekido, Kenneth E. Lipson, Shinya Toyokuni

Oncotarget Vol. 9 ( 26 ) page： 18494 - 18509 2018.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Impact Journals LLC

Malignant mesothelioma is an aggressive neoplasm with no particularly effective treatments. We previously reported that overexpression of connective tissue growth factor (CTGF/CCN2) promotes mesothelioma growth, thus suggesting it as a novel molecular target. A human monoclonal antibody that antagonizes CTGF (FG-3019, pamrevlumab) attenuates malignant properties of different kinds of human cancers and is currently under clinical trial for the treatment of pancreatic cancer. This study reports the effects of FG-3019 on human mesothelioma in vitro and in vivo. We analyzed the effects of FG-3019 on the proliferation, apoptosis, migration/invasion, adhesion and anchorage-independent growth in three human mesothelioma cell lines, among which ACC-MESO-4 was most efficiently blocked with FG-3019 and was chosen for in vivo experiments. We also evaluated the coexistent effects of fibroblasts on mesothelioma in vitro, which are also known to produce CTGF in various pathologic situations. Coexistent fibroblasts in transwell systems remarkably promoted the proliferation and migration/invasion of mesothelioma cells. In orthotopic nude mice model, FG-3019 significantly inhibited mesothelioma growth. Histological analyses revealed that FG-3019 not only inhibited the proliferation but also induced apoptosis in both mesothelioma cells and fibroblasts. Our data suggest that FG-3019 antibody therapy could be a novel additional choice for the treatment of mesothelioma.

DOI： 10.18632/oncotarget.24892

Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification Reviewed International journal

Kyoko Yamashita, Kenichi Kohashi, Yuichi Yamada, Takeaki Ishii, Yoshihiro Nishida, Hiroshi Urakawa, Ichiro Ito, Mitsuru Takahashi, Takeshi Inoue, Masafumi Ito, Yuuki Ohara, Yoshinao Oda, Shinya Toyokuni

Histopathology Vol. 72 ( 5 ) page： 729 - 738 2018.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Blackwell Publishing Ltd

Aims: Ossification is found occasionally in dedifferentiated liposarcoma (DDLPS). The aims of this study were to elucidate whether the formed bone tissue is usually produced by tumour cells or by reactive non-neoplastic cells, and to reveal the clinicopathological characteristics of DDLPS with ossification. Methods and results: We examined 36 cases of ossified DDLPS by comparing them to 31 cases of non-ossified DDLPS. MDM2 amplification was confirmed in osteocytes and/or osteoblastic cells in all but one ossified DDLPS cases (27 of 28) using fluorescence in-situ hybridisation, although the morphological impression of ossification appeared to be mainly metaplastic (27 of 36) or high-grade osteosarcoma-like (six of 36). The bone tissue was often formed predominantly at the periphery of the DDLPS area near the well-differentiated liposarcoma component (18 of 36), and an organised structure such as bone marrow-like differentiation was not uncommon (12 of 36). According to a modified French Fédération Nationale des Centers de Lutte Contre le Cancer (FNCLCC) grading system, ossified DDLPS tended to be lower grade than non-ossified DDLPS (mean grade: 1.88 and 2.15, respectively). Ossification in DDLPS was associated significantly with shorter local recurrence-free survival by multivariate analysis (P = 0.02347), but metaplastic-appearing ossification tended to be associated with longer overall survival (P = 0.1400). Conclusions: The bone tissue formed in DDLPS was mainly neoplastic regardless of its morphology and maturity, which highlighted the osteogenic differentiation of the tumour cells. DDLPS patients with osteogenic differentiation tended to suffer from earlier local recurrences, which did not necessarily lead to poor life outcomes.

DOI： 10.1111/his.13421

脱分化型脂肪肉腫における骨形成の特徴と予後との関連

山下享子, 孝橋賢一, 山田裕一, 伊藤以知郎, 小田義直, 豊國伸哉

日本病理学会会誌 Vol. 107 ( 1 ) page： 291 - 291 2018.4

Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats Reviewed International journal

Yuuki Ohara, Shan-Hwu Chew, Takahiro Shibata, Yasumasa Okazaki, Kyoko Yamashita, Shinya Toyokuni

Cancer Science Vol. 109 ( 2 ) page： 330 - 339 2018.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Blackwell Publishing Ltd

Malignant mesothelioma (MM) is a rare but socially important neoplasm due to its association with asbestos exposure. Malignant mesothelioma is difficult to diagnose at an early stage, yet there are no particularly effective treatments available at the advanced stage, thus necessitating efficient strategies to prevent MM in individuals already exposed to asbestos. We previously showed that persistent oxidative damage caused by foreign body reaction and affinity of asbestos both to hemoglobin and histones is one of the major pathogeneses. Accordingly, as an effective strategy to prevent asbestos-induced MM, we undertook the use of an iron chelator, deferasirox, which decreased the epithelial–mesenchymal transition in a crocidolite-induced rat MM model. However, this agent may show adverse effects. Here, we studied the effects of iron removal by phlebotomy as a realistic measure on the same rat model. We injected a total of 5 mg crocidolite i.p. to F1 hybrid rats between the Fischer-344 and Brown-Norway strains at the age of 6 weeks. We repeated weekly or biweekly phlebotomy of 6-8 mL/kg/time from 10 to 60 weeks of age. The animals were observed until 120 weeks. In male rats, phlebotomy significantly decreased the weight and nuclear grade of MM, and modestly reduced the associated ascites and the fraction of more malignant sarcomatoid subtype. Weekly phlebotomy prolonged long-term survival. Our results indicate that appropriate phlebotomy may be a practical preventive measure to attenuate the initiation and promotion capacity of asbestos towards MM by reducing iron in individuals exposed to asbestos.

DOI： 10.1111/cas.13460

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Papers - TOYOKUNI Shinya