Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Asbestos surface provides a niche for oxidative modification: A novel role of free radicals in carcinogenesis

H. Nagai, Y. Okazaki, L. Jiang, S. Akatsuka, Y. Yamashita, S. Toyokuni

FREE RADICAL BIOLOGY AND MEDICINE Vol. 53 page： S51 - S52 2012.9

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

Yasumasa Okazaki, Isato Kono, Takayoshi Kuriki, Satomi Funahashi, Soichiro Fushimi, Mohammad Iqbal, Shigeru Okada, Shinya Toyokuni

Journal of clinical biochemistry and nutrition Vol. 51 ( 2 ) page： 84 - 90 2012.9

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

Milk provides a well-balanced source of amino acids and other ingredients. One of the functional ingredients in milk is lactoferrin (LF). LF presents a wide variety of bioactivities and functions as a radical scavenger in models using iron-ascorbate complexes and asbestos. Human clinical trials of oral LF administration for the prevention of colon polyps have been successful and demonstrated that dietary compounds exhibit direct interactions. However, antioxidative properties of IF in distant organs require further investigation. To study the antioxidant property of LF, we employed bovine lactoferrin (bLF) using the rat model of ferric nitrilotriacetate (Fe-NTA)-induced renal tubular oxidative injury. We fed rats with bLF (0.05%, w/w) in basal chow for 4 weeks and sacrificed them after Fe-NTA treatment. After intraperitoneal administration of 9.0 mg iron/kg Fe-NTA for 4 and 24 h, bLF pretreatment suppressed elevation of serum creatinine and blood urea nitrogen levels. In addition, we observed protective effects against renal oxidative tubular damage and maintenance of antioxidant enzyme activities in the bLF-pretreated group. We thus demonstrated the antioxidative effect of bLF against Fe-NTA-induced renal oxidative injury. These results suggest that LF intake is useful for the prevention of renal tubular oxidative damage mediated by iron.

DOI： 10.3164/jcbn.11-100

Iron overload signature in chrysotile-induced malignant mesothelioma. Reviewed

Jiang L, Akatsuka S, Nagai H, Chew SH, Ohara H, Okazaki Y, Yamashita Y, Yoshikawa Y, Yasui H, Ikuta K, Sasaki K, Kohgo Y, Hirano S, Shinohara Y, Kohyama N, Takahashi T, Toyokuni S

J Pathol Vol. 228 page： 366-377 2012.8

Differences and similarities between carbon nanotubes and asbestos fibers during mesothelial carcinogenesis: shedding light on fiber entry mechanism. International journal

Hirotaka Nagai, Shinya Toyokuni

Cancer science Vol. 103 ( 8 ) page： 1378 - 1390 2012.8

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

The emergence of nanotechnology represents an important milestone, as it opens the way to a broad spectrum of applications for nanomaterials in the fields of engineering, industry and medicine. One example of nanomaterials that have the potential for widespread use is carbon nanotubes, which have a tubular structure made of graphene sheets. However, there have been concerns that they may pose a potential health risk due to their similarities to asbestos, namely their high biopersistence and needle-like structure. We recently found that despite these similarities, carbon nanotubes and asbestos differ in certain aspects, such as their mechanism of entry into mesothelial cells. In the study, we showed that non-functionalized, multi-walled carbon nanotubes enter mesothelial cells by directly piercing through the cell membrane in a diameter- and rigidity-dependent manner, whereas asbestos mainly enters these cells through the process of endocytosis, which is independent of fiber diameter. In this review, we discuss the key differences, as well as similarities, between asbestos fibers and carbon nanotubes. We also summarize previous reports regarding the mechanism of carbon nanotube entry into non-phagocytic cells. As the entry of fibers into mesothelial cells is a crucial step in mesothelial carcinogenesis, we believe that a comprehensive study on the differences by which carbon nanotubes and asbestos fibers enter into non-phagocytic cells will provide important clues for the safer manufacture of carbon nanotubes through strict regulation on fiber characteristics, such as diameter, surface properties, length and rigidity. (Cancer Sci 2012; 103: 13781390)

DOI： 10.1111/j.1349-7006.2012.02326.x

Mitochondria and free radical studies on health, disease and pollution. Invited International journal

Hideyuki J Majima, Shinya Toyokuni

Free radical research Vol. 46 ( 8 ) page： 925 - 6 2012.8

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

Hiroharu Kobayashi, Yoriko Yamashita, Akira Iwase, Yutaka Yoshikawa, Hiroyuki Yasui, Yoshichika Kawai, Koji Uchida, Nozomi Uno, Shinya Akatsuka, Takashi Takahashi, Fumitaka Kikkawa, Shinya Toyokuni

Fertility and sterility Vol. 98 ( 2 ) page： 415 - 22.e1 2012.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Objective: To understand the role of ectopic endometriotic stromal cells in ovarian endometriosis (OEM) and the associated risks for infertility and carcinogenesis.
Design: Analyses of secreted proteins and gene expression using immortalized eutopic/ectopic endometrial(-otic) stromal cells from OEM.
Setting: University.
Patient(s): Women with and without OEM.
Intervention(s): Samples of endometrial(-otic) tissue from women with or without OEM.
Main Outcome Measure(s): Immunohistochemical analysis of oxidative stress in OEM, gene expression profiles, and the identification of secreted proteins by mass spectrometry in immortalized endometrial(-otic) stromal cells.
Result(s): 4-Hydroxy-2-nonenal-modified proteins and carboxymethyllysine were abundant in the stroma, rather than epithelia, of OEM patients, indicating the presence of oxidative stress. Immortalized ectopic endometriotic stromal cells exhibited high IRP1/IRP2/HIF-1 beta expression and contained lower amounts of iron and copper than their eutopic counterparts. Expression profiles, in combination with protein identification, revealed that complement component 3 (C3) and pentraxin-3 (PTX3) are the major proteins secreted from immortalized ectopic endometriotic stromal cells. Complement-3/PTX3 promoted the secretion of various cytokines by THP1 macrophage cells and thus supported M1 differentiation.
Conclusion(s): Immortalized ectopic endometriotic stromal cells in OEM predominantly secrete C3 and PTX3 and exhibit a differential regulation of iron metabolism. (Fertil Steril (R) 2012;98:415-22. (C) 2012 by American Society for Reproductive Medicine.)

DOI： 10.1016/j.fertnstert.2012.04.047

Transient but not stable ZEB1 knockdown dramatically inhibits growth of malignant pleural mesothelioma cells. International journal

Mihoko Horio, Mitsuo Sato, Yoshihiro Takeyama, Momen Elshazley, Ryo Yamashita, Tetsunari Hase, Kenya Yoshida, Noriyasu Usami, Kohei Yokoi, Yoshitaka Sekido, Masashi Kondo, Shinya Toyokuni, Adi F Gazdar, John D Minna, Yoshinori Hasegawa

Annals of surgical oncology Vol. 19 Suppl 3 ( Suppl 3 ) page： S634 - 45 2012.7

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

Background. The role of ZEB1, a master epithelial-to-mesenchymal transition gene, in malignant pleural mesothelioma (MPM) is unclear.
Methods. The expression of ZEB1, E-cadherin, vimentin, and epithelial cell adhesion molecule (EpCAM) in 18 MPM cell lines and a normal pleural mesothelial cell line MeT-5A was determined by quantitative real-time polymerase chain reaction and Western blot testing. RNA interference-mediated transient and/or stable knockdown of ZEB1 and EpCAM was performed. Microarray expression analysis was performed with a TORAY-3D gene chip. Growth was evaluated by colorimetric proliferation and colony formation assays. Luciferase reporter assay was performed to access the effects of ZEB1 knockdown on EpCAM promoter activity.
Results. Most MPM cell lines exhibited mesenchymal phenotype and expressed ZEB1. Transient ZEB1 knockdown suppressed growth in all four cell lines studied (ACC-MESO-1, H2052, Y-MESO-8A, Y-MESO-29) while stable ZEB1 knockdown suppressed growth only in Y-MESO-29. Genome-wide gene expression analysis revealed that EpCAM was the most prominently up-regulated gene by both transient and stable ZEB1 knockdown in ACC-MESO-1, with more marked up-regulation in stable knockdown. We hypothesized that EpCAM up-regulation counteracts the stable ZEB1 knockdown-induced growth inhibition in ACC-MESO-1. Transient EpCAM knockdown suppressed growth dramatically in ACC-MESO-1 cells expressing shZEB1 but only modestly in those expressing shGFP, supporting our hypothesis. Luciferase reporter assay showed that ZEB1 knockdown resulted in increased EpCAM promoter activity. EpCAM was also up-regulated in Y-MESO-29 expressing shZEB1, but this EpCAM up-regulation did not counteract ZEB1knockdown-induced growth suppression, suggesting that the counteracting effects of EpCAM may be cellular context dependent.
Conclusions. RNA interference-mediated ZEB1 knockdown may be a promising therapeutic strategy for MPM, but one has to consider the possibility of diminished growth inhibitory effects of long-term ZEB1 knockdown, possibly as a result of EpCAM up-regulation and/or other gene expression changes resulting from ZEB1 knockdown.

DOI： 10.1245/s10434-011-2142-0

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

Kei Ishii, Mito Kanatsu-Shinohara, Shinya Toyokuni, Takashi Shinohara

Development (Cambridge, England) Vol. 139 ( 10 ) page： 1734 - 1743 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：COMPANY OF BIOLOGISTS LTD

Fibroblast growth factor 2 (FGF2) and glial cell line-derived neurotrophic factor (GDNF) are required to recapitulate spermatogonial stem cell (SSC) self-renewal in vitro. Although studies have revealed the role of the GDNF signaling pathway in SSCs, little is known about how FGF2 is involved. In the present study, we assessed the role of the FGF2 signaling pathway using a mouse germline stem (GS) cell culture system that allows in vitro expansion of SSCs. Adding GDNF or FGF2 induced phosphorylation of MAPK1/3, and adding the MAP2K1 inhibitor PD0325091 reduced GS cell proliferation and MAPK1/3 phosphorylation. Moreover, GS cells transfected with an activated form of Map2k1 not only upregulated Etv5 and Bcl6b gene expression, but also proliferated in an FGF2-independent manner, suggesting that they act downstream of MAP2K1 signaling to drive SSC self-renewal. Although GS cells transfected with Map2k1, Etv5 or Bcl6b showed normal spermatogonial markers, transplanting GS cells expressing Bcl6b into infertile mouse testes resulted in the formation of a germ cell tumor, suggesting that excessive self-renewal signals causes tumorigenic conversion. These results show that FGF2 depends on MAP2K1 signaling to drive SSC self-renewal via upregulation of the Etv5 and Bcl6b genes.

DOI： 10.1242/dev.076539

In vitro transformation of mouse testis cells by oncogene transfection. Reviewed

Morimoto H, Lee J, Tanaka T, Ishii K, Toyokuin S, Kanatsu-Shinohara M and Shinohara T.

Biol Reprod Vol. 86 ( 5 ) page： 1-11 2012.5

In vitro transformation of mouse testis cells by oncogene transfection. International journal

Hiroko Morimoto, Jiyoung Lee, Takashi Tanaka, Kei Ishii, Shinya Toyokuni, Mito Kanatsu-Shinohara, Takashi Shinohara

Biology of reproduction Vol. 86 ( 5 ) page： 148, 1 - 11 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SOC STUDY REPRODUCTION

Germ cell tumors (GCTs) are unique in that they exhibit diverse biological characteristics and pathological features. Although several in vivo GCT models are available, studies on GCTs are hampered because in vivo development of GCTs is time consuming and prevents a detailed molecular analysis of the transformation process. Here we developed a novel strategy to transform mouse testis cells in vitro. Lentivirus-mediated transfection of dominant negative Trp53, Myc, and activated Hras1 into a CD9-expressing testis cells caused tumorigenic conversion in vitro. Although these cells resembled embryonic stem (ES) cells, they were aneuploid and lacked Nanog expression, which is involved in the maintenance of the undifferentiated state in ES cells. Euploid ES-like cells were produced by transfecting the Yamanaka factors (Pou5f1, Myc, Klf4, and Sox2) into the same cell population. Although these cells expressed Nanog, they were distinct from ES cells in that they expressed CD44, a cancer stem cell antigen. Both treatments induced similar changes in the DNA methylation patterns in differentially methylated regions of imprinted genes. Moreover, despite the differences in their phenotype and karyotype, both cell types similarly produced mixed GCTs on transplantation, which were composed of teratomas, seminomas, and embryonal carcinomas. Thus, in vitro testis cell transformation facilitates an analysis of the GCT formation process, and our results also suggest the close similarity between GCT formation and reprogramming.

DOI： 10.1095/biolreprod.111.095307

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

TOYOKUNI Shinya

Vol. 53 ( 4 ) page： 401 - 408 2012.4

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

TOYOKUNI Shinya

Vol. 53 ( 4 ) page： 401 - 408 2012.4

Genome-wide assessment of oxidatively generated DNA damage. International journal

Shinya Akatsuka, Shinya Toyokuni

Free radical research Vol. 46 ( 4 ) page： 523 - 30 2012.4

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

In the tide of science nouveau after the completion of genome projects of various species, there appeared a movement to understand an organism as a system rather than the sum of cells directed for certain functions. With the advent and spread of microarray techniques, systematic and comprehensive genome-wide approaches have become reasonably possible and more required on the investigation of DNA damage and the subsequent repair. The immunoprecipitation-based technique combined with high-density microarrays or next-generation sequencing is one of the promising methods to provide access to such novel research strategies. Oxygen is necessary for most of the life on earth for electron transport. However, reactive oxygen species are inevitably generated, giving rise to steady-state levels of DNA damage in the genome, that may cause mutations leading to cancer, ageing and degenerative diseases. Previously, we showed that there are many factors involved in the genomic distribution of oxidatively generated DNA damage including chromosome territory, and proposed this sort of research area as oxygenomics. Recently, RNA is also recognized as a target of this kind of modification.

DOI： 10.3109/10715762.2011.633212

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

Toyokuni S

[Rinsho ketsueki] The Japanese journal of clinical hematology Vol. 53 ( 4 ) page： 401 - 8 2012.4

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

Toyokuni S

[Rinsho ketsueki] The Japanese journal of clinical hematology Vol. 53 ( 4 ) page： 401 - 8 2012.4

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

Akira Kawada, Akira Date, Shinya Toyokuni

JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Vol. 66 ( 4 ) page： AB174 - AB174 2012.4

多層カーボンナノチューブの直径と剛性は、中皮細胞傷害と中皮腫形成に重要な因子である

永井裕崇, 岡崎泰昌, 周珊瑚, 三澤伸明, 山下依子, 赤塚慎也, 石原敏和, 山下享子, 吉川豊, 安井裕之, 蒋麗, 高橋隆, 市原学, 宮田耕充, 篠原久典, 豊國伸哉

日本病理学会会誌 Vol. 101 ( 1 ) page： 280 - 280 2012.3

Array CGH Analysis Reveals Amplification of Met and AKT2 in Clear Cell Carcinoma of the Ovary

Y. Yamashita, S. Akatsuka, Y. Yatabe, S. Toyokuni

LABORATORY INVESTIGATION Vol. 92 page： 302A - 302A 2012.2

Array CGH Analysis Reveals Amplification of Met and AKT2 in Clear Cell Carcinoma of the Ovary

Y. Yamashita, S. Akatsuka, Y. Yatabe, S. Toyokuni

MODERN PATHOLOGY Vol. 25 page： 302A - 302A 2012.2

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 and Shinohara T.

Development Vol. 139 page： 1734-1743 2012

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