Onodera Yasuhito
| Faculty of Medicine Global Center for BiomedicalScience and Engineering | Associate Professor |
Last Updated :2025/06/07
■Researcher basic information
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J-Global ID
Educational Organization
- Bachelor's degree program, Departments of Medicine, School of Medicine
- Master's degree program, Graduate School of Biomedical Science and Engineering
- Doctoral (PhD) degree program, Graduate School of Biomedical Science and Engineering
■Career
Career
■Research activity information
Papers
- Phosphorylation of annexin A2 at serine 25 is required for endothelin-1 stimulated cell proliferation and AKT activation in melanoma cells
Yuichi Mazaki, Takahiro Horinouchi, Yasuhito Onodera, Jin-Min Nam
Biochemical and Biophysical Research Communications, 743, 151168, 151168, Elsevier BV, Jan. 2025
Scientific journal - Development of a Myogenin minimal promoter-based system for visualizing the degree of myogenic differentiation
Yoshizuki Fumoto, Shingo Takada, Yasuhito Onodera, Shigetsugu Hatakeyama, Tsukasa Oikawa
Biochemical and Biophysical Research Communications, 741, 151091, 151091, Elsevier BV, Dec. 2024
Scientific journal - MitoNEET reduces the mitochondrial oxidative phosphorylation during epithelial-mesenchymal transition
Haruka Handa, Yasuhito Onodera, Tsukasa Oikawa, Shingo Takada, Koji Ueda, Daiki Setoyama, Takashi Yokota, Miwako Yamasaki, Masahiko Watanabe, Yoshizuki Fumoto, Ari Hashimoto, Soichiro Hata, Masaaki Murakami, Hisataka Sabe
Cold Spring Harbor Laboratory, 29 Jul. 2024
Mitochondrial functions range from catabolic to anabolic, which are tightly coordinated to meet cellular demands for proliferation and motility. MitoNEET is a mitochondrial outer membrane protein with a CDGSH domain and is involved in mitochondrial function. Epithelial-to-mesenchymal transition (EMT) is the process in which cells lose their epithelial characteristics and acquire mesenchymal traits, such as motility, which is a vital step for organism development and wound-healing. Cellular motility is associated with high ATP consumption owing to lamellipodia formation, which is supported by upregulated oxidative phosphorylation (OXPHOS) capacity. However, how mitoNEET is involved in the regulation of OXPHOS capacity and subsequent cellular motility remains unclear. Here we show that loss of mitoNEET regulation during EMT impairs both OXPHOS enhancement and cell motility in non-transformed NMuMG mouse mammary gland epithelial cells. We found that mitoNEET is downregulated during EMT, and that the aberrant expression of mitoNEET abolishes the upregulation of OXPHOS, leading to the inhibition of cell motility. Furthermore, we found that mitoNEET topology may be crucial for the regulation of the mitochondrial electron transfer chain, suggesting an additional regulatory pathway for OXPHOS capacity. Our results demonstrate that mitochondrial OXPHOS capacity during EMT is partly regulated by the dynamics of the outer membrane protein. We believe that our findings are the first step towards understanding the mechanisms by which mitochondrial outer membrane protein topology affects organelle functions - p53 ensures the normal behavior and modification of G1/S-specific histone H3.1 in the nucleus
Tsukasa Oikawa, Junya Hasegawa, Haruka Handa, Naomi Ohnishi, Yasuhito Onodera, Ari Hashimoto, Junko Sasaki, Takehiko Sasaki, Koji Ueda, Hisataka Sabe
Life Science Alliance, 7, 9, e202402835, Jun. 2024, [Peer-reviewed]
English, Scientific journal - The lipid-binding D4 domain of perfringolysin O facilitates the active loading of exogenous cargo into extracellular vesicles.
Abayomi Emmanuel Opadele, Soichiro Nishioka, Ping-Hsiu Wu, Quynh-Thu Le, Hiroki Shirato, Jin-Min Nam, Yasuhito Onodera
FEBS letters, 598, 4, 446, 456, Feb. 2024, [International Magazine]
English, Scientific journal, Whereas extracellular vesicles (EVs) have been engineered for cargo loading, innovative strategies for it can still be developed. Here, we describe domain 4 (D4), a cholesterol-binding domain derived from perfringolysin O, as a viable candidate for EV cargo loading. D4 and its mutants localized to the plasma membrane and the membranes of different vesicular structures in the cytoplasm, and facilitate the transport of proteins of interest (POIs) into EVs. D4-EVs were internalized by recipient cells analogous to EVs engineered with CD9. Intracellular cargo discharge from D4-EVs was successfully detected with the assistance of vesicular stomatitis virus glycoprotein. This study presents a novel strategy for recruiting POIs into EVs via a lipid-binding domain that ensures content release in recipient cells. - LRRK2 is involved in the chemotaxis of neutrophils and differentiated HL-60 cells, and the inhibition of LRRK2 kinase activity increases fMLP-induced chemotactic activity.
Yuichi Mazaki, Haruka Handa, Yoshizuki Fumoto, Takahiro Horinouchi, Yasuhito Onodera
Cell communication and signaling : CCS, 21, 1, 300, 300, 30 Oct. 2023, [International Magazine]
English, Scientific journal, BACKGROUND: Neutrophils depend heavily on glycolysis for energy production under normal conditions. In contrast, neutrophils require energy supplied by mitochondrial oxidative phosphorylation (OXPHOS) during chemotaxis. However, the mechanism by which the energy supply changes from glycolysis to OXPHOS remains unknown. Leucine-rich repeat kinase 2 (LRRK2) is partially present in the outer mitochondrial membrane fraction. Lrrk2-deficient cells show mitochondrial fragmentation and reduced OXPHOS activity. We have previously reported that mitofusin (MFN) 2 is involved in chemotaxis and OXPHOS activation upon chemoattractant N-formyl-Met-Leu-Phe (fMLP) stimulation in differentiated HL-60 (dHL-60) cells. It has been previously reported that LRRK2 binds to MFN2 and partially colocalizes with MFN2 at the mitochondrial membranes. This study investigated the involvement of LRRK2 in chemotaxis and MFN2 activation in neutrophils and dHL-60 cells. METHODS: Lrrk2 knockout neutrophils and Lrrk2 knockdown dHL-60 cells were used to examine the possible involvement of LRRK2 in chemotaxis. Lrrk2 knockdown dHL-60 cells were used a tetracycline-inducible small hairpin RNA (shRNA) system to minimize the effects of LRRK2 knockdown during cell culture. The relationship between LRRK2 and MFN2 was investigated by measuring the GTP-binding activity of MFN2 in Lrrk2 knockdown dHL-60 cells. The effects of LRRK2 kinase activity on chemotaxis were examined using the LRRK2 kinase inhibitor MLi-2. RESULTS: fMLP-induced chemotactic activity was reduced in Lrrk2 knockout neutrophils in vitro and in vivo. Lrrk2 knockdown in dHL-60 cells expressing Lrrk2 shRNA also reduced fMLP-induced chemotactic activity. Lrrk2 knockdown dHL-60 cells showed reduced OXPHOS activity and suppressed mitochondrial morphological change, similar to Mfn2 knockdown dHL-60 cells. The amount of LRRK2 in the mitochondrial fraction and the GTP-binding activity of MFN2 increased upon fMLP stimulation, and the MFN2 GTP-binding activity was suppressed in Lrrk2 knockdown dHL-60 cells. Furthermore, the kinase activity of LRRK2 and Ser935 phosphorylation of LRRK2 were reduced upon fMLP stimulation, and LRRK2 kinase inhibition by MLi-2 increased the migration to fMLP. CONCLUSIONS: LRRK2 is involved in neutrophil chemotaxis and the GTP-binding activity of MFN2 upon fMLP stimulation. On the other hand, the kinase activity of LRRK2 shows a negative regulatory effect on fMLP-induced chemotactic activity in dHL-60 cells. Video Abstract. - p53 secures the normal behavior of H3.1 histone in the nucleus by regulating nuclear phosphatidic acid and EZH2 during the G1/S phase
Tsukasa Oikawa, Junya Hasegawa, Haruka Handa, Naomi Ohnishi, Yasuhito Onodera, Ari Hashimoto, Junko Sasaki, Takehiko Sasaki, Koji Ueda, Hisataka Sabe
Cold Spring Harbor Laboratory, 28 Jun. 2023
Abstract
Histones are key molecules of epigenetic regulation and inheritance, and are thought to be chaperoned and transported into the nucleus appropriately prior to being integrated into nucleosomes. H3.1 histone is predominantly synthesized and enters the nucleus during the G1/S phase of the cell cycle, as a new component of duplicating nucleosomes. Here we found that p53 is necessary to secure the normal behavior and modification of H3.1 in the nucleus during the G1/S phase, in which p53 increases C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1) levels and decreases enhancer of zeste homolog 2 (EZH2) levels in the H3.1 interactome. In the absence of p53, H3.1 molecules tended to be tethered at or near the nuclear envelope (NE), where they were predominantly trimethylated at lysine 27 (H3K27me3) by EZH2, without forming nucleosomes. This accumulation was likely caused by the high affinity of H3.1 towards phosphatidic acid (PA). p53 reduced nuclear PA levels by increasing levels of CTDNEP1, which activates lipin to convert PA into diacylglycerol. Induction of theTMEM255Agene by p53 linked p53 with CTDNEP1, in which TMEM255A stabilized CTDNEP1. We moreover found that the cytosolic H3 chaperone HSC70 attenuates the H3.1-PA interaction, and our molecular imaging analyses suggested that H3.1 molecules may be anchored around the NE after their nuclear entry. Our results expand our knowledge of p53 function in regulation of the nuclear behavior of H3.1 during the G1/S phase, in which p53 may primarily target nuclear PA and EZH2. - p53 controls the nuclear entry and epigenetic modification of H3.1 by downregulating nuclear phosphatidic acid
Tsukasa Oikawa, Junya Hasegawa, Naomi Ohnishi, Yasuhito Onodera, Ari Hashimoto, Junko Sasaki, Takehiko Sasaki, Koji Ueda, Hisataka Sabe
28 Jun. 2023 - Angiogenic inhibitor pre-administration improves the therapeutic effects of immunotherapy.
Mineyoshi Sato, Nako Maishi, Yasuhiro Hida, Aya Yanagawa-Matsuda, Mohammad Towfik Alam, Jun Sakakibara-Konishi, Jin-Min Nam, Yasuhito Onodera, Satoshi Konno, Kyoko Hida
Cancer medicine, 19 Feb. 2023, [International Magazine]
English, Scientific journal, In lung cancer, immune checkpoint inhibitors (ICIs) are often inadequate for tumor growth inhibition. Angiogenic inhibitors (AIs) are required to normalize tumor vasculature for improved immune cell infiltration. However, in clinical practice, ICIs and cytotoxic antineoplastic agents are simultaneously administered with an AI when tumor vessels are abnormal. Therefore, we examined the effects of pre-administering an AI for lung cancer immunotherapy in a mouse lung cancer model. Using DC101, an anti-vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody, a murine subcutaneous Lewis lung cancer (LLC) model was used to determine the timing of vascular normalization. Microvessel density (MVD), pericyte coverage, tissue hypoxia, and CD8-positive cell infiltration were analyzed. The effects of an ICI and paclitaxel after DC101 pre-administration were investigated. On Day 3, increased pericyte coverage and alleviated tumor hypoxia represented the highest vascular normalization. CD8+ T-cell infiltration was also highest on Day 3. When combined with an ICI, DC101 pre-administration significantly reduced PD-L1 expression. When combined with an ICI and paclitaxel, only DC101 pre-administration significantly inhibited tumor growth, but simultaneous administration did not. AI pre-administration, and not simultaneous administration, may increase the therapeutic effects of ICIs due to improved immune cell infiltration. - The oral bacterium Streptococcus mutans promotes tumor metastasis by inducing vascular inflammation
Li Yu, Nako Maishi, Erika Akahori, Akira Hasebe, Ryo Takeda, Aya Yanagawa Matsuda, Yasuhiro Hida, Jin‐Min Nam, Yasuhito Onodera, Yoshimasa Kitagawa, Kyoko Hida
Cancer Science, Wiley, 23 Aug. 2022, [Peer-reviewed]
Scientific journal - The oxidized‐LDL/LOX‐1 axis in tumor endothelial cells enhances metastasis by recruiting neutrophils and cancer cells
Takuya Tsumita, Nako Maishi, Dorcas Akuba‐Muhyia Annan, Mohammad Alam Towfik, Aya Matsuda, Yasuhito Onodera, Jin‐Min Nam, Yasuhiro Hida, Kyoko Hida
International Journal of Cancer, Wiley, 09 Jun. 2022
Scientific journal - A Consistent Protocol Reveals a Large Heterogeneity in the Biological Effectiveness of Proton and Carbon-Ion Beams for Various Sarcoma and Normal-Tissue-Derived Cell Lines.
Masashi Yagi, Yutaka Takahashi, Kazumasa Minami, Taeko Matsuura, Jin-Min Nam, Yasuhito Onodera, Takashi Akagi, Takuya Maeda, Tomoaki Okimoto, Hiroki Shirato, Kazuhiko Ogawa
Cancers, 14, 8, 15 Apr. 2022, [International Magazine]
English, Scientific journal, This study investigated variations in the relative biological effectiveness (RBE) values among various sarcoma and normal-tissue-derived cell lines (normal cell line) in proton beam and carbon-ion irradiations. We used a consistent protocol that specified the timing of irradiation after plating cells and detailed the colony formation assay. We examined the cell type dependence of RBE for proton beam and carbon-ion irradiations using four human sarcoma cell lines (MG63 osteosarcoma, HT1080 fibrosarcoma, SW872 liposarcoma, and SW1353 chondrosarcoma) and three normal cell lines (HDF human dermal fibroblast, hTERT-HME1 mammary gland, and NuLi-1 bronchus epithelium). The cells were irradiated with gamma rays, proton beams at the center of the spread-out Bragg peak, or carbon-ion beams at 54.4 keV/μm linear energy transfer. In all sarcoma and normal cell lines, the average RBE values in proton beam and carbon-ion irradiations were 1.08 ± 0.11 and 2.08 ± 0.36, which were consistent with the values of 1.1 and 2.13 used in current treatment planning systems, respectively. Up to 34% difference in the RBE of the proton beam was observed between MG63 and HT1080. Similarly, a 32% difference in the RBE of the carbon-ion beam was observed between SW872 and the other sarcoma cell lines. In proton beam irradiation, normal cell lines had less variation in RBE values (within 10%), whereas in carbon-ion irradiation, RBE values differed by up to 48% between hTERT-HME1 and NuLi-1. Our results suggest that specific dose evaluations for tumor and normal tissues are necessary for treatment planning in both proton and carbon-ion therapies. - Proteolysis of a histone acetyl reader, ATAD2, induces chemoresistance of cancer cells under severe hypoxia by inhibiting cell cycle progression in S phase
Takao Haitani, Minoru Kobayashi, Sho Koyasu, Shusuke Akamatsu, Tatsuya Suwa, Yasuhito Onodera, Jin-Min Nam, Phuong Thi Lien Nguyen, Toshi Menju, Hiroshi Date, Osamu Ogawa, Hiroshi Harada
Cancer Letters, 528, 76, 84, Elsevier BV, Mar. 2022, [Peer-reviewed]
Scientific journal - Roles of MFN2 and MFN2 associated protein in chemotaxis of neutrophil-like differentiated HL-60 cells
Mazaki Yuichi, Higashi Tsunehito, Nio-Kobayashi Junko, Onodera Yasuhito
Proceedings for Annual Meeting of The Japanese Pharmacological Society, 96, 2-B-P-112, Japanese Pharmacological Society, 2022
Japanese, Neutrophils are important in innate immunity and in the initiation of an acute response to infection. Under normal conditions, the mitochondrial membrane potential of neutrophils is low, and neutrophils energy depends fundamentally on glycolysis. In contrast, neutrophils require energy supplied from mitochondrial oxidative phosphorylation (OXPHOS) during infection. The inhibition of mitochondrial OXPHOS blocks the chemotaxis of neutrophils. Here, we examined the mitochondrial morphology of neutrophil-like differentiated HL-60 cells after chemoattractant N-formyl-Met-Leu-Phe (fMLP) stimulation. We found that mitochondrial morphology changes to a tubular form after fMLP stimulation. Mitochondrial OXPHOS activity and mitochondrial complex II significantly increased after fMLP stimulation. On the other hand, the silencing of mitochondrial fusion protein mitofusin 2 (MFN2) suppresses mitochondrial morphological changes. MFN2 silencing suppressed OXPHOS activation and chemotaxis after fMLP stimulation. Furthermore, the silencing of MFN2 associated protein suppresses also mitochondrial morphological changes and chemotaxis upon fMLP stimulation. These results suggest that MFN2 and MFN2 associated protein are involved in chemotaxis of differentiated HL-60 cells. - Dual roles of AMAP1 in the transcriptional regulation and intracellular trafficking of carbonic anhydrase IX
Mei Horikawa, Hisataka Sabe, Yasuhito Onodera
Translational Oncology, 15, 1, 101258, 101258, Elsevier BV, Jan. 2022, [Peer-reviewed], [Last author, Corresponding author], [International Magazine]
English, Scientific journal, BACKGROUND: The cell-surface enzyme carbonic anhydrase IX (CAIX/CA9) promotes tumor growth, survival, invasion, and metastasis, mainly via its pH-regulating functions. Owing to its tumor-specific expression, CAIX-targeting antibodies/chemicals are utilized for therapeutic and diagnostic purposes. However, mechanisms of CAIX trafficking, which affects such CAIX-targeting modalities remain unclear. In this study, roles of the AMAP1-PRKD2 pathway, which mediates integrin recycling of invasive cancer cells, in CAIX trafficking were investigated. METHODS: Using highly invasive MDA-MB-231 breast cancer cells, the physical association and colocalization of endogenous proteins were analyzed by immunoprecipitation and immunofluorescence, protein/mRNA levels were quantified by western blotting/qPCR, and cell-surface transport and intracellular/extracellular pH regulation were measured by biotin-labeling and fluorescent dye-based assays, respectively. The correlation between mRNA levels and patients' prognoses was analyzed using a TCGA breast cancer dataset. RESULTS: AMAP1 associated with the CAIX protein complex, and they colocalized at the plasma membrane and tubulovesicular structures. AMAP1 knockdown reduced total/surface CAIX, induced its lysosomal accumulation and degradation, and affected intracellular/extracellular pH. PRKD2 knockdown excluded AMAP1 from the CAIX complex and reduced total CAIX in a lysosome-dependent manner. Unexpectedly, AMAP1 knockdown also reduced CAIX mRNA. AMAP1 interacted with PIAS3, which stabilizes HIF-1α, a transcriptional regulator of CA9. AMAP1 knockdown inhibited the PIAS3-HIF-1α interaction and destabilized the HIF-1α protein. High-ASAP1 (AMAP1-encoding gene) together with high-PIAS3 correlated with high-CA9 and an unfavorable prognosis in breast cancer. CONCLUSION: The AMAP1-PRKD2 pathway regulates CAIX trafficking, and modulates its total/surface expression. The AMAP1-PIAS3 interaction augments CA9 transcription by stabilizing HIF-1α, presumably contributing to an unfavorable prognosis. - Strategies for all-at-once and stepwise selection of cells with multiple genetic manipulations
Mei Horikawa, Hisataka Sabe, Yasuhito Onodera
Biochemical and Biophysical Research Communications, 582, 93, 99, Elsevier BV, Oct. 2021, [Peer-reviewed], [Last author, Corresponding author], [International Magazine]
English, Scientific journal, The genetic manipulation of cells followed by their selection is indispensable for cell biological research. Although antibiotics-resistant genes are commonly used as selection markers, optimization of the condition for each selective agent is required. Here we utilized split-inteins and the drug-selectable marker puromycin N-acetyltransferase (PAC) to develop a system that enables the selection of cells simultaneously or sequentially transfected with multiple genetic constructs, using only puromycin. The active PAC enzyme was reconstituted by intein-mediated trans-splicing at several inherent or engineered serine/cysteine residues. Multiple splitting and reconstitution of active PAC was readily achieved by selecting optimum division sites based on the cellular tolerance to various puromycin concentrations. To achieve the stepwise selection method, PAC-intein fragments were transduced into cells using a virus-like particle (VLP) composed of HIV-1 gag-pol and VSV-G. The PAC-intein-VLP successfully conferred sufficient PAC activity for puromycin selection, which was quickly diminished in the absence of the VLP. Our findings demonstrate a versatile strategy for establishing markers for all-at-once or stepwise selection of multiple genetic manipulations, which will be useful in many fields of biology. - Lysosomal trafficking mediated by Arl8b and BORC promotes invasion of cancer cells that survive radiation
Ping-Hsiu Wu, Yasuhito Onodera, Amato J. Giaccia, Quynh-Thu Le, Shinichi Shimizu, Hiroki Shirato, Jin-Min Nam
Communications Biology, 3, 1, Springer Science and Business Media LLC, Dec. 2020, [Peer-reviewed], [Corresponding author]
English, Scientific journal,Abstract Enhanced invasiveness, a critical determinant of metastasis and poor prognosis, has been observed in cancer cells that survive cancer therapy, including radiotherapy. Here, we show that invasiveness in radiation-surviving cancer cells is associated with alterations in lysosomal exocytosis caused by the enhanced activation of Arl8b, a small GTPase that regulates lysosomal trafficking. The binding of Arl8b with its effector, SKIP, is increased after radiation through regulation of BORC-subunits. Knockdown of Arl8b or BORC-subunits decreases lysosomal exocytosis and the invasiveness of radiation-surviving cells. Notably, high expression ofARL8B and BORC-subunit genes is significantly correlated with poor prognosis in breast cancer patients. Sp1, an ATM-regulated transcription factor, is found to increase BORC-subunit genes expression after radiation. In vivo experiments show that ablation of Arl8b decreases IR-induced invasive tumor growth and distant metastasis. These findings suggest that BORC-Arl8b-mediated lysosomal trafficking is a target for improving radiotherapy by inhibiting invasive tumor growth and metastasis. - 核ラミナにおいてp53はEZH2を妨害してH3K27高メチル化を阻害する(p53 counteracts EZH2 at the nuclear lamina to prevent H3K27 hypermethylation)
及川 司, 大西 なおみ, 小野寺 康仁, 橋本 あり, 植田 幸嗣, 佐邊 壽孝
日本生化学会大会プログラム・講演要旨集, 93回, [P, 466], (公社)日本生化学会, Sep. 2020
English - Rab27b contributes to radioresistance and exerts a paracrine effect via epiregulin in glioblastoma
Soichiro Nishioka, Ping-Hsiu Wu, Toshiaki Yakabe, Amato J Giaccia, Quynh-Thu Le, Hidefumi Aoyama, Shinichi Shimizu, Hiroki Shirato, Yasuhito Onodera, Jin-Min Nam
Neuro-Oncology Advances, 2, 1, Oxford University Press (OUP), 01 Jan. 2020, [Peer-reviewed], [Corresponding author]
English, Scientific journal,Abstract
Background
Radiotherapy is the standard treatment for glioblastoma (GBM). However, radioresistance of GBM cells leads to recurrence and poor patient prognosis. Recent studies suggest that secretion factors have important roles in radioresistance of tumor cells. This study aims to determine whether Rab27b, a small GTPase involved in secretory vesicle trafficking, plays a role in radioresistance of GBM.
Methods
Microarray analysis, cell viability analysis, apoptosis assay, immunostaining, and in vivo experiments were performed to assess the effect of Rab27b on radioresistance of GBM. We further investigated paracrine effects mediated by Rab27b after X-ray irradiation using coculture systems of glioma cell lines.
Results
Rab27b was specifically upregulated in irradiated U87MG cells. Furthermore, Rab27b knockdown decreased the proliferation of GBM cells after irradiation. Knockdown of Rab27b in U87MG cells combined with radiation treatment suppressed orthotopic tumor growth in the mouse brain and prolonged the survival of recipient mice. Interestingly, the co-upregulation of Rab27b and epiregulin (EREG), a member of the epidermal growth factor (EGF) family, correlated with radioresistance in glioma cell lines. Additionally, EREG, which was secreted from U87MG cells via Rab27b-mediated mechanism, activated EGF receptor and contributed to H4 cell proliferation in a paracrine manner.
Conclusions
Our results show that Rab27b mediates the radioresistance of highly malignant GBM cells. Rab27b promotes the proliferation of adjacent cells through EREG-mediated paracrine signaling after irradiation. Thus, the Rab27b-EREG pathway is a novel potential target to improve the efficacy of radiotherapy in GBM.
- Targeting Integrins in Cancer Nanomedicine: Applications in Cancer Diagnosis and Therapy
Ping-Hsiu Wu, Abayomi Emmanuel Opadele, Yasuhito Onodera, Jin-Min Nam
Cancers, 11, 11, 1783, 1783, MDPI AG, 13 Nov. 2019
Scientific journal, Due to advancements in nanotechnology, the application of nanosized materials (nanomaterials) in cancer diagnostics and therapeutics has become a leading area in cancer research. The decoration of nanomaterial surfaces with biological ligands is a major strategy for directing the actions of nanomaterials specifically to cancer cells. These ligands can bind to specific receptors on the cell surface and enable nanomaterials to actively target cancer cells. Integrins are one of the cell surface receptors that regulate the communication between cells and their microenvironment. Several integrins are overexpressed in many types of cancer cells and the tumor microvasculature and function in the mediation of various cellular events. Therefore, the surface modification of nanomaterials with integrin-specific ligands not only increases their binding affinity to cancer cells but also enhances the cellular uptake of nanomaterials through the intracellular trafficking of integrins. Moreover, the integrin-specific ligands themselves interfere with cancer migration and invasion by interacting with integrins, and this finding provides a novel direction for new treatment approaches in cancer nanomedicine. This article reviews the integrin-specific ligands that have been used in cancer nanomedicine and provides an overview of the recent progress in cancer diagnostics and therapeutic strategies involving the use of integrin-targeted nanomaterials. - DNA複製中の核内におけるK27トリメチル化ヒストンH3の挙動に対するp53の必要性(Requirement for p53 in intra-nuclear dynamics of the K27-trimethylated histone H3 during DNA replication)
及川 司, 大西 なおみ, 小野寺 康仁, 橋本 あり, 植田 幸嗣, 佐邊 壽孝
日本生化学会大会プログラム・講演要旨集, 92回, [2T13m, 01], (公社)日本生化学会, Sep. 2019
English - Lambda-Carrageenan Enhances the Effects of Radiation Therapy in Cancer Treatment by Suppressing Cancer Cell Invasion and Metastasis through Racgap1 Inhibition
Ping-Hsiu Wu, Yasuhito Onodera, Frances C. Recuenco, Amato J. Giaccia, Quynh-Thu Le, Shinichi Shimizu, Hiroki Shirato, Jin-Min Nam
Cancers, 11, 8, 1192, 1192, MDPI AG, 16 Aug. 2019
Scientific journal, Radiotherapy is used extensively in cancer treatment, but radioresistance and the metastatic potential of cancer cells that survive radiation remain critical issues. There is a need for novel treatments to improve radiotherapy. Here, we evaluated the therapeutic benefit of λ-carrageenan (CGN) to enhance the efficacy of radiation treatment and investigated the underlying molecular mechanism. CGN treatment decreased viability in irradiated cancer cells and enhanced reactive oxygen species accumulation, apoptosis, and polyploid formation. Additionally, CGN suppressed radiation-induced chemoinvasion and invasive growth in 3D lrECM culture. We also screened target molecules using a gene expression microarray analysis and focused on Rac GTPase-activating protein 1 (RacGAP1). Protein expression of RacGAP1 was upregulated in several cancer cell lines after radiation, which was significantly suppressed by CGN treatment. Knockdown of RacGAP1 decreased cell viability and invasiveness after radiation. Overexpression of RacGAP1 partially rescued CGN cytotoxicity. In a mouse xenograft model, local irradiation followed by CGN treatment significantly decreased tumor growth and lung metastasis compared to either treatment alone. Taken together, these results suggest that CGN may enhance the effectiveness of radiation in cancer therapy by decreasing cancer cell viability and suppressing both radiation-induced invasive activity and distal metastasis through downregulating RacGAP1 expression. - ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer.
Hashimoto S, Furukawa S, Hashimoto A, Tsutaho A, Fukao A, Sakamura Y, Parajuli G, Onodera Y, Otsuka Y, Handa H, Oikawa T, Hata S, Nishikawa Y, Mizukami Y, Kodama Y, Murakami M, Fujiwara T, Hirano S, Sabe H
Proceedings of the National Academy of Sciences of the United States of America, 116, 35, 17450, 17459, Aug. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, Although KRAS and TP53 mutations are major drivers of pancreatic ductal adenocarcinoma (PDAC), the incurable nature of this cancer still remains largely elusive. ARF6 and its effector AMAP1 are often overexpressed in different cancers and regulate the intracellular dynamics of integrins and E-cadherin, thus promoting tumor invasion and metastasis when ARF6 is activated. Here we show that the ARF6-AMAP1 pathway is a major target by which KRAS and TP53 cooperatively promote malignancy. KRAS was identified to promote eIF4A-dependent ARF6 mRNA translation, which contains a quadruplex structure at its 5'-untranslated region, by inducing TEAD3 and ETV4 to suppress PDCD4; and also eIF4E-dependent AMAP1 mRNA translation, which contains a 5'-terminal oligopyrimidine-like sequence, via up-regulating mTORC1. TP53 facilitated ARF6 activation by platelet-derived growth factor (PDGF), via its known function to promote the expression of PDGF receptor β (PDGFRβ) and enzymes of the mevalonate pathway (MVP). The ARF6-AMAP1 pathway was moreover essential for PDGF-driven recycling of PD-L1, in which KRAS, TP53, eIF4A/4E-dependent translation, mTOR, and MVP were all integral. We moreover demonstrated that the mouse PDAC model KPC cells, bearing KRAS/TP53 mutations, express ARF6 and AMAP1 at high levels and that the ARF6-based pathway is closely associated with immune evasion of KPC cells. Expression of ARF6 pathway components statistically correlated with poor patient outcomes. Thus, the cooperation among eIF4A/4E-dependent mRNA translation and MVP has emerged as a link by which pancreatic driver mutations may promote tumor cell motility, PD-L1 dynamics, and immune evasion, via empowering the ARF6-based pathway and its activation by external ligands. - 乳癌における腫瘍関連MUC1の発現変化とその臨床的意義
清水 亜衣, 畑中 佳奈子, 畑中 豊, 南家 綾江, 奥村 麻美, 燕 果歩, 成地 健太郎, 佐藤 正治, 加瀬 廣, 小野寺 康仁, 三橋 智子, 山下 啓子, 松野 吉宏
日本乳癌学会総会プログラム抄録集, 27回, 593, 593, (一社)日本乳癌学会, Jul. 2019
Japanese - 乳癌の進展過程における腫瘍関連MUC1の発現変化
清水 亜衣, 畑中 佳奈子, 畑中 豊, 南家 綾江, 奥村 麻美, 燕 果歩, 小野寺 康仁, 三橋 智子, 山下 啓子, 松野 吉宏
日本病理学会会誌, 108, 1, 393, 393, (一社)日本病理学会, Apr. 2019
Japanese - Mitofusin 2 is involved in chemotaxis of neutrophil-like differentiated HL-60 cells.
Mazaki Y, Takada S, Nio-Kobayashi J, Maekawa S, Higashi T, Onodera Y, Sabe H
Biochemical and biophysical research communications, 513, 3, 708, 713, Apr. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, Neutrophils rapidly migrate to infection sites after the recognition of invaders. During chemotaxis, neutrophils require energy supplied by mitochondria oxidative phosphorylation (OXPHOS), whereas neutrophils rely heavily on glycolysis under normal conditions. Mitochondrial OXPHOS correlates with mitochondrial morphology. Here, we examined the mitochondrial morphology of neutrophil-like differentiated HL-60 cells after chemoattractant N-formyl-Met-Leu-Phe (fMLP) stimulation. We found that mitochondrial morphology changes to a tubular form after fMLP stimulation. Mitochondrial OXPHOS activity and mitochondrial complex II significantly increased after fMLP stimulation. On the other hand, the silencing of mitochondrial fusion protein mitofusin 2 (MFN2) suppresses mitochondrial morphological changes. Furthermore, MFN2 silencing suppressed OXPHOS activation and chemotaxis after fMLP stimulation. These results suggest that MFN2 is involved in chemotaxis of differentiated HL-60 cells depending on mitochondria. - Endothelin type B receptor interacts with the 78-kDa glucose-regulated protein.
Yuichi Mazaki, Shingo Takada, Junko Nio-Kobayashi, Satoshi Maekawa, Tsunehito Higashi, Yasuhito Onodera, Hisataka Sabe
FEBS letters, 593, 6, 644, 651, Wiley, Mar. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, Endothelin (ET)-1 is involved in the vascular system, cell proliferation and apoptosis. ET receptors consist of ET type A receptor (ETA R) and ET type B receptor (ETB R). ETA R and ETB R generally exhibit opposite responses, although many exceptions exist. In the present study, we attempted to identify ETA R- or ETB R-specific binding proteins to understand the differences in ETA R- and ETB R-mediated responses after ET-1 stimulation. The 78-kDa glucose-regulated protein (GRP78) showed a stronger binding affinity towards ETB R than towards ETA R. Moreover, GRP78 overexpression promoted ETB R-mediated ERK activation and GRP78 silencing suppressed ETB R-mediated ERK activation. Furthermore, ETB R can localize GRP78 to the cell periphery. These results suggest that the interaction of ETB R with GRP78 affects ERK activation and GRP78 localization. - GRP78 promotes ERK activation through endothelin type B receptor
Mazaki Yuichi, Higashi Tsunehito, Onodera Yasuhito, Nam Jin-Min, Hashimoto Ari, Hashimoto Shigeru, Horinouchi Takahiro, Miwa Soichi
Proceedings for Annual Meeting of The Japanese Pharmacological Society, 92, 1-P-110, Japanese Pharmacological Society, 2019
Japanese, Endothelin (ET)-1 is involved in various diseases, including cancer, hypertension, atherosclerosis, diabetes, and fibrotic diseases, although ET-1 is originally identified as endothelium-derived vasocontractile peptide. ET receptors belong to the class A of G protein-coupled receptor, and consist of ET type A receptor (ETAR) and ET type B receptor (ETBR). ETAR and ETBR generally exhibit the opposite responses, although many exceptions exist. Here, we attempted to identify ETAR or ETBR specific binding proteins to understand difference of ETAR- and ETBR-mediated responses upon ET-1 stimulation. We found that GRP78 exhibited a stronger binding affinity toward ETBR than ETAR. Overexpression of GRP78 promotes ETBR-mediated ERK activation. In addition, the silencing of GRP78 suppressed ETBR-mediated ERK activation. On the other hand, ETBR can localize GRP78 to cell periphery. Our results suggest that interaction of ETBR with GRP78 affects the ERK activation and GRP78 localization. - Arf6-driven cell invasion is intrinsically linked to TRAK1-mediated mitochondrial anterograde trafficking to avoid oxidative catastrophe.
Onodera Y, Nam JM, Horikawa M, Shirato H, Sabe H
Nature Communications, 9, 1, 2682, 2682, Jul. 2018, [Peer-reviewed], [Corresponding author], [International Magazine]
English, Scientific journal, Mitochondria dynamically alter their subcellular localization during cell movement, although the underlying mechanisms remain largely elusive. The small GTPase Arf6 and its signaling pathway involving AMAP1 promote cell invasion via integrin recycling. Here we show that the Arf6-AMAP1 pathway promote the anterograde trafficking of mitochondria. Blocking the Arf6-based pathway causes mitochondrial aggregation near the microtubule-organizing center, and subsequently induces detrimental reactive oxygen species (ROS) production, likely via a mitochondrial ROS-induced ROS release-like mechanism. The Arf6-based pathway promotes the localization of ILK to focal adhesions to block RhoT1-TRAK2 association, which controls mitochondrial retrograde trafficking. Blockade of the RhoT1-TRAK1 machinery, rather than RhoT1-TRAK2, impairs cell invasion, but not two-dimensional random cell migration. Weakly or non-invasive cells do not notably express TRAK proteins, whereas they clearly express their mRNAs. Our results identified a novel association between cell movement and mitochondrial dynamics, which is specific to invasion and is necessary for avoiding detrimental ROS production. - Necessity of p53-binding to the CDH1 locus for its expression defines two epithelial cell types differing in their integrity.
Oikawa T, Otsuka Y, Onodera Y, Horikawa M, Handa H, Hashimoto S, Suzuki Y, Sabe H
Scientific Reports, 8, 1, 1595, 1595, Jan. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, TP53 mutation (i.e., loss of normal-p53) may evoke epithelial-mesenchymal transition (EMT), which was previously attributed to loss of certain miRNAs. However, not all epithelial cells undergo EMT upon TP53 mutation, and the p53-miRNA axis may not fully explain p53 function in epithelial integrity. We here show two modes of epithelial integrity: one involves p53-binding to a nucleotide region and the other does not. In the former, p53 binds to the CDH1 (encoding E-cadherin) locus to antagonize EZH2-mediated H3K27 trimethylation (H3K27me3) to maintain high levels of acetylation of H3K27 (H3K27ac). In the latter, the same locus is not highly acetylated at H3K27, and does not allow p53-binding, nor needs to antagonize EZH2. We moreover demonstrated that although the CDH1 locus in the p53-independent cells, but not in fibroblasts, becomes high-H3K27ac by butyrate and allows p53-biniding, their CDH1 expression does not become dependent on p53. Our results identified novel modes of the epithelial integrity, in which the same epithelial-specific gene locus exhibits different requirement for p53 with different histone modifications among different epithelial cells to warrant its expression. - ARF1 recruits RAC1 to leading edge in neutrophil chemotaxis
Yuichi Mazaki, Yasuhito Onodera, Tsunehito Higashi, Takahiro Horinouchi, Tsukasa Oikawa, Hisataka Sabe
CELL COMMUNICATION AND SIGNALING, 15, 1, 36, Oct. 2017, [Peer-reviewed]
English, Scientific journal - がん代謝にもとづく生物像の理解(代謝ネットワーク) インテグリンシグナルとがん代謝
小野寺 康仁, 佐邊 壽孝
日本癌学会総会記事, 76回, S3, 4, 日本癌学会, Sep. 2017
English - Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes
Shunsuke Kon, Kojiro Ishibashi, Hiroto Katoh, Sho Kitamoto, Takanobu Shirai, Shinya Tanaka, Mihoko Kajita, Susumu Ishikawa, Hajime Yamauchi, Yuta Yako, Tomoko Kamasaki, Tomohiro Matsumoto, Hirotaka Watanabe, Riku Egami, Ayana Sasaki, Atsuko Nishikawa, Ikumi Kameda, Takeshi Maruyama, Rika Narumi, Tomoko Morita, Yoshiteru Sasaki, Ryosuke Enoki, Sato Honma, Hiromi Imamura, Masanobu Oshima, Tomoyoshi Soga, Jun-ichi Miyazaki, Michael R. Duchen, Jin-Min Nam, Yasuhito Onodera, Shingo Yoshioka, Junichi Kikuta, Masaru Ishii, Masamichi Imajo, Eisuke Nishida, Yoichiro Fujioka, Yusuke Ohba, Toshiro Sato, Yasuyuki Fujita
NATURE CELL BIOLOGY, 19, 5, 530, +, May 2017, [Peer-reviewed]
English, Scientific journal - Targeting integrins with RGD-conjugated gold nanoparticles in radiotherapy decreases the invasive activity of breast cancer cells
Ping-Hsiu Wu, Yasuhito Onodera, Yuki Ichikawa, Erinn B. Rankin, Amato J. Giaccia, Yuko Watanabe, Wei Qian, Takayuki Hashimoto, Hiroki Shirato, Jin-Min Nam
INTERNATIONAL JOURNAL OF NANOMEDICINE, 12, 5069, 5085, 2017, [Peer-reviewed]
English, Scientific journal - High expression of EPB41L5, an integral component of the Arf6-driven mesenchymal program, correlates with poor prognosis of squamous cell carcinoma of the tongue
Yutaro Otsuka, Hiroki Sato, Tsukasa Oikawa, Yasuhito Onodera, Jin-Min Nam, Ari Hashimoto, Kiyoshi Fukunaga, Kanako C. Hatanaka, Yutaka Hatanaka, Yoshihiro Matsuno, Satoshi Fukuda, Hisataka Sabe
CELL COMMUNICATION AND SIGNALING, 14, 1, 28, Nov. 2016, [Peer-reviewed]
English, Scientific journal - ZEB1 induces EPB41L5 in the cancer mesenchymal program that drives ARF6-based invasion, metastasis and drug resistance
A. Hashimoto, S. Hashimoto, H. Sugino, A. Yoshikawa, Y. Onodera, H. Handa, T. Oikawa, H. Sabe
ONCOGENESIS, 5, 9, e259, Sep. 2016, [Peer-reviewed]
English, Scientific journal - The Rho guanine nucleotide exchange factor ARHGEF5 promotes tumor malignancy via epithelial-mesenchymal transition
Y. Komiya, Y. Onodera, M. Kuroiwa, S. Nomimura, Y. Kubo, J-M Nam, K. Kajiwara, S. Nada, C. Oneyama, H. Sabe, M. Okada
ONCOGENESIS, 5, 9, e258, Sep. 2016, [Peer-reviewed]
English, Scientific journal - P53-and mevalonate pathway-driven malignancies require Arf6 for metastasis and drug resistance
Ari Hashimoto, Tsukasa Oikawa, Shigeru Hashimoto, Hirokazu Sugino, Ayumu Yoshikawa, Yutaro Otsuka, Haruka Handa, Yasuhito Onodera, Jin-Min Nam, Chitose Oneyama, Masato Okada, Mitsunori Fukuda, Hisataka Sabe
JOURNAL OF CELL BIOLOGY, 213, 1, 81, 95, Apr. 2016, [Peer-reviewed]
English, Scientific journal - Lysophosphatidic acid activates Arf6 to promote the mesenchymal malignancy of renal cancer
Shigeru Hashimoto, Shuji Mikami, Hirokazu Sugino, Ayumu Yoshikawa, Ari Hashimoto, Yasuhito Onodera, Shotaro Furukawa, Haruka Handa, Tsukasa Oikawa, Yasunori Okada, Mototsugu Oya, Hisataka Sabe
NATURE COMMUNICATIONS, 7, 10656, Feb. 2016, [Peer-reviewed]
English, Scientific journal - Post-transcriptional regulation and metabolism
Yasuhito Onodera
Seikagaku, 88, 3, 308, 313, Japanese Biochemical Society, 2016, [Peer-reviewed], [Invited]
Japanese, Scientific journal - Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways
Yasuhito Onodera, Jin-Min Nam, Mina J. Bissell
JOURNAL OF CLINICAL INVESTIGATION, 124, 1, 367, 384, Jan. 2014, [Peer-reviewed], [Corresponding author]
English, Scientific journal - Intracellular trafficking of integrins in cancer cells
Yasuhito Onodera, Jin-Min Nam, Hisataka Sabe
PHARMACOLOGY & THERAPEUTICS, 140, 1, 1, 9, Oct. 2013, [Peer-reviewed]
English - Co-Overexpression of GEP100 and AMAP1 Proteins Correlates with Rapid Local Recurrence after Breast Conservative Therapy
Rumiko Kinoshita, Jin-Min Nam, Yoichi M. Ito, Kanako C. Hatanaka, Ari Hashimoto, Haruka Handa, Yutaro Otsuka, Shigeru Hashimoto, Yasuhito Onodera, Mitsuchika Hosoda, Shunsuke Onodera, Shinichi Shimizu, Shinya Tanaka, Hiroki Shirato, Mishie Tanino, Hisataka Sabe
PLOS ONE, 8, 10, e76791, Oct. 2013, [Peer-reviewed]
English, Scientific journal - Lysyl oxidase secreted by tumour endothelial cells promotes angiogenesis and metastasis
T. Osawa, N. Ohga, K. Akiyama, Y. Hida, K. Kitayama, T. Kawamoto, K. Yamamoto, N. Maishi, M. Kondoh, Y. Onodera, M. Fujie, N. Shinohara, K. Nonomura, M. Shindoh, K. Hida
BRITISH JOURNAL OF CANCER, 109, 8, 2237, 2247, Oct. 2013, [Peer-reviewed]
English, Scientific journal - β1-integrin via NF-κB signaling is essential for acquisition of invasiveness in a model of radiation treated in situ breast cancer
Jin-Min Nam, Kazi M. Ahmed, Sylvain Costes, Hui Zhang, Yasuhito Onodera, Adam B. Olshen, Kanako C. Hatanaka, Rumiko Kinoshita, Masayori Ishikawa, Hisataka Sabe, Hiroki Shirato, Catherine C. Park
Breast Cancer Research, 15, 4, R60, 4, 25 Jul. 2013, [Peer-reviewed]
English, Scientific journal - beta 1-integrin via NF-kappa B signaling is essential for acquisition of invasiveness in a model of radiation treated in situ breast cancer
Jin-Min Nam, Kazi M. Ahmed, Sylvain Costes, Hui Zhang, Yasuhito Onodera, Adam B. Olshen, Kanako C. Hatanaka, Rumiko Kinoshita, Masayori Ishikawa, Hisataka Sabe, Hiroki Shirato, Catherine C. Park
BREAST CANCER RESEARCH, 15, 4, 2013, [Peer-reviewed]
English, Scientific journal - ['Molecular biology' of breast cancer].
Onodera Y
Nihon rinsho. Japanese journal of clinical medicine, 70 Suppl 7, 61, 65, Sep. 2012, [Peer-reviewed] - Rab5c promotes AMAP1-PRKD2 complex formation to enhance beta 1 integrin recycling in EGF-induced cancer invasion
Yasuhito Onodera, Jin-Min Nam, Ari Hashimoto, Jim C. Norman, Hiroki Shirato, Shigeru Hashimoto, Hisataka Sabe
JOURNAL OF CELL BIOLOGY, 197, 7, 983, 996, Jun. 2012, [Peer-reviewed]
English, Scientific journal - Biglycan is a specific marker and an autocrine angiogenic factor of tumour endothelial cells
Yamamoto K, Ohga N, Hida Y, Maishi N, Kawamoto T, Kitayama K, Akiyama K, Osawa T, Kondoh M, Matsuda K, Onodera Y, Fujie M, Kaga K, Hirano S, Shinohara N, Shindoh M, Hida K
Br J Cancer, 106, 6, 1214, 1223, 2012, [Peer-reviewed]
English, Scientific journal - Breast Cancer Cells in Three-dimensional Culture Display an Enhanced Radioresponse after Coordinate Targeting of Integrin alpha 5 beta 1 and Fibronectin
Jin-Min Nam, Yasuhito Onodera, Mina J. Bissell, Catherine C. Park
CANCER RESEARCH, 70, 13, 5238, 5248, Jul. 2010, [Peer-reviewed]
English, Scientific journal - The EGFR-GEP100-Arf6-AMAP1 Signaling Pathway Specific to Breast Cancer Invasion and Metastasis(dagger)
Hisataka Sabe, Shigeru Hashimoto, Masaki Morishige, Eiji Ogawa, Ari Hashimoto, Jin-Min Nam, Koichi Miura, Hajime Yano, Yasuhito Onodera
TRAFFIC, 10, 8, 982, 993, Aug. 2009, [Peer-reviewed]
English - 【シグナル伝達研究 2008'09 疾患発症の分子メカニズムと実現化する分子標的薬開発】シグナル伝達研究 因子から現象へ がんの浸潤形質獲得過程における低分子量Gタンパク質Arf6シグナル伝達
橋本 茂, 森重 真毅, 小川 栄治, 橋本 あり, 小野寺 康仁, 佐邊 壽孝
実験医学, 26, 15, 2349, 2355, (株)羊土社, Sep. 2008
Japanese - Fbx8 makes Arf6 refractory to function via ubiquitination
Hajime Yano, Itaru Kobayashi, Yasuhito Onodera, Frederic Luton, Michel Franco, Yuichi Mazaki, Shigeru Hashimoto, Kazuhiro Iwai, Ze'ev Ronai, Hisataka Sabe
MOLECULAR BIOLOGY OF THE CELL, 19, 3, 822, 832, Mar. 2008, [Peer-reviewed]
English, Scientific journal - [Breast neoplasms: invasion and metastasis].
Onodera Y, Nam JM
Nihon rinsho. Japanese journal of clinical medicine, 65 Suppl 6, 33, 38, Jun. 2007, [Peer-reviewed] - CIN85, a Cbl-interacting protein, is a component of AMAP1-mediated breast cancer invasion machinery
Jin-Min Nam, Yasuhito Onodera, Yuichi Mazaki, Hiroyuki Miyoshi, Shigeru Hashimoto, Hisataka Sabe
EMBO JOURNAL, 26, 3, 647, 656, Feb. 2007, [Peer-reviewed]
English, Scientific journal - ArfGAP family proteins in cell adhesion, migration and tumor invasion
Hisataka Sabe, Yasuhito Onodera, Yuichi Mazaki, Shigeru Hashimoto
CURRENT OPINION IN CELL BIOLOGY, 18, 5, 558, 564, Oct. 2006, [Peer-reviewed]
English, Scientific journal - [Breast cancer invasiveness: how does it emerge?].
Hashimoto S, Onodera Y
Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme, 51, 803, 810, 6 Suppl, May 2006, [Peer-reviewed] - Regulation of epithelial cell-cell interaction by Arf6 signaling
Miura Koichi, Yano Hajime, Onodera Yasuhito, Kojima Chie, Hashimoto Shigeru, Sabe Hisataka
CELL STRUCTURE AND FUNCTION, 30, 5, Jun. 2005, [Peer-reviewed] - Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive activities
Y Onodera, S Hashimoto, A Hashimoto, M Morishige, Y Mazaki, A Yamada, E Ogawa, M Adachi, T Sakurai, T Manabe, H Wada, N Matsuura, H Sabe
EMBO JOURNAL, 24, 5, 963, 973, Mar. 2005, [Peer-reviewed]
English, Scientific journal - Assays and properties of the ArfGAPs, AMAP1 and AMAP2, in Arf6 function
S Hashimoto, A Hashimoto, A Yamada, Y Onodera, H Sabe
GTPASES REGULATING MEMBRANE DYNAMICS, 404, 216, 231, 2005, [Peer-reviewed]
English, In book - Requirement for Arf6 in breast cancer invasive activities
S Hashimoto, Y Onodera, A Hashimoto, M Tanaka, M Hamaguchi, A Yamada, H Sabe
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 101, 17, 6647, 6652, Apr. 2004, [Peer-reviewed]
English, Scientific journal - Interaction of POB1, a downstream molecule of small G protein Ral, with PAG2, a paxillin-binding protein, is involved in cell migration
T Oshiro, S Koyama, S Sugiyama, A Kondo, Y Onodera, T Asahara, H Sabe, A Kikuchi
JOURNAL OF BIOLOGICAL CHEMISTRY, 277, 41, 38618, 38626, Oct. 2002, [Peer-reviewed]
English, Scientific journal
Other Activities and Achievements
- 分泌因子を介した細胞外コミュニケーションによるがん治療抵抗性のメカニズム がんの治療抵抗性における分泌因子の役割
西岡蒼一郎, 有光妃斗美, 小野寺康仁, NAM Jin-Min, 化学と生物, 61, 5, 2023 - 上皮間葉転換におけるmitoNEETの働き
半田悠, 小野寺康仁, 高田真吾, 高田真吾, 佐邊壽孝, 日本生化学会大会(Web), 96th, 2023 - Radiation-induced intracellular trafficking and secretory factors
NAM Jin-Min, 小野寺康仁, WU Ping-Hsiu, 西岡蒼一郎, 白土博樹, 放射線生物研究, 56, 4, 2022 - Macroscopic order formation in myoblast populations driven by intracellular molecular dynamics
麓佳月, 高田真吾, 小野寺康仁, 川口喬吾, 畠山鎮次, 佐邊壽孝, 及川司, 日本分子生物学会年会プログラム・要旨集(Web), 45th, 2022 - 好中球様細胞に分化させたHL-60細胞のケモタキシスにおける小胞体とミトコンドリアの接触
真崎雄一, 高田真吾, 小林純子, 前川聡, 小野寺康仁, 佐邊壽孝, 日本分子生物学会年会プログラム・要旨集(Web), 43rd, 2020 - p53 counteracts EZH2 at the nuclear lamina to prevent H3K27 hypermethylation
及川司, 大西なおみ, 小野寺康仁, 橋本あり, 植田幸嗣, 佐邊壽孝, 日本生化学会大会(Web), 93rd, 2020 - グリオブラストーマの放射線治療抵抗性におけるRab27bの関与
西岡蒼一郎, 西岡蒼一郎, 呉秉修, 小野寺康仁, 小野寺康仁, 清水伸一, 清水伸一, 白土博樹, 白土博樹, 南しんびん, 南しんびん, 日本分子生物学会年会プログラム・要旨集(Web), 42nd, 2019 - MFN2は好中球様細胞に分化させたHL-60細胞のケモタキシスに関与する
真崎雄一, 高田真吾, 小林純子, 前川聡, 東恒仁, 小野寺康仁, 佐邊壽孝, 日本分子生物学会年会プログラム・要旨集(Web), 42nd, 2019 - Requirement for p53 in intra-nuclear dynamics of the K27-trimethylated histone H3 during DNA replication
及川司, 大西なおみ, 小野寺康仁, 橋本あり, 植田幸嗣, 佐邊壽孝, 日本生化学会大会(Web), 92nd, 2019 - 膵癌ドライバー変異はARF6-AMAP1経路を活性化し悪性度と免疫回避能を促進する(Pancreatic KRAS and TP53 oncogenes cooperatively activate ARF6-AMAP1 pathway to drive malignancy and immune evasion)
橋本 あり, 橋本 茂, 古川 聖太郎, 蔦保 暁生, 小野寺 康仁, 大塚 勇太郎, 半田 悠, 及川 司, 水上 裕輔, 村上 正晃, 平野 聡, 佐邊 壽孝, 日本癌学会総会記事, 77回, 2219, 2219, Sep. 2018
日本癌学会, English - エンドセリンB受容体はGRP78と相互作用する
真崎雄一, 東恒仁, 堀之内孝広, 橋本あり, 橋本茂, 南ジンミン, 小野寺康仁, 日本分子生物学会年会プログラム・要旨集(Web), 41st, 2018 - 上皮細胞においてp53はE-cadherin遺伝子発現制御部位に結合し、EZH2による発現抑制に拮抗する
及川 司, 大塚 勇太郎, 小野寺 康仁, 堀川 芽衣, 橋本 あり, 橋本 茂, 鈴木 穣, 佐邊 壽孝, 生命科学系学会合同年次大会, 2017年度, [3PT18, 06(3P, Dec. 2017
生命科学系学会合同年次大会運営事務局, English - 膵癌ドライバー変異はARF6経路を介して癌悪性度とPD‐L1発現を促進する
橋本あり, 橋本茂, 古川聖太郎, 古川聖太郎, 蔦保暁生, 蔦保暁生, 大塚勇太郎, 半田悠, 小野寺康仁, 及川司, 平野聡, 佐邊壽孝, 日本生化学会大会(Web), 90th, ROMBUNNO.1P‐1028 (WEB ONLY), 1028], Dec. 2017
生命科学系学会合同年次大会運営事務局, Japanese - がんの浸潤・転移研究の新機軸 Arf6経路 難治性癌の悪性度進展・抗癌剤抵抗性に根幹的経路
佐邊 壽孝, 橋本 あり, 小野寺 康仁, 及川 司, 橋本 茂, 日本癌学会総会記事, 76回, S1, 2, Sep. 2017
日本癌学会, English - 上皮形質安定性をp53に依存する上皮細胞と依存しない上皮細胞の差異に関する解析
及川 司, 大塚 勇太郎, 小野寺 康仁, 堀川 芽衣, 橋本 あり, 橋本 茂, 鈴木 穣, 佐邊 壽孝, 日本癌学会総会記事, 76回, P, 1107, Sep. 2017
日本癌学会, English - Targeting integrins with RGD-conjugated gold nanoparticles in radiotherapy decreases the invasive activity of breast cancer cells
Ping-Hsiu Wu, Yasuhito Onodera, Yuki Ichikawa, Erinn B. Rankin, Amato J. Giaccia, Yuko Watanabe, Wei Qian, Takayuki Hashimoto, Hiroki Shirato, Jin-Min Nam, International Journal of Nanomedicine, 12, 5069, 5085, 14 Jul. 2017
Dove Medical Press Ltd., English - がん細胞のミトコンドリア分布制御による浸潤亢進と酸化ストレス回避
小野寺康仁, 佐邊壽孝, 臨床ストレス応答学会大会抄録集, 12th, 2017 - 好中球のケモタキシスにおいて,ARF1の活性化は,ARF1‐RAC1の相互制御回路を開始する
真崎雄一, 小野寺康仁, 東恒仁, 堀之内孝広, 及川司, 佐邊壽孝, 日本細胞生物学会大会(Web), 69th, ROMBUNNO.T8‐11(P1‐077) (WEB ONLY), 63, 2017
(一社)日本細胞生物学会, Japanese - Gold Nanoparticles With RGD Peptide in Radiation Therapy Suppress the Invasion Activity of Breast Cancer Cells
P. H. Wu, Y. Onodera, Y. Ichikawa, Y. Watanabe, W. Qian, T. Hashimoto, H. Shirato, J. M. Nam, INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 96, 2, E574, E574, Oct. 2016
English, Summary international conference - p53はEZH2と機能的に競合することで上皮性維持に寄与する
及川 司, 大塚 勇太郎, 小野寺 康仁, 半田 悠, 橋本 あり, 橋本 茂, 鈴木 穣, 佐邊 壽孝, 日本癌学会総会記事, 75回, J, 3030, Oct. 2016
日本癌学会, English - メバロン酸経路阻害剤スタチンはArf6経路を高発現する癌に有効である
橋本 あり, 橋本 茂, 及川 司, 大塚 勇太郎, 半田 悠, 小野寺 康仁, 佐邊 壽孝, 日本生化学会大会プログラム・講演要旨集, 89回, [1P, 268], Sep. 2016
(公社)日本生化学会, Japanese - 代謝と細胞動態 細胞動態・運命決定を司る内なるチカラ 代謝と輸送および区画化を介したがん形質の誘導
小野寺 康仁, Bissell Mina, 佐邊 壽孝, 日本細胞生物学会大会講演要旨集, 68回, 21, 21, May 2016
(一社)日本細胞生物学会, Japanese - 膵癌細胞の浸潤・転移および化学療法抵抗性メカニズムの解明
古川聖太郎, 橋本あり, 橋本茂, 小野寺康仁, 及川司, 大塚勇太郎, 佐邊壽孝, 平野聡, 日本外科学会定期学術集会(Web), 116th, PS-002-2 (WEB ONLY), 002, Apr. 2016
(一社)日本外科学会, Japanese - がん細胞における小胞輸送経路を介したミトコンドリア分布制御と活性酸素および放射線への耐性
小野寺康仁, 南ジンミン, 白土博樹, 佐邊壽孝, 日本放射線影響学会大会抄録(Web), 59th, ROMBUNNO.W12‐1 (WEB ONLY), 26, 2016
(一社)日本放射線影響学会, Japanese - p53はエピジェネティック制御を介して上皮性を維持する
及川 司, 小野寺 康仁, 大塚 勇太郎, 半田 悠, 橋本 あり, 橋本 茂, 鈴木 穣, 佐邊 壽孝, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 88回・38回, [2P1108], [2P1108], Dec. 2015
(公社)日本生化学会, English - Arf6-AMAP1経路によるROS制御は乳癌の放射線抵抗性に寄与する
小野寺 康仁, 南 ジンミン, 及川 司, 白土 博樹, 佐邊 壽孝, 日本癌学会総会記事, 74回, E, 1049, Oct. 2015
日本癌学会, English - 放射線照射後の乳腺上皮細胞の3次元構造維持に関わる分子機序の解析
南 ジンミン, 小野寺 康仁, 佐邊 壽孝, 白土 博樹, 日本癌学会総会記事, 74回, P, 2343, Oct. 2015
日本癌学会, English - Arf6-AMAP1経路によるROS制御は乳癌の放射線抵抗性に寄与する
小野寺 康仁, 南 ジンミン, 及川 司, 白土 博樹, 佐邊 壽孝, 日本癌学会総会記事, 74回, E, 1049, Oct. 2015
日本癌学会, English - 放射線照射後の乳腺上皮細胞の3次元構造維持に関わる分子機序の解析
南 ジンミン, 小野寺 康仁, 佐邊 壽孝, 白土 博樹, 日本癌学会総会記事, 74回, P, 2343, Oct. 2015
日本癌学会, English - The invasion activity after radiation treatment is suppressed by RGD peptide conjugated gold nanoparticles in breast cancer cells
P. Wu, Y. Onodera, Y. Ichikawa, Y. Watanabe, W. Qian, T. Hashimoto, H. Shirato, J. Nam, MOLECULAR BIOLOGY OF THE CELL, 26, 2015
English, Summary international conference - 糖代謝と小胞輸送の相互作用を介したがん形質の誘導
小野寺康仁, 南ジンミン, 白土博樹, BISSELL Mina, 佐邊壽孝, がんと代謝研究会プログラム&抄録集, 3rd, 44, 2015
Japanese - Arf6-AMAP1経路による酸化還元状態の恒常性維持は乳癌の放射線抵抗性に寄与する(Robust redox homeostasis mediated by Arf6-AMAP1 pathway confers resistance to ionizing radiation in breast cancer)
小野寺 康仁, 南 ジンミン, 及川 司, 白土 博樹, 佐邊 壽孝, 日本癌学会総会記事, 73回, E, 3010, Sep. 2014
日本癌学会, English - 乳癌において変異p53がリガンド反応性の間葉型浸潤分子装置を創出する機序(TP53 alterations generate Arf6-based mesenchymal invasion pathway that is activated by RTKs and TGFβ1 in breast cancer)
橋本 あり, 橋本 茂, 杉野 弘和, 吉河 歩, 及川 司, 小野寺 康仁, 半田 悠, 大塚 勇太郎, 岩見 昴亮, 小根山 千歳, 岡田 雅人, 福田 光則, 佐邊 壽孝, 日本癌学会総会記事, 73回, J, 2077, Sep. 2014
日本癌学会, English - p53は間葉系形質を持つ乳がん細胞に上皮系形質を再獲得させる(p53 recalls epithelial memory in mammary cancer cells with mesenchymal phenotypes)
及川 司, 小野寺 康仁, 橋本 あり, 橋本 茂, 佐邊 壽孝, 日本癌学会総会記事, 73回, P, 1159, Sep. 2014
日本癌学会, English - 乳癌における放射線照射後の浸潤能獲得過程に関わる分子機序の解析(Analysis of molecular mechanism involved in invasiveness of radiation treated breast cancer cells)
南 ジンミン, 小野寺 康仁, 佐邊 壽孝, 白土 博樹, 日本癌学会総会記事, 73回, P, 1450, Sep. 2014
日本癌学会, English - 癌放射線治療への分子生物学的アプローチ 変異p53が放射線抵抗性に根幹的な間葉型浸潤経路を創出する機構(Toward the improvement of radiotherapy: Approaches from the molecular biological point of view Mechanisms by which oncogenic mutant-p53 generates mesenchymal invasive pathway pivotal to a radiation resis
佐邊 壽孝, 橋本 あり, 橋本 茂, 小野寺 康仁, 及川 司, Nam Jin-Min, 小根山 千歳, 杉野 弘和, 吉河 歩, 大塚 勇太郎, 半田 悠, 芳野 正修, 岡田 雅人, 日本癌学会総会記事, 72回, 64, 64, Oct. 2013
日本癌学会, English - 放射線照射後の乳癌再発に関わるシグナルの解析(Possible mechanisms of non-invasive to invasive phenotypic conversion of breast cancer cells upon radiation)
南 ジンミン, 小野寺 康仁, 石川 正純, 佐邊 壽孝, 白土 博樹, 日本癌学会総会記事, 72回, 219, 219, Oct. 2013
日本癌学会, English - 細胞が持つリサイクルシステム研究の新展開 p53変異によるGEP100-Arf6-AMAP1経路の活性化と乳癌の浸潤形質獲得
橋本 茂, 橋本 あり, 小根山 千歳, 吉河 歩, 杉野 弘和, 半田 悠, 芳野 正修, 大塚 勇太郎, 小野寺 康仁, 岡田 雅人, 佐邊 壽孝, 日本生化学会大会プログラム・講演要旨集, 86回, 2S04a, 3, Sep. 2013
(公社)日本生化学会, Japanese - 乳癌浸潤に中枢的なArf6経路は変異p53により創出される(Mutant-p53 generates GEP100-Arf6-AMAP1 pathway to promote breast cancer cell invasiveness in response to TGFbeta1)
橋本 あり, 橋本 茂, 吉河 歩, 杉野 弘和, 半田 悠, 味藤 静, 佐藤 宏紀, 大塚 勇太郎, 芳野 日南子, 南 ジンミン, 小野寺 康仁, 佐邊 壽孝, 日本癌学会総会記事, 71回, 399, 399, Aug. 2012
日本癌学会, English - 癌浸潤におけるAMAP1-PRKD2複合体によるインテグリンリサイクリングとその制御機構(beta1 integrin recycling via AMAP1-PRKD2 complex regulated by small GTPases in cancer invasion)
小野寺 康仁, 南 ジンミン, 橋本 あり, 白土 博樹, 橋本 茂, 佐邊 壽孝, 日本癌学会総会記事, 71回, 421, 421, Aug. 2012
日本癌学会, English - 変異p53が癌浸潤転移シグナル経路を創出し活性化する
橋本あり, 橋本茂, 吉河歩, 杉野弘和, 半田悠, 木下留美子, 畑中佳奈子, 三上修治, 谷野美智枝, 味藤静, 佐藤宏紀, 大塚勇太郎, 芳野日南子, 加戸由加里, NAM Jin‐Min, 小野寺康仁, 田中伸哉, 白土博樹, 佐邊壽孝, 日本分子生物学会年会プログラム・要旨集(Web), 35th, 2W10II-1 (WEB ONLY), 2012
Japanese - EGF刺激による乳癌細胞浸潤におけるAMAP1の詳細な作用機構(AMAP1 promotes β1 integrin recycling via PRKD2 and Rab5c in EGF-induced invasion of breast cancer cells)
小野寺 康仁, 南 ジンミン, 橋本 茂, 橋本 あり, 白土 博樹, 佐邊 壽孝, 日本癌学会総会記事, 70回, 37, 38, Sep. 2011
日本癌学会, English - 変異p53はArf6活性化経路を介した浸潤獲得形質に必須である(Mutant p53 is essential for TGFβ1-induced breast cancer cell invasiveness via activation of GEP100-Arf6-AMAP1 pathway)
橋本 あり, 橋本 茂, 大塚 勇太郎, 吉河 歩, 杉野 弘和, 半田 悠, 南 ジンミン, 佐藤 宏紀, 福田 諭, 小野寺 康仁, 佐邊 壽孝, 日本癌学会総会記事, 70回, 38, 38, Sep. 2011
日本癌学会, English - TGFβ及び低酸素によるArf6活性化を介した癌浸潤形質獲得におけるエピジェネティック因子の関与(EZH2 is essential to Arf6 activation necessary for TGFβ1- and hypoxia-induced invasiveness of breast cancer cells)
橋本 茂, 橋本 あり, 小野寺 康仁, 大塚 勇太郎, 吉河 歩, 杉野 弘和, 半田 悠, 佐藤 宏紀, 福田 諭, 毛受 暁史, 佐邊 壽孝, 日本癌学会総会記事, 70回, 77, 77, Sep. 2011
日本癌学会, English - 癌の悪性化における糖代謝と小胞輸送の役割(Glucose metabolism and intracellular trafficking in tumor malignancy)
小野寺 康仁, 南 ジンミン, 橋本 茂, 橋本 あり, 佐邊 壽孝, Bissell Mina, 日本細胞生物学会大会講演要旨集, 63回, 119, 119, May 2011
(一社)日本細胞生物学会, English - TGFβ1による癌的EMTにおけるGEP100-Arf6-AMAP1シグナルの機能解析(HGFR/c-Met-mediated activation of GEP100-Arf6-AMAP1 pathway is an integral part for TGFβ-induced cancerous EMT and invasiveness)
橋本 あり, 橋本 茂, 大塚 勇太郎, 佐藤 宏紀, 杉野 弘和, 吉河 歩, 梅本 勉, 小野寺 康仁, 福田 諭, 佐邊 壽孝, 日本細胞生物学会大会講演要旨集, 63回, 151, 151, May 2011
(一社)日本細胞生物学会, English - TGFβ1はGEP100-Arf6-AMAP1経路の活性化によりEMTを誘導し、この活性化は癌幹細胞性と関連する(TGFβ1 activates GEP100-Arf6-AMAP1 pathway to induce EMT, and possible relationship of this activation to cancer stemness)
橋本 あり, 平野 真理子, 谷野 美智枝, 梅本 勉, 小野寺 康仁, 佐藤 宏紀, 木下 留美子, 南 ジンミン, 大塚 勇太郎, 福田 諭, 白土 博樹, 相沢 慎一, 橋本 茂, 田中 伸哉, 佐邊 壽孝, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 83回・33回, 2P, 0237, Dec. 2010
(公社)日本生化学会, English - 癌の悪性化における小胞輸送と糖代謝の役割(Intracellular trafficking and glucose metabolism in tumor malignancy)
小野寺 康仁, 佐邊 壽孝, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 83回・33回, 3P, 1019, Dec. 2010
(公社)日本生化学会, English - 癌の悪性化における小胞輸送と糖代謝の役割(Roles of intracellular trafficking and glucose metabolism in tumor malignancy)
小野寺 康仁, 佐邊 壽孝, 日本癌学会総会記事, 69回, 83, 83, Aug. 2010
日本癌学会, English - 上皮間葉転換 Arf6-AMAP1経路は癌的EMTに寄与する(EMT (Epithelial Mesenchymal Transition) The Arf6-AMAP1 pathway contributes to cancerous EMT)
佐邊 壽孝, 小野寺 康仁, 橋本 あり, 橋本 茂, 日本癌学会総会記事, 69回, 240, 240, Aug. 2010
日本癌学会, English - 低酸素下の癌細胞の浸潤形質獲得とArf6活性化との関連(Hypoxia-induced invasive activity of breast cancer cells involves Arf6 activation)
橋本 茂, 橋本 あり, 小野寺 康仁, 梅本 勉, 佐藤 宏紀, 毛受 暁史, 佐邊 壽孝, 日本癌学会総会記事, 69回, 418, 419, Aug. 2010
日本癌学会, English - TGFβによって誘導される癌的EMTにおけるGEP100-Arf6-AMAP1シグナルとHGFRとの相互作用(HGFR-mediated GEP100-Arf6-AMAP1 pathway is an integral part for TGFβ-induced cancerous EMT and invasiveness)
橋本 あり, 平野 真理子, 梅本 勉, 小野寺 康仁, 佐藤 宏紀, 大塚 勇太郎, 橋本 茂, 佐邊 壽孝, 日本癌学会総会記事, 69回, 419, 419, Aug. 2010
日本癌学会, English - がん増殖を解くシグナル伝達研究の新展開 癌の悪性化における小胞輸送と糖代謝の役割(New frontiers of signal transduction toward understanding cancer growth Intracellular traffic and glucose metabolism in tumor malignancy)
小野寺 康仁, 佐邊 壽孝, 日本細胞生物学会大会講演要旨集, 62回, 105, 105, May 2010
(一社)日本細胞生物学会, English - 低酸素下におけるArf6活性化と癌の浸潤,EMT進行,幹細胞化との関連性
橋本茂, 橋本あり, 小野寺康仁, 梅本勉, 佐藤宏紀, 佐藤宏紀, 毛受暁史, 伊達洋至, 福田諭, 佐邊壽孝, 生化学, 83回・33回, ROMBUNNO.3T4-10, 10, 2010
(公社)日本生化学会, Japanese - シグナル伝達研究 I:因子から現象へ 4.がんの浸潤形質獲得過程における低分子量Gタンパク質Arf6シグナル伝達
橋本茂, 森重真毅, 小川栄治, 橋本あり, 小野寺康仁, 佐邊壽孝, 実験医学, 26, 15, 2349-2355, 15 Sep. 2008
Japanese - GEP100‐Arf6‐AMAP1‐cortactinシグナル経路は癌浸潤と血管新生に共通である
橋本あり, 橋本茂, 小川栄治, 小川栄治, 廣瀬まゆみ, 森重真毅, 毛受暁史, 小野寺康仁, 渋谷正史, 佐邊壽孝, 生化学, 81回・31回, 4S2-3, 3, 2008
(公社)日本生化学会, Japanese - 乳癌浸潤転移におけるEGFR‐GEP100‐Arf6‐AMAP1経路:微小環境との相互作用
佐邊壽孝, 橋本茂, 森重真毅, 橋本あり, 小川栄二, 矢野元, NAM Jinmin, 小野寺康仁, 生化学, 81回・31回, 4S14-3, 3, 2008
(公社)日本生化学会, Japanese - Fbx8によるユビキチン化を介するArf6の抑制的制御と上皮組織形態形成との関連の可能性について(Fbx8 makes Arf6 refractory to function via ubiquitination: implication in epithelial tissue organization)
矢野 元, 小野寺 康仁, 鳥井 郁子, 真崎 雄一, 橋本 茂, 辻村 亨, 佐邊 壽孝, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 80回・30回, 1T21, 3, Nov. 2007
(公社)日本生化学会, English - Invasion and metastasis
小野寺 康仁, Nam Jin-Min, Japanese journal of clinical medicine, 65, 0, 33, 38, Jun. 2007
日本臨床社, Japanese - CIN85, a Cbl-interacting multiadaptor protein, is a component of AMAP1-mediated breast cancer invasion machinery.
J. Nam, Y. Onodera, Y. Mazaki, H. Miyoshi, S. Hashimoto, H. Sabe, Nat. Immunol., 7, 724, 731, 2007 - 乳癌細胞の浸潤におけるAMAP1のユビキチン化の役割(Property of AMAP1 to be monoubiquitinated via binding with CIN85 and Cbl is crucial for breast cancer invasive activity)
Nam Jin-Min, 小野寺 康仁, 橋本 茂, 佐邊 壽孝, 日本癌学会総会記事, 65回, 295, 296, Sep. 2006
日本癌学会, English - 【分子メカニズムから解き明かす疾患のサイエンス】 癌 癌細胞の浸潤・転移におけるタンパク質の相互作用と動態の制御
小野寺 康仁, 佐邊 壽孝, 実験医学, 24, 10, 1433, 1439, Jun. 2006
(株)羊土社, Japanese - Breast cancer invasiveness: How does it emerge?
HASHIMOTO SHIGERU, ONODERA YASUHITO, 蛋白質 核酸 酵素, 51, 6, 803-810,496, 10 May 2006
Japanese - 浸潤性乳癌細胞のAMAP1/コータクチン相互作用インターフェースの癌浸潤阻害剤の標的としての評価
橋本 茂, 廣瀬 まゆみ, 橋本 あり, 森重 真毅, 山田 敦子, 小野寺 康仁, 小川 栄治, 和田 洋巳, 池上 貴久, 中川 敦史, 佐邊 壽孝, 日本癌学会総会記事, 64回, 309, 309, Sep. 2005
日本癌学会, Japanese - 浸潤・転移・血管新生研究の進歩 乳癌における浸潤形質獲得過程
佐邊 壽孝, 小野寺 康仁, ナム・ジンミン, 橋本 あり, 森重 真毅, 橋本 茂, 日本癌学会総会記事, 64回, 513, 513, Sep. 2005
日本癌学会, Japanese - Arf6ユビキチン化機構と乳癌細胞浸潤性獲得過程との関連性
矢野元, 橋本茂, 小野寺康仁, 小野寺康仁, 佐辺寿孝, 佐辺寿孝, 日本癌学会学術総会記事, 64th, 173, 15 Aug. 2005
Japanese - 乳癌細胞におけるArf6蛋白質の量的制御機構と浸潤性獲得
矢野 元, 古林 格, 小野寺 康仁, 橋本 茂, 佐邊 壽孝, 日本癌学会総会記事, 63回, 265, 265, Sep. 2004
日本癌学会, Japanese - Arf6は乳癌細胞の浸潤性獲得において必須の分子装置の一つである
橋本 茂, 小野寺 康仁, 橋本 あり, 森重 真毅, 田中 美和, 浜口 道成, 佐邊 壽孝, 日本癌学会総会記事, 63回, 265, 265, Sep. 2004
日本癌学会, Japanese - 浸潤性乳癌細胞におけるAMAP1の発現と機能
小野寺 康仁, 橋本 茂, 真崎 雄一, 橋本 あり, 森重 真毅, 松浦 成昭, 佐邊 壽孝, 日本癌学会総会記事, 63回, 267, 267, Sep. 2004
日本癌学会, Japanese
Research Themes
- 放射線治療効果向上を目指した新規細胞標的～インフルエンサー・セルの探索～
科学研究費助成事業
01 Apr. 2022 - 31 Mar. 2026
Nam JinMin, 小野寺 康仁, 白土 博樹, 清水 伸一
日本学術振興会, 基盤研究(B), 京都大学, 22H03023 - Optimization of cancer treatment based on intra-tumor metabolic geometry
Grants-in-Aid for Scientific Research
07 Oct. 2021 - 31 Mar. 2026
小野寺 康仁, 西岡 蒼一郎, Nam JinMin
本年度は、腫瘍内の代謝微小環境をより適切に再現するためのin vitro解析系の開発に着手した。超高線量率照射治療（FLASH-RT）による正常組織の保護作用においては、酸素濃度の急激な低下が関与していると考えられている。そこで、三次元培養系において組織内酸素濃度を適切に調整するための条件設定を試みた。酸素濃度により燐光が変化するプローブを用いて、三次元ゲルの高さ（厚み）方向の位置による酸素濃度への影響を検討した。また、酸素とグルコース濃度の同時調整を想定して、三次元培養系における「細胞特異的糖代謝制御法」の有用性の確認を行った。この方法では、特定の細胞にのみグルコースを供給するために特殊な「グルコース前駆体」を用いるが、当該物質は酸素と同様に三次元ゲルによって拡散が影響され得るため、三次元ゲル深部における十分なグルコース供給については検討の余地が残っていた。そこで三次元ゲル深部に培養したがん細胞の生存性や悪性形質を十分に担保できることを指標として、「細胞特異的糖代謝制御法」の適用可能性についての解析を行った。上述の「グルコース前駆体」として用いることができる物質は複数の種類が存在し、細胞内での代謝効率や、細胞への添加可能な濃度などがそれぞれ異なっている。それぞれの物質について、上記の目的における適性や、必要な添加濃度などの検討を行った。その結果、少なくとも一つについては十分な効率での「グルコース供給」が可能であることを確認した。
なお、本課題と関連のある業績として、腫瘍内代謝により起こる微小環境の酸性化に関する論文を発表した。その過程で、本課題においても有用な、細胞内外のpH測定を行うための実験系を確立することができた。
Japan Society for the Promotion of Science, Fund for the Promotion of Joint International Research (Fostering Joint International Research (B)), Hokkaido University, 21KK0140 - Research and development about helium and proton hybrid system with proton CT and Immuno-radiotherapy
Grants-in-Aid for Scientific Research
01 Apr. 2019 - 31 Mar. 2024
白土 博樹, 宮本 直樹, 高尾 聖心, 茶本 健司, 橋本 孝之, Nam JinMin, 西岡 健太郎, 小野寺 康仁, 松浦 妙子, 梅垣 菊男, 平田 雄一, 田中 創大, 清水 伸一
① 2019年度に決定した、短時間（0.1秒以下）でエネルギー変更可能な小型加速器の基本設計に基づき、小型加速器の要素技術の設計を行い、短時間（0.1秒以下）でエネルギー変更を可能とする回転ガントリーを含む照射・輸送系の磁場制御設計を行った。
② 陽子からヘリウムに短時間で加速粒子を変更できる混合加速方式を検討、2023年度に制作開始するべく、陽子線CTの機器としての仕様を検討した。
③ 陽子線CT値-ヘリウムSPR変換プロセスと、X線CT値利用時の精度を比較し、高エネルギー陽子線CTに必要な要素機器と制御方式の仕様を明確化した。
④ 高エネルギー陽子線ビームを照射する場合に、ビームの人体への入射方向を意図的に偏心させ、ノズルの外側から照射野中心に向かったビームアングルとするための加速器・照射系の検討を行った。
⑤ PD-1阻害剤およびPD-L1阻害剤を用いて、がん細胞の制御に最適なLET、ROSとミトコンドリアの分布を計測し、放射線と阻害剤の組み合わせによる相関を検討した。T細胞のPD-1阻害に関する条件検討を行っていたところ、当初の想定に反し、がん細胞での観察と類似の条件ではT細胞の観察が困難であることが判明した。T細胞を観察した上で条件決定することが不可欠であるため、T細胞のPD-1阻害に関する条件決定のための追加検討事項として、培養条件や使用する蛍光色素の種類を複数追加し、T細胞を観察するための至適条件の検討を行った。
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 19H03591 - The development of methods to control enzyme activity using protein-protein splicing and virus-like particles
Grants-in-Aid for Scientific Research
09 Jul. 2021 - 31 Mar. 2023
小野寺 康仁
初年度は、レンチウイルスの仕組みを利用した「ウイルス様粒子（virus-like particle, VLP）」を細胞外からのタンパク質導入法として用いて、これにタンパク質トランススプライシングを媒介するsplit-inteinを組み合わせることで、ピューロマイシン代謝酵素（puromycin N-acetyltransferase, PAC）の活性制御を試みた。レンチウイルスはヒト免疫不全ウイルス（HIV）のgag-pol（gp）遺伝子を用いているが、これにC末端側split-intein（IntC）を付加したPACのC末端側断片（PACC）を融合し、接続部分にはHIVプロテアーゼによる切断配列を挿入した。エンベロープタンパク質であるヒト水疱性口内炎ウイルスのGタンパク質（vesicular stomatitis virus G-protein, VSV-G）をコードするプラスミドDNAと、上記の改変HIV gpをコードするプラスミドDNAを同時に細胞内導入し、得られたVLPを単離したところ、その内部においてIntC-PACCがHIV gpより切り出されていることを確認した。また、N末端側split-intein（IntN）を付加したPACのN末端側断片（PACN）であるPACN-IntNを発現する細胞に上記のVLPを添加するとピューロマイシンへの耐性が生じることを確認した。以上の成果は国際学術誌において報告した。
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Exploratory), Hokkaido University, 21K19397 - Analysis of cell-to-cell communication to identify novel targets of radiotherapy
Grants-in-Aid for Scientific Research
01 Apr. 2019 - 31 Mar. 2022
Nam Jin-Min
Radiation therapy is widely used in cancer treatment, but understanding of the radiation effect on cancer cells is essential to improve therapeutic efficacy. To elucidate the molecular mechanisms of radiotherapy resistance mediated by these pathways, we analyzed vesicular trafficking pathways that specifically regulate factors such as extracellular vesicles secreted from cancer cells after irradiation. In this study, our data suggested that the secreted epiregulin into the extracellular space via Rab27b pathway is involved in radiotherapy resistance of glioblastoma cells.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), 19K08140 - Analysis of the mechanisms by which intra-tumor metabolic microenvironment leads to radioresistance
Grants-in-Aid for Scientific Research
01 Apr. 2018 - 31 Mar. 2021
Onodera Yasuhito
Using cell-specific regulation of glucose metabolism, we co-cultured glucose-sufficient and glucose-deficient cancer cells and established "metabolic cooperation" between them to analyze viability, intracellular metabolism, phenotypic changes, and response to radiation. The above experimental system revealed that cancer cells in a glucose-depleted state maintain their viability by obtaining metabolites from glucose-sufficient cells, and that oxidative stress and ER stress in the former cells are markedly suppressed. Estimation of the mediating substances and mechanisms, as well as the various phenotypic changes that occur in the metabolic cooperative state, are currently under analysis.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 18H02759 - Development of intracellular binary counter for recording the gene expression change
Grants-in-Aid for Scientific Research
01 Apr. 2016 - 31 Mar. 2019
Onodera Yasuhito
In this study, we sought to develop a set of genetic constructions which records the change of the expression (ON/OFF) of the gene of interest in each cell. In order to record as many times of the expression change as possible, we aimed for the construction of the binary counter. For the proper function, these constructs require the single copy integration into the target cell genome, which is currently achieved by genome editing followed by single cell cloning. In these processes, however, heterogeneity of the cells, which is also a primary subject of this study, will be inevitably compromised. In particular, for the analyses of cancer cells, loss of heterogeneity may lead to contradictory results. Therefore, we also sought to establish a novel genetic markers by which single copy integration of multiple genetic constructs can be easily achieved.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Hokkaido University, 16K14603 - Radiosensitization by mitochondrial ROS amplification
Grants-in-Aid for Scientific Research
01 Apr. 2015 - 31 Mar. 2018
Onodera Yasuhito, NAM Jin-Min
Arf6 and AMAP1 are highly expressed in different cancers including breast cancer, and mediate integrin recycling to plasma membrane to promote cancer invasion and metastasis. On the other hand, signaling downstream of integrins is well known to contribute to resistance to radiation and chemotherapy. In this study, we have shown that reduction of the integrin signaling by blockade of the Arf6-AMAP1 pathway inhibits intracellular mitochondrial distribution, resulting in aggregated mitochondria around the nucleus, which induces amplification of the reactive oxygen species (ROS) produced by ionizing radiation. We have also revealed molecules involved in the regulation of mitochondrial distribution downstream of integrins, and how they interact with each other. Further analyses may lead to the establishment of a new modality for radio-sensitization, which is based on the ROS amplification mediated by mitochondrial aggregation.
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (A), Hokkaido University, 15H05674 - Possible molecular mechanisms of normal cells and invasive breast cancer cells after radiation treatment
Grants-in-Aid for Scientific Research
01 Apr. 2013 - 31 Mar. 2016
NAM JINMIN, ONODERA YASUHITO
In this study, we investigated molecular mechanisms to improve the radiation therapy by targeting specific molecules which are involved in not only preservation of the functions in normal cell structure but also suppressing tumor growth, recurrence and metastasis. To find candidate genes, we performed microarray analysis in a mammary epithelial cell line which has basal polarity, or invasive breast cancer cell lines in three-dimensional laminin rich extracellular matrix (3D lrECM). We found that β1-integrin and its downstream molecules are involved in the disruption of basal polarity structure and invasive transition on non-malignant mammary epithelial cells in 3D lrECM. In addition, we also found that up-regulated integrin expression on the cell surface may have important roles in the invasive activity after radiation treatment in breast cancer cells.
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Hokkaido University, 25861050 - Regulation of interaction between cells and microenvironment by metabolic cooperation
Grants-in-Aid for Scientific Research
2013 - 2015
Onodera Yasuhito
We have previously reported that regulation of glucose metabolism is tightly connected to that of signaling cascades, which is fundamental for the establishment and maintenance of tissue architecture. In order to examine whether and how metabolic cooperation between different types of cells regulates the cell-cell and cell-microenvironment interaction and orchestrates cell behaviors, we have investigated new techniques to obtain double-layered structure made of different types of cells, which resembles acinar and tubular structures of mammary gland. We have also established a novel method to incorporate stable isotope-labeled glucose (e.g. 13C glucose) into only specific cells, which enables us to examine and manipulate metabolic cooperation between different types of cells in the microenvironment. Using these methods, the metabolic cooperation between luminal epithelial and myoepithelial cells of mammary gland is now investigated.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Hokkaido University, Principal investigator, Competitive research funding, 25650060 - Analysis of the molecular mechanism of radiation induced invasiveness
Grants-in-Aid for Scientific Research
2011 - 2012
NAM JinMin, ONODERA Yasuhito
Radiation therapy is the common treatment for breast cancer, and the primary goal of therapy is to prevent invasive recurrence. The detailed molecular mechanism of invasive recurrence after radiation therapy is not well understood. This study investigated the effect of radiation on a three-dimensional culture model of non-invasive breast cancer, and identified important molecule and possible molecular mechanism underlying emergence of invasiveness. Our results suggest that α5ss1-integrin via NF-κB signaling is an important mediator of invasive progression after radiation treatment on non-invasive breast cancer cells in three-dimensional extracellular matrix.
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Hokkaido University, 23791376 - Research for Real-time Tracking Medical Science
Grants-in-Aid for Scientific Research
2009 - 2012
SHIRATO Hiroki, HONMA Sato, TAMAKI Nagara, KUGE Yuji, MIZUTA Masahiro, DATE Hiroyuki, TANAKA Masaki, HAGA Hisashi, NISHIOKA Takeshi, KATO Motothugu, CHAMOTO Kenji, OIZUMI Satoshi, MATSUNAGA Naofumi, OKIMOTO Tomoaki, HAYAKAWA Kazushige, NISHIO Teiji, TADANO Shigeru, ISHIKAWA Masayori, ONODERA Yasuhito, SHIBUYA Keiko, HAMADA Toshiyuki, ONIMARU Rikiya, SHIMIZU Shinichi, TSUCHIYA Kazuhiko, KATOH Norio, KINOSHITA Rumiko, INOUE Tetsuya, ONODERA Syunsuke, TAKAO Seishin, KAGA Kichizo, TERAE Satoshi, ONODERA Yuya, SAKUHARA Yusuke, MANABE Noriko, ABO Daisuke, KATO Fumi, KHIN KHIN Tha, NAM Jin-min, SABE Hisataka, INUBUSHI Masayuki, SHINAGAWA Naofumi, KENNETH Sutherland
Up to now, in the field of basic medicine from micro-level to animal level, to track and quantify the three-dimensional spatial information along the time axis in real-time has not caught up with the accuracy in the field of clinical medicine. By handing big data of “motion in life, a new idea of real-time radiotherapy and a new precise four-dimensional computed tomography has been developed based on the data of actual tumor motion in the human body.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (A), Hokkaido University, 21249065 - Molecular mechanisms by which increased glucose metabolism regulates signaling pathways in cancer
Grants-in-Aid for Scientific Research
2010 - 2011
ONODERA Yasuhito
In this study, using three dimensional culture of breast cancer cells, the principal investigator examined mechanisms by which increased glucose metabolism regulates signaling pathways in cancer cells. In particular, the PI focused on hexosamine biosynsethis pathway(HBP), which branches from glycolytic pathway, and found that the enzymes in HBP play fundamental roles in signaling activity and malignant phenotype in cancer cells. Moreover, O-GlcNAc modification of proteins, which is downstream of HBP, and the enzyme responsible for O-GlcNAc modification were also found to be essential. Target proteins modified with O-GlcNAc specifically in cancer cells were also identified, and the roles of the proteins and the modification are now under investigation.
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Hokkaido University, Principal investigator, Competitive research funding, 22700868
