Updated on 2024/02/05

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

      More details

    Country:Japan

    researchmap

  2. Aichi Cancer Center, Research Institute

    2021.4 - 2022.1

      More details

  3. Aichi Cancer Center, Research Institute

    2017.4 - 2021.3

      More details

Professional Memberships 3

  1. 日本質量分析学会

    2021

      More details

  2. 日本癌学会

    2018

      More details

  3. 日本プロテオーム学会

    2008

      More details

 

Papers 11

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

    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     2023.12

     More details

    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

    PubMed

    researchmap

  2. 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

     More details

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

    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

    PubMed

    researchmap

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

    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

     More details

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

    DOI: 10.1021/acschembio.3c00046

    PubMed

    researchmap

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

     More details

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

    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

    PubMed

    researchmap

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

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

    SEPARATION SCIENCE PLUS     page: 2200121 - 2200121   2023.1

     More details

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

    DOI: 10.1002/sscp.202200121

    researchmap

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

    Mishiro-Sato

    Abstracts for Annual Meeting of Japanese Proteomics Society   Vol. 2023 ( 0 ) page: 3O49P31C - 3O49P31C   2023

     More details

    Language:Japanese   Publisher:Japanese Proteomics Society (Japan Human Proteome Organisation)  

    DOI: 10.14889/jhupo.2023.0.3o49p31c.0

    CiNii Research

  7. 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

     More details

    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

    PubMed

    researchmap

  8. 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

     More details

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

    researchmap

  9. 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

     More details

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

    researchmap

  10. 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

     More details

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

    researchmap

  11. Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation. 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

     More details

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

    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

    Web of Science

    PubMed

    researchmap

▼display all

MISC 1

  1. 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

KAKENHI (Grants-in-Aid for Scientific Research) 6

  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

      More details

    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。

    researchmap

  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)

      More details

    Authorship:Coinvestigator(s) 

    researchmap

  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)

      More details

    Authorship:Principal investigator 

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

    researchmap

  4. 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

      More details

    Authorship:Coinvestigator(s) 

    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。

    researchmap

  5. 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

      More details

    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.

    researchmap

  6. 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

      More details

    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.

    researchmap

▼display all