Updated on 2024/09/18

写真a

 
MISHIRO-SATO Emi
 
Organization
Institute of Transformative Bio-Molecules Designated lecturer
Title
Designated lecturer
Other name(s)
MISHIRO-SATO Emi
External link

Degree 1

  1. PhD (Agriculture) ( 2007.3   Kagoshima University ) 

Research Interests 1

  1. proteomics

Research Areas 1

  1. Life Science / Applied biochemistry  / Mass Spectrometry

Research History 3

  1. Nagoya University   Institute of Transformative Bio-Molecules

    2022.2

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    Country:Japan

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  2. Aichi Cancer Center, Research Institute

    2021.4 - 2022.1

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  3. Aichi Cancer Center, Research Institute

    2017.4 - 2021.3

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Professional Memberships 4

  1. Japanese Society for Biomedical Mass Spectrometry

    2022

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  2. 日本質量分析学会

    2021

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  3. 日本癌学会

    2018

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  4. 日本プロテオーム学会

    2008

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Papers 13

  1. Synthesis and preclinical testing of a selective beta-subtype agonist of thyroid hormone receptor ZTA-261

    Masakazu Nambo, Taeko Nishiwaki-Ohkawa, Akihiro Ito, Zachary T. Ariki, Yuka Ito, Yuuki Kato, Muhammad Yar, Jacky C. -H. Yim, Emily Kim, Elizabeth Sharkey, Keiko Kano, Emi Mishiro-Sato, Kosuke Okimura, Michiyo Maruyama, Wataru Ota, Yuko Furukawa, Tomoya Nakayama, Misato Kobayashi, Fumihiko Horio, Ayato Sato, Cathleen M. Crudden, Takashi Yoshimura

    Communications Medicine   Vol. 4 ( 1 ) page: 152   2024.8

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    Abstract

    Background

    Thyroid hormones (TH) regulate the basal metabolic rate through their receptors THRα and THRβ. TH activates lipid metabolism via THRβ, however, an excess amount of TH can lead to tachycardia, bone loss, and muscle wasting through THRα. In recent years, TH analogs that selectively bind to THRβ have gained attention as new agents for treating dyslipidemia and obesity, which continue to pose major challenges to public health worldwide.

    Methods

    We developed a TH analog, ZTA-261, by modifying the existing THRβ-selective agonists GC-1 and GC-24. To determine the THRβ-selectivity of ZTA-261, an in vitro radiolabeled TH displacement assay was conducted. ZTA-261 was intraperitoneally injected into a mouse model of high-fat diet-induced obesity, and its effectiveness in reducing body weight and visceral fat, and improving lipid metabolism was assessed. In addition, its toxicity in the liver, heart, and bone was evaluated.

    Results

    ZTA-261 is more selective towards THRβ than GC-1. Although ZTA-261 is less effective in reducing body weight and visceral fat than GC-1, it is as effective as GC-1 in reducing the levels of serum and liver lipids. These effects are mediated by the same pathway as that of T<sub>3</sub>, a natural TH, as evidenced by similar changes in the expression of TH-induced and lipid metabolism-related genes. The bone, cardiac, and hepatotoxicity of ZTA-261 are significantly lower than those of GC-1.

    Conclusions

    ZTA-261, a highly selective and less toxic THRβ agonist, has the potential to be used as a drug for treating diseases related to lipid metabolism.

    DOI: 10.1038/s43856-024-00574-z

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    Other Link: https://www.nature.com/articles/s43856-024-00574-z

  2. Recovery of extracellular vesicles from liquid samples using polyamine solution

    Kikuchi Arizumi, Naruse Azumi, Nonaka Kenichi, Mori Motoki, Yamada Miyuu, Kano Keiko, Mishiro-Sato Emi, Tsutsumiuchi Kaname

    Medical Mass Spectrometry   Vol. 8 ( 1 ) page: 35 - 42   2024.6

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    <p>Liquid biopsies mainly analyze nucleic acids and proteins in the free-state or extracellular vesicles (EVs) in non-solid biological samples, primarily blood. Collecting and processing liquid biopsy samples is challenging due to the large volume of samples and reagents and the need for special equipment. In a previous study, we reported a method for enriching free nucleic acids using a polyamine solution that is effective for liquid biopsy. We also investigated the reactivity of this method for EV recovery in cell culture supernatants using mass spectrometry. Samples were prepared from the cell line NCI-N87 supernatants after 48 h of culture in a serum-free medium. For comparison, samples were treated using a solution containing polyamines (PA method) or ultracentrifugation (UC method). The liquid chromatography-tandem mass spectrometry (LC-MS/MS) using the single-pot solid-phase-enhanced sample-preparation (SP3) method revealed differences between the two methods in the total ion chromatogram of the sample. However, the results of the Gene Ontology (GO) analysis showed that both methods achieved the best enrichment in GO terms related to EV. In addition, the volcano plot analysis revealed that proteins suggested to exist in EVs were distributed in areas consistent with both methods. These results indicated that the PA method can recover EV proteins in liquid samples, and their comprehensive analysis is possible using the SP3 method.</p>

    DOI: 10.24508/mms.2024.06.006

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  3. Isocitrate dehydrogenase 1 upregulation in urinary extracellular vesicles from proximal tubules of type 2 diabetic rats International journal

    Haruka Sei, Naoya Hirade, Kohei Kamiya, Fumie Nakashima, Jun Yoshitake, Keiko Kano, Emi Mishiro‐Sato, Ryosuke Kikuchi, Koji Uchida, Takahiro Shibata

    The FASEB Journal   Vol. 38 ( 10 ) page: e23688   2024.5

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    Diabetic nephropathy (DN) is a major cause of chronic kidney disease. Microalbuminuria is currently the most common non-invasive biomarker for the early diagnosis of DN. However, renal structural damage may have advanced when albuminuria is detected. In this study, we sought biomarkers for early DN diagnosis through proteomic analysis of urinary extracellular vesicles (uEVs) from type 2 diabetic model rats and normal controls. Isocitrate dehydrogenase 1 (IDH1) was significantly increased in uEVs from diabetic model rats at the early stage despite minimal differences in albuminuria between the groups. Calorie restriction significantly suppressed the increase in IDH1 in uEVs and 24-hour urinary albumin excretion, suggesting that the increase in IDH1 in uEVs was associated with the progression of DN. Additionally, we investigated the origin of IDH1-containing uEVs based on their surface sugar chains. Lectin affinity enrichment and immunohistochemical staining showed that IDH1-containing uEVs were derived from proximal tubules. These findings suggest that the increase in IDH1 in uEVs reflects pathophysiological alterations in the proximal tubules and that IDH1 in uEVs may serve as a potential biomarker of DN in the proximal tubules.

    DOI: 10.1096/fj.202400371R

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  4. Ser/Leu-swapped cell-free translation system constructed with natural/in vitro transcribed-hybrid tRNA set. International journal

    Tomoshige Fujino, Ryogo Sonoda, Taito Higashinagata, Emi Mishiro-Sato, Keiko Kano, Hiroshi Murakami

    Nature communications   Vol. 15 ( 1 ) page: 4143 - 4143   2024.5

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    The Ser/Leu-swapped genetic code can act as a genetic firewall, mitigating biohazard risks arising from horizontal gene transfer in genetically modified organisms. Our prior work demonstrated the orthogonality of this swapped code to the standard genetic code using a cell-free translation system comprised of 21 in vitro transcribed tRNAs. In this study, to advance this system for protein engineering, we introduce a natural/in vitro transcribed-hybrid tRNA set. This set combines natural tRNAs from Escherichia coli (excluding Ser, Leu, and Tyr) and in vitro transcribed tRNAs, encompassing anticodon-swapped tRNASerGAG and tRNALeuGGA. This approach reduces the number of in vitro transcribed tRNAs required from 21 to only 4. In this optimized system, the production of a model protein, superfolder green fluorescent protein, increases to 3.5-fold. With this hybrid tRNA set, the Ser/Leu-swapped cell-free translation system will stand as a potent tool for protein production with reduced biohazard concerns in future biological endeavors.

    DOI: 10.1038/s41467-024-48056-z

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  5. Lipid droplets in Arabidopsis thaliana leaves contain myosin-binding proteins and enzymes associated with furan-containing fatty acid biosynthesis Reviewed

    Yuto Omata, Reina Sato, Emi Mishiro-Sato, Keiko Kano, Haruko Ueda, Ikuko Hara-Nishimura, Takashi L. Shimada

    Frontiers in Plant Science   Vol. 15   page: 1331479   2024.3

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    <jats:p>Lipid droplets (LDs) are lipid storage organelles in plant leaves and seeds. Seed LD proteins are well known, and their functions in lipid metabolism have been characterized; however, many leaf LD proteins remain to be identified. We therefore isolated LDs from leaves of the leaf LD–overaccumulating mutant <jats:italic>high sterol ester 1</jats:italic> (<jats:italic>hise1</jats:italic>) of <jats:italic>Arabidopsis thaliana</jats:italic> by centrifugation or co-immunoprecipitation. We then performed LD proteomics by mass spectrometry and identified 3,206 candidate leaf LD proteins. In this study, we selected 31 candidate proteins for transient expression assays using a construct encoding the candidate protein fused with green fluorescent protein (GFP). Fluorescence microscopy showed that MYOSIN BINDING PROTEIN14 (MYOB14) and two uncharacterized proteins localized to LDs labeled with the LD marker. Subcellular localization analysis of MYOB family members revealed that MYOB1, MYOB2, MYOB3, and MYOB5 localized to LDs. LDs moved along actin filaments together with the endoplasmic reticulum. Co-immunoprecipitation of myosin XIK with MYOB2-GFP or MYOB14-GFP suggested that LD-localized MYOBs are involved in association with the myosin XIK–LDs. The two uncharacterized proteins were highly similar to enzymes for furan fatty acid biosynthesis in the photosynthetic bacterium <jats:italic>Cereibacter sphaeroides</jats:italic>, suggesting a relationship between LDs and furan fatty acid biosynthesis. Our findings thus reveal potential molecular functions of LDs and provide a valuable resource for further studies of the leaf LD proteome.</jats:p>

    DOI: 10.3389/fpls.2024.1331479

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  6. Measurement of the intracellular active metabolites of thiopurine drugs to evaluate the enzymatic activity of nudix hydrolase 15 in human blood samples. Reviewed International journal

    Hitomi Okamoto, Yoichi Tanaka, Yoshio Shibagaki, Satoshi Kuronuma, Yusuke Miyatani, Satoko Umeda, Emi Mishiro-Sato, Osamu Takeuchi, Seisuke Hattori, Taku Kobayashi, Mitsuru Okuwaki

    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences   Vol. 1234   page: 123993 - 123993   2024.2

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    Thiopurine is metabolized to 6-thio-(deoxy) guanosine triphosphate (6-thio-(d) GTP), which is then incorporated into DNA or RNA and causes cytotoxicity. Nudix hydrolase 15 (NUDT15) reduces the cytotoxic effects of thiopurine by converting 6-thio-(d) GTP to 6-thio-(d) guanosine monophosphate (6-thio-(d) GMP). NUDT15 polymorphisms like the Arg139Cys variant are strongly linked to thiopurine-induced severe leukocytopenia and alopecia. Therefore, measurement of NUDT15 enzymatic activity in individual patients can help predict thiopurine tolerability and adjust the dosage. We aimed to develop a quantitative assay for NUDT15 enzymatic activity in human blood samples. Blood samples were collected from donors whose NUDT15 genetic status was determined. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to assess the 6-thio-GTP metabolic activity in cell extracts. Because 6-thio-guanosine diphosphate (6-thio-GDP) and 6-thio-GMP were generated upon incubation of 6-thio-GTP with human blood cell extracts, the method detecting 6-thio-GTP, 6-thio-GDP, and 6-thio-GMP was validated. All three metabolites were linearly detected, and the lower limit of quantification (LLOQ) of 6-thio-GTP, 6-thio-GDP, and 6-thio-GMP were 5 μM, 1 μM, and 2 μM, respectively. Matrix effects of human blood cell extracts to detect 6-thio-GTP, 6-thio-GDP, and 6-thio-GMP were 99.0 %, 100.5 %, and 101.4 %, respectively, relative to the signals in the absence of blood cell extracts. The accuracy and precision of the method and the stability of the samples were also assessed. Using this established method, the genotype-dependent differences in NUDT15 activities were successfully determined using cell extracts derived from human blood cells with NUDT15 wild-type (WT) or Arg139Cys variant and 6-thio-GTP (100 μM) as a substrate (18.1, 14.9, and 6.43 μM/h/106 cells for WT, Arg139Cys heterozygous, and homozygous variant, respectively). We developed a method for quantifying intracellular NUDT15 activity in peripheral blood mononuclear cells (PBMCs), which we defined as the conversion of 6-thio-GTP to 6-thio-GMP. Although PBMCs preparation takes some time, its reproducibility in experiments makes it a promising candidate for clinical application. This method can tell the difference between WT and Arg139Cys homozygous blood samples. Even in patients with WT NUDT15, WT samples showed variations in NUDT15 activity, which may correlate with variations in thiopurine dosage.

    DOI: 10.1016/j.jchromb.2024.123993

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  7. TGF‐β signaling promotes desmoid tumor formation via CSRP2 upregulation Reviewed

    Yu Li, Teruaki Fujishita, Emi Mishiro‐Sato, Yasushi Kojima, Yanqing Niu, Makoto Mark Taketo, Yuya Urano, Tomohisa Sakai, Atsushi Enomoto, Yoshihiro Nishida, Masahiro Aoki

    Cancer Science   Vol. 115 ( 2 ) page: 401 - 411   2023.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    Abstract

    Desmoid tumors (DTs), also called desmoid‐type fibromatoses, are locally aggressive tumors of mesenchymal origin. In the present study, we developed a novel mouse model of DTs by inducing a local mutation in the Ctnnb1 gene, encoding β‐catenin in PDGFRA‐positive stromal cells, by subcutaneous injection of 4‐hydroxy‐tamoxifen. Tumors in this model resembled histologically clinical samples from DT patients and showed strong phosphorylation of nuclear SMAD2. Knockout of SMAD4 in the model significantly suppressed tumor growth. Proteomic analysis revealed that SMAD4 knockout reduced the level of Cysteine‐and‐Glycine‐Rich Protein 2 (CSRP2) in DTs, and treatment of DT‐derived cells with a TGF‐β receptor inhibitor reduced CSRP2 RNA levels. Knockdown of CSRP2 in DT cells significantly suppressed their proliferation. These results indicate that the TGF‐β/CSRP2 axis is a potential therapeutic target for DTs downstream of TGF‐β signaling.

    DOI: 10.1111/cas.16037

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  8. Decreased liver B vitamin-related enzymes as a metabolic hallmark of cancer cachexia Reviewed International journal

    Kojima, Y, Mishiro-Sato, E, Fujishita, T, Satoh, K, Kajino-Sakamoto, R, Oze, I, Nozawa, K, Narita, Y, Ogata, T, Matsuo, K, Muro, K, Taketo, M, Soga, T, Aoki, A

    Nat. Commun.   Vol. 14 ( 1 ) page: 6246 - 6246   2023.10

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    Cancer cachexia is a complex metabolic disorder accounting for ~20% of cancer-related deaths, yet its metabolic landscape remains unexplored. Here, we report a decrease in B vitamin-related liver enzymes as a hallmark of systemic metabolic changes occurring in cancer cachexia. Metabolomics of multiple mouse models highlights cachexia-associated reductions of niacin, vitamin B6, and a glycine-related subset of one-carbon (C1) metabolites in the liver. Integration of proteomics and metabolomics reveals that liver enzymes related to niacin, vitamin B6, and glycine-related C1 enzymes dependent on B vitamins decrease linearly with their associated metabolites, likely reflecting stoichiometric cofactor-enzyme interactions. The decrease of B vitamin-related enzymes is also found to depend on protein abundance and cofactor subtype. These metabolic/proteomic changes and decreased protein malonylation, another cachexia feature identified by protein post-translational modification analysis, are reflected in blood samples from mouse models and gastric cancer patients with cachexia, underscoring the clinical relevance of our findings.

    DOI: 10.1038/s41467-023-41952-w

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  9. Palmitoylation-Dependent Small-Molecule Fluorescent Probes for Live-Cell Golgi Imaging Reviewed

    Shunsuke Sawada, Masaru Yoshikawa, Keita Tsutsui, Tomoki Miyazaki, Keiko Kano, Emi Mishiro-Sato, Shinya Tsukiji

    ACS Chemical Biology   Vol. 18 ( 5 ) page: 1047 - 1053   2023.5

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    DOI: 10.1021/acschembio.3c00046

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  10. Discovery of 2,6-Dihalopurines as Stomata Opening Inhibitors: Implication of an LRX-Mediated H+-ATPase Phosphorylation Pathway Reviewed International journal

    Ayaka Ueda, Yusuke Aihara, Shinya Sato, Keiko Kano, Emi Mishiro-Sato, Hiroyuki Kitano, Ayato Sato, Kazuhiro J. Fujimoto, Takeshi Yanai, Kazuma Amaike, Toshinori Kinoshita, Kenichiro Itami

    ACS Chemical Biology   Vol. 18 ( 2 ) page: 347 - 355   2023.2

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    Stomata are pores in the leaf epidermis of plants and their opening and closing regulate gas exchange and water transpiration. Stomatal movements play key roles in both plant growth and stress responses. In recent years, small molecules regulating stomatal movements have been used as a powerful tool in mechanistic studies, as well as key players for agricultural applications. Therefore, the development of new molecules regulating stomatal movement and the elucidation of their mechanisms have attracted much attention. We herein describe the discovery of 2,6-dihalopurines, AUs, as a new stomatal opening inhibitor, and their mechanistic study. Based on biological assays, AUs may involve in the pathway related with plasma membrane H+-ATPase phosphorylation. In addition, we identified leucine-rich repeat extensin proteins (LRXs), LRX3, LRX4 and LRX5 as well as RALF, as target protein candidates of AUs by affinity based pull down assay and molecular dynamics simulation. The mechanism of stomatal movement related with the LRXs-RALF is an unexplored pathway, and therefore further studies may lead to the discovery of new signaling pathways and regulatory factors in the stomatal movement.

    DOI: 10.1021/acschembio.2c00771

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  11. An efficient in‐gel digestion method on small amounts of protein sample from large intact gel pieces Reviewed

    Keiko Kano, Saki Noda, Shinya Sato, Keiko Kuwata, Emi Mishiro‐Sato

    SEPARATION SCIENCE PLUS     page: 2200121 - 2200121   2023.1

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    DOI: 10.1002/sscp.202200121

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  12. The cAMP/PKA/CREB and TGF-β/SMAD4 pathways regulate stemness and metastatic potential in colorectal cancer cells Reviewed

    Fujishita T, Kojima Y, Kajino-Sakamoto R, Mishiro-Sato E, Shimizu Y, Hosoda W, Yamaguchi R, Taketo MM, Aoki M

    Cancer Research   Vol. 82 ( 22 ) page: 4179 - 4190   2022.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Association for Cancer Research ({AACR})  

    <jats:title>Abstract</jats:title>
    <jats:p>Metastasis is responsible for the majority of deaths of cancer patients. However, mechanisms governing metastasis in colorectal cancer (CRC) remain largely unknown. Here we investigated how CRC cells acquire metastatic potential using a novel mouse model of CRC that spontaneously develops liver metastasis, generated by introducing sporadic mutations of Ctnnb1, Kras, Trp53, and Smad4 (CKPS) genes. Proteomic analyses revealed elevated expression of CRC stem cell markers ALCAM (CD166) and PROM1 (CD133) in CRC cells from the metastatic model compared with those from a non-metastatic model. Spleen-to-liver metastasis assays using CRC cells derived from the CKPS model (CKPS cells) demonstrated the functional importance of ALCAM and PROM1 in initiating metastasis. Genetic and pharmacological analyses using CKPS cells in 2D and spheroid culture revealed that expression of ALCAM and PROM1 is regulated positively and negatively by the cAMP/PKA/CREB and TGF-β/SMAD4 pathways, respectively. Consistently, phospho-CREB was expressed in both primary and metastatic lesions of CKPS mice and CRC patients, and knockout of CREB in CKPS cells reduced their spheroid-forming and metastasis-initiating abilities. Treatment with a CREB inhibitor potentiated the effect of irinotecan in suppressing liver metastasis by CKPS cells. These results reveal the essential roles of ALCAM and PROM1, as well as their upstream regulators, the cAMP/PKA/CREB and TGF-β/SMAD4 pathways, in maintaining the stemness and metastatic potential of CRC cells and indicate that CREB inhibition may be a potential therapeutic strategy against metastatic CRC.</jats:p>

    DOI: 10.1158/0008-5472.can-22-1369

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  13. Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation. Reviewed International journal

    Tatsuhiro Sato, Satomi Mukai, Haruna Ikeda, Emi Mishiro-Sato, Ken Akao, Toshiyuki Kobayashi, Okio Hino, Wataru Shimono, Yoshio Shibagaki, Seisuke Hattori, Yoshitaka Sekido

    Molecular cancer research : MCR   Vol. 19 ( 5 ) page: 921 - 931   2021.5

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    Malignant mesothelioma (MM) is an aggressive tumor that typically develops after a long latency following asbestos exposure. Although mechanistic target of rapamycin complex 1 (mTORC1) activation enhances MM cell growth, the mTORC1 inhibitor everolimus has shown limited efficacy in clinical trials of MM patients. We explored the mechanism underlying mTORC1 activation in MM cells and its effects on cell proliferation and progression. Analysis of the expression profiles of 87 MMs from The Cancer Genome Atlas revealed that 40 samples (46%) displayed altered expression of RPTOR (mTORC1 component) and genes immediately upstream that activate mTORC1. Among them, we focused on RHEB and RHEBL1, which encode direct activators of mTORC1. Exogenous RHEBL1 expression enhanced MM cell growth, indicating that RHEB-mTORC1 signaling acts as a pro-oncogenic cascade. We investigated molecules that directly activate RHEBs, identifying SmgGDS as a novel RHEB-binding protein. SmgGDS knockdown reduced mTORC1 activation and inhibited the proliferation of MM cells with mTORC1 activation. Interestingly, SmgGDS displayed high binding affinity with inactive GDP-bound RHEBL1, and its knockdown reduced cytosolic RHEBL1 without affecting its activation. These findings suggest that SmgGDS retains GDP-bound RHEBs in the cytosol, whereas GTP-bound RHEBs are localized on intracellular membranes to promote mTORC1 activation. We revealed a novel role for SmgGDS in the RHEB-mTORC1 pathway and its potential as a therapeutic target in MM with aberrant mTORC1 activation. IMPLICATIONS: Our data showing that SmgGDS regulates RHEB localization to activate mTORC1 indicate that SmgGDS can be used as a new therapeutic target for MM exhibiting mTORC1 activation.

    DOI: 10.1158/1541-7786.MCR-20-0637

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MISC 24

  1. A hallmark of hepatic metabolic alterations in cancer cachexia

    小島康, 三城恵美, 武藤誠, 曽我朋義, 青木正博

    日本癌学会学術総会抄録集(Web)   Vol. 82nd   2023

  2. Analyzing Induction Mechanisms And Localized Proteins of Lipid Droplets under Stress Conditions in Leaves

    岩井裕也, 三城恵美, 加納圭子, 尾亦雄斗, 島田貴士, 島田貴士, 島田貴士

    日本植物生理学会年会(Web)   Vol. 64th   2023

  3. Guttation Droplets from Arabidopsis Hydathodes Contain Secretory Proteins

    吉田善葵, 三原衣織, 三城恵美, 佐藤伸哉, 加納圭子, 嶋田知生, 西村いくこ, 上田晴子, 上田晴子, 八木宏樹

    日本植物生理学会年会(Web)   Vol. 64th   2023

  4. シロイヌナズナを用いた溢泌液に含まれる分泌タンパク質及び排水組織発生の解析

    吉田善葵, 吉田善葵, 三原衣織, 三城恵美, 佐藤伸哉, 加納圭子, 嶋田知生, 西村いくこ, 近藤侑貴, 上田晴子, 上田晴子, 八木宏樹

    日本植物学会大会研究発表記録(CD-ROM)   Vol. 87th   2023

  5. The effect of orthokeratology lens wear on the protein composition of tear fluid

    清水友梨, 吉満円香, 平田ひかる, 加納圭子, 三城恵美, 角出泰造

    質量分析総合討論会講演要旨集   Vol. 71st   2023

  6. Elucidation of the mechanism of tumor progression via abnormal O-GlcNAcylation of nucleoporins.

    向井智美, 佐藤龍洋, 亀井保博, 加藤輝, 三城恵美, 三城恵美, 青木正博, 藪田紀一, 廣島健三, 廣島健三

    日本分子生物学会年会プログラム・要旨集(Web)   Vol. 46th   2023

  7. Metabolomic analysis of cancer cells by GC-MS using Hydrogen carrier gas

    加納圭子, 佐藤伸哉, 佐藤龍洋, 三城恵美

    JSBMS Letters   Vol. 48 ( Supplement )   2023

  8. The role of RhoC in colorectal cancer metastasis

    藤下晃章, 三城恵美, 武藤誠, 青木正博, 青木正博

    日本癌学会学術総会抄録集(Web)   Vol. 82nd   2023

  9. Functional analysis of acidic loop in polar localization of DPK1

    吉成晃, 吉成晃, 三城恵美, 加納圭子, 桑田啓子, FROMMER Wolf B., FROMMER Wolf B., FROMMER Wolf B., 中村匡良

    日本植物生理学会年会(Web)   Vol. 64th   2023

  10. Examination for the recovery of extracellular vesicles for liquid samples by polyamine

    菊池有純, 菊池有純, 成瀬有純, 野中健一, 野中健一, 森基希, 加納圭子, 三城恵美, 堤内要

    JSBMS Letters   Vol. 48 ( Supplement )   2023

  11. Hippo経路の破綻した悪性中皮腫におけるO-GlcNAc修飾の亢進を標的とした治療の可能性(Therapeutic potential of targeting enhanced O-GlcNAcylation in malignant mesothelioma with disrupted Hippo pathway)

    向井 智美, 佐藤 龍洋, 三城 恵美, 青木 正博, 藪田 紀一, 関戸 好孝

    日本癌学会総会記事   Vol. 81回   page: P - 3046   2022.9

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  12. がん悪液質のメタボロームおよびプロテオーム(Metabolomic and proteomic landscape of cancer cachexia)

    小島 康, 三城 恵美, 武藤 誠, 曽我 朋義, 青木 正博

    日本癌学会総会記事   Vol. 81回   page: P - 3019   2022.9

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  13. がん悪液質の病態生理解明と治療戦略の基盤構築 マウスモデルを用いた網羅的解析

    小島康, 三城恵美, 藤下晃章, 梶野リエ, 曽我朋義, 武藤誠, 青木正博

    愛知県がんセンター年報(Web)   ( 58 )   2022

  14. がんの発症・悪性化における微小環境の役割の解明 腸管腫瘍の悪性化におけるmTORC1経路の役割の解析

    藤下晃章, 三城恵美, 梶野リエ, 新間秀一, 曽我朋義, 武藤誠, 青木正博

    愛知県がんセンター年報(Web)   ( 58 )   2022

  15. TGF-β signaling promotes desmoid tumor formation in a mouse model

    李宇, 李宇, 藤下晃章, 三城恵美, 武藤誠, 榎本篤, 西田佳弘, 青木正博, 青木正博

    日本癌学会学術総会抄録集(Web)   Vol. 81st   2022

  16. Transposon-based screening of metastasis-related genes in a colorectal cancer mouse model

    藤下晃章, 梶野リエ, 三城恵美, 武藤誠, 青木正博, 青木正博

    日本癌学会学術総会抄録集(Web)   Vol. 81st   2022

  17. 転移の分子メカニズムの解明と予防・治療標的の探索 大腸がん自然発症・転移モデルを用いた転移メカニズムの解明と治療標的の同定

    藤下晃章, 三城恵美, 梶野リエ, 小島康, 山口類, 武藤誠, 青木正博

    愛知県がんセンター年報(Web)   ( 58 )   2022

  18. Elucidation of the mechanism of tumor progression via abnormal O-GlcNAc modification in malignant mesothelioma

    向井智美, 佐藤龍洋, 三城恵美, 三城恵美, 藪田紀一, 関戸好孝

    日本分子生物学会年会プログラム・要旨集(Web)   Vol. 45th   2022

  19. がん代謝:ワールブルグを超えて デュアルオミクス解析で明らかとなったがん悪液質に伴う肝臓の代謝変化の概要

    青木 正博, 三城 恵美, 曽我 朋義, 小島 康

    日本癌学会総会記事   Vol. 80回   page: [S6 - 5]   2021.9

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    Language:English   Publisher:(一社)日本癌学会  

    J-GLOBAL

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  20. 転移の分子メカニズムの解明と予防・治療標的の探索 大腸がん自然発症・転移モデルを用いた転移メカニズムの解明と治療標的の同定

    藤下晃章, 三城恵美, 梶野リエ, 小島康, 山口類, 青木正博

    愛知県がんセンター年報(Web)   ( 57 )   2021

  21. Elucidation of the mechanism of tumor progression via abnormal O-GlcNAc modification in malignant mesothelioma

    向井智美, 佐藤龍洋, 三城恵美, 青木正博, 藪田紀一, 関戸好孝

    日本分子生物学会年会プログラム・要旨集(Web)   Vol. 44th   2021

  22. がん悪液質の病態生理解明と治療戦略の基盤構築 マウスモデルを用いた網羅的解析

    小島康, 三城恵美, 藤下晃章, 梶野リエ, 曽我朋義, 武藤誠, 青木正博

    愛知県がんセンター年報(Web)   ( 57 )   2021

  23. Analysis of protein post-translational modifications in colorectal tumors

    三城恵美, 藤下晃章, 小島康, 梶野リエ, 田中努, 田近正洋, 青木正博

    日本プロテオーム学会大会プログラム・抄録集   Vol. 2021 (CD-ROM)   2021

  24. がんの発症・悪性化における微小環境の役割の解明 腸管腫瘍の悪性化におけるmTORC1経路の役割の解析

    藤下晃章, 三城恵美, 梶野リエ, 新間秀一, 曽我朋義, 武藤誠, 青木正博

    愛知県がんセンター年報(Web)   ( 57 )   2021

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KAKENHI (Grants-in-Aid for Scientific Research) 7

  1. 疾患状態を反映する代謝物アダクトームの解明

    Grant number:23K17449  2023.6 - 2027.3

    日本学術振興会  科学研究費助成事業  挑戦的研究(開拓)

    柴田 貴広, 中島 史恵, 三城 恵美, 服部 浩之, 中島 史恵, 佐藤恵美, 服部 浩之

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    Authorship:Coinvestigator(s) 

    疾患状態に起因する内因性代謝物や食品由来成分の代謝物の一部が、生体内のタンパク質に様々な付加体(アダクト)を形成していることが知られている。生体内タンパク質における代謝物アダクトの総体「代謝物アダクトーム」を明らかにすることができれば、ヒトの生体内環境や疾患状態を理解・評価できると考えられる。本研究では、代謝物アダクトーム解析法を確立し、生体内の状態や疾患状態を反映する代謝物アダクトの同定に挑戦する。

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  2. Molecular mechanisms that maintain stemness in metastatic colorectal cancer

    Grant number:22H02909  2022.4 - 2025.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

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    Authorship:Coinvestigator(s) 

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  3. The role and molecular mechanism of NAT10, an RNA-modifying enzyme, in colorectal cancer.

    Grant number:22K07201  2022.4 - 2025.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

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    Authorship:Principal investigator 

    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

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  4. Molecular mechanisms that maintain stemness in metastatic colorectal cancer

    Grant number:23K24170  2022.4 - 2025.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Coinvestigator(s) 

  5. 臨床応用を指向したがん悪液質病態解明

    Grant number:21K07140  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    小島 康, 三城 恵美, 佐藤恵美

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    がん悪液質は、体重減少・骨格筋萎縮・食思不振を主徴とする臨床症候群である。進行がん患者の約8割が、悪液質を発症し、世界では年間900万人近くのがん患者が悪液質を発症していると推定されている。現在、悪液質の本態は不明で、実効性のある早期診断方法や治療介入法が存在しない。本研究では、悪液質モデル動物および臨床検体を組み合わせ、総合的に解析して悪液質治療薬の開発基盤を構築する。
    多くの進行がん患者は、骨格筋萎縮を主徴とする「がん悪液質」に苦しむことが多い。しかし、その病態生理は不明な点が多く、根本的な治療方法は開発されていない。申請者らは、がん悪液質モデルマウスを解析したところ、骨格筋より、むしろ肝臓で激しい代謝変化が生じることを見出した。さらに悪液質肝臓では代謝産物であるNAD(nicotinamide adenine dinucleotide)濃度が半減すること、そしてNAD消費酵素であるNNMTおよびCD38の発現が上昇することを観察した。NADは、酸化還元反応の補酵素として、またSirtuinやPARPなど重要な生理機能に関わる酵素の基質として働く代謝物である。近年、NADの細胞内濃度減少は、ヒトの骨格筋萎縮や神経変性と強く相関することを示唆する報告が相次いでいる。NNMT (nicotinamide N-methyltransferase)は、NAD合成の原材料であるNAM(nicotinamide)をMNA(1-methyl-nicotinamide)に変換する。MNAは尿中に排出されるので、NNMT活性上昇は、NAM濃度低下、NAD合成抑制につながると想定されている。CD38は、NADを分解する酵素である。CD38 ノックアウトマウスでは、生体のNAD濃度が劇的に上昇することが報告されている(肝臓では10倍近く上昇)。この表現型は、CD38が、生体でNAD濃度をコントロールしている主要酵素であることを強く示唆している。NNMTおよびCD38は、NADサルベージ回路から、それぞれNAMおよびNADを取り除き、生体の総NAD量を減少する方向に作用する。本研究では、NNMT阻害剤およびCD38阻害剤を悪液質モデルマウスに投与して検証して、悪液質におけるNAD代謝に与える影響、および悪液質治療薬としての可能性を探ることを目的とする
    先行して取り組んでいたApc/Smad4/Nnmt-/-の繁殖効率が著しく不良で、Apc/Smad4/Nnmt-/-による解析は困難であると判断して中止した。C57BL/6由来のLLCおよびB16細胞株移植を用いた悪液質モデルは、先行論文が多数ある。その作出を試みたが、申請者の研究室ではうまく悪液質を発症させることができなかった。そのため研究室内で樹立されていたC57BL/6由来の大腸がん細胞株を移植、培養尾のサイクルを複数回実施したところ、悪液質症状の発症するサブクローンを得た。またCD38/CD157ノックアウトマウスも入手して繁殖を開始した。さらに大腸がん細胞株のバックアップとして、悪液質発症が可能であるC57BL/6由来のマウス膵がん細胞株も入手した。
    手元にあるマウス大腸がん細胞株、マウス膵臓がん細胞株を用いた悪液質モデルの条件検討を慎重に実施して、NnmtおよびCD38/CD157ノックアウトマウスへの移植実験に移行する。またNnmtおよびCD38阻害剤の薬理実験のセットアップにも着手する。

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  6. Analysis of novel post-translational modifications in colorectal cancer

    Grant number:19K07656  2019.4 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Mishiro-Sato Emi

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    Authorship:Principal investigator 

    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    To explore new therapeutic targets for colorectal cancer, we aimed to elucidate the biological significance of variations in acylation modifications in colorectal cancer tumor tissues with the aim of developing novel colorectal cancer therapies.
    To validate the clinical significance of the modification changes found in mouse models and to explore therapeutic targets, we performed proteomic analysis and comprehensive analysis of acylation-related post-translational modifications using colorectal tumor tissues from familial adenomatous polyposis (FAP) patients. Inhibition of NAT10, which was selected as a target, showed growth inhibition in tumor-derived organoids and colorectal cancer cell lines from FAP patients, and the mechanism is now being elucidated.

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  7. Molecular mechanisms and preventive/therapeutic targets of colon cancer metastasis

    Grant number:18H02686  2018.4 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    AOKI MASAHIRO

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    Authorship:Coinvestigator(s) 

    In this study, we identified a downstream target of the novel colorectal cancer metastasis suppressor HNRNPLL, revealed that its alternative splicing is regulated by HNRNPLL, and uncovered differences in the function and subcellular localization of its splicing isoforms. We also identified a transcription factor, MYB, as a regulator of HNRNPLL expression and found that decreased expression of MYB contributes to decreased expression of HNRNPLL in epithelial-mesenchymal transition of colorectal cancer cells. On the other hand, analysis of a newly developed mouse model of metastatic colorectal cancer revealed that two molecules known as stem cell markers are functionally important for colorectal cancer cell metastasis and that their expression is negatively regulated by SMAD4. Furthermore, we discovered a signaling pathway that positively regulates their expression and demonstrated that inhibition of this pathway reduces the ability of colorectal cancer cells to form metastasis.

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