Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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What has been learned from the studies of oxidative stress-induced carcinogenesis: proposal of the concept of oxygenomics Reviewed

Shinya Toyokuni, Shinya Akatsuka

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 39 ( 1 ) page： 3 - 10 2006.7

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

Epidemiological studies have demonstrated that oxidative stress associated with a variety of pathological conditions is one of the major causes of carcinogenesis. Reactive oxygen and nitrogen species contribute to genomic alterations, presumably followed by selection of the best-adapted proliferating cells in a given environment. Recent data suggest that there exist common signaling pathways for oxidative stress-associated carcinogenesis. So far, oxidative DNA damage has been assumed to be randomly distributed based on in vitro experiments, and localization of oxidative DNA damage in the genome in vivo has rarely been studied. However, by the use of novel techniques in combination with constructed genome databases, it was found that the localization of oxidative DNA appears to be not random in vivo. We propose to call this rather novel research area "oxygenomics". Not a few signaling pathways start from the recognition of DNA damage. Possible underlying principles should be elucidated in association with cell type, the function of each genomic location, and its transcriptional activity as well as chromatin status determining epigenetic information. Furthermore, this concept may contribute to the development of novel oxidative stress biomarkers. Thus, oxygenomics is a promising research area.

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What has been learned from the studies of oxidative stress-induced carcinogenesis: proposal of the concept of oxygenomics

Toyokuni Shinya, Akatsuka Shinya

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 39 ( 1 ) page： 3 - 10 2006.7

Historical aspects of free radical chemistry and biology: What's new in oxidative stress-induced carcinogenesis and its prevention? Reviewed International journal

Toyokuni Shinya

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 39 ( 1 ) page： 1 - 2 2006.7

Production of knockout mice by random or targeted mutagenesis in spermatogonial stem cells Reviewed

M Kanatsu-Shinohara, M Ikawa, M Takehashi, N Ogonuki, H Miki, K Inoue, Y Kazuki, J Lee, S Toyokuni, M Oshimura, A Ogura, T Shinohara

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vol. 103 ( 21 ) page： 8018 - 8023 2006.5

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL ACAD SCIENCES

Stem cells represent a unique population of cells with self-renewal capacity. Although they are important therapeutic targets, the genetic manipulation of tissue-specific stem cells has been limited, which complicates the study and practical application of these cells. Here, we demonstrate successful gene trapping and homologous recombination in spermatogonial stem cells. Cultured spermatogonial stem cells were transfected with gene trap or gene targeting vectors. Mutagenized stem cells were expanded clonally by drug selection. These cells underwent spermatogenesis and produced heterozygous offspring after transplantation into the seminiferous tubules of infertile mouse testes. Heterozygous mutant mice were intercrossed to produce homozygous gene knockouts. Using this strategy, the efficiency of homologous recombination for the occludin gene focus was 1.7% using a nonisogenic DNA construct. These results demonstrate the feasibility of altering genes in tissue-specific stem cells in a manner similar to embryonic stem cells and have important implications for gene therapy and animal transgenesis.

DOI： 10.1073/pnas.0601139103

ヒト大腸癌予後因子としてのNKT細胞腫瘍内浸潤

鶴山竜昭, 橘強, 小野寺久, 幸田晴康, 豊國伸哉, 日合弘, 山邉博彦, 玉木敬二, 真鍋俊明

日本病理学会会誌 Vol. 95 ( 1 ) page： 213 - 213 2006.4

Anchorage-independent growth of mouse male germline stem cells in vitro Reviewed

M Kanatsu-Shinohara, K Inoue, J Lee, H Miki, N Ogonuki, S Toyokuni, A Ogura, T Shinohara

BIOLOGY OF REPRODUCTION Vol. 74 ( 3 ) page： 522 - 529 2006.3

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

Spermatogenesis originates from a small number of spermatogonial stem cells that reside on the basement membrane and undergo self-renewal division to support spermatogenesis throughout the life of adult animals. Although the recent development of a technique to culture spermatogonial stem cells allowed reproduction of self-renewal division in vitro, much remains unknown about how spermatogonial stem cells are regulated. In this study, we found that spermatogonial stem cells could be cultured in an anchorage-independent manner, which is characteristic of stem cells from other types of self-renewing tissues. Although the cultured cells grew slowly (doubling time, similar to 4.7 days), they expressed markers of spermatogonia, and grew exponentially for at least 5 months to achieve 1.5 x 10(10)-fold expansion. The cultured cells underwent spermatogenesis following transplantation into the seminiferous tubules of infertile animals and fertile offspring were obtained by microinsemination of germ cells that had developed within the testes of recipients of the cultured cells. These results indicate that spermatogonial stem cells can undergo anchorage-independent, self-renewal division, and suggest that stem cells have the common property to survive and proliferate in the absence of exogenous substrata.

DOI： 10.1095/biolreprod.105.046441

Differences in oxidative stress dependence between gastric adenocarcinoma subtypes

Bancel Brigitte, Esteve Jacques, Souquet Jean-Christophe, Toyokuni Shinya, Ohshima Hiroshi, Pignatelli Brigitte

WORLD JOURNAL OF GASTROENTEROLOGY Vol. 12 ( 7 ) page： 1005 - 1012 2006.2

Differences in oxidative stress dependence between gastric adenocarcinoma subtypes.

Bancel B, Esteve J, Souquet JC, Toyokuni S, Ohshima H, Pignatelli B

World journal of gastroenterology Vol. 12 ( 7 ) page： 1005 - 12 2006.2

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

Aim: To investigate the extent of oxidative stress in preneoplastic and neoplastic gastric mucosa in relation to their pathological criteria and histological subtypes. Methods: A total of 104 gastric adenocarcinomas from 98 patients (88 infiltrative and 16 intraepithelial tumors) were assessed immunohistochemically for expression of iNOS and occurrence of nitrotyrosine (NTYR)-containing proteins and 8-hydroxy-2′-deoxyguanosine (8-OH-dG)-containing DNA, as markers of NO production and damages to protein and DNA. Results: Tumor cells staining for iNOS, NTYR and 8-OH-dG were detected in 41%, 62% and 50% of infiltrative carcinoma, respectively. The three markers were shown for the first time in intraepithelial carcinoma. The expression of iNOS was significantly more frequent in tubular carcinoma (TC) compared to diffuse carcinoma (DC) (54% vs 18%; P=0.008) or in polymorphous carcinoma (PolyC) (54% vs 21%; P=0.04). NTYR staining was obviously more often found in TC than that in PolyC (72% vs 30%; P=0.03). There was a tendency towards a higher rate of iNOS staining when distant metastasis (pM) was present. In infiltrative TC, the presence of oxidative stress markers was not significantly correlated with histological grade, density of inflammation, the depth of infiltration (pT), lymph nodes dissemination (pN) and pathological stages (pTNM). Conclusion: The iNOS-oxidative pathway may play an important role in TC, but moderately in PolyC and DC. DNA oxidation and protein nitration occur in the three subtypes. Based on the significant differences of NTYR levels, TC and PolyC appear as two distinct subtypes. © 2006 The WJG Press. All rights reserved.

DOI： 10.3748/wjg.v12.i7.1005

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PubMed

An N-glycan structure correlates with pulmonary metastatic ability of cancer cells Reviewed

K Sakuma, Fujimoto, I, S Hitoshi, F Tanaka, T Ikeda, K Tanabe, S Toyokuni, H Wada, T Mio, M Mishima, K Ikenaka

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Vol. 340 ( 3 ) page： 829 - 835 2006.2

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

N-Glycan structures on the surface of cancer cells have diverse structures and play significant roles in metastatic process. However, little is known about their roles in organ-selective metastasis. Our study revealed that an alpha 1,6-fucosylated biantennary N-glycan structure designated A2G2F is characteristic of lungs, with far more abundant expression in normal human and murine lungs than in other organs. In this study, we further examined the role of A2G2F in pulmonary metastasis. We stained metastatic cancers by of alpha 1,6-fucose-specific Lens culinaris agglutinin lectin and revealed that pulmonary metastatic nodules more abundantly expressed alpha 1,6-fucosylated N-glycans than hepatic metastatic nodules from common primary cancers. The most specific alpha 1,6-fucosylated N-glycan structure in pulmonary metastatic cancer was identified to be A2G2F. Using a B16 melanoma cell metastasis model, we showed that A2G2F-rich B16 cells formed more Pulmonary metastatic nodules than A2G2F-poor cells. Our results suggest that A2G2F plays a critical role in Pulmonary metastasis. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2005.12.072

Differences in oxidative stress dependence between gastric adenocarcinoma subtypes Reviewed

Brigitte Bancel, Jacques Esteve, Jean-Christophe Souquet, Shinya Toyokuni, Hiroshi Ohshima, Brigitte Pignatelli

WORLD JOURNAL OF GASTROENTEROLOGY Vol. 12 ( 7 ) page： 1005 - 1012 2006.2

Language：English Publishing type：Research paper (scientific journal) Publisher：W J G PRESS

AIM: To investigate the extent of oxidative stress in pre-neoplastic and neoplastic gastric mucosa in relation to their pathological criteria and histological subtypes.
METHODS: A total of 104 gastric adenocarcinomas from 98 patients (88 infiltrative and 16 intraepithelial tumors) were assessed immunohistochemically for expression of iNOS and occurrence of nitrotyrosine (NTYR)-containing proteins and 8-hydroxy-2'-deoxyguanosine (8-OH-dG)-containing DNA, as markers of NO production and damages to protein and DNA.
RESULTS: Tumor cells staining for NOS, NTYR and 8-OH-dG were detected in 41%, 62% and 50% of infiltrative carcinoma, respectively. The three markers were shown for the first time in intraepithelial carcinoma. The expression of iNOS was significantly more frequent in tubular carcinoma (TC) compared to diffuse carcinoma (DC) (54% vs 18%; P = 0.008) or in polymorphous carcinoma (PolyC) (54% vs 21%; P = 0.04). NTYR staining was obviously more often found in TC than that in PolyC (72% vs 30%; P = 0.03). There was a tendency towards a higher rate of iNOS staining when distant metastasis (pM) was present. In infiltrative TC, the presence of oxidative stress markers was not significantly correlated with histological grade, density of inflammation, the depth of infiltration (pT), lymph nodes dissemination (pN) and pathological stages (pTNM).
CONCLUSION: The iNOS-oxidative pathway may play an important role in TC, but moderately in PolyC and DC. DNA oxidation and protein nitration occur in the three subtypes. Based on the significant differences of NTYR levels, TC and PolyC appear as two distinct subtypes. (C) 2006 The WJG Press. All rights reserved.

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A novel screening method for ultraviolet protection: combination of a human skin-equivalent model and 8-hydroxy-2'-deoxyguanosine. Reviewed

Toyokuni S, Yasui H, Date A, Hakozaki T, Akatsuka S, Kohda H, Yoshii T and Sakurai H.

Pathol. Int. Vol. 56 page： 760-762 2006

Anchorage-independent growth of mouse male germline stem cells in vitro. Reviewed

Shinohara M, Inoue K, Lee J, Miki H, Ogonuki N, Toyokuni S, Ogura A and Shinohara T.

Biol. Reprod. Vol. 74 page： 522-529 2006

An N-glycan structure correlates with pulmonary metastatic ability of cancer cells. Reviewed

Sakuma K, Fujimoto I, Hitoshi S, Tanaka F, Ikeda T, Tanabe K, Toyokuni S, Wada H, Mio T, Mishima M, Ikenaka K.

Biochem. Biophys. Res. Commun. Vol. 349 page： 829-835 2006

Novel aspects of oxidative stress-associated carcinogenesis. Reviewed

Toyokuni S.

Antiox. Redox Signal. Vol. 8 page： 1373-1377 2006

Differences in oxidative stress dependence between gastric adenocarcinoma subtypes. Reviewed

Bancel B, Esteve J, Souquet JC, Toyokuni S, Ohshima H, Pignatelli B.

World J. Gastroenterol. Vol. 12 page： 1005-1012 2006

What has been learned from the studies of oxidative stress-induced carcinogenesis: proposal of the concept of oxygenomics. Reviewed

Toyokuni S, Akatsuka S.

J. Clin. Biochem. Nutr. Vol. 39 page： 3-10 2006

Production of knockout mice by random or targeted mutagenesis in spermatogonial stem cells. Reviewed

Kanatsu-Shinohara M, Ikawa M, Takehashi M, Ogonuki N, Miki H, Inoue K, Kazuki Y, Lee J, Toyokuni S, Oshimura M, Ogura A, Shinohara T.

Proc. Natl. Acad. Sci. USA Vol. 103 page： 8018-8023 2006

alfa-Tocopherol induces calnexin in renal tubular cells: Another protective mechanism against free radical-induced cellular damage. Reviewed

Lee W-H, Akatsuka S, Shirase T, Dutta KK, Jiang L, Liu Y-T, Onuki J, Yamada Y, Okawa K, Wada Y, Watanabe A, Kohro T, Noguchi N and Toyokuni S.

Arch. Biochem. Biophys. Vol. 453 page： 168-178 2006

*Contrasting Genome-wide Distribution of 8-Hydroxyguanine and Acrolein-modified Adenine during Oxidative Stress-induced Renal Carcinogenesis. Reviewed

Akatsuka S, Aung TT, Dutta KK, Jiang L, Lee W-H, Liu Y-T, Onuki J, Shirase T, Yamasaki K, Ochi H, Naito Y, Yoshikawa T, Kasai H, Tominaga Y, Sakumi K, Nakabeppu Y, Kawai Y, Uchida K, Yamasaki A, Tsuruyama T, Yamada Y and Toyokuni S.

Am. J. Pathol. Vol. 169 page： 1328-1342 2006

Deletion and single nucleotide substitution at G:C are major mutations in the kidney of gpt delta transgenic mice after the Fenton reaction. Reviewed

Jiang L, Zhong Y, Akatsuka S, Liu Y-T, Dutta KK, Lee W-H, Onuki J, Masumura K, Nohmi T and Toyokuni S.

Cancer Sci. Vol. 97 page： 1159-1167 2006

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Papers - TOYOKUNI Shinya