Recursos de colección

Hokkaido University Collection of Scholarly and Academic Papers (135.521 recursos)

HUSCAP (Hokkaido University Collection of Scholarly and Academic Papers) contains peer-reviewed journal articles, proceedings, educational resources and any kind of scholarly works of Hokkaido University.

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Mostrando recursos 1 - 20 de 92

  1. Ecrg4 peptide is the ligand of multiple scavenger receptors

    Moriguchi, Tetsuo; Takeda, Shuji; Iwashita, Shinzo; Enomoto, Kei; Sawamura, Tatsuya; Koshimizu, Uichi; Kondo, Toru
    Esophageal cancer-related gene 4 (Ecrg4) encodes a hormone-like peptide that is believed to be involved in a variety of physiological phenomena, including tumour suppression. Recent progress in the study of Ecrg4 has shown that Ecrg4 is a proinflammatory factor and induces the expression of several cytokines and chemokines in macrophages/microglia. However, the detailed molecular mechanisms of Ecrg4 signalling, especially the Ecrg4 receptors, remain poorly understood. Here, using retrovirus-mediated expression cloning, we identified lectin-like oxidised low-density lipoprotein receptor-1 (LOX-1) as a membrane protein that binds amino acid residues 71-132 of Ecrg4 (Ecrg4(71-132)). Moreover, in addition to LOX-1, several scavenger receptors, such...

  2. The paxillin-plectin-EPLIN complex promotes apical elimination of RasV12-transformed cells by modulating HDAC6-regulated tubulin acetylation

    Kasai, Nobuhiro; Kadeer, Ailijiang; Kajita, Mihoko; Saitoh, Sayaka; Ishikawa, Susumu; Maruyama, Takeshi; Fujita, Yasuyuki
    Recent studies have revealed that newly emerging RasV12-transformed cells are often apically extruded from the epithelial layer. During this cancer preventive process, cytoskeletal proteins plectin and Epithelial Protein Lost In Neoplasm (EPLIN) are accumulated in RasV12 cells that are surrounded by normal cells, which positively regulate the apical elimination of transformed cells. However, the downstream regulators of the plectin-EPLIN complex remain to be identified. In this study, we have found that paxillin binds to EPLIN specifically in the mix culture of normal and RasV12-transformed cells. In addition, paxillin is accumulated in RasV12 cells surrounded by normal cells. Paxillin, plectin and...

  3. Lactobacillus helveticus SBT2171 Attenuates Experimental Autoimmune Encephalomyelitis in Mice

    Yamashita, Maya; Ukibe, Ken; Matsubara, Yumi; Hosoya, Tomohiro; Sakai, Fumihiko; Kon, Shigeyuki; Arima, Yasunobu; Murakami, Masaaki; Nakagawa, Hisako; Miyazaki, Tadaaki
    We recently reported that Lactobacillus helveticus SBT2171 (LH2171) inhibited the proliferation and inflammatory cytokine production of primary immune cells in vitro, and alleviated collagen-induced arthritis (CIA) in mice, a model of human rheumatoid arthritis (RA). In this study, we newly investigated whether LH2171 could relieve the severity of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), which is an autoimmune disease, but develop the symptoms by different mechanisms from RA. In MS and EAE, main cause of the disease is the abnormality in CD4+ T cell immunity, whereas in RA and CIA, is that in antibody-mediated immunity....

  4. High co-expression of IL-34 and M-CSF correlates with tumor progression and poor survival in lung cancers

    Baghdadi, Muhammad; Endo, Hiraku; Takano, Atsushi; Ishikawa, Kozo; Kameda, Yosuke; Wada, Haruka; Miyagi, Yohei; Yokose, Tomoyuki; Ito, Hiroyuki; Nakayama, Haruhiko; Daigo, Yataro; Suzuki, Nao; Seino, Ken-ichiro
    Despite recent advances in diagnosis and treatment of lung cancers, the 5-year survival rate remains unsatisfactory, which necessitates the identification of novel factors that associates with disease progression and malignant degree for improving diagnostic and therapeutic strategies. Recent progress in cancer immunology research has unveiled critical roles for colony stimulating factor 1 receptor (CSF1R) in multiple aspects of the tumor microenvironment. CSF1R is expressed on tumor-associated macrophages (TAMS), and mediates important pro-tumorigenic functions. CSF1R also provides critical autocrine signals that promote cancer cell survival and proliferation. Activation of CSF1R can be achieved by two independent ligands; macrophage colony-stimulating factor (M-CSF)...

  5. Tumor endothelial cells with high aldehyde dehydrogenase activity show drug resistance

    Hida, Kyoko; Maishi, Nako; Akiyama, Kosuke; Ohmura-Kakutani, Hitomi; Torii, Chisaho; Ohga, Noritaka; Osawa, Takahiro; Kikuchi, Hiroshi; Morimoto, Hirofumi; Morimoto, Masahiro; Shindoh, Masanobu; Shinohara, Nobuo; Hida, Yasuhiro
    Tumor blood vessels play an important role in tumor progression and metastasis. We previously reported that tumor endothelial cells (TEC) exhibit several altered phenotypes compared with normal endothelial cells (NEC). For example, TEC have chromosomal abnormalities and are resistant to several anticancer drugs. Furthermore, TEC contain stem cell-like populations with high aldehyde dehydrogenase (ALDH) activity (ALDHhigh TEC). ALDHhigh TEC have proangiogenic properties compared with ALDHlow TEC. However, the association between ALDHhigh TEC and drug resistance remains unclear. In the present study, we found that ALDH mRNA expression and activity were higher in both human and mouse TEC than in NEC....

  6. Tumor endothelial cells with high aldehyde dehydrogenase activity show drug resistance

    Hida, Kyoko; Maishi, Nako; Akiyama, Kosuke; Ohmura-Kakutani, Hitomi; Torii, Chisaho; Ohga, Noritaka; Osawa, Takahiro; Kikuchi, Hiroshi; Morimoto, Hirofumi; Morimoto, Masahiro; Shindoh, Masanobu; Shinohara, Nobuo; Hida, Yasuhiro
    Tumor blood vessels play an important role in tumor progression and metastasis. We previously reported that tumor endothelial cells (TEC) exhibit several altered phenotypes compared with normal endothelial cells (NEC). For example, TEC have chromosomal abnormalities and are resistant to several anticancer drugs. Furthermore, TEC contain stem cell-like populations with high aldehyde dehydrogenase (ALDH) activity (ALDHhigh TEC). ALDHhigh TEC have proangiogenic properties compared with ALDHlow TEC. However, the association between ALDHhigh TEC and drug resistance remains unclear. In the present study, we found that ALDH mRNA expression and activity were higher in both human and mouse TEC than in NEC....

  7. Ecrg4 contributes to the anti-glioma immunosurveillance through type-I interferon signaling

    Moriguchi, Tetsuo; Kaneumi, Shun; Takeda, Shuji; Enomoto, Kei; Mishra, Shyam Kumar; Miki, Tetsuro; Koshimizu, Uichi; Kitamura, Hidemitsu; Kondo, Toru
    Esophageal cancer-related gene 4 (Ecrg4), a hormone-like peptide, is thought to be a tumor suppressor, however, little is known about the mechanism of how Ecrg4 suppresses tumorigenesis. Here, we show that the ecrg4 null glioma-initiating cell (GIC) line, which was generated from neural stem cells of ecrg4 knockout (KO) mice, effectively formed tumors in the brains of immunocompetent mice, whereas the transplanted ecrg4 wild type-GIC line GIC(+/+) was frequently eliminated. This was caused by host immune system including adaptive T cell responses, since depletion of CD4+, CD8+, or NK cells by specific antibodies in vivo recovered tumorigenicity of GIC(+/+). We...

  8. Neuropeptide signaling through neurokinin-1 and neurokinin-2 receptors augments antigen presentation by human dendritic cells

    Ohtake, Junya; Kaneumi, Shun; Tanino, Mishie; Kishikawa, Takuto; Terada, Satoshi; Sumida, Kentaro; Masuko, Kazutaka; Ohno, Yosuke; Kita, Toshiyuki; Iwabuchi, Sadahiro; Shinohara, Toshiya; Tanino, Yoshinori; Takemura, Tamiko; Tanaka, Shinya; Kobayashi, Hiroya; Kitamura, Hidemitsu
    Background: Neurotransmitters, including substance P (SP) and neurokinin A (NKA), are widely distributed in both the central and peripheral nervous system and their receptors, neurokinin-1 receptor (NK1R) and neurokinin-2 receptor (NK2R), are expressed on immune cells. However, the role of the NKA-NK2R axis in immune responses relative to the SP-NK1R signaling cascade has not been elucidated. Objective: We sought to examine the effect of neuropeptide signaling through NK1Rand NK2R on antigen presentation by dendritic cells (DCs) and the subsequent activation of effector Th cells. Methods: Expression levels of NK1R, NK2R, HLA-class II and costimulatory molecules of human MoDCs and cytokine...

  9. 1α,25(OH)2D3 downregulates gene expression levels of muscle ubiquitin ligases MAFbx and MuRF1 in human myotubes

    Hayakawa, Naohiko; Fukumura, Junko; Yasuno, Hideyuki; Fujimoto-Ouchi, Kaori; Kitamura, Hidemitsu
    Clinical trials involving in patients with osteoporosis have reported that activated vitamin D3 (1α,25(OH)2D3, calcitriol) can prevent falling by acting on the skeletal muscles. However, pharmacological mechanisms of 1α,25(OH)2D3 with respect to skeletal muscle hypertrophy or atrophy are still poorly understood. Therefore, we examined changes in the expression of several related genes in human myotubes to test whether 1α,25(OH)2D3 influences hypertrophy and atrophy of skeletal muscle. Myotubes treated with 1α,25(OH)2D3 increased interleukin-6 (IL-6) expression and inhibited expression of tumor necrosis factor alpha (TNF-α), whereas the expression of insulin-like growth factor-1 (IGF-1) that is involved in muscle hypertrophy was not affected....

  10. IL-11 induces differentiation of myeloid-derived suppressor cells through activation of STAT3 signalling pathway

    Sumida, Kentaro; Ohno, Yosuke; Ohtake, Junya; Kaneumi, Shun; Kishikawa, Takuto; Takahashi, Norihiko; Taketomi, Akinobu; Kitamura, Hidemitsu
    Myeloid-derived suppressor cells (MDSCs) are immune negative regulators in the tumour microenvironment. Interleukin (IL)-11, a member of IL-6 family cytokines, functions through the unique receptor IL-11 receptor α coupled with the common signal transducer gp130. IL-11-gp130 signalling causes activation of the JAK/STAT3 pathway. IL-11 is highly upregulated in many types of cancers and one of the most important cytokines during tumourigenesis and metastasis. However, the precise effect of IL-11 on differentiation into MDSCs is still unknown. Here, we found that CD11b+CD14+ monocytic MDSCs were generated from peripheral blood mononuclear cells (PBMCs) of healthy donors in the presence of IL-11. IL-11-conditioned...

  11. Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy

    Kitamura, Hidemitsu; Ohno, Yosuke; Toyoshima, Yujiro; Ohtake, Junya; Homma, Shigenori; Kawamura, Hideki; Takahashi, Norihiko; Taketomi, Akinobu
    Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin (IL)-6, a pleiotropic cytokine, is highly produced in the tumor-bearing host. Previous studies have indicated that IL-6 suppresses the antigen presentation ability of dendritic cells (DC) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL-6/STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor-infiltrating CD11b+CD11c+ cells isolated from colorectal cancer tissues showed strong induction of the IL-6 gene, downregulated surface expression of...

  12. Lack of interleukin-6 in the tumor microenvironment augments type-1 immunity and increases the efficacy of cancer immunotherapy

    Ohno, Yosuke; Toyoshima, Yujiro; Yurino, Hideaki; Monma, Norikazu; Xiang, Huihui; Sumida, Kentaro; Kaneumi, Shun; Terada, Satoshi; Hashimoto, Shinichi; Ikeo, Kazuho; Homma, Shigenori; Kawamura, Hideki; Takahashi, Norihiko; Taketomi, Akinobu; Kitamura, Hidemitsu
    Conquering immunosuppression in tumor microenvironments is crucial for effective cancer immunotherapy. It is well known that interleukin (IL)-6, a pleiotropic cytokine, is produced in the tumor-bearing state. In the present study, we investigated the precise effects of IL-6 on antitumor immunity and the subsequent tumorigenesis in tumor-bearing hosts. CT26 cells, a murine colon cancer cell line, were intradermally injected into wild-type and IL-6-deficient mice. As a result, we found that tumor growth was decreased significantly in IL-6-deficient mice compared with wild-type mice and the reduction was abrogated by depletion of CD8+ T cells. We further evaluated the immune status of...

  13. Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes

    Kon, Shunsuke; Ishibashi, Kojiro; Katoh, Hiroto; Kitamoto, Sho; Shirai, Takanobu; Tanaka, Shinya; Kajita, Mihoko; Ishikawa, Susumu; Yamauchi, Hajime; Yako, Yuta; Kamasaki, Tomoko; Matsumoto, Tomohiro; Watanabe, Hirotaka; Egami, Riku; Sasaki, Ayana; Nishikawa, Atsuko; Kameda, Ikumi; Maruyama, Takeshi; Narumi, Rika; Morita, Tomoko; Sasaki, Yoshiteru; Enoki, Ryosuke; Honma, Sato; Imamura, Hiromi; Oshima, Masanobu; Soga, Tomoyoshi; Miyazaki, Jun-ichi; Duchen, Michael R.; Nam, Jin-Min; Onodera, Yasuhito; Yoshioka, Shingo; Kikuta, Junichi; Ishii, Masaru; Imajo, Masamichi; Nishida, Eisuke; Fujioka, Yoichiro; Ohba, Yusuke; Sato, Toshiro; Fujita, Yasuyuki
    Recent studies have revealed that newly emerging transformed cells are often apically extruded from epithelial tissues. During this process, normal epithelial cells can recognize and actively eliminate transformed cells, a process called epithelial defence against cancer (EDAC). Here, we show that mitochondrial membrane potential is diminished in RasV12-transformed cells when they are surrounded by normal cells. In addition, glucose uptake is elevated, leading to higher lactate production. The mitochondrial dysfunction is driven by upregulation of pyruvate dehydrogenase kinase 4 (PDK4), which positively regulates elimination of RasV12-transformed cells. Furthermore, EDAC from the surrounding normal cells, involving filamin, drives the Warburg-effect-like metabolic...

  14. Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit

    Arima, Yasunobu; Ohki, Takuto; Nishikawa, Naoki; Higuchi, Kotaro; Ota, Mitsutoshi; Tanaka, Yuki; Nio-Kobayashi, Junko; Elfeky, Mohamed; Sakai, Ryota; Mori, Yuki; Kawamoto, Tadafumi; Stofkova, Andrea; Sakashita, Yukihiro; Morimoto, Yuji; Kuwatani, Masaki; Iwanaga, Toshihiko; Yoshioka, Yoshichika; Sakamoto, Naoya; Yoshimura, Akihiko; Takiguchi, Mitsuyoshi; Sakoda, Saburo; Prinz, Marco; Kamimura, Daisuke; Murakami, Masaaki
    Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress-gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-of-hypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the...

  15. Chemotherapy-Induced IL34 Enhances Immunosuppression by Tumor-Associated Macrophages and Mediates Survival of Chemoresistant Lung Cancer Cells

    Baghdadi, Muhammad; Wada, Haruka; Nakanishi, Sayaka; Abe, Hirotake; Han, Nanumi; Putra, Wira Eka; Endo, Daisuke; Watari, Hidemichi; Sakuragi, Noriaki; Hida, Yasuhiro; Kaga, Kichizo; Miyagi, Yohei; Yokose, Tomoyuki; Takano, Atsushi; Daigo, Yataro; Seino, Ken-ichiro
    The ability of tumor cells to escape immune destruction and their acquired resistance to chemotherapy are major obstacles to effective cancer therapy. Although immune checkpoint therapies such as anti-PD-1 address these issues in part, clinical responses remain limited to a subpopulation of patients. In this report, we identified IL34 produced by cancer cells as a driver of chemoresistance. In particular, we found that IL34 modulated the functions of tumor-associated macrophages to enhance local immunosuppression and to promote the survival of chemoresistant cancer cells by activating AKT signaling. Targeting IL34 in chemoresistant tumors resulted in a remarkable inhibition of tumor growth...

  16. Chemotherapy-Induced IL34 Enhances Immunosuppression by Tumor-Associated Macrophages and Mediates Survival of Chemoresistant Lung Cancer Cells

    Baghdadi, Muhammad; Wada, Haruka; Nakanishi, Sayaka; Abe, Hirotake; Han, Nanumi; Putra, Wira Eka; Endo, Daisuke; Watari, Hidemichi; Sakuragi, Noriaki; Hida, Yasuhiro; Kaga, Kichizo; Miyagi, Yohei; Yokose, Tomoyuki; Takano, Atsushi; Daigo, Yataro; Seino, Ken-ichiro
    The ability of tumor cells to escape immune destruction and their acquired resistance to chemotherapy are major obstacles to effective cancer therapy. Although immune checkpoint therapies such as anti-PD-1 address these issues in part, clinical responses remain limited to a subpopulation of patients. In this report, we identified IL34 produced by cancer cells as a driver of chemoresistance. In particular, we found that IL34 modulated the functions of tumor-associated macrophages to enhance local immunosuppression and to promote the survival of chemoresistant cancer cells by activating AKT signaling. Targeting IL34 in chemoresistant tumors resulted in a remarkable inhibition of tumor growth...

  17. Chemotherapy-Induced IL34 Enhances Immunosuppression by Tumor-Associated Macrophages and Mediates Survival of Chemoresistant Lung Cancer Cells

    Baghdadi, Muhammad; Wada, Haruka; Nakanishi, Sayaka; Abe, Hirotake; Han, Nanumi; Putra, Wira Eka; Endo, Daisuke; Watari, Hidemichi; Sakuragi, Noriaki; Hida, Yasuhiro; Kaga, Kichizo; Miyagi, Yohei; Yokose, Tomoyuki; Takano, Atsushi; Daigo, Yataro; Seino, Ken-ichiro
    The ability of tumor cells to escape immune destruction and their acquired resistance to chemotherapy are major obstacles to effective cancer therapy. Although immune checkpoint therapies such as anti-PD-1 address these issues in part, clinical responses remain limited to a subpopulation of patients. In this report, we identified IL34 produced by cancer cells as a driver of chemoresistance. In particular, we found that IL34 modulated the functions of tumor-associated macrophages to enhance local immunosuppression and to promote the survival of chemoresistant cancer cells by activating AKT signaling. Targeting IL34 in chemoresistant tumors resulted in a remarkable inhibition of tumor growth...

  18. Rab5-regulated endocytosis plays a crucial role in apical extrusion of transformed cells

    Saitoh, Sayaka; Maruyama, Takeshi; Yako, Yuta; Kajita, Mihoko; Fujioka, Yoichiro; Ohba, Yusuke; Kasai, Nobuhiro; Sugama, Natsu; Kon, Shunsuke; Ishikawa, Susumu; Hayashi, Takashi; Yamazaki, Tomohiro; Tada, Masazumi; Fujita, Yasuyuki
    Newly emerging transformed cells are often eliminated from epithelial tissues. Recent studies have revealed that this cancer-preventive process involves the interaction with the surrounding normal epithelial cells; however, the molecular mechanisms underlying this phenomenon remain largely unknown. In this study, using mammalian cell culture and zebrafish embryo systems, we have elucidated the functional involvement of endocytosis in the elimination of RasV12-transformed cells. First, we show that Rab5, a crucial regulator of endocytosis, is accumulated in RasV12-transformed cells that are surrounded by normal epithelial cells, which is accompanied by up-regulation of clathrin-dependent endocytosis. Addition of chlorpromazine or coexpression of a dominant-negative...

  19. Rab5-regulated endocytosis plays a crucial role in apical extrusion of transformed cells

    Saitoh, Sayaka; Maruyama, Takeshi; Yako, Yuta; Kajita, Mihoko; Fujioka, Yoichiro; Ohba, Yusuke; Kasai, Nobuhiro; Sugama, Natsu; Kon, Shunsuke; Ishikawa, Susumu; Hayashi, Takashi; Yamazaki, Tomohiro; Tada, Masazumi; Fujita, Yasuyuki
    Newly emerging transformed cells are often eliminated from epithelial tissues. Recent studies have revealed that this cancer-preventive process involves the interaction with the surrounding normal epithelial cells; however, the molecular mechanisms underlying this phenomenon remain largely unknown. In this study, using mammalian cell culture and zebrafish embryo systems, we have elucidated the functional involvement of endocytosis in the elimination of RasV12-transformed cells. First, we show that Rab5, a crucial regulator of endocytosis, is accumulated in RasV12-transformed cells that are surrounded by normal epithelial cells, which is accompanied by up-regulation of clathrin-dependent endocytosis. Addition of chlorpromazine or coexpression of a dominant-negative...

  20. ROS enhance angiogenic properties via regulation of NRF2 in tumor endothelial cells

    Hojo, Takayuki; Maishi, Nako; Towfik, Alam Mohammad; Akiyama, Kosuke; Ohga, Noritaka; Shindoh, Masanobu; Hida, Yasuhiro; Minowa, Kazuyuki; Fujisawa, Toshiaki; Hida, Kyoko
    Reactive oxygen species (ROS) are unstable molecules that activate oxidative stress. Because of the insufficient blood flow in tumors, the tumor microenvironment is often exposed to hypoxic condition and nutrient deprivation, which induces ROS accumulation. We isolated tumor endothelial cells (TECs) and found that they have various abnormalities, although the underlying mechanisms are not fully understood. Here we showed that ROS were accumulated in tumor blood vessels and ROS enhanced TEC migration with upregulation of several angiogenesis related gene expressions. It was also demonstrated that these genes were upregulated by regulation of Nuclear factor erythroid 2-related factor 2 (NRF2). Among...

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