Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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

Nagai H and Toyokuni S.

Cancer Sci Vol. 103 page： 1378-1390 2012

The ferroimmunomodulatory role of ectopic endometriotic stromal cells in ovarian endometriosis. Reviewed

Kobayashi H, Yamashita Y, Iwase A, Yoshikawa Y, Yasui H, Kawai Y, Uchida K, Uno N, Akatsuka S, Takahashi T, Kikkawa F, Toyokuni S.

Fertil Steril Vol. 98 page： 415-422 2012

Mitochondria and free radical studies on health, disease and pollusion (editorial). Invited

Majima HJ and Toyokuni S.

Free Radic Res Vol. 46 page： 925-926 2012

Distinct affinity of nuclear proteins to the surface of chrysotile and crocidolite. Invited Reviewed

Kubo Y, Takenaka H, Nagai H and Toyokuni S.

J Clin Biochem Nutr Vol. 51 page： 221-226 2012

The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma. Reviewed

Elshazley M, Sato M, Hase T, Yamashita R, Yoshida K, Toyokuni S, Ishiguro F, Osada H, Sekido Y, Yokoi K, Usami N, Shames DS, Kondo M, Gazdar AF, Minna JD and Hasegawa Y.

INt J Cancer Vol. 131 page： 2820-2831 2012

YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle promoting genes. Reviewed

Mizuno T, Murakami H, Fujii M, Ishiguro F, Tanaka I, Kondo Y, Akatsuka S, Toyokuni S and Sekido Y.

Oncogene Vol. 31 page： 5117-5122 2012

Transient but not stable ZEB1 knockdown dramatically inhibits growth of malignant pleural mesothalioma cells. Reviewed

Horio M, Sato M, Takayama Y, Elshazley M, Yamashita R, Hase T, Yoshida K, Usami N, Yokoi K, Sekido Y, Kondo M, Toyokuni S, Gazdar AF, Minna JD and Hasegawa Y.

Ann Surg Oncol Vol. 19 ( Suppl 3 ) page： 634-645 2012

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

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

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

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

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. 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 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 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. 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.

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

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

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Papers - TOYOKUNI Shinya