Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Mechanisms of Asbestos-Induced Carcinogenesis International journal Open Access

TOYOKUNI Shinya, JIANG Li, HU Qian, NAGAI Hirotaka, OKAZAKI Yasumasa, AKATSUKA Shinya, YAMASHITA Yoriko

Nippon Eiseigaku Zasshi (Japanese Journal of Hygiene) Vol. 66 ( 3 ) page： 562 - 7 2011.5

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society for Hygiene

Several types of fibrous stone called asbestos have been an unexpected cause of human cancer in the history. This form of mineral is considered precious in that they are heat-, friction-, and acid-resistant, are obtained easily from mines, and can be modified to any form with many industrial merits. However, it became evident that the inspiration of asbestos causes a rare cancer called malignant mesothelioma. Because of the long incubation period, the peak year for malignant mesothelioma is expected to be 2025 in Japan. Thus, it is necessary to elucidate the mechanisms of asbestos-induced mesothelial carcinogenesis. In this review, we summarize the cutting edge results of our 5-year project funded by a MEXT grant, in which local iron deposition and the characteristics of mesothelial cells are the key issues.<br>

DOI： 10.1265/jjh.66.562

Roles of ASH1-miR-375 pathway in development of lung cancers with neuroendocrine features

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

CANCER RESEARCH Vol. 71 2011.4

XCR1 expression and biased VH gene usage are distinct features of diffuse large B-cell lymphoma initially manifesting in the bone marrow. Reviewed International journal

Yoriko Yamashita, Dai Kajiura, Lee Tang, Yuichi Hasegawa, Tomohiro Kinoshita, Shigeo Nakamura, Shinya Akatsuka, Shinya Toyokuni, Naoyoshi Mori

American journal of clinical pathology Vol. 135 ( 4 ) page： 556 - 64 2011.4

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC CLINICAL PATHOLOGY

A total of 29 cases of diffuse large B-cell lymphoma initially manifesting in the bone marrow (BM-DLBCL) were analyzed for V-H gene sequence, and expression microarray of chemokines and chemokine receptors and immunohistochemical analysis were done. Seminested polymerase chain reaction (PCR) and sequencing analyses of 18 cases revealed that the V-H gene usage in 6 cases was restricted to V(H)3-7, in 3 cases to V(H)4-34, and in 2 cases to V(H)4-39, which were all previously reported to be autoreactive. In total, 14 of 18 V-H genes were those associated with autoimmune diseases, including V(H)3-21, V(H)3-23, and V(H)3-48. Furthermore, cDNA microarray analysis specific for chemokine and chemokine receptors revealed that chemokine receptor XCR1 expression was significantly elevated in the BM-DLBCL cases (P < .05), which was confirmed by quantitative reverse transcriptase PCR and immunohistochemical analysis. Expression of the chemokine receptor XCR1 and frequent usage of autoreactive V-H genes seem to be distinct characteristics of BM-DLBCL.

DOI： 10.1309/AJCPCTDC5PY3LXBP

LATS2 is a tumor suppressor gene of malignant mesothelioma

Murakami H.

Cancer Research Vol. 71 ( 3 ) page： 873 - 883 2011.2

LATS2 is a tumor suppressor gene of malignant mesothelioma.

Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, Akatsuka S, Horio Y, Hida T, Kondo Y, Toyokuni S, Osada H, Sekido Y

Cancer research Vol. 71 ( 3 ) page： 873 - 83 2011.2

Stage-specific roles of fibulin-5 during oxidative stress-induced renal carcinogenesis in rats. Reviewed International journal

Hiroki Ohara, Shinya Akatsuka, Hirotaka Nagai, Yu-Ting Liu, Li Jiang, Yasumasa Okazaki, Yoriko Yamashita, Tomoyuki Nakamura, Shinya Toyokuni

Free radical research Vol. 45 ( 2 ) page： 211 - 20 2011.2

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

By using a rat model of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA), this study performed genome-wide analysis to identify target genes during carcinogenesis. It screened for genes with decreased expression in RCCs, with simultaneous loss of heterozygosity, eventually to focus on the fibulin-5 (fbln5) gene. Oxidative damage via Fe-NTA markedly increased Fbln5 in the proximal tubules. RCCs presented lower levels of Fbln5. However, a fraction of RCCs presenting pulmonary metastasis revealed significantly higher levels of Fbln5 than those without metastasis, accompanied by immunopositivity of RCC cells and myofibroblast proliferation. Experiments revealed that RCC cell lines showed lower expression of fbln5 than its non-transformed counterpart NRK52E, but that fbln5 transfection to RCC cell lines changed neither proliferation nor migration/invasion. The data suggest that Fbln5 plays a role not only in the tissue repair and remodelling after renal tubular oxidative damage but also in RCC metastasis, presumably as a cytokine.

DOI： 10.3109/10715762.2010.523702

LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma Reviewed

Hideki Murakami, Tetsuya Mizuno, Tetsuo Taniguchi, Makiko Fujii, Futoshi Ishiguro, Takayuki Fukui, Shinya Akatsuka, Yoshitsugu Horio, Toyoaki Hida, Yutaka Kondo, Shinya Toyokuni, Hirotaka Osada, Yoshitaka Sekido

CANCER RESEARCH Vol. 71 ( 3 ) page： 873 - 883 2011.2

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

Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive activation of YAP, which induces deregulation of MM cell proliferation. Cancer Res; 71(3); 873-83. (C)2011 AACR.

DOI： 10.1158/0008-5472.CAN-10-2164

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CD8+CD122+ regulatory T cells (Tregs) and CD4+ Tregs cooperatively prevent and cure CD4+ cell-induced colitis. Reviewed International journal Open Access

Agustina Tri Endharti, Yusuke Okuno, Zhe Shi, Nobuaki Misawa, Shinya Toyokuni, Masafumi Ito, Ken-ichi Isobe, Haruhiko Suzuki

Journal of immunology (Baltimore, Md. : 1950) Vol. 186 ( 1 ) page： 41 - 52 2011.1

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

We identified CD8(+)CD122(+) regulatory T cells (Tregs) and demonstrated their importance in the maintenance of immune homeostasis and in the recovery from experimental autoimmune encephalomyelitis. In this paper, we show that CD8(+)CD122(+) Tregs effectively prevent and cure colitis in a mouse model. In our experiments, colitis was induced in lymphocyte-deficient RAG-2(-/-) mice by transferring CD4(+)CD45RB(high) cells that were excluded with CD4(+) Tregs. Cotransfer of CD8(+)CD122(+) cells clearly suppressed the development of colitis, and this suppressive effect was similar to that of CD4(+)CD45RB(low) cells that were mostly CD4(+) Tregs. CD8(+)CD122(+) cells obtained from IL-10(-/-) mice were unable to suppress colitis, indicating that IL-10 is an important effect-transmitting factor in the suppression of colitis. CD8(+)CD122(+) cells showed a suppressive effect when they were transferred 4 wk after CD4(+)CD45RB(high) cells, indicating the therapeutic potential of CD8(+)CD122(+) cells. A mixture of CD8(+)CD122(+) cells and CD4(+)CD45RB(low) cells was far more effective than single Tregs, indicating the synergistic effect of these Tregs. These overall findings demonstrate the potential role of CD8(+) Tregs, and possibly together with CD4(+) Tregs, in the medical care of inflammatory bowel disease patients.

DOI： 10.4049/jimmunol.1000800

3-morpholinosydnonimine participates in the attenuation of neointima formation via inhibition of annexin A2-mediated vascular smooth muscle cell migration. International journal

Kyung-Jong Won, Philyoung Lee, Seung Hyo Jung, Xiaowen Jiang, Chang-Kwon Lee, Hai Yue Lin, Hyun Kang, Hwan Myung Lee, Junghwan Kim, Shinya Toyokuni, Bokyung Kim

Proteomics Vol. 11 ( 2 ) page： 193 - 201 2011.1

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

3-Morpholinosydnonimine (SIN-1) affects vascular smooth muscle cell migration and proliferation, processes essential for atherosclerosis. However, the mechanism by which SIN-1 exerts these effects has not been elucidated. We used 2-DE followed by MALDI-TOF/TOF MS to identify responses in protein expression to SIN-1 in rat aortic smooth muscle. Platelet-derived growth factor-BB increased cell migration and proliferation in rat aortic smooth muscle cells, and subsequent SIN-1 treatment inhibited it. Administration of SIN-1 in vivo attenuated neointima formation in balloon-injured rat carotid arteries. Proteomic analysis showed that glutathione peroxidase and 40S ribosomal protein S12 were differentially expressed in aortic strips exposed to SIN-1. Expression of annexin A2 was decreased by SIN-1. Platelet-derived growth factor-BB-induced cell migration was increased and inhibited in rat aortic smooth muscle cells with overexpression and knockdown of annexin A2 gene, respectively. The expression of annexin A2 was increased in vascular neointima compared with the intact control, which was inhibited by SIN-1 treatment. These results demonstrate that SIN-1 may attenuate vascular neointima formation by inhibiting annexin A2-mediated migration. Therefore, annexin A2 may be a potential target for therapeutic strategies for atherosclerosis.

DOI： 10.1002/pmic.200900834

Iron as a target of chemoprevention for longevity in humans. Reviewed

Toyokuni S.

Free Radic Res Vol. 45 page： 906-917 2011

The human cytomegalovirus gene products essential for late viral gene expression assemble into prereplication complexes before viral DNA replication. Reviewed

Isomura H, Stinski MF, Murata T, Yamashita Y, Kanda T, Toyokuni S and Tsurumi T.

J Virol Vol. 85 page： 6629-6644 2011

Dietary fish oil promotes colonic apoptosis and mitochondrial proton leak in oxidatively stressed mice. Reviewed

Fan YY, Ran Q, Toyokuni S, Okazaki Y, Callaway ES, Lupton JR, and Chapkin RS.

Cancer Prev Res Vol. 4 page： 1267-1274 2011

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

Toyokuni S, Hirao A, Wada T, Nagai R, Date A, Yoshii T, Akatsuka S, Yamashita Y, and Kawada A.

J Clin Biochem Nutr Vol. 49 page： 1-4 2011

Mysterious link between iron overload and CDKN2A/2B. Reviewed

Toyokuni S.

J Vol. 48 page： 46-49 2011

LATS2 is a tumor suppressor gene of malignancy mesothelioma. Reviewed

Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, Akatsuka S, Horio Y, HIda T, Kondo Y, Toyokuni S, Osada H and Sekido Y.

Cancer Res Vol. 71 page： 873-883 2011

XCR1 expression and biased VH gene usage are distinct features of diffuse large B-cell lymphoma initially manifesting in the bone marrow. Reviewed

Yamashita Y, Kajiura D, Tang L, Hasegawa Y, Kinoshita T, Nakamura S, Akatsuka S, Toyokuni S and Mori N.

Am J Clin Pathol Vol. 135 page： 556-564 2011

Asbetos provides a niche for oxidative modification. Reviewed

Nagai H, Ishihara T, Lee WH, Ohara H, Okazaki Y, Okawa K and Toyokuni S.

Cancer Sci Vol. 102 page： 2118-2125 2011

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

Nishikawa E, Osada H, Okazaki Y, Arima C, Tomida S, Tatematsu Y, Taguchi A, Shimada Y, Yanagisawa K, Yatabe Y, Toyokuni S, Sekido Y and Takahashi T

Cancer Res Vol. 71 page： 6165-6173 2011

Oxidative DNA Damage and Carcinogenesis

Jiang, L; Toyokuni, S

FREE RADICAL BIOLOGY IN DIGESTIVE DISEASES Vol. 29 page： 55 - 63 2011

Iron as a target of chemoprevention for longevity in humans. Reviewed

Toyokuni S

Free Radic Res Vol. 45 page： 906-917 2011

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Papers - TOYOKUNI Shinya