2023/12/14 更新

写真a

マツバラ ミサコ
松原 三佐子
MATSUBARA Misako
担当
大学院獣医学研究科 獣医学専攻 准教授
獣医学部 獣医学科
職名
准教授
所属
獣医学研究院

担当・職階

  • 大学院獣医学研究科 獣医学専攻 

    准教授  2022年04月 - 継続中

  • 獣医学部 獣医学科 

    准教授  2022年04月 - 継続中

取得学位

  • 医学博士 ( 和歌山県立医科大学 )

研究分野

  • ライフサイエンス / 細胞生物学

論文

  • Nitric Oxide Derived from Cytoglobin-Deficient Hepatic Stellate Cells Causes Suppression of Cytochrome c Oxidase Activity in Hepatocytes

    Okina Y.

    Antioxidants and Redox Signaling   38 ( 7-9 )   463 - 479   2023年03月( ISSN:15230864

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  • Cytoglobin attenuates pancreatic cancer growth via scavenging reactive oxygen species

    Hoang D.V.

    Oncogenesis   11 ( 1 )   2022年12月

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  • Cloaking the ACE2 receptor with salivary cationic proteins inhibits SARS-CoV-2 entry

    Yoshizato K.

    Journal of Biochemistry   172 ( 4 )   205 - 216   2022年10月( ISSN:0021924X

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  • Soluble Immune Checkpoint Protein CD27 Is a Novel Prognostic Biomarker of Hepatocellular Carcinoma Development in Hepatitis C Virus–Sustained Virological Response Patients

    Dong M.P.

    American Journal of Pathology   192 ( 10 )   1379 - 1396   2022年10月( ISSN:00029440

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  • Cancer cells produce liver metastasis via gap formation in sinusoidal endothelial cells through proinflammatory paracrine mechanisms

    Hoang T.H.

    Science Advances   8 ( 39 )   2022年09月

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  • Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion 査読

    澤井 仁美, 松原 三佐子, 及川 大輔, 徳永 文稔, 河田 則文

    Redox Biology   52   102286   2022年( ISSN:22132317

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  • Anti-fibrotic treatments for chronic liver diseases: The present and the future

    Odagiri N.

    Clinical and Molecular Hepatology   27 ( 3 )   2021年07月( ISSN:22872728

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  • Hexa Histidine–Tagged Recombinant Human Cytoglobin Deactivates Hepatic Stellate Cells and Inhibits Liver Fibrosis by Scavenging Reactive Oxygen Species

    Dat N.Q.

    Hepatology   73 ( 6 )   2527 - 2545   2021年06月( ISSN:02709139

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  • Stress can attenuate hepatic lipid accumulation via elevation of hepatic β-muricholic acid levels in mice with nonalcoholic steatohepatitis

    Takada S.

    Laboratory Investigation   101 ( 2 )   193 - 203   2021年02月( ISSN:00236837

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  • TGF-β1-driven reduction of cytoglobin leads to oxidative DNA damage in stellate cells during non-alcoholic steatohepatitis

    Okina Y.

    Journal of Hepatology   73 ( 4 )   882 - 895   2020年10月( ISSN:01688278

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  • 抗線維化薬開発の最新情報

    松原 三佐子, 河田 則文

    日本消化器病学会雑誌   117 ( 1 )   52 - 63   2020年01月( ISSN:04466586

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    <p>肝線維化は,慢性的に繰り返し発生する細胞傷害に呼応して肝臓内に過剰な結合組織が蓄積することに由来する,組織の瘢痕化を反映する.その終末像である肝硬変では肝機能不全や門脈圧亢進症,さらには高頻度に肝細胞癌を合併する.しかし,肝線維症はいまだ有効な治療法が確立されておらず,重症化した場合の根本的治療法は肝移植に限られる.肝線維化の病態生理に関する研究は,その中心的な役割を担う肝星細胞の活性化機序やコラーゲン産生と分解の制御機構の解明が進み,この数十年で飛躍的な進歩を遂げた.本稿では,肝線維化研究の現状を概説するとともに,新規抗線維化治療法の開発に向けた今後の展望に言及する.</p>

    DOI: 10.11405/nisshoshi.117.52

    PubMed

    CiNii Article

  • Involvement of ERK1/2 activation in the gene expression of senescence-associated secretory factors in human hepatic stellate cells

    Odagiri N.

    Molecular and Cellular Biochemistry   455 ( 1-2 )   7 - 19   2019年05月( ISSN:03008177

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  • Association between HLA-DQA1/DRB1 polymorphism and development of hepatocellular carcinoma during entecavir treatment

    Kozuka R.

    Journal of Gastroenterology and Hepatology (Australia)   34 ( 5 )   937 - 946   2019年05月( ISSN:08159319

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  • Selective overexpression of cytoglobin in stellate cells attenuates thioacetamide-induced liver fibrosis in mice. 査読

    Nguyen Thi Thanh Hai, Le Thi Thanh Thuy, Akira Shiota, Chiho Kadono, Atsuko Daikoku, Dinh Viet Hoang, Ninh Quoc Dat, Misako Sato-Matsubara, Katsutoshi Yoshizato, Norifumi Kawada

    Scientific reports   8 ( 1 )   17860 - 17860   2018年12月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Cytoglobin (CYGB), discovered in hepatic stellate cells (HSCs), is known to possess a radical scavenger function, but its pathophysiological roles remain unclear. Here, for the first time, we generated a new transgenic (TG) mouse line in which both Cygb and mCherry reporter gene expression were under the control of the native Cygb gene promoter. We demonstrated that the expression of Cygb-mCherry was related to endogenous Cygb in adult tissues by tracing mCherry fluorescence together with DNA, mRNA, and protein analyses. Administration of a single dose (50 mg/kg) of thioacetamide (TAA) in Cygb-TG mice resulted in lower levels of alanine transaminase and oxidative stress than those in WT mice. After 10 weeks of TAA administration, Cygb-TG livers exhibited reduced neutrophil accumulation, cytokine expression and fibrosis but high levels of quiescent HSCs. Primary HSCs isolated from Cygb-TG mice (HSCCygb-TG) exhibited significantly decreased mRNA levels of α-smooth muscle actin (αSMA), collagen 1α1, and transforming growth factor β-3 after 4 days in culture relative to WT cells. HSCsCygb-TG were resistant to H2O2-induced αSMA expression. Thus, cell-specific overexpression of Cygb attenuates HSC activation and protects mice against TAA-induced liver fibrosis presumably by maintaining HSC quiescence. Cygb is a potential new target for antifibrotic approaches.

    DOI: 10.1038/s41598-018-36215-4

    PubMed

  • 今月の特集1 肝線維化をcatch 肝線維化のメカニズム

    小田桐 直志, 松原 三佐子, 河田 則文

    臨床検査   62 ( 5 )   586 - 592   2018年05月( ISSN:04851420

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  • Fibroblast growth factor 2 (FGF2) regulates cytoglobin expression and activation of human hepatic stellate cells via JNK signaling. 査読

    Misako Sato-Matsubara, Tsutomu Matsubara, Atsuko Daikoku, Yoshinori Okina, Lisa Longato, Krista Rombouts, Le Thi Thanh Thuy, Jun Adachi, Takeshi Tomonaga, Kazuo Ikeda, Katsutoshi Yoshizato, Massimo Pinzani, Norifumi Kawada

    The Journal of biological chemistry   292 ( 46 )   18961 - 18972   2017年11月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Cytoglobin (CYGB) belongs to the mammalian globin family and is exclusively expressed in hepatic stellate cells (HSCs) in the liver. In addition to its gas-binding ability, CYGB is relevant to hepatic inflammation, fibrosis, and cancer because of its anti-oxidative properties; however, the regulation of CYGB gene expression remains unknown. Here, we sought to identify factors that induce CYGB expression in HSCs and to clarify the molecular mechanism involved. We used the human HSC cell line HHSteC and primary human HSCs isolated from intact human liver tissues. In HHSteC cells, treatment with a culture supplement solution that included fibroblast growth factor 2 (FGF2) increased CYGB expression with concomitant and time-dependent α-smooth muscle actin (αSMA) down-regulation. We found that FGF2 is a key factor in inducing the alteration in both CYGB and αSMA expression in HHSteCs and primary HSCs and that FGF2 triggered the rapid phosphorylation of both c-Jun N-terminal kinase (JNK) and c-JUN. Both the JNK inhibitor PS600125 and transfection of c-JUN-targeting siRNA abrogated FGF2-mediated CYGB induction, and conversely, c-JUN overexpression induced CYGB and reduced αSMA expression. Chromatin immunoprecipitation analyses revealed that upon FGF2 stimulation, phospho-c-JUN bound to its consensus motif (5'-TGA(C/G)TCA), located -218 to -222 bases from the transcription initiation site in the CYGB promoter. Of note, in bile duct-ligated mice, FGF2 administration ameliorated liver fibrosis and significantly reduced HSC activation. In conclusion, FGF2 triggers CYGB gene expression and deactivation of myofibroblastic human HSCs, indicating that FGF2 has therapeutic potential for managing liver fibrosis.

    DOI: 10.1074/jbc.M117.793794

    PubMed

  • Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection.

    Matsuura K, Sawai H, Ikeo K, Ogawa S, Iio E, Isogawa M, Shimada N, Komori A, Toyoda H, Kumada T, Namisaki T, Yoshiji H, Sakamoto N, Nakagawa M, Asahina Y, Kurosaki M, Izumi N, Enomoto N, Kusakabe A, Kajiwara E, Itoh Y, Ide T, Tamori A, Matsubara M, Kawada N, Shirabe K, Tomita E, Honda M, Kaneko S, Nishina S, Suetsugu A, Hiasa Y, Watanabe H, Genda T, Sakaida I, Nishiguchi S, Takaguchi K, Tanaka E, Sugihara J, Shimada M, Kondo Y, Kawai Y, Kojima K, Nagasaki M, Tokunaga K, Tanaka Y, Japanese Genome-Wide Association Study Group for Viral Hepatitis

    Gastroenterology   152 ( 6 )   1383 - 1394   2017年05月( ISSN:0016-5085

  • New player in tumor-stromal interaction: Granulin as a novel therapeutic target for pancreatic ductal adenocarcinoma liver metastasis 査読

    Misako Sato-Matsubara, Norifumi Kawada

    Hepatology   65 ( 1 )   374 - 376   2017年01月( ISSN:1527-3350

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/hep.28849

    PubMed

  • Improved proteome and phosphoproteome analysis on a cation exchanger by a combined acid and salt gradient 査読

    Jun Adachi, Kazunari Hashiguchi, Maiko Nagano, Misako Sato-Matsubara, Ayako Sato, Kazuna Fukamizu, Yasushi Ishihama, Takeshi Tomonaga

    Analytical Chemistry   88 ( 16 )   7899 - 7903   2016年08月( ISSN:1520-6882

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    掲載種別:研究論文(学術雑誌)  

    Currently used elution methods for strong cation exchange (SCX) chromatography are based on two principles: salt and pH gradient. In this paper, we report the first observation of peptide elution by acid gradient. The degree of peptide separation using C18-SCX StageTip was greatly improved by our acid and salt-based elution method compared with a salt-based elution method. This development enabled us to identify over 22 000 phosphopeptides from 2 mg of protein without labor-intensive sample preparation. Our method is simple, robust, scalable, and low-cost and can be easily implemented without any special equipment or techniques.

    DOI: 10.1021/acs.analchem.6b01232

  • 肝線維化進展の分子機構

    松原 三佐子

    肝胆膵   73巻6号   873   2016年

  • Differential Proteome Analysis Identifies TGF-β-Related Pro-Metastatic Proteins in a 4T1 Murine Breast Cancer Model. 査読

    Misako Sato-Matsubara, Tsutomu Matsubara, Jun Adachi, Yuuki Hashimoto, Kazuna Fukamizu, Marina Kishida, Yu-An Yang, Lalage M Wakefield, Takeshi Tomonaga

    PloS one   10 ( 5 )   e0126483   2015年

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Transforming growth factor-β (TGF-β) has a dual role in tumorigenesis, acting as either a tumor suppressor or as a pro-oncogenic factor in a context-dependent manner. Although TGF-β antagonists have been proposed as anti-metastatic therapies for patients with advanced stage cancer, how TGF-β mediates metastasis-promoting effects is poorly understood. Establishment of TGF-β-related protein expression signatures at the metastatic site could provide new mechanistic information and potentially allow identification of novel biomarkers for clinical intervention to discriminate TGF-β oncogenic effects from tumor suppressive effects. In the present study, we found that systemic administration of the TGF-β receptor kinase inhibitor, SB-431542, significantly inhibited lung metastasis from transplanted 4T1 mammary tumors in Balb/c mice. The differentially expressed proteins in the comparison of lung metastases from SB-431542 treated and control vehicle-treated groups were analyzed by a quantitative LTQ Orbitrap Velos system coupled with stable isotope dimethyl labeling. A total of 36,239 peptides from 6,694 proteins were identified, out of which 4,531 proteins were characterized as differentially expressed. A subset of upregulated proteins in the control group was validated by western blotting and immunohistochemistry. The eukaryotic initiation factor (eIF) family members constituted the most enriched protein pathway in vehicle-treated compared with SB-43512-treated lung metastases, suggesting that increased protein expression of specific eIF family members, especially eIF4A1 and eEF2, is related to the metastatic phenotype of advanced breast cancer and can be down-regulated by TGF-β pathway inhibitors. Thus our proteomic approach identified eIF pathway proteins as novel potential mediators of TGF-β tumor-promoting activity.

    DOI: 10.1371/journal.pone.0126483

    PubMed

  • Brightfield proximity ligation assay reveals both canonical and mixed transforming growth factor-β/bone morphogenetic protein Smad signaling complexes in tissue sections. 査読

    Kathleen C Flanders, Christopher D Heger, Catherine Conway, Binwu Tang, Misako Sato-Matsubara, Samuel L Dengler, Paul K Goldsmith, Stephen M Hewitt, Lalage M Wakefield

    The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society   62 ( 12 )   846 - 63   2014年12月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Transforming growth factor-β (TGF-β) is an important regulator of cellular homeostasis and disease pathogenesis. Canonical TGF-β signaling occurs through Smad2/3-Smad4 complexes; however, recent in vitro studies suggest that elevated levels of TGF-β may activate a novel mixed Smad complex (Smad2/3-Smad1/5/9), which is required for some of the pro-oncogenic activities of TGF-β. To determine if mixed Smad complexes are evident in vivo, we developed antibodies that can be used with a proximity ligation assay to detect either canonical or mixed Smad complexes in formalin-fixed paraffin-embedded sections. We demonstrate high expression of mixed Smad complexes in the tissues from mice genetically engineered to express high levels of TGF-β1. Mixed Smad complexes were also prominent in 15-16 day gestation mouse embryos and in breast cancer xenografts, suggesting important roles in embryonic development and tumorigenesis. In contrast, mixed Smad complexes were expressed at extremely low levels in normal adult mouse tissue, where canonical complexes were correspondingly higher. We show that this methodology can be used in archival patient samples and tissue microarrays, and we have developed an algorithm to quantitate the brightfield read-out. These methods will allow quantitative analysis of cell type-specific Smad signaling pathways in physiological and pathological processes.

    DOI: 10.1369/0022155414550163

    PubMed

  • Definition of Smad3 phosphorylation events that affect malignant and metastatic behaviors in breast cancer cells 査読

    Eunjin Bae, Misako Sato-Matsubara, Ran-Ju Kim, Mi-Kyung Kwak, Kazuhito Naka, Jungsoo Gim, Mitsutaka Kadota, Binwu Tang, Kathleen C. Flanders, Tae-Aug Kim, Sun-Hee Leem, Taesung Park, Fang Liu, Lalage M. Wakefield, Seong-Jin Kim, Akira Ooshima

    Cancer Research   74 ( 21 )   6139 - 6149   2014年11月( ISSN:1538-7445

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    掲載種別:研究論文(学術雑誌)  

    Smad3, a major intracellular mediator of TGFβ signaling, functions as both a positive and negative regulator in carcinogenesis. In response to TGFβ, the TGFβ receptor phosphorylates serine residues at the Smad3 C-tail. Cancer cells often contain high levels of the MAPK and CDK activities, which can lead to the Smad3 linker region becoming highly phosphorylated. Here, we report, for the first time, that mutation of the Smad3 linker phosphorylation sites markedly inhibited primary tumor growth, but significantly increased lung metastasis of breast cancer cell lines. In contrast, mutation of the Smad3 C-tail phosphorylation sites had the opposite effect. We show that mutation of the Smad3 linker phosphorylation sites greatly intensifies all TGFβ-induced responses, including growth arrest, apoptosis, reduction in the size of putative cancer stem cell population, epithelial-mesenchymal transition, and invasive activity. Moreover, all TGFβ responses were completely lost on mutation of the Smad3 C-tail phosphorylation sites. Our results demonstrate a critical role of the counterbalance between the Smad3 C-tail and linker phosphorylation in tumorigenesis and metastasis. Our findings have important implications for therapeutic intervention of breast cancer.

    DOI: 10.1158/0008-5472.CAN-14-0803

    PubMed

  • An integrated genomic approach identifies persistent tumor suppressive effects of transforming growth factor-β in human breast cancer. 査読

    Misako Sato-Matsubara, Mitsutaka Kadota, Binwu Tang, Howard H Yang, Yu-an Yang, Mengge Shan, Jia Weng, Michael A Welsh, Kathleen C Flanders, Yoshiko Nagano, Aleksandra M Michalowski, Robert J Clifford, Maxwell P Lee, Lalage M Wakefield

    Breast cancer research : BCR   16 ( 3 )   R57   2014年06月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    INTRODUCTION: Transforming growth factor-βs (TGF-βs) play a dual role in breast cancer, with context-dependent tumor-suppressive or pro-oncogenic effects. TGF-β antagonists are showing promise in early-phase clinical oncology trials to neutralize the pro-oncogenic effects. However, there is currently no way to determine whether the tumor-suppressive effects of TGF-β are still active in human breast tumors at the time of surgery and treatment, a situation that could lead to adverse therapeutic responses. METHODS: Using a breast cancer progression model that exemplifies the dual role of TGF-β, promoter-wide chromatin immunoprecipitation and transcriptomic approaches were applied to identify a core set of TGF-β-regulated genes that specifically reflect only the tumor-suppressor arm of the pathway. The clinical significance of this signature and the underlying biology were investigated using bioinformatic analyses in clinical breast cancer datasets, and knockdown validation approaches in tumor xenografts. RESULTS: TGF-β-driven tumor suppression was highly dependent on Smad3, and Smad3 target genes that were specifically enriched for involvement in tumor suppression were identified. Patterns of Smad3 binding reflected the preexisting active chromatin landscape, and target genes were frequently regulated in opposite directions in vitro and in vivo, highlighting the strong contextuality of TGF-β action. An in vivo-weighted TGF-β/Smad3 tumor-suppressor signature was associated with good outcome in estrogen receptor-positive breast cancer cohorts. TGF-β/Smad3 effects on cell proliferation, differentiation and ephrin signaling contributed to the observed tumor suppression. CONCLUSIONS: Tumor-suppressive effects of TGF-β persist in some breast cancer patients at the time of surgery and affect clinical outcome. Carefully tailored in vitro/in vivo genomic approaches can identify such patients for exclusion from treatment with TGF-β antagonists.

    DOI: 10.1186/bcr3668

    PubMed

  • A novel mechanism of keratin cytoskeleton organization through casein kinase Ia and FAM83H in colorectal cancer 査読

    Takahisa Kuga, Hideaki Kume, Naoko Kawasaki, Misako Sato, Jun Adachi, Takashi Shiromizu, Isamu Hoshino, Takanori Nishimori, Hisahiro Matsubara, Takeshi Tomonaga

    Journal of Cell Science   126 ( 20 )   4721 - 4731   2013年( ISSN:0021-9533

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    掲載種別:研究論文(学術雑誌)  

    Keratin filaments form cytoskeletal networks in epithelial cells. Dynamic rearrangement of keratin filament networks is required for epithelial cells to perform cellular processes such as cell migration and polarization
    however, the mechanism governing keratin filament rearrangement remains unclear. Here, we describe a novel mechanism of keratin cytoskeleton organization mediated by casein kinase Ia (CK-1a) and a newly identified keratin-associated protein, FAM83H. Knockdown of FAM83H induces keratin filament bundling, whereas overexpression of FAM83H disassembles keratin filaments, suggesting that FAM83H regulates the filamentous state of keratins. Intriguingly, keratin filament bundling is concomitant with the dissociation of CK-1a from keratin filaments, whereas aberrant speckle-like localization of CK-1a is observed concomitantly with keratin filament disassembly. Furthermore, CK-1a inhibition, similar to FAM83H knockdown, causes keratin filament bundling and reverses keratin filament disassembly induced by FAM83H overexpression, suggesting that CK-1a mediates FAM83H-dependent reorganization of keratin filaments. Because the N-terminal region of FAM83H interacts with CK-1a and the C-terminal region interacts with keratins, FAM83H might tether CK-1a to keratins. Colorectal cancer tissue also shows keratin filament disassembly accompanied with FAM83H overexpression and aberrant CK-1a localization, and FAM83H-overexpressing cancer cells exhibit loss or alteration of epithelial cell polarity. Importantly, knockdown of FAM83H inhibits cell migration accompanied by keratin cytoskeleton rearrangement in colorectal cancer cells. These results suggest that keratin cytoskeleton organization is regulated by FAM83H-mediated recruitment of CK-1a to keratins, and that keratin filament disassembly caused by overexpression of FAM83H and aberrant localization of CK-1a could contribute to the progression of colorectal cancer. © 2013. Published by The Company of Biologists Ltd.

    DOI: 10.1242/jcs.129684

    PubMed

  • TGF-β-SMAD3 signaling mediates hepatic bile acid and phospholipid metabolism following lithocholic acid-induced liver injury. 査読

    Tsutomu Matsubara, Naoki Tanaka, Misako Sato-Matsubara, Dong Wook Kang, Kristopher W Krausz, Kathleen C Flanders, Kazuo Ikeda, Hans Luecke, Lalage M Wakefield, Frank J Gonzalez

    Journal of lipid research   53 ( 12 )   2698 - 707   2012年12月

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Transforming growth factor-β (TGFβ) is activated as a result of liver injury, such as cholestasis. However, its influence on endogenous metabolism is not known. This study demonstrated that TGFβ regulates hepatic phospholipid and bile acid homeostasis through MAD homolog 3 (SMAD3) activation as revealed by lithocholic acid-induced experimental intrahepatic cholestasis. Lithocholic acid (LCA) induced expression of TGFB1 and the receptors TGFBR1 and TGFBR2 in the liver. In addition, immunohistochemistry revealed higher TGFβ expression around the portal vein after LCA exposure and diminished SMAD3 phosphorylation in hepatocytes from Smad3-null mice. Serum metabolomics indicated increased bile acids and decreased lysophosphatidylcholine (LPC) after LCA exposure. Interestingly, in Smad3-null mice, the metabolic alteration was attenuated. LCA-induced lysophosphatidylcholine acyltransferase 4 (LPCAT4) and organic solute transporter β (OSTβ) expression were markedly decreased in Smad3-null mice, whereas TGFβ induced LPCAT4 and OSTβ expression in primary mouse hepatocytes. In addition, introduction of SMAD3 enhanced the TGFβ-induced LPCAT4 and OSTβ expression in the human hepatocellular carcinoma cell line HepG2. In conclusion, considering that Smad3-null mice showed attenuated serum ALP activity, a diagnostic indicator of cholangiocyte injury, these results strongly support the view that TGFβ-SMAD3 signaling mediates an alteration in phospholipid and bile acid metabolism following hepatic inflammation with the biliary injury.

    DOI: 10.1194/jlr.M031773

    PubMed

  • Strategy for SRM-based verification of biomarker candidates discovered by iTRAQ method in limited breast cancer tissue samples 査読

    Satoshi Muraoka, Hideaki Kume, Shio Watanabe, Jun Adachi, Masayoshi Kuwano, Misako Sato-Matsubara, Naoko Kawasaki, Yoshio Kodera, Makoto Ishitobi, Hideo Inaji, Yasuhide Miyamoto, Kikuya Kato, Takeshi Tomonaga

    Journal of Proteome Research   11 ( 8 )   4201 - 4210   2012年08月( ISSN:1535-3893

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    掲載種別:研究論文(学術雑誌)  

    Since LC-MS-based quantitative proteomics has become increasingly applied to a wide range of biological applications over the past decade, numerous studies have performed relative and/or absolute abundance determinations across large sets of proteins. In this study, we discovered prognostic biomarker candidates from limited breast cancer tissue samples using discovery-through- verification strategy combining iTRAQ method followed by selected reaction monitoring/multiple reaction monitoring analysis (SRM/MRM). We identified and quantified 5122 proteins with high confidence in 18 patient tissue samples (pooled high-risk (n = 9) or low-risk (n = 9)). A total of 2480 proteins (48.4%) of them were annotated as membrane proteins, 16.1% were plasma membrane and 6.6% were extracellular space proteins by Gene Ontology analysis. Forty-nine proteins with &gt
    2-fold differences in two groups were chosen for further analysis and verified in 16 individual tissue samples (high-risk (n = 9) or low-risk (n = 7)) using SRM/MRM. Twenty-three proteins were differentially expressed among two groups of which MFAP4 and GP2 were further confirmed by Western blotting in 17 tissue samples (high-risk (n = 9) or low-risk (n = 8)) and Immunohistochemistry (IHC) in 24 tissue samples (high-risk (n = 12) or low-risk (n = 12)). These results indicate that the combination of iTRAQ and SRM/MRM proteomics will be a powerful tool for identification and verification of candidate protein biomarkers. © 2012 American Chemical Society.

    DOI: 10.1021/pr300322q

    PubMed

  • Delineating Genetic Alterations for Tumor Progression in the MCF10A Series of Breast Cancer Cell Lines

    Mitsutaka Kadota, Howard H. Yang, Bianca Gomez, Misako Sato, Robert J. Clifford, Daoud Meerzaman, Barbara K. Dunn, Lalage M. Wakefield, Maxwell P. Lee

    PLoS ONE   5 ( 2 )   e9201 - e9201   2010年02月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1371/journal.pone.0009201

  • Identification of novel gene amplifications in breast cancer and coexistence of gene amplification with an activating mutation of PIK3CA 査読

    Mitsutaka Kadota, Misako Sato-Matsubara, Beverly Duncan, Akira Ooshima, Howard H. Yang, Natacha Diaz-Meyer, Sheryl Gere, Shun-Ichiro Kageyama, Junya Fukuoka, Takuya Nagata, Kazuhiro Tsukada, Barbara K. Dunn, Lalage M. Wakefield, Maxwell P. Lee

    Cancer Research   69 ( 18 )   7357 - 7365   2009年( ISSN:0008-5472

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    掲載種別:研究論文(学術雑誌)  

    To identify genetic events that characterize cancer progression, we conducted a comprehensive genetic evaluation of 161 primary breast tumors. Similar to the "mountain-and-hill" view of mutations, gene amplification also shows high- and low-frequency alterations in breast cancers. The frequently amplified genes include the well-known oncogenes ERBB2, FGFR1, MYC, CCND1, and PIK3CA, whereas other known oncogenes that are amplified, although less frequently, include CCND2, EGFR, FGFR2, and NOTCH3. More importantly, by honing in on minimally amplified regions containing three or fewer genes, we identified six new amplified genes: POLD3, IRAK4, IRX2, TBL1XR1, ASPH, and BRD4. We found that both the IRX2 and TBL1XR1 proteins showed higher expression in the malignant cell lines MCF10CA1h and MCF10CA1a than in their precursor, MCF10A, a normal immortalized mammary epithelial cell line. To study oncogenic roles of TBL1XR1, we performed knockdown experiments using a short hairpin RNA approach and found that depletion of TBL1XR1 in MCF10CA1h cells resulted in reduction of cell migration and invasion as well as suppression of tumorigenesis in mouse xenografts. Intriguingly, our mutation analysis showed the presence of activation mutations in the PIK3CA gene in a subset of tumors that also had DNA copy number increases in the PIK3CA locus, suggesting an additive effect of coexisting activating amino acid substitution and dosage increase from amplification. Our gene amplification and somatic mutation analysis of breast primary tumors provides a coherent picture of genetic events, both corroborating and novel, offering insight into the genetic underpinnings of breast cancer progression. ©2009 American Association for Cancer Research.

    DOI: 10.1158/0008-5472.CAN-09-0064

    PubMed

  • Trps1 regulates proliferation and apoptosis of chondrocytes through Stat3 signaling 査読

    Hiroki Suemoto, Yasuteru Muragaki, Katsuhiro Nishioka, Misako Sato-Matsubara, Akira Ooshima, Shunji Itoh, Ikuji Hatamura, Michitaka Ozaki, Attila Braun, Erika Gustafsson, Reinhard Fässler

    Developmental Biology   312 ( 2 )   572 - 581   2007年12月( ISSN:0012-1606

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    掲載種別:研究論文(学術雑誌)  

    Mutations in the TRPS1 gene lead to the tricho-rhino-phalangeal syndrome, which is characterized by skeletal defects and abnormal hair development. The TRPS1 gene encodes an atypical member of the GATA-type family of transcription factors. Here we show that mice with a disrupted Trps1 gene develop a chondrodysplasia characterized by diminished chondrocyte proliferation and decreased apoptosis in growth plates. Our analyses revealed that Trps1 is a repressor of Stat3 expression, which in turn controls chondrocyte proliferation and survival by regulating the expression of cyclin D1 and Bcl2. Our conclusion is supported (i) by siRNA-mediated depletion of Stat3 in Trps1-deficient chondrocytes, which normalized the expression of cyclin D1 and Bcl2, (ii) by overexpression of Trps1 in ATDC5 chondrocytes, which diminished Stat3 levels and increased proliferation and apoptosis, and (iii) by mutational analysis of the GATA-binding sites in the Stat3 gene, which revealed that their integrity is critical for the direct association with Trps1 and for Trps1-mediated repression of Stat3. Altogether our findings identify Trps1 as a novel regulator of chondrocytes proliferation and survival through the control of Stat3 expression. © 2007 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.ydbio.2007.10.001

    PubMed

  • Expression of Smad7 in mouse eyes accelerates healing of corneal tissue after exposure to alkali. 査読

    Shizuya Saika, Kazuo Ikeda, Osamu Yamanaka, Takeshi Miyamoto, Yoshitaka Ohnishi, Misako Sato-Matsubara, Yasuteru Muragaki, Akira Ooshima, Yuji Nakajima, Winston W-Y Kao, Kathleen C Flanders, Anita B Roberts

    The American journal of pathology   166 ( 5 )   1405 - 18   2005年05月( ISSN:0002-9440

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    掲載種別:研究論文(学術雑誌)   国際・国内誌:国際誌  

    Damage to the cornea from chemical burns is a serious clinical problem that often leads to permanent visual impairment. Because transforming growth factor (TGF)-beta has been implicated in the response to corneal injury, we evaluated the effects of altered TGF-beta signaling in a corneal alkali burn model using mice treated topically with an adenovirus (Ad) expressing inhibitory Smad7 and mice with a targeted deletion of the TGF-beta/activin signaling mediator Smad3. Expression of exogenous Smad7 in burned corneal tissue resulted in reduced activation of Smad signaling and nuclear factor-kappaB signaling via RelA/p65. Resurfacing of the burned cornea by conjunctival epithelium and its differentiation to cornea-like epithelium were both accelerated in Smad7-Ad-treated corneas with suppressed stromal ulceration, opacification, and neovascularization 20 days after injury. Introduction of the Smad7 gene suppressed invasion of monocytes/macrophages and expression of monocyte/macrophage chemotactic protein-1, TGF-beta1, TGF-beta2, vascular endothelial growth factor, matrix metalloproteinase-9, and tissue inhibitors of metalloproteinase-2 and abolished the generation of myofibroblasts. Although acceleration of healing of the burned cornea was also observed in mice lacking Smad3, the effects on epithelial and stromal healing were less pronounced than those in corneas treated with Smad7. Together these data suggest that overexpression of Smad7 may have effects beyond those of simply blocking Smad3/TGF-beta signaling and may represent an effective new strategy for treatment of ocular burns.

    PubMed

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    細胞   51 ( 11 )   530 - 534   2019年10月( ISSN:1346-7557

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    受傷肝臓は、炎症反応を誘導し、これが慢性化すると、線維化し、さらには癌化に至る。障害肝では肝星細胞が活性化し線維化の発症に主導的役割を果たしている。星細胞の活性化は障害肝細胞が分泌する障害シグナルによるものと考えられて来た。本稿では、このような星細胞の活性化を受動的活性化ととらえ、新たに、障害肝細胞非依存的な星細胞の自発的(自立的)活性化の概念を提案し、このような視点での肝細胞と星細胞の構造的、機能的な緊密な相互作用の仕組みの存在に言及する。(著者抄録)

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    <文献概要>Point ●星細胞の活性化が肝線維化の進行における中心的イベントである.●慢性肝障害では星細胞が持続活性化し,組織にI型コラーゲンが蓄積することで,肝線維化の進行へとつながる.●肝の常在細胞に加えて,B細胞,NK細胞,NKT細胞,マクロファージ系細胞など,多くの免疫細胞も線維化の進行や改善に関与している.●慢性肝疾患における肝線維化は可逆的であり,肝硬変に至っても原因に対する治療介入によって線維化の改善が得られる.

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    翁良徳, 松原三佐子, 松原三佐子, 松原勤, 大黒敦子, 池田一雄, 吉里勝利, 吉里勝利, 河田則文

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役職

  • 全学管理職

    臨床医科学専攻

    特任助教  2014年04月 - 継続中