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図書 |
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edited by Hiroyuki Mano ... [et al.]
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Sakai, Eri ; Nakayama, Mizuho ; Oshima, Hiroko ; Kouyama, Yuta ; Niida, Atsushi ; Fujii, Satoshi ; Ochiai, Atsushi ; Nakayama, Keiichi ; Mimori, Koshi ; Suzuki, Yutaka ; Hong, Chang Pyo ; Ock, Chan-Young ; Kim, Seong-Jin ; Oshima, Masanobu ; 大島, 正伸
概要:
金沢大学新学術創成研究機構ナノ生命科学研究所<br />Embargo Period 12 months
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Han, Tae-Su ; Oshima, Masanobu ; 大島, 正伸
概要:
金沢大学新学術創成研究機構ナノ生命科学研究所<br />Cancer tissues are composed of various cell types including cancer cells, cancer-associated
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fibroblasts (CAFs), tumor-associated macrophages (TAMs) and endothelial cells. These surrounding stromal cells form the tumor microenvironment, partly through the inflammatory response, which plays an important role in the development and malignant progression of cancer. It is therefore important to examine the expression profiles and protein modifications of each cellular component independently to decipher the interaction between the tumor cells and the microenvironment. We herein describe a protocol for laser microdissection, which allows for the individual cellular compartments to be collected separately. This will allow us to perform real-time RT-PCRs and microarray analyses of specific cell types in tumor tissues. © 2018, Springer Science+Business Media, LLC.<br />Embargo Period 12 months
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Echizen, Kanae ; Horiuchi, Keigo ; Aoki, Yayoi ; Yamada, Yoichi ; Minamoto, Toshinari ; Oshima, Hiroko ; Oshima, Masanobu ; 源, 利成 ; 大島, 浩子 ; 大島, 正伸
概要:
金沢大学ナノ生命科学研究所<br />We previously showed that NADPH oxidase organizer 1 (Noxo1), a component of NADPH oxidase 1 (NOX1), i
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s a TNF-α-induced tumor-promoting factor in gastric tumorigenesis. However, the mechanism of NOX1-induced reactive oxygen species (ROS) signaling for the gastric tumorigenesis has not been understood. Here, we showed that expression of NOX1 complex components, including Noxo1, but not other NOX family members was significantly upregulated in both mouse models for gastritis and gastric tumors, which was associated with increased ROS levels. We also found that NF-κB directly regulated NOXO1 expression in TNF-α-stimulated gastric cancer cells, suggesting that inflammation induces NOX1 complex activation through TNF-α/NF-κB pathway. Notably, in situ hybridization indicated that Noxo1 mRNA was detected in proliferating cells of gastritis and gastric tumors, and pharmacological inhibition of NOX activity significantly suppressed the proliferation of MKN45 gastric cancer cells and gastric hyperplasia of K19-C2mE mice. These results suggest that NOX1/ROS signaling has an important role in increased proliferation of stomach epithelial cells in the inflamed mucosa. Moreover, we found that expression of SOX2, a marker of gastric epithelial stem cells, was increased by NOX1/ROS signaling. Furthermore, disruption of Noxo1 in K19-C2mE mice significantly suppressed gastritis-associated metaplastic hyperplasia, a potent preneoplastic lesion, which was associated with decreased number of SOX2-positive cells. These results indicate that inflammation-induced Noxo1 expression is responsible for development of metaplastic hyperplasia in the stomach through an increase in SOX2-expressing undifferentiated epithelial cells. Therefore, inhibition of the NOX1/ROS signaling pathway is a possible strategy for prevention and therapy for gastric cancer development. © 2019, The Author(s).<br />Embargo Period 6 months
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Tae, Su Han ; Voon, Dominic Chih-Cheng ; Oshima, Hiroko ; Nakayama, Mizuho ; Echizen, Kanae ; Sakai, Eri ; Yong, Zachary Wei Ern ; Murakami, Kazuhiro ; Yu, Liang ; Minamoto, Toshinari ; Ock, Chan-Young ; Jenkins, Brendan J. ; Kim, Seong-Jin ; Yang, Han-Kwang ; Oshima, Masanobu ; 大島, 浩子 ; 中山, 瑞穂 ; 村上, 和弘 ; 源, 利成 ; 大島, 正伸
概要:
金沢大学ナノ生命科学研究所<br />Background & Aims: Gastritis is associated with development of stomach cancer, but little is known ab
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out changes in microRNA expression patterns during gastric inflammation. Specific changes in gene expression in epithelial cells are difficult to monitor because of the heterogeneity of the tissue. We investigated epithelial cell-specific changes in microRNA expression during gastric inflammation and gastritis-associated carcinogenesis in mice. Methods: We used laser microdissection to enrich epithelial cells from K19-C2mE transgenic mice, which spontaneously develop gastritis-associated hyperplasia, and Gan mice, which express activated prostaglandin E2 and Wnt in the gastric mucosa and develop gastric tumors. We measured expression of epithelial cell-enriched microRNAs and used bioinformatics analyses to integrate data from different systems to identify inflammation-associated microRNAs. We validated our findings in gastric tissues from mice and evaluated protein functions in gastric cell lines (SNU-719, SNU-601, SNU-638, AGS, and GIF-14) and knockout mice. Organoids were cultured from gastric corpus tissues of wild-type and miR-135b–knockout C57BL/6 mice. We measured levels of microRNAs in pairs of gastric tumors and nontumor mucosa from 28 patients in Japan. Results: We found microRNA 135b (miR-135B) to be the most overexpressed microRNA in gastric tissues from K19-C2mE and Gan mice: levels increased during the early stages of gastritis-associated carcinogenesis. Levels of miR-135B were also increased in gastric tumor tissues from gp130 F/F mice and patients compared with nontumor tissues. In gastric organoids and immortalized cell lines, expression of miR-135B was induced by interleukin 1 signaling. K19-C2mE mice with disruption of Mir-135b developed hyperplastic lesions that were 50% smaller than mice without Mir-135b disruption and had significant reductions in cell proliferation. Expression of miR-135B in gastric cancer cell lines increased their colony formation, migration, and sphere formation. We identified FOXN3 and RECK messenger RNAs (mRNAs) as targets of miR-135B; their knockdown reduced migration of gastric cancer cell lines. Levels of FOXN3 and RECK mRNAs correlated inversely with levels of miR-135B in human gastric tumors and in inflamed mucosa from K19-C2mE mice. Conclusions: We found expression of miR-135B to be up-regulated by interleukin L1 signaling in gastric cancer cells and organoids. miR-135B promotes invasiveness and stem-cell features of gastric cancer cells in culture by reducing FOXN3 and RECK messenger RNAs. Levels of these messenger RNA targets, which encode tumor suppressor, are reduced in human gastric tumors. © 2019 AGA Institute<br />Embargo Period 12 months
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Oshima, Hiroko ; Kok, Sau-Yee ; Nakayama, Mizuho ; Murakami, Kazuhiro ; Voon, Dominic Chih-Cheng ; Kimura, Takashi ; Oshima, Masanobu ; 大島, 浩子 ; 中山, 瑞穂 ; 村上, 和弘 ; 大島, 正伸
概要:
金沢大学ナノ生命科学研究所<br />Signal transducer and activator of transcription 3 (Stat3) has been shown to play a role in intestina
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l regeneration and colitis-associated colon carcinogenesis. However, the role of Stat3 in the Wnt-driven sporadic intestinal tumorigenesis remains poorly understood. We examined the roles of Stat3 in intestinal regeneration and tumorigenesis by organoid culture experiments using Stat3∆IEC mouse-derived intestinal epithelial cells in which Stat3 was disrupted. The regeneration of intestinal mucosa and organoid formation were significantly suppressed by Stat3 disruption, which was compensated by Wnt activation. Furthermore, once organoids were recovered, Stat3 was no longer required for organoid growth. These results indicate that Stat3 and Wnt signaling cooperatively protect epithelial cells at the early phase of intestinal regeneration. In contrast, intestinal tumorigenesis was not suppressed by Stat3 disruption in adenomatous polyposis coli ( Apc) Δ716 and Apc∆716 Tgfbr2∆IEC mice, thus indicating that Stat3 is not required for Wnt activation-driven intestinal tumorigenesis. Mechanistically, Itga5 and Itga6 were down-regulated by Stat3 disruption, and focal adhesion kinase (FAK) activation was also suppressed. Notably, FAK inhibitor suppressed the organoid formation of wild-type epithelial cells. These results indicate that Stat3 is indispensable for the survival of epithelial cells through the activation of integrin signaling and the downstream FAK pathway; however, it is not required for the Wnt signaling-activated normal or tumor epithelial cells.-Oshima, H., Kok, S.-Y., Nakayama, M., Murakami, K., Voon, D. C.-C., Kimura, T., Oshima, M. Stat3 is indispensable for damage-induced crypt regeneration but not for Wnt-driven intestinal tumorigenesis.
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Nakayama, Mizuho ; Oshima, Masanobu ; 中山, 瑞穂 ; 大島, 正伸
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金沢大学ナノ生命科学研究所<br />The accumulation of genetic alterations in driver genes is responsible for the development and malign
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ant progression of colorectal cancer. Comprehensive genome analyses have revealed the driver genes, including APC, KRAS, TGFBR2, and TP53, whose mutations are frequently found in human colorectal cancers. Among them, the p53 mutation is found in ~60% of colorectal cancers, and a majority of mutations are missense-type at ‘hot spots’, suggesting an oncogenic role of mutant p53 by ‘gain-of-function’ mechanisms. Mouse model studies have shown that one of these missense-type mutations, p53 R270H (corresponding to human R273H), causes submucosal invasion of intestinal tumors, while the loss of wild-type p53 has a limited effect on the invasion process. Furthermore, the same mutant p53 promotes metastasis when combined with Kras activation and TGF-β suppression. Importantly, either missense-type p53 mutation or loss of wild-type p53 induces NF-κB activation by a variety of mechanisms, such as increasing promoter accessibility by chromatin remodeling, which may contribute to progression to epithelial–mesenchymal transition. These results indicate that missense-type p53 mutations together with loss of wild-type p53 accelerate the late stage of colorectal cancer progression through the activation of both oncogenic and inflammatory pathways. Accordingly, the suppression of the mutant p53 function via the inhibition of nuclear accumulation is expected to be an effective strategy against malignant progression of colorectal cancer.
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論文
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Du, Yu-Chen ; Oshima, Hiroko ; Jin, Jing-Chun ; Nomura, Masaaki ; Yoshimoto, Tanihiro ; Oshima, Masanobu
概要:
Accumulating evidence suggests that platelet-type 12-lipoxygenase (p12-LOX) plays an important role in tumor development
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. However, how p12-LOX contributes to tumorigenesis is still not understood. The role of p12-LOX was therefore examined in tumor promotion using mouse epidermal JB6 P+ cells that are sensitive to 12-O- tetradecanoylphorbol-13-acetate-induced transformation. The expression of p12-LOX was significantly higher in JB6 P+ cells than in JB6 P- cells that were resistant to transformation, and its expression was further increased by tumor necrosis factor (TNF)-α. Importantly, the inhibition of p 12-LOX in JB6 P+ cells by baicalein, a specific inhibitor or small interfering RNA significantly suppressed TPA-induced transformation. Moreover, treatment with 12(S)-hydroxyeicosatetraenoic acid (HETE), a metabolite of p12-LOX, enhanced TPA-induced neoplastic transformation either in the presence or absence of baicalein. These results indicate that p12-LOX is required for tumor promotion of epidermal cells and that 12(S)-HETE functions as a rate-limiting factor. Notably, treatment with baicalein significantly suppressed the proliferation of JB6 P+ cells when cells were seeded at a low density in a culture plate. Moreover, the cloning efficiency of JB6 P+ cells was dramatically decreased by inhibition of p12-LOX. In contrast, baicalein treatment did not affect the cloning efficiency of most malignant cancer cells. These results indicate that p12-LOX is induced by the inflammatory cytokine TNF-α in the early stage of tumorigenesis, and is required for tumor promotion through enhancing efficient proliferation of a small number of initiated cells. The present results suggest that the p12-LOX pathway may be an effective target of chemoprevention for skin carcinogenesis. © The Author 2008. Published by Oxford University Press. All rights reserved.
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論文
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Oshima, Hiroko ; Taketo, Makoto Mark ; Oshima, Masanobu
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金沢大学がん研究所附属がん幹細胞研究センター <br />Type 2 diabetes mellitus is characterized by insulin resistance of peripheral tissues and d
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ysfunction of pancreatic β-cells. Furthermore, the number of pancreatic β-cells decreases as a secondary effect of advanced type 2 diabetes, although the molecular mechanism has not been elucidated. Recently, it has been shown that hyperglycemic conditions induce the expression of cyclooxygenase-2 in pancreatic islets and increase the downstream product prostaglandin E2 (PGE2). To investigate whether high glucose-induced PGE2 has an adverse effect on pancreatic β-cells, we generated transgenic mice (RIP-C2mE) that express cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in their β-cells using the rat insulin-2 gene promoter (RIP). The homozygous RIP-C2mE (Tg/Tg) mice showed severe hyperglycemia from six weeks of age. Although the heterozygous RIP-C2mE (Tg/-) mice showed normal blood glucose levels throughout their lifetime, this level increased significantly compared with that of wild-type mice when glucose was loaded. The relative number of β-cells to the total islet cell number was reduced to 54 and 14% in the RIP-C2mE (Tg/-) and (Tg/Tg) mice, respectively, whereas that in the wild-type mice was 84%. Importantly, the proliferation rate in the islets of the RIP-C2mE (Tg/Tg) mice at four weeks of age decreased significantly in comparison to that in the wild-type mice. Because β-cells replicate not only during the postnatal period but also in the adult pancreas at a basal level, it is possible that increased PGE2 signaling thus contributes to the reduction of the pancreatic β-cell mass through inhibition of proliferation, thereby aggravating diabetes further. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
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論文
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Oshima, Hiroko ; Matsunaga, Akihiro ; Fujimura, Takashi ; Tsukamoto, Tetsuya ; Taketo, Makoto Mark ; Oshima, Masanobu
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金沢大学がん研究所附属がん幹細胞研究センター <br />Background & Aims: Accumulating evidence indicates that prostaglandin E2 (PGE2), a downstre
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am product of cyclooxygenase 2 (COX-2), plays a key role in gastric tumorigenesis. The Wnt pathway is also suggested to play a causal role in gastric carcinogenesis. However, the molecular mechanism remains poorly understood of how the Wnt and PGE2 pathways contribute to gastric tumorigenesis. To investigate the role of Wnt and PGE2 in gastric cancer, we have generated transgenic mice that activate both pathways and examined their phenotypes. Methods: We constructed K19-Wnt1 transgenic mice expressing Wnt1 in the gastric mucosa using the keratin 19 promoter. We then crossed K19-Wnt1 mice with another transgenic line, K19-C2mE, to obtain K19-Wnt1/C2mE compound transgenic mice. The K19-C2mE mice express COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) in the stomach, showing an increased gastric PGE2 level. We examined the gastric phenotypes of both K19-Wnt1 and K19-Wnt1/C2mE mice. Results: K19-Wnt1 mice had a significant suppression of epithelial differentiation and developed small preneoplastic lesions consisting of undifferentiated epithelial cells with macrophage accumulation. Importantly, additional expression of COX-2 and mPGES-1 converted the preneoplastic lesions in the K19-Wnt1 mice into dysplastic gastric tumors by 20 weeks of age. Notably, we found mucous cell metaplasia in the glandular stomach of the K19-Wnt1/C2mE mice as early as 5 weeks of age, before the dysplastic tumor development. Conclusions: Wnt signaling keeps the gastric progenitor cells undifferentiated. Simultaneous activation of both Wnt and PGE2 pathways causes dysplastic gastric tumors through the metaplasia-carcinoma sequence. © 2006 American Gastroenterological Association (AGA) Institute.
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