Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress

Yamaguchi Ken, Mandai Masaki, Toyokuni Shinya, Hamanishi Junzo, Higuchi Toshihiro, Takakura Kenji, Fujii Shingo

CLINICAL CANCER RESEARCH Vol. 14 ( 1 ) page： 32 - 40 2008.1

Overexpression of CYP3A aggravates endotoxin-induced liver injury in hypophysectomized female rats Reviewed International journal

Shigekazu Takemura, Yukiko Minamiyama, Shinya Toyokuni, Susumu Imaoka, Seikan Hai, Shoji Kubo, Kazuhiro Hirohashi, Yoshihiko Funae, Shigeru Okada

HEPATOLOGY RESEARCH Vol. 38 ( 1 ) page： 70 - 78 2008.1

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

Aim: CYP3A2 is a male-specific isoform of cytochrome P450 enzyme which is expressed abundantly in male rats but not in intact female rats. Having previously reported that hepatic CYP3A2 promotes lipopolysaccharide (LPS)-induced liver injury in male rats, we further examined the impact of CYP3A on LPS-induced liver injury by comparing intact and hypophysectomized female rats. In hypophysectomized female rats, phenobarbital (PB), a cytochrome P450 inducer, markedly increased the hepatic content and activity of CYP3A1/2, but did not do so in intact rats. CYP2B1 increased to similar levels in PB-treated hypophysectomized and intact rats.
Methods: Rats were administered 10 mg/kg LPS intravenously and some were given PB for three days before LPS injection. Liver injury was analyzed 8 h after LPS injection.
Results: PB-LPS increased plasma alanine aminotransferase significantly more in hypophysectomized female rats than in intact female rats. Ketoconazole, a CYP3A inhibitor, inhibited the increase of liver injury. Hepatic 8-hydroxydeoxyguanosine in nuclei and 4-hydroxy-2-nonenal-modified proteins, measured to evaluate oxidative stress by LPS treatment, increased markedly more in PB-treated, hypophysectomized female rats, than in intact female rats.
Conclusions: Overexpression of CYP3A aggravated LPS-induced liver injury in rats, apparently through the formation of reactive oxygen species.

DOI： 10.1111/j.1872-034X.2007.00212.x

Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress Reviewed

Ken Yamaguchi, Masaki Mandai, Shinya Toyokuni, Junzo Hamanishi, Toshihiro Higuchi, Kenji Takakura, Shingo Fujii

CLINICAL CANCER RESEARCH Vol. 14 ( 1 ) page： 32 - 40 2008.1

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

Purpose: Endometriotic cysts are known to transform into ovarian cancers, such as clear cell and enclometrioid carcinomas. We hypothesized that an iron-rich environment produced by the repetition of hemorrhage in the endometriotic cysts during the reproductive period may play a crucial role in carcinogenesis in the cysts through the iron-induced persistent oxidative stress.
Experimental Design: Contents of human ovarian cysts, including 21 enclometriotic cysts, 4 clear cell carcinomas, and 11 nonendometriotic cysts, were analyzed for the concentrations of free "catalytic" iron, lactose clehydrogenase, potential antioxiclant, lipid peroxide, and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Iron deposition and 8-OHdG levels were also analyzed histologically. Reactive oxygen species and the mutagenicity of the contents in enclometriotic cyst were determined in vitro.
Results: The concentration of free iron in endometriotic cysts (100.9 mmol/L) was significantly higher than that in nonendometriotic cysts (0.075 mmol/L; P < 0.01). The average concentrations of lactose dehydrogenase, potential antioxiclant, lipid peroxide, and 8-OHdG were also significantly higher in enclometriotic cysts (P < 0.01).There was a correlation between the concentration of free iron and that of 8-OHdG (P < 0.01). Histologically, we could observe iron deposits more abundantly in endometriotic cysts than in nonendometriotic cysts (P < 0.01).The level of 8-OHdG in carcinoma associated with endometriosis was higher than that of carcinoma without endometriosis (P < 0.05). In vitro analyses showed that the contents of enclometriotic cyst could produce more reactive oxygen species and could induce gene mutations more frequently than the contents in the other cysts.
Conclusions: Abundant free iron in the contents of enclometriotic cysts was strongly associated with greater oxidative stress and frequent DNA mutations. A long-standing history of the RBCs accumulated in the ovarian endometriotic cysts during the reproductive period produces oxidative stress that is a possible cause for the malignant change of the endometriotic cyst.

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Pluripotency of a single spermatogonial stem cell. Reviewed

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

Biol. Reprod. Vol. 78 page： 681-687 2008

Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress. Reviewed

Yamaguchi K, Mandai M, Toyokuni S, Hamanishi J, Higuchi T, Takakura K and Fujii S.

Clin. Cancer Res. Vol. 14 page： 32-40 2008

Molecular mechanisms of oxidative stress-induced carcinogenesis: from epidemiology to oxygenomics. Invited Reviewed

Toyokuni S.

IUBMB Life Vol. 60 page： 441-447 2008

Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice. Reviewed

Liao J, Seril DN, Lu GG, Zhang M, Toyokuni S, Yang AL and Yang GY.

Mol. Carcinog. Vol. 47 page： 638-646 2008

Protein N-acylation: H2O2-mediated covalent modification of protein by lipid peroxidation-derived saturated aldehydes. Reviewed

Ishino K, Shibata T, Ishii T, Liu YT, Toyokuni S, Zhu X, Sayre LM and Uchida K.

Chem. Res. Toxicol. Vol. 21 page： 1261-1270 2008

A reporter gene assay to prove the ability of natural compounds to modulate gluthathione peroxidase, superoxide dismutase and catalase gene promoters in V79 cells. Reviewed

Ullmann K, Wiencierz A M, Müller C, Thierbach R, Steege A, Toyokuni S and Steinberg P.

Free Radic. Res. Vol. 42 page： 746-753 2008

The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Reviewed

Kamitsuji Y, Kuroda J, Kimura S, Toyokuni S, Watanabe K, Ashihara E, Tanaka H, Yui Y, Watanabe M, Matsubara H, Mizushima Y, Hiraumi Y, Kawata E, Yoshikawa T, Maekawa T, Nakahata T, Adachi S.

Cell Death Differ. Vol. 15 page： 1712-1722 2008

Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inihibitor FK228 through AIF translocation. Reviewed

Watanabe M, Adachi S, Matsubara H, Imai T, Yui Y, Mizushima Y, Hiraumi Y, Watanabe KI, Kamitsuji Y, Toyokuni S, Hosoi H, Sugimoto T, Tokuchida J and Nakahata T.

Int. J. Cancer Vol. 124 page： 55-67 2008

Genome-wide analysis identifies a tumor suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma. Reviewed

Zhong Y, Onuki J, Yamasaki T. Ogawa O, Akatsuka S and Toyokuni S.

Carcinogenesis page： in press 2008

Overexpression of CYP3A aggravates endotoxin-induced liver injury in hypophysectomized female rats. Reviewed

Takemura S, Minamiyama Y, Toyokuni S, Imaoka S, Hai S, Kubo S, Hirohashi K, Funae Y and Okada S.

Hepatol. Res. Vol. 38 page： 70-78 2008

A high-throughput reporter gene assay to prove the ability of natural compounds to modulate glutathione peroxidase, superoxide dismutase and catalase gene promoters in V79 cells. Reviewed International journal

Kristina Ullmann, Anne Maria Wiencierz, Carsten Müller, Rene Thierbach, Andreas Steege, Shinya Toyokuni, Pablo Steinberg

Free radical research Vol. 42 ( 8 ) page： 746 - 753 2008

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

The aim of the study was to establish a 96-well microtiter plate-based reporter gene assay to test the influence of natural compounds on the promoter activities of rat catalase, human glutathione peroxidase and human superoxide dismutase expressed in V79 cells. Luciferase expression vectors with the promoter regions of the genes coding for the three above-mentioned enzymes were constructed and transfected into V79 cells. Thereafter the ability of sodium ascorbate, L-carnitine, catechin, epigallocatechin gallate, genistein, paraquat, quercetin, 12-O-tetradecanoylphorbol-13-acetate and Trolox to enhance the promoter activities was evaluated. Genistein, paraquat and quercetin led to a statistically significant increase in the glutathione peroxidase and superoxide dismutase gene promoter activities. None of the compounds tested enhanced the catalase gene promoter activity. The reporter gene assay described in this report is easy to perform, fast and allows one to test a high number of compounds and different concentrations of a single compound at the same time.

DOI： 10.1080/10715760802337273

Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inihibitor FK228 through AIF translocation. Reviewed

Watanabe M, Adachi S, Matsubara H, Imai T, Yui Y, Mizushima Y, Hiraumi Y, Watanabe KI, Kamitsuji Y, Toyokuni S, Hosoi H, Sugimoto T, Tokuchida J, Nakahata T

Int. J. Cancer Vol. 124 page： 55-67 2008

Molecular mechanisms of oxidative stress-induced carcinogenesis: from epidemiology to oxygenomics. Invited Reviewed

Toyokuni S

IUBMB Life Vol. 60 page： 441-447 - 447 2008

Association of microRNA-34a overexpression with proliferation is cell type-dependent

DUTTA Khokon Kumar, ZHONG Yi, LIU Yu-Ting, YAMADA Takuji, AKATSUKA Shinya, HU Qian, YOSHIHARA Minako, OHARA Hiroki, TAKEHASHI Masanori, SHINOHARA Takashi, MASUTANI Hiroshi, ONUKI Janice, TOYOKUNI Shinya

Cancer Sci. Vol. 98 ( 12 ) page： 1845 - 1852 2007.12

Production of knockout mice by gene targeting in multipotent germline stem cells Reviewed International journal Open Access

Masanori Takehashi, Mito Kanatsu-Shinohara, Hiromi Miki, Jiyoung Lee, Yasuhiro Kazuki, Kimiko Inoue, Narumi Ogonuki, Shinya Toyokuni, Mitsuo Oshimura, Atsuo Ogura, Takashi Shinohara

DEVELOPMENTAL BIOLOGY Vol. 312 ( 1 ) page： 344 - 52 2007.12

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

Spermatogonial stein cells can convert into embryonic stem (ES) cell-like multipotent germline stem (mGS) cells in vitro and produce germline chimeras by blastocyst microinjection. Although homologous recombination was previously demonstrated in mGS cells, spermatogenesis was not found in chimeras, suggesting that they are not competent for germline modification. Here we conducted detailed analysis of chimeric animals to determine whether mGS cells retain germline potential after genetic manipulation. Spermatozoa that were deficient in the occludin gene could be recovered from animals that were chimeric with mGS cells that underwent homologous recombination. The phenotypes of the occludin knockout (KO) mice were similar to those reported for KO mice produced using ES cells, and the animals showed growth retardation, gastritis and male infertility. Furthermore, we found that heterozygous mGS cells acquire two copies of the G418-resistant genes and become homozygous for the targeted allele by culturing at high concentrations of G418. Cytogenetic analysis showed that the aneuploid mGS cells observed during genetic manipulation were trisomic for chromosome 8 or 11, which is a common chromosomal abnormality in ES cells. Thus, mGS cells can be used to produce KO animals, and this novel method of germline manipulation may prove useful in diverse mammalian species. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ydbio.2007.09.029

Association of microRNA-34a overexpression with proliferation is cell type-dependent Reviewed International journal Open Access

Khokon Kumar Dutta, Yi Zhong, Yu-Ting Liu, Takuji Yamada, Shinya Akatsuka, Qian Hu, Minako Yoshihara, Hiroki Ohara, Masanori Takehashi, Takashi Shinohara, Hiroshi Masutani, Janice Onuki, Shinya Toyokuni

CANCER SCIENCE Vol. 98 ( 12 ) page： 1845 - 52 2007.12

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

Recently Welch et al. reported that microRNA (miRNA)-34a functions as a potential tumor suppressor in neuroblastoma cells (Oncogene 26: 5017-22, 2007). Here, we conversely show that miRNA-34a supports cell proliferation in rat oxidative stress-induced renal carcinogenesis and is overexpressed in various types of human cancers. While searching for genetically unstable chromosomal areas in rat renal carcinogenesis, we found the miRNA-34 family reciprocally overexpressed in chromosomal areas with frequent allelic loss. By in situ hybridization and reverse transcription-polymerase chain reaction, cerebral neurons and Purkinje cells showed the highest expression of a major type, miRNA-34a, followed by a variety of endocrine cells and proliferating cells including germinal center lymphocytes and mouse embryonic fibroblasts and stem cells. In contrast, normal renal tubules, hepatocytes and myocardial cells showed faint expression. After 3 weeks of ferric nitrilotriacetate (Fe-NTA)-induced oxidative stress, regenerating renal proximal tubular cells showed high miRNA-34a expression. All of the Fe-NTA-induced rat renal carcinomas and an array of human cancers (151 positive cases of 177) showed high expression of miRNA-34a. Furthermore, knockdown of miRNA-34a with small interfering RNA significantly suppressed proliferation not only of renal carcinoma cells but also of HeLa and MCF7 cells. These results indicate that miRNA-34a overexpression, an acquired trait during carcinogenesis, supports cell proliferation in the majority of cancers suggesting an unexpected link in the cellular metabolism between cancer and neuronal and/or endocrine cells, which warrants further investigation.

DOI： 10.1111/j.1349-7006.2007.00619.x

Chronic oxidative stress causes amplification and overexpression of ptprz1 protein tyrosine phosphatase to activate beta-catenin pathway

Liu Yu-Ting, Shang Donghao, Akatsuka Shinya, Ohara Hiroki, Dutta Khokon Kumar, Mizushima Katsura, Naito Yuji, Yoshikawa Toshikazu, Izumiya Masashi, Abe Kouichiro, Nakagama Hitoshi, Noguchi Noriko, Toyokuni Shinya

AMERICAN JOURNAL OF PATHOLOGY Vol. 171 ( 6 ) page： 1978 - 1988 2007.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：American Journal of Pathology

Ferric nitrilotriacetate induces oxidative renal tubular damage via Fenton-reaction, which subsequently leads to renal cell carcinoma (RCC) in rodents. Here, we used gene expression microarray and array-based comparative genomic hybridization analyses to find target oncogenes in this model. At the common chromosomal region of amplification (4q22) in rat RCCs, we found ptprz1, a tyrosine phosphatase (also known as protein tyrosine phosphatase ζ or receptor tyrosine phosphatase β) highly expressed in the RCCs. Analyses revealed genomic amplification up to eightfold. Despite scarcity in the control kidney, the amounts of PTPRZ1 were increased in the kidney after 3 weeks of oxidative stress, and mRNA levels were increased 16∼552-fold in the RCCs. Network analysis of the expression revealed the involvement of the β-catenin pathway in the RCCs. In the RCCs, dephosphorylated β-catenin was translocated to nuclei, resulting in the expression of its target genes cyclin D1, c-myc, c-jun, fra-1, and CD44. Furthermore, knockdown of ptprz1 with small interfering RNA (siRNA), in FRCC-001 and FRCC-562 cell lines established from the induced RCCs, decreased the amounts of nuclear β-catenin and suppressed cellular proliferation concomitant with a decrease in the expression of target genes. These results demonstrate that chronic oxidative stress can induce genomic amplification of ptprz1, activating β-catenin pathways without the involvement of Wnt signaling for carcinogenesis. Thus, iron-mediated persistent oxidative stress confers an environment for gene amplification. Copyright © American Society for Investigative Pathology.

DOI： 10.2353/ajpath.2007.070741

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Papers - TOYOKUNI Shinya