Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Genome-wide assessment of oxidatively generated DNA damage. Reviewed

Akatsuka S and Toyokuni S.

Free Radic Res Vol. 46 page： 523-530 2012

Bovine lactoferrin ameliorates ferric nitrilotriacetate-induced renal oxidative damage in rats. Reviewed

Okazaki Y, Kono H, Kuriki R, Funahashi S, Fushimi S, Iqbal M, Okada S and Toyokuni S.

J Clin Biochem Nutr Vol. 51 page： 84-90 2012

Differences and similarities between carbon nanotubes and asbestos fibers during mesothelial carcinogenesis. Reviewed

Nagai H, Toyokuni S

Cancer Sci Vol. 103 page： 1378-1390 2012

Fenton Reaction Induced Cancer in Wild Type Rats Recapitulates Genomic Alterations Observed in Human Cancer Reviewed International journal

Shinya Akatsuka, Yoriko Yamashita, Hiroki Ohara, Yu-Ting Liu, Masashi Izumiya, Koichiro Abe, Masako Ochiai, Li Jiang, Hirotaka Nagai, Yasumasa Okazaki, Hideki Murakami, Yoshitaka Sekido, Eri Arai, Yae Kanai, Okio Hino, Takashi Takahashi, Hitoshi Nakagama, Shinya Toyokuni

PLOS ONE Vol. 7 ( 8 ) page： e43403 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC) after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis.

DOI： 10.1371/journal.pone.0043403

FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b genes through MAP2K1 activation. Reviewed

Ishii K, Kanatsu-Shinohara M, Toyokuni S, Shinohara T

Development Vol. 139 page： 1734-1743 2012

Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy

Rinsho Ketsueki Vol. 53 ( 4 ) page： 401 - 408 2012

酸化ストレスによるゲノム変化と発がん

赤塚慎也, 豊國伸哉

実験医学 Vol. vol.30 page： 2779 - 2785 2012

Asbestos surface provides a niche for oxidative modification

NAGAI Hirotaka, ISHIHARA Toshikazu, LEE Wen-Hua, OHARA Hiroki, OKAZAKI Yasumasa, OKAWA Katsuya, TOYOKUNI Shinya

Cancer Sci. Vol. 102 ( 12 ) page： 2118 - 2125 2011.12

Diameter and rigidity of multiwalled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis. Reviewed International journal

Hirotaka Nagai, Yasumasa Okazaki, Shan Hwu Chew, Nobuaki Misawa, Yoriko Yamashita, Shinya Akatsuka, Toshikazu Ishihara, Kyoko Yamashita, Yutaka Yoshikawa, Hiroyuki Yasui, Li Jiang, Hiroki Ohara, Takashi Takahashi, Gaku Ichihara, Kostas Kostarelos, Yasumitsu Miyata, Hisanori Shinohara, Shinya Toyokuni

Proceedings of the National Academy of Sciences of the United States of America Vol. 108 ( 49 ) page： E1330-8 - 8 2011.12

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

Multiwalled carbon nanotubes (MWCNTs) have the potential for widespread applications in engineering and materials science. However, because of their needle-like shape and high durability, concerns have been raised that MWCNTs may induce asbestos-like pathogenicity. Although recent studies have demonstrated that MWCNTs induce various types of reactivities, the physicochemical features of MWCNTs that determine their cytotoxicity and carcinogenicity in mesothelial cells remain unclear. Here, we showed that the deleterious effects of nonfunctionalized MWCNTs on human mesothelial cells were associated with their diameter-dependent piercing of the cell membrane. Thin MWCNTs (diameter ∼ 50 nm) with high crystallinity showed mesothelial cell membrane piercing and cytotoxicity in vitro and subsequent inflammogenicity and mesotheliomagenicity in vivo. In contrast, thick (diameter ∼ 150 nm) or tangled (diameter ∼ 2-20 nm) MWCNTs were less toxic, inflammogenic, and carcinogenic. Thin and thick MWCNTs similarly affected macrophages. Mesotheliomas induced by MWCNTs shared homozygous deletion of Cdkn2a/2b tumor suppressor genes, similar to mesotheliomas induced by asbestos. Thus, we propose that different degrees of direct mesothelial injury by thin and thick MWCNTs are responsible for the extent of inflammogenicity and carcinogenicity. This work suggests that control of the diameter of MWCNTs could reduce the potential hazard to human health.

DOI： 10.1073/pnas.1110013108

Asbestos surface provides a niche for oxidative modification Reviewed International journal

Hirotaka Nagai, Toshikazu Ishihara, Wen-Hua Lee, Hiroki Ohara, Yasumasa Okazaki, Katsuya Okawa, Shinya Toyokuni

CANCER SCIENCE Vol. 102 ( 12 ) page： 2118 - 25 2011.12

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Asbestos is a potent carcinogen associated with increased risks of malignant mesothelioma and lung cancer in humans. Although the mechanism of carcinogenesis remains elusive, the physicochemical characteristics of asbestos play a role in the progression of asbestos-induced diseases. Among these characteristics, a high capacity to adsorb and accommodate biomolecules on its abundant surface area has been linked to cellular and genetic toxicity. Several previous studies identified asbestos-interacting proteins. Here, with the use of matrix-assisted laser desorption ionization-time of flight mass spectrometry, we systematically identified proteins from various lysates that adsorbed to the surface of commercially used asbestos and classified them into the following groups: chromatin/nucleotide/RNA-binding proteins, ribosomal proteins, cytoprotective proteins, cytoskeleton-associated proteins, histones and hemoglobin. The surfaces of crocidolite and amosite, two iron-rich types of asbestos, caused more protein scissions and oxidative modifications than that of chrysotile by in situ-generated 4-hydroxy-2-nonenal. In contrast, we confirmed the intense hemolytic activity of chrysotile and found that hemoglobin attached to chrysotile, but not silica, can work as a catalyst to induce oxidative DNA damage. This process generates 8-hydroxy-2'-deoxyguanosine and thus corroborates the involvement of iron in the carcinogenicity of chrysotile. This evidence demonstrates that all three types of asbestos adsorb DNA and specific proteins, providing a niche for oxidative modification via catalytic iron. Therefore, considering the affinity of asbestos for histones/DNA and the internalization of asbestos into mesothelial cells, our results suggest a novel hypothetical mechanism causing genetic alterations during asbestos-induced carcinogenesis. (Cancer Sci 2011; 102: 21182125)

DOI： 10.1111/j.1349-7006.2011.02087.x

miR-375 is activated by ASH1 and inhibits YAP1 in a lineage-dependent manner in lung cancer. Reviewed International journal

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

Cancer research Vol. 71 ( 19 ) page： 6165 - 73 2011.10

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

Lung cancers with neuroendocrine (NE) features are often very aggressive but the underlying molecular mechanisms remain elusive. The transcription factor ASH1/ASCL1 is a master regulator of pulmonary NE cell development that is involved in the pathogenesis of lung cancers with NE features (NE-lung cancers). Here we report the definition of the microRNA miR-375 as a key downstream effector of ASH1 function in NE-lung cancer cells. miR-375 was markedly induced by ASH1 in lung cancer cells where it was sufficient to induce NE differentiation. miR-375 upregulation was a prerequisite for ASH1-mediated induction of NE features. The transcriptional coactivator YAP1 was determined to be a direct target of miR-375. YAP1 showed a negative correlation with miR-375 in a panel of lung cancer cell lines and growth inhibitory activities in NE-lung cancer cells. Our results elucidate an ASH1 effector axis in NE-lung cancers that is functionally pivotal in controlling NE features and the alleviation from YAP1-mediated growth inhibition. Cancer Res; 71(19); 6165-73. (C)2011 AACR.

DOI： 10.1158/0008-5472.CAN-11-1020

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

Shinya Toyokuni, Ayaka Hirao, Tamae Wada, Ryoji Nagai, Akira Date, Takashi Yoshii, Shinya Akatsuka, Yoriko Yamashita, Akira Kawada

Journal of clinical biochemistry and nutrition Vol. 49 ( 2 ) page： 121 - 124 2011.9

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

Aging and exposure to sunlight are two major factors in the deterioration of skin function. In this study, thirty-six fixed human skin samples from sun-exposed and unexposed areas from young and old individuals were used to evaluate the localization of oxidative stress according to levels and distribution of 8-hydroxy-2'-deoxyguanosine and N-epsilon-(carboxymethyl)lysine in samples using immunohistochemistry. In the epidermis of the young, negligible amounts of 8-hydroxy-2'-deoxyguanosine and N-epsilon-(carboxymethyl)lysine were detected in unexposed areas, whereas nuclear 8-hydroxy-2'-deoxyguanosine and cytoplasmic N-epsilon-(carboxymethyl)lysine were increased in the lower epidermis in sun-exposed areas. In contrast, the aged presented prominent nuclear 8-hydroxy-2'-deoxyguanosine and nuclear N-epsilon-(carboxymethyl)lysine in the epidermis of unexposed areas, concomitant with dermal increase in N-epsilon-(carboxymethyl)lysine. However, the immunostaining of 8-hydroxy-2'-deoxyguanosine and N-epsilon-(carboxymethyl)lysine revealed a decrease in the epidermis of sun-exposed areas in the aged. These results suggest an age-dependent difference in the adaptation and protective mechanisms of the epidermis against sunlight-associated oxidative stress, thus necessitating distinct standards for evaluation in each age group. Further investigation is warranted to elucidate underlying molecular mechanisms.

DOI： 10.3164/jcbn.11-05

BMAL1 depletion represses growth of mesothelioma through induction of mitotic catastrophe Reviewed International coauthorship International journal

Elshazley, MHKA; Hasegawa, Y; Sato, M; Hase, T; Yoshida, K; Toyokuni, S; Seikido, Y; Yokoi, K; Usami, N; Kondo, M

CANCER RESEARCH Vol. 71 2011.9

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

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 International journal Open Access

JIANG Li, TOYOKUNI Shinya

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

Language：English 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. Reviewed International journal

Shinya Toyokuni

Free radical research Vol. 45 ( 8 ) page： 906 - 17 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 Reviewed International journal

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 Reviewed International journal

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 Open Access

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 - 552 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

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Papers - TOYOKUNI Shinya