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論文
Yang, Xiaoqin ; Lu, Peirong ; Fujii, Chifumi ; Nakamoto, Yasunari ; Gao, Ji Liang ; Kaneko, Shuichi ; Murphy, Philip M. ; Mukaida, Naofumi
出版情報: International Journal of Cancer.  118  pp.1869-1876,  2006-04-15.  Wiley-Liss
URL: http://hdl.handle.net/2297/6666
概要: 金沢大学がん研究所がん病態制御<br />We previously observed that a chemokine, macrophage inflammatory protein-1 α/CCL3, and its receptor, CCR1, were aberrantly expressed in human hepatocellular carcinoma (HCC) tissues. Here, we show that CCL3 and CCR1 are also expressed in 2 different models of this cancer; N-nitrosodiethylamine (DEN)-induced HCC and HCC induced by hepatitis B virus surface (HBs) antigen-primed splenocyte transfer to myelo-ablated syngeneic HBs antigen transgenic mice. At 10 months after DEN treatment, foci number and sizes were remarkably reduced in CCR1- and CCL3-deficient mice, compared with those of wild-type (WT) mice, although tumor incidence were marginally, but significantly, higher in CCR1- and CCL3-deficient mice than in WT mice. Of note is that tumor angiogenesis was also markedly diminished in CCL3- and CCR1-deficient mice, with a concomitant reduction in the number of intratumoral Kupffer cells, a rich source of growth factors and matrix metalloproteinases (MMPs). Among growth factors and MMPs that we examined, only MMP9 and MMP13 gene expression was augmented progressively in liver of WT mice after DEN treatment. Moreover, MMP9, but not MMP13, gene expression was attenuated in CCR1- and CCL3-deficient mice, compared with that of WT mice. Furthermore, MMP9 was expressed mainly by mononuclear cells but not hepatoma cells, and MMP9-expressing cell numbers were decreased in CCR1- or CCL3-deficient mice, compared with WT mice. These observations suggest the contribution of the CCR1-CCL3 axis to HCC progression. © 2005 Wiley-Liss, Inc. 続きを見る
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Fujii, Chifumi ; Nakamoto, Yasunari ; Lu, Peirong ; Tsuneyama, Koichi ; Popivanova, Boryana K. ; Kaneko, Shuichi ; Mukaida, Naofumi
出版情報: International Journal of Cancer.  114  pp.209-218,  2005-03-20.  Wiley-Liss
URL: http://hdl.handle.net/2297/6664
概要: 金沢大学がん研究所がん病態制御<br />Most cases of human hepatocellular carcinoma develop after persistent chronic infection with human hepatitis B virus or hepatitis C virus, and host responses are presumed to have major roles in this process. To recapitulate this process, we have developed the mouse model of hepatocellular carcinoma using hepatitis B virus surface antigen transgenic mice. To identify the genes associated with hepatocarcinogenesis in this model, we compared the gene expression patterns between pre-malignant lesions surrounded by hepatocellular carcinoma tissues and control liver tissues by using a fluorescent differential display analysis. Among the genes that were expressed differentially in the pre-malignant lesions, we focused on Pim-3, a member of a proto-oncogene Pim family, because its contribution to hepatocarcinogenesis remains unknown. Moreover, the unavailability of the nucleotide sequence of full-length human Pim-3 cDNA prompted us to clone it from the cDNA library constructed from a human hepatoma cell line, HepG2. The obtained 2,392 bp human Pim-3 cDNA encodes a predicted open reading frame consisting of 326 amino acids. Pim-3 mRNA was selectively expressed in human hepatoma cell lines, but not in normal liver tissues. Moreover, Pim-3 protein was detected in human hepatocellular carcinoma tissues and cell lines but not in normal hepatocytes. Furthermore, cell proliferation was attenuated and apoptosis was enhanced in human hepatoma cell lines by the ablation of Pim-3 gene with RNA interference. These observations suggest that aberrantly expressed Pim-3 can cause autonomous cell proliferation or prevent apoptosis in hepatoma cell lines. © 2004 Wiley-Liss, Inc. 続きを見る
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論文
Yang, Xiaoqin ; Lu, Peirong ; Ishida, Yuko ; Kuziel, William A. ; Fujii, Chifumi ; Mukaida, Naofumi
出版情報: International Journal of Cancer.  118  pp.335-345,  2006-11-15.  Wiley-Liss
URL: http://hdl.handle.net/2297/6665
概要: 金沢大学がん研究所がん病態制御<br />The liver parenchyma is populated by hepatocytes and several nonparenchymal cell types, inclu ding Kupffer cells and hepatic stellate cells. Both Kupffer cells and hepatic stellate cells are responsive to the chemokine CCL2, but the precise roles of CCL2 and these cells in liver tumor formation remain undefined. Hence, we investigated the effects of the lack of the major CCL2 receptor, CCR2, on liver tumor formation induced by intraportal injection of the murine colon adenocarcinoma cell line, colon 26. Wild-type mice showed macroscopic tumor foci in the liver 10 days after injection of colon 26 cells. After 10 days, CCL2 proteins were detected predominantly in tumor cells, coincident with increased intratumoral macrophage and hepatic stellate cell numbers. Although tumor formation occurred at similar rates in wild-type and CCR2-deficient mice up to 10 days after tumor cell injection, the number and size of tumor foci were significantly attenuated in CCR2-deficient mice relative to wild-type mice thereafter. Moreover, neovascularization and matrix metalloproteinase 2 expression were diminished in CCR2-deficient mice with a concomitant reduction in the accumulation of macrophages and hepatic stellate cells. Furthermore, matrix metalloproteinase 2 was detected predominantly in hepatic stellate cells but not in macrophages. We provided the first definitive evidence that the absence of CCR2-mediated signals can reduce the trafficking of hepatic stellate cells, a main source of matrix metalloproteinase 2, and consequently can diminish neovascularization during liver tumor formation. © 2005 Wiley-Liss, Inc. 続きを見る
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Popivanova, Boryana K. ; Kitamura, Kazuya ; Wu, Yu ; Kondo, Toshikazu ; Kagaya, Takashi ; Kaneko, Shuichi ; Oshima, Masanobu ; Fujii, Chifumi ; Mukaida, Naofumi
出版情報: Journal of Clinical Investigation.  118  pp.560-570,  2008-02-01.  American Society for Clinical Investigation
URL: http://hdl.handle.net/2297/9041
概要: 金沢大学がん研究所がん病態制御<br />The inflammatory bowel disease ulcerative colitis (UC) frequently progresses to colon cancer. To understand the mechanisms by which UC patients develop colon carcinomas, we used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. We found that treating WT mice with AOM and DSS increased TNF-α expression and the number of infiltrating leukocytes expressing its major receptor, p55 (TNF-Rp55), in the lamina propria and submucosal regions of the colon. This was followed by the development of multiple colonic tumors. Mice lacking TNF-Rp55 and treated with AOM and DSS showed reduced mucosal damage, reduced infiltration of macrophages and neutrophils, and attenuated subsequent tumor formation. WT mice transplanted with TNF-Rp55-deficient bone marrow also developed significantly fewer tumors after AOM and DSS treatment than either WT mice or TNF-Rp55-deficient mice transplanted with WT bone marrow. Furthermore, administration of etanercept, a specific antagonist of TNF-α, to WT mice after treatment with AOM and DSS markedly reduced the number and size of tumors and reduced colonic infiltration by neutrophils and macrophages. These observations identify TNF-α as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-α may be useful in treating colon cancer in individuals with UC. 続きを見る
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論文
Lu, Peirong ; Li, Longbiao ; Wu, Yu Ying ; Mukaida, Naofumi ; Zhang, Xueguang Guang
出版情報: Molecular Vision.  14  pp.1614-1622,  2008-09-01.  Molecular Vision
URL: http://hdl.handle.net/2297/19634
概要: 金沢大学がん研究所がん病態制御<br />Purpose: To evaluate the roles of CCL3 and its specific chemokine receptors, CCR1 and CCR5, i n alkali-induced corneal neovascularization (CNV). Methods: Chemical denudation of corneal and limbal epithelium was performed on wild-type (WT) BALB/c mice and CCL3-, CCR1-, and CCR5-deficienct (knockout [KO]) counterparts. Two weeks after injury CNV was quantified by immunostaining with anti-CD31. Angiogenic factor expression and leukocyte accumulation in the early phase after injury were quantified by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical analysis, respectively. Results: Alkali injury augmented the intraocular mRNA expression of CCL3 and its receptors, CCR1 and CCR5, together with a transient infiltration of F4/80 positive macrophages and Gr-1 positive neutrophils. Compared with WT mice, CCL3-KO and CCR5-KO mice but not CCR1-KO mice exhibited reduced CNV two weeks after injury both macroscopically and microscopically as evidenced by CD31 positive areas. Concomitantly, the infiltration of F4/80 positive macrophages but not Gr-1 positive neutrophils was significantly attenuated in CCL3-KO mice compared with WT mice. Intracorneal infiltration of CCR5 expressing cells was significantly impaired in CCL3-KO mice compared with WT mice. Alkali injury induced a massive increase in the intraocular mRNA expression of a potent angiogenic factor, vascular endothelial growth factor (VEGF), in WT mice whereas these increments were severely retarded in CCL3-KO mice. Moreover, CCL3 enhanced VEGF expression by murine peritoneal macrophages at both the mRNA and the protein level. Furthermore, topical CCL3 application restored CNV, which was macroscopically and microscopically reduced in CCL3-KO mice after two weeks to levels similar to those found in WT mice. Conclusions: In alkali-induced CNV, CCL3 induced macrophages to infiltrate and produce VEGF by binding to CCR5 but not to CCR1 and eventually promoted angiogenesis. © 2008 Molecular Vision. 続きを見る
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Popivanova, Boryana Konstantinova ; Kostadinova, Feodora Ivanova ; Furuichi, Kengo ; Shamekh, Mohamed M. ; Kondo, Toshikazu ; Wada, Takashi ; Egashira, Kensuke ; Mukaida, Naofumi
出版情報: Cancer Research.  69  pp.7884-7892,  2009-10-01.  American Association for Cancer Research
URL: http://hdl.handle.net/2297/19814
概要: 金沢大学がん研究所がん病態制御<br />Accumulating evidence indicates the crucial contribution of chronic inflammation to various t ypes of carcinogenesis, including colon carcinoma associated with ulcerative colitis and asbestosis-induced malignant mesothelioma. Ulcerative colitis-associated colon carcinogenesis can be recapitulated in mice by azoxymethane administration followed by repetitive dextran sulfate sodium ingestion. In the course of this carcinogenesis process, the expression of a macrophage-tropic chemokine, CCL2, was enhanced together with intracolonic massive infiltration of macrophages, which were a major source of cyclooxygenase (COX)-2, a crucial mediator of colon carcinogenesis. Mice deficient in CCL2-specific receptor, CCR2, exhibited less macrophage infiltration and lower tumor numbers with attenuated COX-2 expression. Moreover, CCL2 antagonists decreased intracolonic macrophage infiltration and COX-2 expression, attenuated neovascularization, and eventually reduced the numbers and size of colon tumors, even when given after multiple colon tumors have developed. These observations identify CCL2 as a crucial mediator of the initiation and progression of chronic colitis-associated colon carcinogenesis and suggest that targeting CCL2 may be useful in treating colon cancers, particularly those associated with chronic inflammation. ©2009 American Association for Cancer Research. 続きを見る
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Wu, Yu ; Wang, Ying Ying ; Nakamoto, Yasunari ; Li, Ying-Yi ; Baba, Tomohisa ; Kaneko, Shuichi ; Fujii, Chifumi ; Mukaida, Naofumi
出版情報: Oncogene.  29  pp.2228-2237,  2010-04-01.  Nature Publishing Group
URL: http://hdl.handle.net/2297/24282
概要: 金沢大学がん研究所<br />Pim-3, a proto-oncogene with serine/threonine kinase activity, was enhanced in hepatocellular carci noma (HCC) tissues. To address the roles of Pim-3 in HCC development, we prepared transgenic mice that express human Pim-3 selectively in liver. The mice were born at a Mendelian ratio, were fertile and did not exhibit any apparent pathological changes in the liver until 1 year after birth. Pim-3-transgenic mouse-derived hepatocytes exhibited accelerated cell cycle progression. The administration of a potent hepatocarcinogen, diethylnitrosamine (DEN), induced accelerated proliferation of liver cells in Pim-3 transgenic mice in the early phase, compared with that observed for wild-type mice. Treatment with DEN induced lipid droplet accumulation with increased proliferating cell numbers 6 months after the treatment. Eventually, wild-type mice developed HCC with a frequency of 40% until 10 month after the treatment. Lipid accumulation was accelerated in Pim-3 transgenic mice with higher proliferating cell numbers, compared with that observed for wild-type mice. Pim-3 transgenic mice developed HCC with a higher incidence (80%) and a heavier burden, together with enhanced intratumoral CD31-positive vascular areas, compared with that observed for wild-type mice. These observations indicate that Pim-3 alone cannot cause, but can accelerate HCC development when induced by a hepatocarcinogen, such as DEN. © 2010 Macmillan Publishers Limited. All rights reserved. 続きを見る
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Popivanova, Boryana Konstantinova ; Li, Ying-Yi ; Zheng, Huachuan ; Omura, Kenji ; Fujii, Chifumi ; Tsuneyama, Koichi ; Mukaida, Naofumi
出版情報: Cancer Science.  98  pp.321-328,  2007-03-01.  Japanese Cancer Association / Wiley-Blackwell
URL: http://hdl.handle.net/2297/6755
概要: 金沢大学がん研究所がん病態制御<br />We previously observed that Pim-3 with serine/threonine kinase activity, was aberrantly expre ssed in malignant lesions of endoderm-derived organs, liver and pancreas. Because Pim-3 protein was not detected in normal colon mucosal tissues, we evaluated Pim-3 expression in malignant lesions of human colon, another endoderm-derived organ. Pim-3 was detected immunohistochemically in well-differentiated (43/68 cases) and moderately differentiated (23/41 cases) but not poorly differentiated colon adenocarcinomas (0/5 cases). Moreover, Pim-3 proteins were detected in adenoma (35/40 cases) and normal mucosa (26/111 cases), which are adjacent to adenocarcinoma. Pim-3 was constitutively expressed in SW480 cells and the transfection with Pim-3 short hairpin RNA promoted apoptosis. In the same cell line, a pro-apoptotic molecule, Bad, was phosphorylated at Ser112 and Ser 136 sites of phosphorylation that are representative of its inactive form. Ser112 but not Ser136 phosphorylation in this cell line was abrogated by Pim-3 knockdown. Furthermore, in human colon cancer tissues, Pim-3 co-localized with Bad in all cases (9/9) and with phospho-Ser112 Bad in most cases (6/9). These observations suggest that Pim-3 can inactivate Bad by phosphorylating its Ser112 in human colon cancer cells and thus may prevent apoptosis and promote progression of human colon cancer. © 2007 Japanese Cancer Association. 続きを見る
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論文
Mukaida, Naofumi ; Wang, Ying-Ying ; Li, Ying-Yi
出版情報: Cancer Science.  102  pp.1437-1442,  2011-08-01.  Japanese Cancer Association = 日本癌学会 / Wiley-Blackwell
URL: http://hdl.handle.net/2297/29195
概要: Pim-3 is a member of the Provirus integrating site Moloney murine leukemia virus (Pim) family, which belongs to the Ca2+/calmodulin-dependent protein kinase (CaMK) group and exhibits serine/threonine kinase activity. Similar to other members of the Pim family (i.e. Pim-1 and Pim-2), Pim-3 can prevent apoptosis and promote cell survival and protein translation, thereby enhancing cell proliferation of normal and malignant cells. Pim-3 is expressed in vital organs, such as the heart, lung, and brain. However, minimal phenotypic changes in Pim-3-deficient mice suggest that Pim-3 may be physiologically dispensable. Pim-3 expression is enhanced in several cancer tissues, particularly those of endoderm-derived organs, including the liver, pancreas, colon, and stomach. The development of hepatocellular carcinoma is accelerated in mice expressing the Pim-3 gene selectively in the liver only when these mice are treated with a hepatocarcinogen, indicating that Pim-3 can act as a promoter but not as an initiator. Moreover, inhibition of Pim-3 expression can retard in vitro cell proliferation of hepatocellular, pancreatic, and colon carcinoma cell lines by promoting cell apoptosis. Furthermore, a Pim-3 kinase inhibitor has been reported to inhibit cell proliferation in an in vivo xenograft model using a human pancreatic cancer cell line without inducing any major adverse effects. Thus, Pim-3 kinase may be a candidate molecule for the development of molecular targeting drugs against cancer. © 2011 Japanese Cancer Association. 続きを見る
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Mukaida, Naofumi ; Sasakki, So-ichiro ; Popivanova, Boryana K.
出版情報: Cancers.  3  pp.2811-2826,  2011-09-01.  MDPI
URL: http://hdl.handle.net/2297/29461
概要: The connection between inflammation and tumorigenesis has been well established, based on a great deal of supporting evidence obtained from epidemiological, pharmacological, and genetic studies. One representative example is inflammatory bowel disease, because it is an important risk factor for the development of colon cancer. Moreover, intratumoral infiltration of inflammatory cells suggests the involvement of inflammatory responses also in other forms of sporadic as well as heritable colon cancer. Inflammatory responses and tumorigenesis activate similar sets of transcription factors such as NF-κB, Stat3, and hypoxia inducible factor and eventually enhances the expression of inflammatory cytokines including tumor necrosis factor (TNF) and chemokines. The expression of TNF and chemokines is aberrantly expressed in a mouse model of colitis-associated carcinogenesis as well as in inflammatory bowel disease and colon cancer in humans. Here, after summarizing the presumed actions of TNF and chemokines in tumor biology, we will discuss the potential roles of TNF and chemokines in chronic inflammation-associated colon cancer in mice. © 2011 by the authors; licensee MDPI, Basel, Switzerland. 続きを見る