Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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MET Amplification is a Molecular Hallmark in Endometriosis-associated Ovarian Clear Cell Carcinoma and Correlates With Worse Prognosis

Y. Yamashita, Y. Yatabe, S. Akatsuka, H. Kajiyama, F. Kikkawa, T. Takahashi, S. Toyokuni

EUROPEAN JOURNAL OF CANCER Vol. 47 page： S529 - S529 2011.9

Elucidation of Asbestos-induced Mesothelial Carcinogenesis toward Its Prevention

JIANG Li, TOYOKUNI Shinya

Environmental Mutagen Research Vol. 33 ( 1 ) page： 4 - 9 2011.8

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Environmental Mutagen Society

Human exposure to asbestos fibers has been associated with diffuse malignant mesothelioma (DMM) in the pleural and abdominal cavity. Despite advancements in the molecular analyses of human cases of DMM and animal models, the understanding of the carcinogenic mechanisms remains still limited. There are basically three hypotheses regarding the pathogenesis of asbestos-induced DMM, which may be integrated as follows; (1) the "oxidative stress theory" is based on the fact that phagocytic cells that engulf asbestos fibers produce large amounts of reactive oxygen species (ROS) due to their inability to digest the fibers, and that iron contained in crocidolite and amosite fibers works as a catalyst for the generation of ROS, (2) the "chromosome tangling theory" postulates that asbestos fibers impair the equivalent distribution of chromosomes during mitosis, and (3) the "theory of adsorbing many specific proteins as well as carcinogenic molecules" states that asbestos fibers <i>in vivo</i> concentrate specific proteins or chemicals including the components of cigarette smoke and radioactive chemical element. Recent studies suggest that local iron overload is a key event. Elucidation of the major mechanisms underlying DMM would be helpful for the development of strategies to prevent DMM generation in people who have been exposed to asbestos.<br>

DOI： 10.3123/jemsge.33.4

Iron as a target of chemoprevention for longevity in humans. International journal

Shinya Toyokuni

Free radical research Vol. 45 ( 8 ) page： 906 - 917 2011.8

Language：English Publishing type：Research paper (scientific journal) Publisher：INFORMA HEALTHCARE

Iron is universally abundant and no life can exist without it. However, iron levels should be maintained within a narrow range. Iron deficiency causes anaemia, whereas excessive iron increases cancer risk, presumably by free radical generation. Several pathological conditions such as genetic haemochromatosis, chronic viral hepatitis B and C, conditions related to asbestos fibre exposure and ovarian endometriosis have been recognized as iron overload-associated conditions that also increase human cancer risks. Iron's carcinogenicity has been documented in animal experiments. Surprisingly, these studies have revealed that the homozygous deletion of CDKN2A/2B is a major hallmark of iron-induced carcinogenesis. Recently, the hormonal regulation of iron metabolism has been elucidated. A commonly hypothesized mechanism may be the lack of any iron disposal pathway other than for bleeding and a mechanism of iron re-uptake as catechol chelate has been discovered. Iron overload in neurons via the ferroportin block may play a role in Alzheimer's disease. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy was associated with decreased cancer risks in a general population. Given that the required amounts of iron decrease during ageing, the fine control of body iron stores would be a wise strategy for chemoprevention of several diseases.

DOI： 10.3109/10715762.2011.564170

Dietary fish oil promotes colonic apoptosis and mitochondrial proton leak in oxidatively stressed mice. Reviewed International journal

Yang-Yi Fan, Qitao Ran, Shinya Toyokuni, Yasumasa Okazaki, Evelyn S Callaway, Joanne R Lupton, Robert S Chapkin

Cancer prevention research (Philadelphia, Pa.) Vol. 4 ( 8 ) page： 1267 - 74 2011.8

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

An alteration of mitochondrial function can result in disruption of redox homeostasis and is associated with abnormal cancer cell growth. Manganese superoxide dismutase (SOD2) and glutathione peroxidase 4 (Gpx4) are two of the most important antioxidant defense enzymes that protect cells against oxidative stress. We had previously shown that n-3 polyunsaturated fatty acids (PUFA) promote colonocyte apoptosis, a marker of colon cancer risk, in part by enhancing phospholipid oxidation. To elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, we fed heterozygous SOD2(Het), Gpx4(Het), and transgenic Gpx4(Tg) mice diets containing either 15% corn oil by weight (CO, enriched in n-6 PUFA) or 3.5% CO + 11.5% fish oil (FO, enriched in n-3 PUFA) for 4 weeks. Our data showed that (i) genetic predeposition to oxidative stress facilitates apoptosis in the mouse colon (Gpx4(Het) > SOD2(Het) > Wt > Gpx4(Tg)), (ii) dietary n-3 PUFA have an additive effect on the induction of apoptosis in Gpx4(Het) and SOD2(Het) mice; and (iii) dietary n-3 PUFA reverse the phenotype in oxidatively protected Gpx4(Tg) mice by elevating apoptosis to a level observed in wild-type (Wt; control) animals. Complimentary experiments examining colonic mitochondrial bioenergetic profiles indicate that FO-fed mice exhibit a significantly (P < 0.05) increased respiration-induced proton leak relative to control CO treatment. This finding was consistent with a loss of membrane potential in response to chronic oxidative stress and supports the contention that n-3 PUFA alter mitochondrial metabolic activity, thereby enhancing apoptosis and reducing colon cancer risk. Cancer Prev Res; 4(8); 1267-74. (C) 2011 AACR.

DOI： 10.1158/1940-6207.CAPR-10-0368

The Human Cytomegalovirus Gene Products Essential for Late Viral Gene Expression Assemble into Prereplication Complexes before Viral DNA Replication

Hiroki Isomura, Mark F. Stinski, Takayuki Murata, Yoriko Yamashita, Teru Kanda, Shinya Toyokuni, Tatsuya Tsurumi

JOURNAL OF VIROLOGY Vol. 85 ( 13 ) page： 6629 - 6644 2011.7

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC MICROBIOLOGY

The regulation of human cytomegalovirus (HCMV) late gene expression by viral proteins is poorly understood, and these viral proteins could be targets for novel antivirals. HCMV open reading frames (ORFs) UL79, -87, and -95 encode proteins with homology to late gene transcription factors of murine gammaherpesvirus 68 ORFs 18, 24, and 34, respectively. To determine whether these HCMV proteins are also essential for late gene transcription of a betaherpesvirus, we mutated HCMV ORFs UL79, -87, and -95. Cells were infected with the recombinant viruses at high and low multiplicities of infection (MOIs). While viral DNA was detected with the recombinant viruses, infectious virus was not detected unless the wild-type viral proteins were expressed in trans. At a high MOI, mutation of ORF UL79, -87, or -95 had no effect on the level of major immediate-early (MIE) gene expression or viral DNA replication, but late viral gene expression from the UL44, -75, and -99 ORFs was not detected. At a low MOI, preexpression of UL79 or -87, but not UL95, in human fibroblast cells negatively affected the level of MIE viral gene expression and viral DNA replication. The products of ORFs UL79, -87, and -95 were expressed as early viral proteins and recruited to prereplication complexes (pre-RCs), along with UL44, before the initiation of viral DNA replication. All three HCMV ORFs are indispensable for late viral gene expression and viral growth. The roles of UL79, -87, and -95 in pre-RCs for late viral gene expression are discussed.

DOI： 10.1128/JVI.00384-11

YAP TRANSCRIPTION COACTIVATOR INDUCES MALIGNANT MESOTHELIOMA CELL PROLIFERATION BY UP-REGULATING CELL CYCLE PROGRESSION

Tetsuya Mizuno, Hideki Murakami, Makiko Fujii, Futoshi Ishiguro, Yutaka Kondo, Shinya Akatsuka, Shinya Toyokuni, Kohei Yokoi, Hirotaka Osada, Yoshitaka Sekido

JOURNAL OF THORACIC ONCOLOGY Vol. 6 ( 6 ) page： S707 - S708 2011.6

[Archives of "comprehensive approach on asbestos-related diseases" supported by the "special coordination funds for promoting science and technology (H18-1-3-3-1)"-- overview of group research project, care and specimen registration, cellular characteristics of mesothelioma and immunological effects of asbestos]. Reviewed

Takemi Otsuki, Takashi Nakano, Seiki Hasegawa, Morihito Okada, Tohru Tsujimura, Yoshitaka Sekido, Shinya Toyokuni, Hiroshi Nishimoto, Kazuya Fukuoka, Fumihiro Tanaka, Naoko Kumagai, Megumi Maeda, Yasumitsu Nishimura

Nihon eiseigaku zasshi. Japanese journal of hygiene Vol. 66 ( 3 ) page： 543 - 52 2011.5

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society for Hygiene

The research project entitled "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Funds for Promoting Science and Technology (H18-1-3-3-1)" began in 2006 and was completed at the end of the Japanese fiscal year of 2010. This project included four parts; (1) malignant mesothelioma (MM) cases and specimen registration, (2) development of procedures for the early diagnosis of MM, (3) commencement of clinical investigations including multimodal approaches, and (4) basic research comprising three components; (i) cellular and molecular characterization of mesothelioma cells, (ii) immunological effects of asbestos, and (iii) elucidation of asbestos-induced carcinogenesis using animal models. In this special issue of the Japanese Journal of Hygiene, we briefly introduce the achievements of our project. The second and third parts and the third component of the fourth part are described in other manuscripts written by Professors Fukuoka, Hasegawa, and Toyokuni. In this manuscript, we introduce a brief summary of the first part "MM cases and specimen registration", the first component of the fourth part "Cellular and molecular characterization of mesothelioma cells" and the second component of the fourth part "Immunological effects of asbestos". In addition, a previous special issue presented by the Study Group of Fibrous and Particulate Substances (SGFPS) (chaired by Professor Otsuki, Kawasaki Medical School, Japan) for the Japanese Society of Hygiene and published in Environmental Health and Preventive Medicine Volume 13, 2008, included reviews of the aforementioned first component of the fourth part of the project. Taken together, our project led medical investigations regarding asbestos and MM progress and contributed towards the care and examination of patients with asbestos-related diseases during these five years. Further investigations are required to facilitate the development of preventive measures and the cure of asbestos-related diseases, particularly in Japan, where asbestos-related diseases are predicted to increase in the next 10 to 20 years.

DOI： 10.1265/jjh.66.543

PubMed

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Mechanisms of Asbestos-Induced Carcinogenesis

TOYOKUNI Shinya, JIANG Li, HU Qian, NAGAI Hirotaka, OKAZAKI Yasumasa, AKATSUKA Shinya, YAMASHITA Yoriko

Nippon Eiseigaku Zasshi (Japanese Journal of Hygiene) Vol. 66 ( 3 ) page： 562 - 7 2011.5

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society for Hygiene

Several types of fibrous stone called asbestos have been an unexpected cause of human cancer in the history. This form of mineral is considered precious in that they are heat-, friction-, and acid-resistant, are obtained easily from mines, and can be modified to any form with many industrial merits. However, it became evident that the inspiration of asbestos causes a rare cancer called malignant mesothelioma. Because of the long incubation period, the peak year for malignant mesothelioma is expected to be 2025 in Japan. Thus, it is necessary to elucidate the mechanisms of asbestos-induced mesothelial carcinogenesis. In this review, we summarize the cutting edge results of our 5-year project funded by a MEXT grant, in which local iron deposition and the characteristics of mesothelial cells are the key issues.<br>

DOI： 10.1265/jjh.66.562

Scopus

PubMed

CiNii Research

Roles of ASH1-miR-375 pathway in development of lung cancers with neuroendocrine features

Osada Hirotaka, Eri Nishikawa, Chinatsu Arima, Yasumasa Okazaki, Shuta Tomida, Yoshio Tatematsu, Ayumu Taguchi, Yukako Shimada, Kiyoshi Yanagisawa, Shinya Toyokuni, Yoshitaka Sekido, Takashi Takahashi

CANCER RESEARCH Vol. 71 2011.4

XCR1 expression and biased VH gene usage are distinct features of diffuse large B-cell lymphoma initially manifesting in the bone marrow. International journal

Yoriko Yamashita, Dai Kajiura, Lee Tang, Yuichi Hasegawa, Tomohiro Kinoshita, Shigeo Nakamura, Shinya Akatsuka, Shinya Toyokuni, Naoyoshi Mori

American journal of clinical pathology Vol. 135 ( 4 ) page： 556 - 64 2011.4

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC CLINICAL PATHOLOGY

A total of 29 cases of diffuse large B-cell lymphoma initially manifesting in the bone marrow (BM-DLBCL) were analyzed for V-H gene sequence, and expression microarray of chemokines and chemokine receptors and immunohistochemical analysis were done. Seminested polymerase chain reaction (PCR) and sequencing analyses of 18 cases revealed that the V-H gene usage in 6 cases was restricted to V(H)3-7, in 3 cases to V(H)4-34, and in 2 cases to V(H)4-39, which were all previously reported to be autoreactive. In total, 14 of 18 V-H genes were those associated with autoimmune diseases, including V(H)3-21, V(H)3-23, and V(H)3-48. Furthermore, cDNA microarray analysis specific for chemokine and chemokine receptors revealed that chemokine receptor XCR1 expression was significantly elevated in the BM-DLBCL cases (P < .05), which was confirmed by quantitative reverse transcriptase PCR and immunohistochemical analysis. Expression of the chemokine receptor XCR1 and frequent usage of autoreactive V-H genes seem to be distinct characteristics of BM-DLBCL.

DOI： 10.1309/AJCPCTDC5PY3LXBP

LATS2 is a tumor suppressor gene of malignant mesothelioma

Murakami H.

Cancer Research Vol. 71 ( 3 ) page： 873 - 883 2011.2

LATS2 is a tumor suppressor gene of malignant mesothelioma.

Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, Akatsuka S, Horio Y, Hida T, Kondo Y, Toyokuni S, Osada H, Sekido Y

Cancer research Vol. 71 ( 3 ) page： 873 - 83 2011.2

Stage-specific roles of fibulin-5 during oxidative stress-induced renal carcinogenesis in rats. International journal

Hiroki Ohara, Shinya Akatsuka, Hirotaka Nagai, Yu-Ting Liu, Li Jiang, Yasumasa Okazaki, Yoriko Yamashita, Tomoyuki Nakamura, Shinya Toyokuni

Free radical research Vol. 45 ( 2 ) page： 211 - 220 2011.2

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

By using a rat model of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA), this study performed genome-wide analysis to identify target genes during carcinogenesis. It screened for genes with decreased expression in RCCs, with simultaneous loss of heterozygosity, eventually to focus on the fibulin-5 (fbln5) gene. Oxidative damage via Fe-NTA markedly increased Fbln5 in the proximal tubules. RCCs presented lower levels of Fbln5. However, a fraction of RCCs presenting pulmonary metastasis revealed significantly higher levels of Fbln5 than those without metastasis, accompanied by immunopositivity of RCC cells and myofibroblast proliferation. Experiments revealed that RCC cell lines showed lower expression of fbln5 than its non-transformed counterpart NRK52E, but that fbln5 transfection to RCC cell lines changed neither proliferation nor migration/invasion. The data suggest that Fbln5 plays a role not only in the tissue repair and remodelling after renal tubular oxidative damage but also in RCC metastasis, presumably as a cytokine.

DOI： 10.3109/10715762.2010.523702

LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma Reviewed

Hideki Murakami, Tetsuya Mizuno, Tetsuo Taniguchi, Makiko Fujii, Futoshi Ishiguro, Takayuki Fukui, Shinya Akatsuka, Yoshitsugu Horio, Toyoaki Hida, Yutaka Kondo, Shinya Toyokuni, Hirotaka Osada, Yoshitaka Sekido

CANCER RESEARCH Vol. 71 ( 3 ) page： 873 - 883 2011.2

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive activation of YAP, which induces deregulation of MM cell proliferation. Cancer Res; 71(3); 873-83. (C)2011 AACR.

DOI： 10.1158/0008-5472.CAN-10-2164

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Mysterious link between iron overload and CDKN2A/2B.

Shinya Toyokuni

Journal of clinical biochemistry and nutrition Vol. 48 ( 1 ) page： 46 - 49 2011.1

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION

Persistent oxidative stress has been associated with carcinogenesis. Iron overload is considered one such condition that causes oxidative stress. Epidemiological studies support a close link between iron overload and carcinogenesis. Reportedly, regular semiannual phlebotomies reduced cancer risk in an otherwise normal population. More specifically, genetic hemochromatosis, chronic viral hepatitis, ovarian endometriosis and asbestosis induce iron overload, which can lead to hepatocellular carcinoma, ovarian carcinoma or mesothelioma in humans. Through a combination of animal experiments and microarray analyses, homozygous deletion of CDKN2A/2B has been recognized as one of the major target genes involved in iron overload-induced carcinogenesis. CDKN2A/2B are the second most frequently inactivated tumor suppressing genes in human cancers. Currently, when infection is becoming sufficiently controlled worldwide, iron regulation may be the next target for human longevity.

DOI： 10.3164/jcbn.11-001FR

3-morpholinosydnonimine participates in the attenuation of neointima formation via inhibition of annexin A2-mediated vascular smooth muscle cell migration. International journal

Kyung-Jong Won, Philyoung Lee, Seung Hyo Jung, Xiaowen Jiang, Chang-Kwon Lee, Hai Yue Lin, Hyun Kang, Hwan Myung Lee, Junghwan Kim, Shinya Toyokuni, Bokyung Kim

Proteomics Vol. 11 ( 2 ) page： 193 - 201 2011.1

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

3-Morpholinosydnonimine (SIN-1) affects vascular smooth muscle cell migration and proliferation, processes essential for atherosclerosis. However, the mechanism by which SIN-1 exerts these effects has not been elucidated. We used 2-DE followed by MALDI-TOF/TOF MS to identify responses in protein expression to SIN-1 in rat aortic smooth muscle. Platelet-derived growth factor-BB increased cell migration and proliferation in rat aortic smooth muscle cells, and subsequent SIN-1 treatment inhibited it. Administration of SIN-1 in vivo attenuated neointima formation in balloon-injured rat carotid arteries. Proteomic analysis showed that glutathione peroxidase and 40S ribosomal protein S12 were differentially expressed in aortic strips exposed to SIN-1. Expression of annexin A2 was decreased by SIN-1. Platelet-derived growth factor-BB-induced cell migration was increased and inhibited in rat aortic smooth muscle cells with overexpression and knockdown of annexin A2 gene, respectively. The expression of annexin A2 was increased in vascular neointima compared with the intact control, which was inhibited by SIN-1 treatment. These results demonstrate that SIN-1 may attenuate vascular neointima formation by inhibiting annexin A2-mediated migration. Therefore, annexin A2 may be a potential target for therapeutic strategies for atherosclerosis.

DOI： 10.1002/pmic.200900834

CD8+CD122+ regulatory T cells (Tregs) and CD4+ Tregs cooperatively prevent and cure CD4+ cell-induced colitis. International journal

Agustina Tri Endharti, Yusuke Okuno, Zhe Shi, Nobuaki Misawa, Shinya Toyokuni, Masafumi Ito, Ken-ichi Isobe, Haruhiko Suzuki

Journal of immunology (Baltimore, Md. : 1950) Vol. 186 ( 1 ) page： 41 - 52 2011.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Immunology

We identified CD8(+)CD122(+) regulatory T cells (Tregs) and demonstrated their importance in the maintenance of immune homeostasis and in the recovery from experimental autoimmune encephalomyelitis. In this paper, we show that CD8(+)CD122(+) Tregs effectively prevent and cure colitis in a mouse model. In our experiments, colitis was induced in lymphocyte-deficient RAG-2(-/-) mice by transferring CD4(+)CD45RB(high) cells that were excluded with CD4(+) Tregs. Cotransfer of CD8(+)CD122(+) cells clearly suppressed the development of colitis, and this suppressive effect was similar to that of CD4(+)CD45RB(low) cells that were mostly CD4(+) Tregs. CD8(+)CD122(+) cells obtained from IL-10(-/-) mice were unable to suppress colitis, indicating that IL-10 is an important effect-transmitting factor in the suppression of colitis. CD8(+)CD122(+) cells showed a suppressive effect when they were transferred 4 wk after CD4(+)CD45RB(high) cells, indicating the therapeutic potential of CD8(+)CD122(+) cells. A mixture of CD8(+)CD122(+) cells and CD4(+)CD45RB(low) cells was far more effective than single Tregs, indicating the synergistic effect of these Tregs. These overall findings demonstrate the potential role of CD8(+) Tregs, and possibly together with CD4(+) Tregs, in the medical care of inflammatory bowel disease patients.

DOI： 10.4049/jimmunol.1000800

Age- and sun exposure-dependent differences in 8-hydroxy-2'-deoxyguanosine and Nε-(carboxymethyl)lysine in human epidermis. Reviewed

Toyokuni S, Hirao A, Wada T, Nagai R, Date A, Yoshii T, Akatsuka S, Yamashita Y, and Kawada A.

J Clin Biochem Nutr Vol. 49 page： 1-4 2011

Mysterious link between iron overload and CDKN2A/2B. Reviewed

Toyokuni S.

J Vol. 48 page： 46-49 2011

LATS2 is a tumor suppressor gene of malignancy mesothelioma. Reviewed

Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, Akatsuka S, Horio Y, HIda T, Kondo Y, Toyokuni S, Osada H and Sekido Y.

Cancer Res Vol. 71 page： 873-883 2011

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Papers - TOYOKUNI Shinya