研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes 査読有り国際誌 Open Access

Mizuno, T; Murakami, H; Fujii, M; Ishiguro, F; Tanaka, I; Kondo, Y; Akatsuka, S; Toyokuni, S; Yokoi, K; Osada, H; Sekido, Y

ONCOGENE 31 巻 ( 49 ) 頁： 5117 - 5122 2012年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oncogene

Malignant mesothelioma (MM) shows frequent inactivation of the neurofibromatosis type 2 (NF2)-tumor-suppressor gene. Recent studies have documented that the Hippo signaling pathway, a downstream cascade of Merlin (a product of NF2), has a key role in organ size control and carcinogenesis by regulating cell proliferation and apoptosis. We previously reported that MMs show overexpression of Yes-associated protein (YAP) transcriptional coactivator, the main downstream effector of the Hippo signaling pathway, which results from the inactivation of NF2, LATS2 and/or SAV1 genes (the latter two encoding core components of the mammalian Hippo pathway) or amplification of YAP itself. However, the detailed roles of YAP remain unclear, especially the target genes of YAP that enhance MM cell growth and survival. Here, we demonstrated that YAP-knockdown inhibited cell motility, invasion and anchorage-independent growth as well as cell proliferation of MM cells in vitro. We analyzed genes commonly regulated by YAP in three MM cell lines with constitutive YAP-activation, and found that the major subsets of YAP-upregulating genes encode cell cycle regulators. Among them, YAP directly induced the transcription of CCND1 and FOXM1, in cooperation with TEAD transcription factor. We also found that knockdown of CCND1 and FOXM1 suppressed MM cell proliferation, although the inhibitory effects were less evident than those of YAP knockdown. These results indicate that constitutive YAP activation in MM cells promotes cell cycle progression giving more aggressive phenotypes to MM cells. © 2012 Macmillan Publishers Limited All rights reserved.

DOI： 10.1038/onc.2012.5

Distinct affinity of nuclear proteins to the surface of chrysotile and crocidolite. 査読有り国際誌 Open Access

Kubo Y, Takenaka H, Nagai H, Toyokuni S

Journal of clinical biochemistry and nutrition 51 巻 ( 3 ) 頁： 221 - 6 2012年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人　日本酸化ストレス学会

The inhalation of asbestos is a risk factor for the development of malignant mesothelioma and lung cancer. Based on the broad surface area of asbestos fibers and their ability to enter the cytoplasm and nuclei of cells, it was hypothesized that proteins that adsorb onto the fiber surface play a role in the cytotoxicity and carcinogenesis of asbestos fibers. However, little is known about which proteins adsorb onto asbestos. Previously, we systematically identified asbestos-interacting proteins and classified them into eight sub-categories: chromatin/nucleotide/RNA-binding proteins, ribosomal proteins, cytoprotective proteins, cytoskeleton-associated proteins, histones and hemoglobin. Here, we report an adsorption profile of proteins for the three commercially used asbestos compounds: chrysotile, crocidolite and amosite. We quantified the amounts of adsorbed proteins by analyzing the silver-stained gels of sodium dodecyl sulfate-polyacrylamide gel electrophoresis with ImageJ software, using the bands for amosite as a standard. We found that histones were most adsorptive to crocidolite and that chromatin-binding proteins were most adsorptive to chrysotile. The results suggest that chrysotile and crocidolite directly interact with chromatin structure through different mechanisms. Furthermore, RNA-binding proteins preferably interacted with chrysotile, suggesting that chrysotile may interfere with transcription and translation. Our results provide novel evidence demonstrating that the specific molecular interactions leading to carcinogenesis are different between chrysotile and crocidolite. ©2012 JCBN.

DOI： 10.3164/jcbn.12-39

Iron overload signature in chrysotile-induced malignant mesothelioma

Jiang L., Akatsuka S., Nagai H., Chew S.H., 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.

Journal of Pathology 228 巻 ( 3 ) 頁： 366 - 377 2012年11月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Pathology

Exposure to asbestos is a risk for malignant mesothelioma (MM) in humans. Among the commercially used types of asbestos (chrysotile, crocidolite, and amosite), the carcinogenicity of chrysotile is not fully appreciated. Here, we show that all three asbestos types similarly induced MM in the rat peritoneal cavity and that chrysotile caused the earliest mesothelioma development with a high fraction of sarcomatoid histology. The pathogenesis of chrysotile-induced mesothelial carcinogenesis was closely associated with iron overload: repeated administration of an iron chelator, nitrilotriacetic acid, which promotes the Fenton reaction, significantly reduced the period required for carcinogenesis; massive iron deposition was found in the peritoneal organs with high serum ferritin; and homozygous deletion of the CDKN2A/2B/ARF tumour suppressor genes, the most frequent genomic alteration in human MM and in iron-induced rodent carcinogenesis, was observed in 92.6% of the cases studied with array-based comparative genomic hybridization. The induced rat MM cells revealed high expression of mesoderm-specific transcription factors, Dlx5 and Hand1, and showed an iron regulatory profile of active iron uptake and utilization. These data indicate that chrysotile is a strong carcinogen when exposed to mesothelia, acting through the induction of local iron overload. Therefore, an intervention to remove local excess iron might be a strategy to prevent MM after asbestos exposure. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DOI： 10.1002/path.4075

Scopus

PubMed

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

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

FREE RADICAL BIOLOGY AND MEDICINE 53 巻頁： S51 - S52 2012年9月

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

Okazaki Y, Kono I, Kuriki T, Funahashi S, Fushimi S, Iqbal M, Okada S, Toyokuni S

Journal of clinical biochemistry and nutrition 51 巻 ( 2 ) 頁： 84 - 90 2012年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人　日本酸化ストレス学会

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 LF 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. ©2012 JCBN.

DOI： 10.3164/jcbn.11-100

Iron overload signature in chrysotile-induced malignant mesothelioma. 査読有り

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 228 巻頁： 366-377 2012年8月

Differences and similarities between carbon nanotubes and asbestos fibers during mesothelial carcinogenesis: shedding light on fiber entry mechanism. 査読有り国際誌 Open Access

Nagai H, Toyokuni S

Cancer science 103 巻 ( 8 ) 頁： 1378 - 90 2012年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Science

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. © 2012 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2012.02326.x

Mitochondria and free radical studies on health, disease and pollution 招待有り国際誌 Open Access

Majima, HJ; Toyokuni, S

FREE RADICAL RESEARCH 46 巻 ( 8 ) 頁： 925 - 6 2012年8月

The ferroimmunomodulatory role of ectopic endometriotic stromal cells in ovarian endometriosis. 査読有り国際誌

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

Fertility and sterility 98 巻 ( 2 ) 頁： 415 - 22 2012年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Fertility and Sterility

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-1β 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. Copyright © 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.

DOI： 10.1016/j.fertnstert.2012.04.047

Transient but not stable ZEB1 knockdown dramatically inhibits growth of malignant pleural mesothelioma cells. 査読有り国際誌 Open Access

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

Annals of surgical oncology 19 Suppl 3 巻 ( Suppl 3 ) 頁： S634-45 - S645 2012年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Annals of Surgical Oncology

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. © 2011 Society of Surgical Oncology.

DOI： 10.1245/s10434-011-2142-0

In vitro transformation of mouse testis cells by oncogene transfection. 査読有り

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

Biol Reprod 86 巻 ( 5 ) 頁： 1-11 2012年5月

FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b through MAP2K1 activation. 査読有り国際誌

Ishii K, Kanatsu-Shinohara M, Toyokuni S, Shinohara T

Development (Cambridge, England) 139 巻 ( 10 ) 頁： 1734 - 43 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Development

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. © 2012. Published by The Company of Biologists Ltd.

DOI： 10.1242/dev.076539

In vitro transformation of mouse testis cells by oncogene transfection. 査読有り国際誌

Morimoto H, Lee J, Tanaka T, Ishii K, Toyokuni S, Kanatsu-Shinohara M, Shinohara T

Biology of reproduction 86 巻 ( 5 ) 頁： 148, 1 - 11 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Biology of 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. © 2012 by the Society for the Study of Reproduction, Inc.

DOI： 10.1095/biolreprod.111.095307

過剰鉄と活性酸素を介した発がん機構と予防・治療への展開

豊國伸哉

臨床血液 53 巻 ( 4 ) 頁： 401 - 408 2012年4月

過剰鉄と活性酸素を介した発がん機構と予防・治療への展開国際誌

豊國伸哉

臨床血液 53 巻 ( 4 ) 頁： 401 - 408 2012年4月

Genome-wide assessment of oxidatively generated DNA damage. 査読有り国際誌

Akatsuka S, Toyokuni S

Free radical research 46 巻 ( 4 ) 頁： 523 - 30 2012年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Free Radical Research

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. © 2012 Informa UK, Ltd.

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 53 巻 ( 4 ) 頁： 401 - 8 2012年4月

[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 53 巻 ( 4 ) 頁： 401 - 8 2012年4月

Age- and sun exposure-dependent differences in 8-hydroxy-2′-deoxyguanosine and Nε-(carboxymethyl)lysine in human epidermis 査読有り国際誌

Kawada, A; Date, A; Toyokuni, S

JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY 66 巻 ( 4 ) 頁： AB174 - AB174 2012年4月

[Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy]. 査読有り国際誌

Toyokuni S.

[Rinshō ketsueki] The Japanese journal of clinical hematology 53 巻 ( 4 ) 頁： 401 - 408 2012年4月

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