Updated on 2024/03/12

写真a

 
MII Shinji
 
Organization
Graduate School of Medicine Program in Integrated Medicine Pathology Associate professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Associate professor
Contact information
メールアドレス

Degree 1

  1. 博士(医学) ( 2012.7   名古屋大学 ) 

Research Interests 2

  1. cancer

  2. malignant tumors

Research Areas 1

  1. Life Science / Experimental pathology

Research History 1

  1. Nagoya University Graduate School of Medicine   Department of Pathology   Associate professor

    2021.7

Professional Memberships 1

  1. 日本病理学会

Awards 2

  1. 令和5年度 日本病理学会学術研究賞

    2023.11   日本病理学会   GPIアンカー型タンパク質CD109に着目した恒常性維持および腫瘍進展機構の解明

  2. Pathology International High Citation Award 2022

    2022.12   日本病理学会  

 

Papers 61

  1. Single-cell colocalization analysis using a deep generative model. Reviewed

    Kojima Y, Mii S, Hayashi S, Hirose H, Ishikawa M, Akiyama M, Enomoto A, Shimamura T

    Cell systems   Vol. 15 ( 2 ) page: 180 - 192.e7   2024.2

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    Language:English  

    DOI: 10.1016/j.cels.2024.01.007

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  2. Significance of expression of CD109 in osteosarcoma and its involvement in tumor progression via BMP signaling. Reviewed

    Mori N, Esaki N, Shimoyama Y, Shiraki Y, Asai N, Sakai T, Nishida Y, Takahashi M, Enomoto A, Mii S

    Pathology, research and practice   Vol. 245   page: 154443   2023.4

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.prp.2023.154443

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  3. CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-β signaling. Reviewed International journal

    Tetsuro Taki, Yukihiro Shiraki, Atsushi Enomoto, Liang Weng, Chen Chen, Naoya Asai, Yoshiki Murakumo, Kohei Yokoi, Masahide Takahashi, Shinji Mii

    Cancer science   Vol. 111 ( 12 ) page: 4616 - 4628   2020.12

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    Stromal invasion is considered an important prognostic factor in patients with lung adenocarcinoma. The mechanisms underlying the formation of tumor stroma and stromal invasion have been studied in the lung; however, they are still unclear. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein highly expressed in several types of human malignant tumors including lung cancers. In this study, we investigated the in vivo functions of CD109 protein in malignant lung tumors. Initially, we identified an association between higher expression of CD109 protein in human lung adenocarcinoma and a significantly worse prognosis, according to immunohistochemical analysis. We also showed that CD109 deficiency significantly reduced the area of stromal invasive lesions in a genetically engineered CD109-deficient lung adenocarcinoma mouse model, which correlated with the results observed in human lung adenocarcinoma. Furthermore, we identified latent TGF-β binding protein-1 (LTBP1) as a CD109-interacting protein using mass spectrometry and confirmed their interaction by co-immunoprecipitation. Importantly, increased CD109 expression enhanced stromal TGF-β activation in the presence of LTBP1. Therefore, these data suggest the significance of the regulation of TGF-β signaling through CD109 and LTBP1 interaction in tumor stroma and also reveal the importance of CD109 expression levels in promoting lung cancer cell proliferation, migration, and invasion, and thus predicting the outcome of patients suffering from lung adenocarcinoma. Therefore, CD109 protein could be a potential therapeutic target for this disease.

    DOI: 10.1111/cas.14673

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  4. CD109: a multifunctional GPI-anchored protein with key roles in tumor progression and physiological homeostasis. Reviewed International journal

    Shinji Mii, Atsushi Enomoto, Yukihiro Shiraki, Tetsuro Taki, Yoshiki Murakumo, Masahide Takahashi

    Pathology international   Vol. 69 ( 5 ) page: 249 - 259   2019.5

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    CD109 is a glycosylphosphatidylinositol-anchored glycoprotein and a member of the α2 -macroglobulin/C3,C4,C5 family of thioester-containing proteins first identified as being expressed on blood cells, including activated T cells and platelets, and a subset of CD34 + bone marrow cells containing megakaryocyte progenitors. Although CD109 carries the biallelic platelet-specific alloantigen Gov, the physiological functions or roles of CD109 in human disease remain largely unknown. It was recently demonstrated that CD109 is expressed in many malignant tumors, including various squamous cell carcinomas and adenocarcinomas, and plays a role as a multifunctional coreceptor. CD109 reportedly associates with transforming growth factor (TGF)-β receptors and negatively regulates TGF-β signaling in keratinocytes. Additionally, CD109 is potentially related to signal transducer and activator of transcription-3 signaling and aberrant cell proliferation. In this review, we describe recent evidence of CD109-specific significance in malignant tumors shown in mouse models and human tissues. Furthermore, we discuss the physiological functions of CD109 in vitro and in vivo, including results of phenotype analyses of CD109-deficient mice exhibiting epidermal hyperplasia and osteopenia.

    DOI: 10.1111/pin.12798

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  5. CD109 deficiency induces osteopenia with an osteoporosis-like phenotype in vivo. Reviewed International journal

    Shinji Mii, Akiyoshi Hoshino, Atsushi Enomoto, Yoshiki Murakumo, Masako Ito, Akira Yamaguchi, Masahide Takahashi

    Genes to cells : devoted to molecular & cellular mechanisms   Vol. 23 ( 7 ) page: 590 - 598   2018.7

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    Osteoporosis is a global public health problem that is increasing along with an aging population. A major determinant of osteoporosis is high bone turnover, which results from osteoclast activation. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein, a deficiency that leads to a psoriasis-like skin inflammation in mice. Although the expression of CD109 has been reported in mouse pre-osteoclast cells, its function in osteoclasts in vivo remains largely unknown. To investigate the physiological role of CD109 in bone metabolism, we analyzed bones from wild-type and CD109-deficient adult mice. Micro-computed tomography analysis of the femur (thigh bone) showed that bone volume was lower in CD109-deficient mice than in wild-type mice. Bone histomorphometric analysis showed not only a reduction in bone volume but also an increase in bone turnover in CD109-deficient mice as compared with wild-type mice. Additionally, we measured serum levels of several markers of bone turnover and found a significant increase in the N-terminal telopeptide of type I collagen, a bone resorption marker, as well as alkaline phosphatase, a bone formation marker, in CD109-deficient mice. These results indicate that CD109 deficiency induces a high-turnover, osteoporosis-like phenotype, which suggests that CD109 plays a role in bone metabolism in vivo.

    DOI: 10.1111/gtc.12593

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  6. Significance of perivascular tumour cells defined by CD109 expression in progression of glioma. Reviewed International journal

    Yukihiro Shiraki, Shinji Mii, Atsushi Enomoto, Hiroyuki Momota, Yi-Peng Han, Takuya Kato, Kaori Ushida, Akira Kato, Naoya Asai, Yoshiki Murakumo, Kosuke Aoki, Hiromichi Suzuki, Fumiharu Ohka, Toshihiko Wakabayashi, Tomoki Todo, Seishi Ogawa, Atsushi Natsume, Masahide Takahashi

    The Journal of pathology   Vol. 243 ( 4 ) page: 468 - 480   2017.12

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

    In the progression of glioma, tumour cells often exploit the perivascular microenvironment to promote their survival and resistance to conventional therapies. Some of these cells are considered to be brain tumour stem cells (BTSCs); however, the molecular nature of perivascular tumour cells has not been specifically clarified because of the complexity of glioma. Here, we identified CD109, a glycosylphosphatidylinositol-anchored protein and regulator of multiple signalling pathways, as a critical regulator of the progression of lower-grade glioma (World Health Organization grade II/III) by clinicopathological and whole-genome sequencing analysis of tissues from human glioma. The importance of CD109-positive perivascular tumour cells was confirmed not only in human lower-grade glioma tissues but also in a mouse model that recapitulated human glioma. Intriguingly, BTSCs isolated from mouse glioma expressed high levels of CD109. CD109-positive BTSCs exerted a proliferative effect on differentiated glioma cells treated with temozolomide. These data reveal the significance of tumour cells that populate perivascular regions during glioma progression, and indicate that CD109 is a potential therapeutic target for the disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    DOI: 10.1002/path.4981

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  7. Suppression of skin tumorigenesis in CD109-deficient mice. Reviewed

    Sunagawa M, Mii S, Enomoto A, Kato T, Murakumo Y, Shiraki Y, Asai N, Asai M, Nagino M, Takahashi M.

    Oncotarget.   Vol. 7   page: 82836 - 82850   2016

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  8. Role of Girdin in intimal hyperplasia in vein grafts and efficacy of atelocollagen-mediated application of small interfering RNA for vein graft failure. Reviewed

    Miyachi H, Mii S, Enomoto A, Murakumo Y, Kato T, Asai N, Komori K, Takahashi M.

    J Vasc Surg.   Vol. 60   page: 479 - 489   2014

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  9. The REV7 subunit of DNA polymerase ζ is essential for primordial germ cell maintenance in the mouse. Reviewed

    Watanabe N, Mii S, Asai N, Asai M, Niimi K, Ushida K, Kato T, Enomoto A, Ishii H, Takahashi M, Murakumo Y.

    J Biol Chem.   Vol. 288   page: 10459 - 10471   2013

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    Authorship:Lead author   Language:English  

  10. Epidermal hyperplasia and appendage abnormalities in mice lacking CD109. Reviewed

    Mii S, Murakumo Y, Asai N, Jijiwa M, Hagiwara S, Kato T, Asai M, Enomoto A, Ushida K, Sobue S, Ichihara M, Takahashi M.

    Am J Pathol.   Vol. 181   page: 1180 - 1189   2012

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  11. CD109 Attenuates Bleomycin-induced Pulmonary Fibrosis by Inhibiting TGF-β Signaling.

    Naoi H, Suzuki Y, Miyagi A, Horiguchi R, Aono Y, Inoue Y, Yasui H, Hozumi H, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Inui N, Mii S, Ichihara M, Takahashi M, Suda T

    Journal of immunology (Baltimore, Md. : 1950)     2024.2

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    DOI: 10.4049/jimmunol.2300285

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  12. Meflin is a marker of pancreatic stellate cells involved in fibrosis and epithelial regeneration in the pancreas. International journal

    Ryota Ando, Yukihiro Shiraki, Yuki Miyai, Hiroki Shimizu, Kazuhiro Furuhashi, Shun Minatoguchi, Katsuhiro Kato, Akira Kato, Tadashi Iida, Yasuyuki Mizutani, Kisuke Ito, Naoya Asai, Shinji Mii, Nobutoshi Esaki, Masahide Takahashi, Atsushi Enomoto

    The Journal of pathology   Vol. 262 ( 1 ) page: 61 - 75   2024.1

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    Pancreatic stellate cells (PSCs) are stromal cells in the pancreas that play an important role in pancreatic pathology. In chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC), PSCs are known to get activated to form myofibroblasts or cancer-associated fibroblasts (CAFs) that promote stromal fibroinflammatory reactions. However, previous studies on PSCs were mainly based on the findings obtained using ex vivo expanded PSCs, with few studies that addressed the significance of in situ tissue-resident PSCs using animal models. Their contributions to fibrotic reactions in CP and PDAC are also lesser-known. These limitations in our understanding of PSC biology have been attributed to the lack of specific molecular markers of PSCs. Herein, we established Meflin (Islr), a glycosylphosphatidylinositol-anchored membrane protein, as a PSC-specific marker in both mouse and human by using human pancreatic tissue samples and Meflin reporter mice. Meflin-positive (Meflin+ ) cells contain lipid droplets and express the conventional PSC marker Desmin in normal mouse pancreas, with some cells also positive for Gli1, the marker of pancreatic tissue-resident fibroblasts. Three-dimensional analysis of the cleared pancreas of Meflin reporter mice showed that Meflin+ PSCs have long and thin cytoplasmic protrusions, and are localised on the abluminal side of vessels in the normal pancreas. Lineage tracing experiments revealed that Meflin+ PSCs constitute one of the origins of fibroblasts and CAFs in CP and PDAC, respectively. In these diseases, Meflin+ PSC-derived fibroblasts showed a distinctive morphology and distribution from Meflin+ PSCs in the normal pancreas. Furthermore, we showed that the genetic depletion of Meflin+ PSCs accelerated fibrosis and attenuated epithelial regeneration and stromal R-spondin 3 expression, thereby implying that Meflin+ PSCs and their lineage cells may support tissue recovery and Wnt/R-spondin signalling after pancreatic injury and PDAC development. Together, these data indicate that Meflin may be a marker specific to tissue-resident PSCs and useful for studying their biology in both health and disease. © 2023 The Pathological Society of Great Britain and Ireland.

    DOI: 10.1002/path.6211

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  13. CD109 on Dendritic Cells Regulates Airway Hyperreactivity and Eosinophilic Airway Inflammation. Reviewed International journal

    Yuya Aono, Yuzo Suzuki, Ryo Horiguchi, Yusuke Inoue, Masato Karayama, Hironao Hozumi, Kazuki Furuhashi, Noriyuki Enomoto, Tomoyuki Fujisawa, Yutaro Nakamura, Naoki Inui, Shinji Mii, Masahide Takahashi, Takafumi Suda

    American journal of respiratory cell and molecular biology   Vol. 68 ( 2 ) page: 201 - 212   2023.2

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    Asthma is a chronic airway inflammatory disease characterized by airway hyperreactivity (AHR) and eosinophilic airway inflammation. Dendritic cells (DCs) are essential for the development of asthma via presenting allergens, causing Th2 skewing and eosinophil inflammation. Recent studies have revealed that CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is involved in the pathogenesis of inflammatory diseases such as rheumatoid arthritis and psoriasis. However, no study has addressed the role of CD109 in asthma. This study sought to address the role of CD109 on DCs in the development of AHR and allergic inflammation. CD109 deficient mice (CD109-/- mice) were sensitized with house dust mite (HDM) or ovalbumin and compared to wild-type (WT) mice for induction of AHR and allergic inflammation. CD109-deficient mice had reduced AHR and eosinophilic inflammation together with lower Th2 cytokine expression compared to WT mice. Interestingly, CD109 expression was induced in lung conventional DC2s (cDC2s), but not lung cDC1s, upon allergic challenge. Lung cDC2s from CD109-/- mice had a poor ability to induce cytokine production in ex vivo DC-T cell cocultures with high expression of RUNX3, resulting in suppression of Th2 differentiation. Adoptive transfer of bone-marrow-derived CD109-/- DCs loaded with HDM failed to develop AHR and eosinophilic inflammation. Finally, administration of monoclonal anti-CD109 antibody reduced airway eosinophils and significantly decreased AHR. Our results suggest the involvement of CD109 in asthma pathogenesis. CD109 is a novel therapeutic target for asthma.

    DOI: 10.1165/rcmb.2022-0109OC

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  14. Downregulation of ROBO4 in Pancreatic Cancer Serves as a Biomarker of Poor Prognosis and Indicates Increased Cell Motility and Proliferation Through Activation of MMP-9 Reviewed International journal

    Yamanaka, M., Hayashi, M., Sonohara, F., Yamada, S., Tanaka, H., Sakai, A., Mii, S., Kobayashi, D., Kurimoto, K., Tanaka, N., Inokawa, Y., Takami, H., Hattori, N., Kanda, M., Tanaka, C., Nakayama, G., Koike, M., Kodera, Y.

    Annals of Surgical Oncology   Vol. 29 ( 11 ) page: 7180 - 7189   2022.10

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    BACKGROUND: The axon guidance gene family, SLIT/ROBO pathway, controls neural network formation, which correlates with the development of several cancers. METHODS: We found through analysis of the public database that ROBO4, one of the axon guidance molecules among the SLIT/ROBO family, is significantly downregulated in primary pancreatic cancer tissues compared with adjacent normal tissues. We carried out transfection experiments using three pancreatic cancer cell lines (MiaPaCa-2, BxPC-3, and SW1990) and one pancreatic duct epithelial cell line (HPDE6c7). A total of 51 clinical samples were then examined by immunohistochemical staining to find an association between ROBO4 expression at the protein level, clinical characteristics, and surgical outcomes. RESULTS: ROBO4 overexpression suppressed the invasion and migration abilities in MiaPaCa-2 and BxPC-3, while ROBO4 siRNA transfection to SW1990 and HPDE6c7 enhanced those activities. PCR-based profiling detected MMP-9 as a candidate downstream target of ROBO4, which was validated by decreased MMP-9 activity after the ROBO4 overexpression assay. High ROBO4 expression clinical samples had significantly better overall survival rather than low ROBO4 cases (P = 0.048). CONCLUSION: These findings suggest that decreased ROBO4 expression activates malignant phenotypes in cancer cells and is correlated with poor survival outcomes in pancreatic cancer.

    DOI: 10.1245/s10434-022-12039-5

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  15. Possible disease-protective roles of fibroblasts in cancer and fibrosis and their therapeutic application Reviewed

    Shiraki, Yukihiro, Mii, Shinji, Esaki, Nobutoshi, Enomoto, Atsushi

      Vol. 84 ( 3 ) page: 484 - 496   2022.8

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  16. Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics Reviewed

    Tadashi Iida, Yasuyuki Mizutani, Nobutoshi Esaki, Suzanne M. Ponik, Brian M. Burkel, Liang Weng, Keiko Kuwata, Atsushi Masamune, Seiichiro Ishihara, Hisashi Haga, Kunio Kataoka, Shinji Mii, Yukihiro Shiraki, Takuya Ishikawa, Eizaburo Ohno, Hiroki Kawashima, Yoshiki Hirooka, Mitsuhiro Fujishiro, Masahide Takahashi, Atsushi Enomoto

    Oncogene   Vol. 41 ( 19 ) page: 2764 - 2777   2022.5

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

    DOI: 10.1038/s41388-022-02288-9

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    Other Link: https://www.nature.com/articles/s41388-022-02288-9

  17. CD109 expression in tumor cells and stroma correlates with progression and prognosis in pancreatic cancer. Reviewed International journal

    Kai Adachi, Yasutaka Sakurai, Masaaki Ichinoe, Masayoshi Tadehara, Akihiro Tamaki, Yurika Kesen, Takuya Kato, Shinji Mii, Atsushi Enomoto, Masahide Takahashi, Wasaburo Koizumi, Yoshiki Murakumo

    Virchows Archiv : an international journal of pathology   Vol. 480 ( 4 ) page: 819 - 829   2022.4

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    CD109 is a glycosylphosphatidylinositol-anchored glycoprotein, whose expression is upregulated in some types of malignant tumors. High levels of CD109 in tumor cells have been reported to correlate with poor prognosis; however, significance of CD109 stromal expression in human malignancy has not been elucidated. In this study, we investigated the tumorigenic properties of CD109 in pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analysis of 92 PDAC surgical specimens revealed that positive CD109 expression in tumor cells was significantly associated with poor prognosis (disease-free survival, p = 0.003; overall survival, p = 0.002), and was an independent prognostic factor (disease-free survival, p = 0.0173; overall survival, p = 0.0104) in PDAC. Furthermore, CD109 expression was detected in the stroma surrounding tumor cells, similar to that of α-smooth muscle actin, a histological marker of cancer-associated fibroblasts. The stromal CD109 expression significantly correlated with tumor progression in PDAC (TNM stage, p = 0.033; N factor, p = 0.024; lymphatic invasion, p = 0.028). In addition, combined assessment of CD109 in tumor cells and stroma could identify the better prognosis group of patients from the entire patient population. In MIA PaCa-2 PDAC cell line, we demonstrated the involvement of CD109 in tumor cell motility, but not in PANC-1. Taken together, CD109 not only in the tumor cells but also in the stroma is involved in the progression and prognosis of PDAC, and may serve as a useful prognostic marker in PDAC.

    DOI: 10.1007/s00428-021-03230-2

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  18. Meflin-positive cancer-associated fibroblasts enhance tumor response to immune checkpoint blockade. Reviewed International journal

    Yuki Miyai, Daisuke Sugiyama, Tetsunari Hase, Naoya Asai, Tetsuro Taki, Kazuki Nishida, Takayuki Fukui, Toyofumi Fengshi Chen-Yoshikawa, Hiroki Kobayashi, Shinji Mii, Yukihiro Shiraki, Yoshinori Hasegawa, Hiroyoshi Nishikawa, Yuichi Ando, Masahide Takahashi, Atsushi Enomoto

    Life science alliance   Vol. 5 ( 6 )   2022.3

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    Cancer-associated fibroblasts (CAFs) are an integral component of the tumor microenvironment (TME). Most CAFs shape the TME toward an immunosuppressive milieu and attenuate the efficacy of immune checkpoint blockade (ICB) therapy. However, the detailed mechanism of how heterogeneous CAFs regulate tumor response to ICB therapy has not been defined. Here, we show that a recently defined CAF subset characterized by the expression of Meflin, a glycosylphosphatidylinositol-anchored protein marker of mesenchymal stromal/stem cells, is associated with survival and favorable therapeutic response to ICB monotherapy in patients with non-small cell lung cancer (NSCLC). The prevalence of Meflin-positive CAFs was positively correlated with CD4-positive T-cell infiltration and vascularization within non-small cell lung cancer tumors. Meflin deficiency and CAF-specific Meflin overexpression resulted in defective and enhanced ICB therapy responses in syngeneic tumors in mice, respectively. These findings suggest the presence of a CAF subset that promotes ICB therapy efficacy, which adds to our understanding of CAF functions and heterogeneity.

    DOI: 10.26508/lsa.202101230

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  19. Matrix remodeling-associated protein 8 is a marker of a subset of cancer-associated fibroblasts in pancreatic cancer. Reviewed International journal

    Ryosuke Ichihara, Yukihiro Shiraki, Yasuyuki Mizutani, Tadashi Iida, Yuki Miyai, Nobutoshi Esaki, Akira Kato, Shinji Mii, Ryota Ando, Masamichi Hayashi, Hideki Takami, Tsutomu Fujii, Masahide Takahashi, Atsushi Enomoto

    Pathology international   Vol. 72 ( 3 ) page: 161 - 175   2022.3

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    Cancer-associated fibroblasts (CAFs), a compartment of the tumor microenvironment, were previously thought to be a uniform cell population that promotes cancer progression. However, recent studies have shown that CAFs are heterogeneous and that there are at least two types of CAFs, that is, cancer-promoting and -restraining CAFs. We previously identified Meflin as a candidate marker of cancer-restraining CAFs (rCAFs) in pancreatic ductal adenocarcinoma (PDAC). The precise nature of rCAFs, however, has remained elusive owing to a lack of understanding of their comprehensive gene signatures. Here, we screened genes whose expression correlated with Meflin in single-cell transcriptomic analyses of human cancers. Among the identified genes, we identified matrix remodeling-associated protein 8 (MXRA8), which encodes a type I transmembrane protein with unknown molecular function. Analysis of MXRA8 expression in human PDAC samples showed that MXRA8 was differentially co-expressed with other CAF markers. Moreover, in patients with PDAC or syngeneic tumors developed in MXRA8-knockout mice, MXRA8 expression did not affect the roles of CAFs in cancer progression, and the biological importance of MXRA8+ CAFs is still unclear. Overall, we identified MXRA8 as a new CAF marker; further studies are needed to determine the relevance of this marker.

    DOI: 10.1111/pin.13198

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  20. Anti-Malignant Effect of Tensile Loading to Adherens Junctions in Cutaneous Squamous Cell Carcinoma Cells. Reviewed International journal

    Oleg Dobrokhotov, Masaki Sunagawa, Takeru Torii, Shinji Mii, Keiko Kawauchi, Atsushi Enomoto, Masahiro Sokabe, Hiroaki Hirata

    Frontiers in cell and developmental biology   Vol. 9   page: 728383 - 728383   2021.11

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    Actomyosin contractility regulates various cellular processes including proliferation and differentiation while dysregulation of actomyosin activity contributes to cancer development and progression. Previously, we have reported that actomyosin-generated tension at adherens junctions is required for cell density-dependent inhibition of proliferation of normal skin keratinocytes. However, it remains unclear how actomyosin contractility affects the hyperproliferation ability of cutaneous squamous cell carcinoma (cSCC) cells. In this study, we find that actomyosin activity is impaired in cSCC cells both in vitro and in vivo. External application of tensile loads to adherens junctions by sustained mechanical stretch attenuates the proliferation of cSCC cells, which depends on intact adherens junctions. Forced activation of actomyosin of cSCC cells also inhibits their proliferation in a cell-cell contact-dependent manner. Furthermore, the cell cycle arrest induced by tensile loading to adherens junctions is accompanied by epidermal differentiation in cSCC cells. Our results show that the degree of malignant properties of cSCC cells can be reduced by applying tensile loads to adherens junctions, which implies that the mechanical status of adherens junctions may serve as a novel therapeutic target for cSCC.

    DOI: 10.3389/fcell.2021.728383

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  21. Meflin defines mesenchymal stem cells and/or their early progenitors with multilineage differentiation capacity. Reviewed International journal

    Akitoshi Hara, Katsuhiro Kato, Toshikazu Ishihara, Hiroki Kobayashi, Naoya Asai, Shinji Mii, Yukihiro Shiraki, Yuki Miyai, Ryota Ando, Yasuyuki Mizutani, Tadashi Iida, Mikito Takefuji, Toyoaki Murohara, Masahide Takahashi, Atsushi Enomoto

    Genes to cells : devoted to molecular & cellular mechanisms   Vol. 26 ( 7 ) page: 495 - 512   2021.7

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    Mesenchymal stem cells (MSCs) are the likely precursors of multiple lines of mesenchymal cells. The existence of bona fide MSCs with self-renewal capacity and differentiation potential into all mesenchymal lineages, however, has been unclear because of the lack of MSC-specific marker(s) that are not expressed by the terminally differentiated progeny. Meflin, a glycosylphosphatidylinositol-anchored protein, is an MSC marker candidate that is specifically expressed in rare stromal cells in all tissues. Our previous report showed that Meflin expression becomes down-regulated in bone marrow-derived MSCs cultured on plastic, making it difficult to examine the self-renewal and differentiation of Meflin-positive cells at the single-cell level. Here, we traced the lineage of Meflin-positive cells in postnatal and adult mice, showing that those cells differentiated into white and brown adipocytes, osteocytes, chondrocytes and skeletal myocytes. Interestingly, cells derived from Meflin-positive cells formed clusters of differentiated cells, implying the in situ proliferation of Meflin-positive cells or their lineage-committed progenitors. These results, taken together with previous findings that Meflin expression in cultured MSCs was lost upon their multilineage differentiation, suggest that Meflin is a useful potential marker to localize MSCs and/or their immature progenitors in multiple tissues.

    DOI: 10.1111/gtc.12855

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  22. Detection of serum/salivary exosomal Alix in patients with oral squamous cell carcinoma. Reviewed International journal

    Eiji Nakamichi, Hiroki Sakakura, Shinji Mii, Noriyuki Yamamoto, Hideharu Hibi, Masato Asai, Masahide Takahashi

    Oral diseases   Vol. 27 ( 3 ) page: 439 - 447   2021.4

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    OBJECTIVE: Owing to variations in the exterior appearances of noncancerous diseases in the oral cavity, clinicians may have difficulty diagnosing oral squamous cell carcinoma (OSCC). Tissue biopsy is confirmatory, but invasive. Therefore, reliable tumor markers for OSCC are required. Here, exosomal Alix (exoAlix) levels were measured in serum/salivary samples from patients with OSCC and healthy controls (HCs). METHODS: Fifty-seven patients admitted to Nagoya University Hospital from 2017 through 2019 were enrolled, and serum samples (OSCC, n = 29; HC, n = 21) and/or saliva samples (OSCC, n = 23; HC, n = 20) were collected. Exosomal fractions were isolated using ultracentrifugation. ExoAlix levels were measured using enzyme-linked immunosorbent assay. RESULTS: Serum/salivary exoAlix levels were significantly higher in patients with OSCC than in HCs. Receiver operating characteristic analyses revealed that sensitivity, specificity, positive predictive value, and area under the curve were 0.345, 1.000, 1.000, and 0.685, respectively, for serum exoAlix and 0.348, 1.000, 1.000, and 0.712, respectively, for salivary exoAlix at optimal cut-off values (serum, 0.205; saliva, 0.193). All tested OSCC tissue sections (n = 21) were immuno-reactive for Alix. CONCLUSION: Serum and salivary exoAlix were identified as potential diagnostic OSCC biomarkers. Serum exoAlix was suitable for prediction of therapeutic responses.

    DOI: 10.1111/odi.13565

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  23. The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis. Reviewed International journal

    Hiroki Kobayashi, Krystyna A Gieniec, Josephine A Wright, Tongtong Wang, Naoya Asai, Yasuyuki Mizutani, Tadashi Lida, Ryota Ando, Nobumi Suzuki, Tamsin R M Lannagan, Jia Q Ng, Akitoshi Hara, Yukihiro Shiraki, Shinji Mii, Mari Ichinose, Laura Vrbanac, Matthew J Lawrence, Tarik Sammour, Kay Uehara, Gareth Davies, Leszek Lisowski, Ian E Alexander, Yoku Hayakawa, Lisa M Butler, Andrew C W Zannettino, M Omar Din, Jeff Hasty, Alastair D Burt, Simon J Leedham, Anil K Rustgi, Siddhartha Mukherjee, Timothy C Wang, Atsushi Enomoto, Masahide Takahashi, Daniel L Worthley, Susan L Woods

    Gastroenterology   Vol. 160 ( 4 ) page: 1224 - +   2021.3

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    BACKGROUND & AIMS: Cancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored. METHODS: Using human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC. RESULTS: We identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor β and FOXL1, providing an underlying mechanism to explain fibroblast biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5+ intestinal stem cell differentiation. Finally, adeno-associated virus 8 (AAV8)-mediated delivery of Islr to hepatocytes increased BMP signaling and improved survival in our mouse model of hepatic metastasis. CONCLUSIONS: Stromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.

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  24. The Daple-CK1ε complex regulates Dvl2 phosphorylation and canonical Wnt signaling. Reviewed International journal

    Nobutoshi Esaki, Atsushi Enomoto, Maki Takagishi, Yasuyuki Mizutani, Tadashi Iida, Kaori Ushida, Yukihiro Shiraki, Shinji Mii, Masahide Takahashi

    Biochemical and biophysical research communications   Vol. 532 ( 3 ) page: 406 - 413   2020.11

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    The canonical Wnt signaling pathway plays a crucial role in embryonic development, tissue homeostasis and cancer progression. The binding of Wnt ligands to their cognate receptors, the Frizzled (Fzd) family of proteins, recruits Dishevelled segment polarity protein (Dvl) to the plasma membrane and induces its phosphorylation via casein kinase 1 (CK1), which leads to the activation of β-catenin. Previous studies showed that Dishevelled-associating protein with a high frequency of leucine residues (Daple) is an important component of the Wnt signaling pathway and essential for Dvl phosphorylation. However, the mechanism by which Daple promotes CK1-mediated phosphorylation of Dvl is not fully understood. In this study, we found that Daple overexpression induced CK1ε-mediated Dvl2 phosphorylation at threonine 224 (Thr224). A Daple mutant (Daple ΔGCV) that lacks a carboxyl-terminal motif to associate with Dvl, retained the ability to interact with CK1ε, but did not induce Dvl phosphorylation, suggesting the importance of the Daple/Dvl/CK1ε trimeric protein complex. We further found that Thr224 phosphorylation of Dvl was required for full activation of β-catenin transcriptional activity. Consistent with this, wild-type Daple promoted β-catenin transcriptional activity, following dissociation of β-catenin and axin. Finally, Wnt3a stimulation increased the membrane localization of Daple and its association with Dvl, and Daple knockdown attenuated Wnt3a-mediated β-catenin transcriptional activity. Collectively, these data suggested a essential role of spatial Daple localization in CK1ε-mediated activation of Dvl in the canonical Wnt signaling pathway.

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  25. Complex roles of the actin-binding protein Girdin/GIV in DNA damage-induced apoptosis of cancer cells. Reviewed International journal

    Chen Chen, Atsushi Enomoto, Liang Weng, Tetsuro Taki, Yukihiro Shiraki, Shinji Mii, Ryosuke Ichihara, Mitsuro Kanda, Masahiko Koike, Yasuhiro Kodera, Masahide Takahashi

    Cancer science   Vol. 111 ( 11 ) page: 4303 - 4317   2020.11

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    The actin-binding protein Girdin is a hub protein that interacts with multiple proteins to regulate motility and Akt and trimeric G protein signaling in cancer cells. Girdin expression correlates with poor outcomes in multiple human cancers. However, those findings are not universal, as they depend on study conditions. Those data suggest that multiple aspects of Girdin function and its role in tumor cell responses to anticancer therapeutics must be reconsidered. In the present study, we found that Girdin is involved in DNA damage-induced cancer cell apoptosis. An esophageal cancer cell line that exhibited high Girdin expression showed a marked sensitivity to UV-mediated DNA damage compared to a line with low Girdin expression. When transcriptional activation of endogenous Girdin was mediated by an engineered CRISPR/Cas9 activation system, sensitivity to DNA damage increased in both stationary and migrating HeLa cancer cells. High Girdin expression was associated with dysregulated cell cycle progression and prolonged G1 and M phases. These features were accompanied by p53 activation, which conceivably increases cancer cell vulnerability to UV exposure. These data highlight the importance of understanding complex Girdin functions that influence cancer cell sensitivity to therapeutics.

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  26. Stromal imbalance of bone morphogenetic protein signaling drives colorectal carcinogenesis

    Kobayashi, H; Gieniec, K; Wright, J; Wang, T; Asai, N; Mizutani, Y; Ida, T; Ando, R; Suzuki, N; Lannagan, T; Ng, J; Hara, A; Shiraki, Y; Mii, S; Ichinose, M; Vrbanac, L; Lawrence, M; Sammour, T; Uehara, K; Davies, G; Lisowski, L; Alexander, I; Hayakawa, Y; Butler, L; Zannettino, A; Din, MO; Hasty, J; Burt, A; Leedham, S; Rustgi, A; Wang, ST; Wang, TC; Enomoto, A; Takahashi, M; Worthley, D; Woods, S

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   Vol. 35   page: 160 - 160   2020.11

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  27. Connective tissue growth factor produced by cancer‑associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma. Reviewed International journal

    Yuuki Ohara, Atsushi Enomoto, Yuta Tsuyuki, Kotaro Sato, Tadashi Iida, Hiroki Kobayashi, Yasuyuki Mizutani, Yuki Miyai, Akitoshi Hara, Shinji Mii, Jun Suzuki, Kyoko Yamashita, Fumiya Ito, Yashiro Motooka, Nobuaki Misawa, Takayuki Fukui, Koji Kawaguchi, Kohei Yokoi, Shinya Toyokuni

    Oncology reports   Vol. 44 ( 3 ) page: 838 - 848   2020.9

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    Malignant mesothelioma is an aggressive neoplasm for which effective treatments are lacking. We often encounter mesothelioma cases with a profound desmoplastic reaction, suggesting the involvement of cancer‑associated fibroblasts (CAFs) in mesothelioma progression. While the roles of CAFs have been extensively studied in other tumors and have led to the view that the cancer stroma contains heterogeneous populations of CAFs, their roles in mesothelioma remain unknown. We previously showed that connective tissue growth factor (CTGF), a secreted protein, is produced by both mesothelioma cells and fibroblasts and promotes the invasion of mesothelioma cells in vitro. In this study, we examined the clinical relevance of CAFs in mesothelioma. Using surgical specimens of epithelioid malignant pleural mesothelioma, we evaluated the clinicopathological significance of the expression of α‑smooth muscle actin (αSMA), the most widely used marker of CAFs, the expression of CTGF, and the extent of fibrosis by immunohistochemistry and Elastica‑Masson staining. We also analyzed the expression of mesenchymal stromal cell‑ and fibroblast‑expressing Linx paralogue (Meflin; ISLR), a recently reported CAF marker that labels cancer‑restraining CAFs and differ from αSMA‑positive CAFs, by in situ hybridization. The extent of fibrosis and CTGF expression in mesothelioma cells did not correlate with patient prognosis. However, the expression of αSMA and CTGF, but not Meflin, in CAFs correlated with poor prognosis. The data suggest that CTGF+ CAFs are involved in mesothelioma progression and represent a potential molecular target for mesothelioma therapy.

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  28. Hydrogen water alleviates obliterative airway disease in mice. Reviewed

    Naoki Ozeki, Aika Yamawaki-Ogata, Yuji Narita, Shinji Mii, Kaori Ushida, Mikako Ito, Shin-Ichi Hirano, Ryosuke Kurokawa, Kinji Ohno, Akihiko Usui

    General thoracic and cardiovascular surgery   Vol. 68 ( 2 ) page: 158 - 163   2020.2

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    OBJECTIVE: Bronchiolitis obliterans syndrome arising from chronic airway inflammation is a leading cause of death following lung transplantation. Several studies have suggested that inhaled hydrogen can protect lung grafts from ischemia-reperfusion injury via anti-inflammatory and -oxidative mechanisms. We investigated whether molecular hydrogen-saturated water can preserve lung allograft function in a heterotopic tracheal allograft mouse model of obliterative airway disease METHODS: Obliterative airway disease was induced by heterotopically transplanting tracheal allografts from BALB/c donor mice into C57BL/6 recipient mice, which were subsequently administered hydrogen water (10 ppm) or tap water (control group) (n = 6 each) daily without any immunosuppressive treatment. Histological and immunohistochemical analyses were performed on days 7, 14, and 21. RESULTS: Hydrogen water decreased airway occlusion on day 14. No significant histological differences were observed on days 7 or 21. The cluster of differentiation 4/cluster of differentiation 3 ratio in tracheal allografts on day 14 was higher in the hydrogen water group than in control mice. Enzyme-linked immunosorbent assay performed on day 7 revealed that hydrogen water reduced the level of the pro-inflammatory cytokine interleukin-6 and increased that of forkhead box P3 transcription factor, suggesting an enhancement of regulatory T cell activity. CONCLUSIONS: Hydrogen water suppressed the development of mid-term obliterative airway disease in a mouse tracheal allograft model via anti-oxidant and -inflammatory mechanisms and through the activation of Tregs. Thus, hydrogen water is a potential treatment strategy for BOS that can improve the outcome of lung transplant patients.

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  29. The Significance of Molecular Biomarkers on Clinical Survival Outcome Differs Depending on Colon Cancer Sidedness. Reviewed International journal

    Sho Hirabayashi, Masamichi Hayashi, Goro Nakayama, Shinji Mii, Norifumi Hattori, Hiroshi Tanabe, Mitsuro Kanda, Chie Tanaka, Daisuke Kobayashi, Suguru Yamada, Masahiko Koike, Michitaka Fujiwara, Masahide Takahashi, Yasuhiro Kodera

    Anticancer research   Vol. 40 ( 1 ) page: 201 - 211   2020.1

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    BACKGROUND/AIM: This retrospective study focused on the correlation between molecular markers and prognostic outcomes of colon cancer patients depending on sidedness. MATERIALS AND METHODS: A total of 117 stage I-III colon cancer patients who underwent colectomy were enrolled. Novel methylation markers (KIF1A, PAX5 and VGF) were selected for epigenetic evaluation and p53 and ERCC1 protein expression was examined for the investigation of genetic alterations. RESULTS: High frequency of methylation was observed in 68.2% of right-sided and 39.7% of left-sided colon cancer cases (p=0.004). Abnormal p53 was identified in 52.3% of right-sided and 75.3% of left-sided cases (p=0.015). In right-sided cases, highly methylated genes demonstrated significantly favorable disease-free survival (p=0.049). Regarding left-sided cases, advanced T stage (p=0.028) and abnormal p53 (p=0.028) were revealed to be significant predictive factors of the disease-free survival outcome. CONCLUSION: Molecular alterations, as significant prognostic factors, might differ depending on the sidedness of colon cancers.

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  30. Acute Exacerbation of Pleuroparenchymal Fibroelastosis Secondary to Allogenic Hematopoietic Stem Cell Transplantation. Reviewed

    Yasushi Murakami, Koji Sakamoto, Yuki Okumura, Atsushi Suzuki, Shinji Mii, Mitsuo Sato, Toyoharu Yokoi, Naozumi Hashimoto, Yoshinori Hasegawa

    Internal medicine (Tokyo, Japan)   Vol. 59 ( 21 ) page: 2737 - 2743   2020

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    In this article, we report a case with pleuroparenchymal fibroelastosis (PPFE) following hematopoietic stem cell transplantation (HSCT) that developed acute respiratory failure with new bilateral ground glass opacity, which could not be explained by either a pulmonary infection, drug toxicity or extraparenchymal causes. Although combination therapy with multiple immunosuppressants was transiently effective, the patient died from a recurrent exacerbation. Autopsied lungs demonstrated diffuse alveolar damage superimposed on PPFE. There was no evidence of any coexisting interstitial pneumonia with the usual interstitial pneumonia (UIP) pattern. Our case suggests that acute exacerbation can occur in patients with post-HSCT PPFE, even when a coexisting UIP pattern is absent.

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  31. Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis. Reviewed International journal

    Yasuyuki Mizutani, Hiroki Kobayashi, Tadashi Iida, Naoya Asai, Atsushi Masamune, Akitoshi Hara, Nobutoshi Esaki, Kaori Ushida, Shinji Mii, Yukihiro Shiraki, Kenju Ando, Liang Weng, Seiichiro Ishihara, Suzanne M Ponik, Matthew W Conklin, Hisashi Haga, Arata Nagasaka, Takaki Miyata, Makoto Matsuyama, Tomoe Kobayashi, Tsutomu Fujii, Suguru Yamada, Junpei Yamaguchi, Tongtong Wang, Susan L Woods, Daniel Worthley, Teppei Shimamura, Mitsuhiro Fujishiro, Yoshiki Hirooka, Atsushi Enomoto, Masahide Takahashi

    Cancer research   Vol. 79 ( 20 ) page: 5367 - 5381   2019.10

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    Cancer-associated fibroblasts (CAF) constitute a major component of the tumor microenvironment. Recent observations in genetically engineered mouse models and clinical studies have suggested that there may exist at least two functionally different populations of CAFs, that is, cancer-promoting CAFs (pCAF) and cancer-restraining CAFs (rCAF). Although various pCAF markers have been identified, the identity of rCAFs remains unknown because of the lack of rCAF-specific marker(s). In this study, we found that Meflin, a glycosylphosphatidylinositol-anchored protein that is a marker of mesenchymal stromal/stem cells and maintains their undifferentiated state, is expressed by pancreatic stellate cells that are a source of CAFs in pancreatic ductal adenocarcinoma (PDAC). In situ hybridization analysis of 71 human PDAC tissues revealed that the infiltration of Meflin-positive CAFs correlated with favorable patient outcome. Consistent herewith, Meflin deficiency led to significant tumor progression with poorly differentiated histology in a PDAC mouse model. Similarly, genetic ablation of Meflin-positive CAFs resulted in poor differentiation of tumors in a syngeneic transplantation model. Conversely, delivery of a Meflin-expressing lentivirus into the tumor stroma or overexpression of Meflin in CAFs suppressed the growth of xenograft tumors. Lineage tracing revealed that Meflin-positive cells gave rise to α-smooth muscle actin-positive CAFs that are positive or negative for Meflin, suggesting a mechanism for generating CAF heterogeneity. Meflin deficiency or low expression resulted in straightened stromal collagen fibers, which represent a signature for aggressive tumors, in mouse or human PDAC tissues, respectively. Together, the data suggest that Meflin is a marker of rCAFs that suppress PDAC progression. SIGNIFICANCE: Meflin marks and functionally contributes to a subset of cancer-associated fibroblasts that exert antitumoral effects.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5367/F1.large.jpg.

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  32. Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin in Cardiac Tissue Repair and the Development of Diastolic Dysfunction. Reviewed International journal

    Akitoshi Hara, Hiroki Kobayashi, Naoya Asai, Shigeyoshi Saito, Takahiro Higuchi, Katsuhiro Kato, Takahiro Okumura, Yasuko K Bando, Mikito Takefuji, Yasuyuki Mizutani, Yuki Miyai, Shoji Saito, Shoichi Maruyama, Keiko Maeda, Noriyuki Ouchi, Arata Nagasaka, Takaki Miyata, Shinji Mii, Noriyuki Kioka, Daniel L Worthley, Toyoaki Murohara, Masahide Takahashi, Atsushi Enomoto

    Circulation research   Vol. 125 ( 4 ) page: 414 - 430   2019.8

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    RATIONALE: Myofibroblasts have roles in tissue repair following damage associated with ischemia, aging, and inflammation and also promote fibrosis and tissue stiffening, causing organ dysfunction. One source of myofibroblasts is mesenchymal stromal/stem cells that exist as resident fibroblasts in multiple tissues. We previously identified meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue), a glycosylphosphatidylinositol-anchored membrane protein, as a specific marker of mesenchymal stromal/stem cells and a regulator of their undifferentiated state. The roles of meflin in the development of heart disease, however, have not been investigated. OBJECTIVE: We examined the expression of meflin in the heart and its involvement in cardiac repair after ischemia, fibrosis, and the development of heart failure. METHODS AND RESULTS: We found that meflin has an inhibitory role in myofibroblast differentiation of cultured mesenchymal stromal/stem cells. Meflin expression was downregulated by stimulation with TGF (transforming growth factor)-β, substrate stiffness, hypoxia, and aging. Histological analysis revealed that meflin-positive fibroblastic cells and their lineage cells proliferated in the hearts after acute myocardial infarction and pressure-overload heart failure mouse models. Analysis of meflin knockout mice revealed that meflin is essential for the increase in the number of cells that highly express type I collagen in the heart walls after myocardial infarction induction. When subjected to pressure overload by transverse aortic constriction, meflin knockout mice developed marked cardiac interstitial fibrosis with defective compensation mechanisms. Analysis with atomic force microscopy and hemodynamic catheterization revealed that meflin knockout mice developed stiff failing hearts with diastolic dysfunction. Mechanistically, we found that meflin interacts with bone morphogenetic protein 7, an antifibrotic cytokine that counteracts the action of TGF-β and augments its intracellular signaling. CONCLUSIONS: These data suggested that meflin is involved in cardiac tissue repair after injury and has an inhibitory role in myofibroblast differentiation of cardiac fibroblastic cells and the development of cardiac fibrosis.

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  33. Girdin/GIV regulates collective cancer cell migration by controlling cell adhesion and cytoskeletal organization. Reviewed International journal

    Xiaoze Wang, Atsushi Enomoto, Liang Weng, Yasuyuki Mizutani, Shaniya Abudureyimu, Nobutoshi Esaki, Yuta Tsuyuki, Chen Chen, Shinji Mii, Naoya Asai, Hisashi Haga, Sumire Ishida, Kenji Yokota, Masashi Akiyama, Masahide Takahashi

    Cancer science   Vol. 109 ( 11 ) page: 3643 - 3656   2018.11

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    Pathological observations show that cancer cells frequently invade the surrounding stroma in collective groups rather than through single cell migration. Here, we studied the role of the actin-binding protein Girdin, a specific regulator of collective migration of neuroblasts in the brain, in collective cancer cell migration. We found that Girdin was essential for the collective migration of the skin cancer cell line A431 on collagen gels as well as their fibroblast-led collective invasion in an organotypic culture model. We provide evidence that Girdin binds to β-catenin that plays important roles in the Wnt signaling pathway and in E-cadherin-mediated cell-cell adhesion. Girdin-depleted cells displayed scattering and impaired E-cadherin-specific cell-cell adhesion. Importantly, Girdin depletion led to impaired cytoskeletal association of the β-catenin complex, which was accompanied by changes in the supracellular actin cytoskeletal organization of cancer cell cohorts on collagen gels. Although the underlying mechanism is unclear, this observation is consistent with the established role of the actin cytoskeletal system and cell-cell adhesion in the collective behavior of cells. Finally, we showed the correlation of the expression of Girdin with that of the components of the E-cadherin complex and the differentiation of human skin cancer. Collectively, our results suggest that Girdin is an important modulator of the collective behavior of cancer cells.

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  34. Giant biatrial myxoma with two different gross findings. Reviewed

    Taiyo Kuroda, Yukifusa Yokoyama, Satoshi Yuhara, Hideyuki Okawa, Hiroki Hasegawa, Jun Yokote, Shuji Tamaki, Shinji Mii

    General thoracic and cardiovascular surgery   Vol. 66 ( 6 ) page: 358 - 360   2018.6

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    We experienced a giant biatrial myxoma concomitant with hepatocellular carcinoma. Most of myxomas originate from the left atrium, and biatrial myxomas are extremely rare. Excision of the giant cardiac tumor was performed to avoid risks of life-threatening complications. The resected mass was grossly composed of two parts with the border of interatrial septum and with the shape of peanut shell. Although microscopic examinations revealed enlarged vessels, hemorrhages and hemosiderosis in the left part and high cellularity with chronic inflammation in the right part, spindle-shaped cells in a loose myxoid stroma were observed in both parts of the tumor, consistent with the diagnosis of myxoma. His second operation for hepatic cancer was successfully performed following 1 month after the first operation. Surgical treatment should be considered for giant atrium tumor which has risk of life-threatening complications even if patients have another cancer.

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  35. Essential Role of Linx/Islr2 in the Development of the Forebrain Anterior Commissure. Reviewed International journal

    Shaniya Abudureyimu, Naoya Asai, Atsushi Enomoto, Liang Weng, Hiroki Kobayashi, Xiaoze Wang, Chen Chen, Shinji Mii, Masahide Takahashi

    Scientific reports   Vol. 8 ( 1 ) page: 7292 - 7292   2018.5

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    Linx is a member of the leucine-rich repeat and immunoglobulin family of membrane proteins which has critical roles in the development of the peripheral nervous system and forebrain connectivity. A previous study showed that Linx is expressed in projection neurons in the cortex and in cells that comprise the passage to the prethalamus that form the internal capsule, indicating the involvement of Linx in axon guidance and cell-cell communication. In this study, we found that Linx-deficient mice develop severe hydrocephalus and die perinatally by unknown mechanisms. Importantly, mice heterozygous for the linx gene exhibited defects in the development of the anterior commissure in addition to hydrocephalus, indicating haploinsufficiency of the linx gene in forebrain development. In N1E-115 neuroblastoma cells and primary cultured hippocampal neurons, Linx depletion led to impaired neurite extension and an increase in cell body size. Consistent with this, but of unknown significance, we found that Linx interacts with and upregulates the activity of Rho-kinase, a modulator of many cellular processes including cytoskeletal organization. These data suggest a role for Linx in the regulation of complex forebrain connectivity, and future identification of its extracellular ligand(s) will help clarify this function.

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  36. Regulation of keratin 5/14 intermediate filaments by CDK1, Aurora-B, and Rho-kinase. Reviewed International journal

    Hironori Inaba, Daishi Yamakawa, Yasuko Tomono, Atsushi Enomoto, Shinji Mii, Kousuke Kasahara, Hidemasa Goto, Masaki Inagaki

    Biochemical and biophysical research communications   Vol. 498 ( 3 ) page: 544 - 550   2018.4

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    We previously reported that vimentin, GFAP, and desmin (type III intermediate filament [IF] proteins) are mitotically phosphorylated by CDK1, Aurora-B, and Rho-kinase. This phosphorylation is critical for efficient separation of these IFs and completion of cytokinesis. Keratin 5 (K5) and K14 form a heterodimer, which constitutes IF network in basal layer cells of stratified squamous epithelia. Here, we report that the solubility of K5/K14 increased in mitosis. The in vitro assays revealed that three mitotic kinases phosphorylate K5 more than K14. We then identified Thr23/Thr144, Ser30, and Thr159 on murine K5 as major phosphorylation sites for CDK1, Aurora-B, and Rho-kinase, respectively. Using site- and phosphorylation-state-specific antibodies, we demonstrated that K5-Thr23 was phosphorylated in entire cytoplasm from prometaphase to metaphase, whereas K5-Ser30 phosphorylation occurred specifically at the cleavage furrow from anaphase to telophase. Efficient K5/K14-IF separation was impaired by K5 mutations at the sites phosphorylated by these mitotic kinases. K5-Thr23 phosphorylation was widely detected in dividing K5-positive cells of murine individuals. These results suggested that mitotic reorganization of K5/K14-IF network is governed largely through K5 phosphorylation by CDK1, Aurora-B, and Rho-kinase.

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  37. Negative regulation of amino acid signaling by MAPK-regulated 4F2hc/Girdin complex. Reviewed International journal

    Liang Weng, Yi-Peng Han, Atsushi Enomoto, Yasuyuki Kitaura, Shushi Nagamori, Yoshikatsu Kanai, Naoya Asai, Jian An, Maki Takagishi, Masato Asai, Shinji Mii, Takashi Masuko, Yoshiharu Shimomura, Masahide Takahashi

    PLoS biology   Vol. 16 ( 3 ) page: e2005090   2018.3

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    Amino acid signaling mediated by the activation of mechanistic target of rapamycin complex 1 (mTORC1) is fundamental to cell growth and metabolism. However, how cells negatively regulate amino acid signaling remains largely unknown. Here, we show that interaction between 4F2 heavy chain (4F2hc), a subunit of multiple amino acid transporters, and the multifunctional hub protein girders of actin filaments (Girdin) down-regulates mTORC1 activity. 4F2hc interacts with Girdin in mitogen-activated protein kinase (MAPK)- and amino acid signaling-dependent manners to translocate to the lysosome. The resultant decrease in cell surface 4F2hc leads to lowered cytoplasmic glutamine (Gln) and leucine (Leu) content, which down-regulates amino acid signaling. Consistently, Girdin depletion augments amino acid-induced mTORC1 activation and inhibits amino acid deprivation-induced autophagy. These findings uncovered the mechanism underlying negative regulation of amino acid signaling, which may play a role in tightly regulated cell growth and metabolism.

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  38. Tyrosine Phosphorylation of an Actin-Binding Protein Girdin Specifically Marks Tuft Cells in Human and Mouse Gut. Reviewed International journal

    Daisuke Kuga, Kaori Ushida, Shinji Mii, Atsushi Enomoto, Naoya Asai, Masato Nagino, Masahide Takahashi, Masato Asai

    The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society   Vol. 65 ( 6 ) page: 347 - 366   2017.6

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    Tuft cells (TCs) are minor components of gastrointestinal epithelia, characterized by apical tufts and spool-shaped somas. The lack of reliable TC-markers has hindered the elucidation of its role. We developed site-specific and phosphorylation-status-specific antibodies against Girdin at tyrosine-1798 (pY1798) and found pY1798 immunostaining of mouse jejunum clearly depicted epithelial cells closely resembling TCs. This study aimed to validate pY1798 as a TC-marker. Double-fluorescence staining of intestines was performed with pY1798 and known TC-markers, for example, hematopoietic-prostaglandin-D-synthase (HPGDS), or doublecortin-like kinase 1 (DCLK1). Odds ratios (ORs) were calculated from cell counts to determine whether two markers were attracting (OR<1) or repelling (OR>1). In consequence, pY1798 signals strongly attracted those of known TC-markers. ORs for HPGDS in mouse stomach, small intestine, and colon were 0 for all, and 0.08 for DCLK1 in human small intestine. pY1798-positive cells in jejunum were distinct from other minor epithelial cells, including goblet, Paneth, and neuroendocrine cells. Thus, pY1798 was validated as a TC-marker. Interestingly, apoptosis inducers significantly increased relative TC frequencies despite the absence of proliferation at baseline. In conclusion, pY1798 is a novel TC-marker. Selective tyrosine phosphorylation and possible resistance to apoptosis inducers implied the activation of certain kinase(s) in TCs, which may become a clue to elucidate the enigmatic roles of TCs. .

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  39. Increased expression levels of ppGalNAc-T13 in lung cancers: Significance in the prognostic diagnosis. Reviewed

    Nogimori K, Hori T, Kawaguchi K, Fukui T, Mii S, Nakada H, Matsumoto Y, Yamauchi Y, Takahashi M, Furukawa K, Tetsuya O, Yokoi K, Hasegawa Y, Furukawa K.

    Int J Oncol.   Vol. 49   page: 1369 - 1376   2016

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  40. CD109 is a component of exosome secreted from cultured cells. Reviewed

    Sakakura H, Mii S, Hagiwara S, Kato T, Yamamoto N, Hibi H, Takahashi M, Murakumo Y.

    Biochem Biophys Res Commun.   Vol. 469   page: 816 - 822   2016

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    Language:English  

  41. Identification of Meflin as a potential marker for mesenchymal stromal cells. Reviewed

    Maeda K, Enomoto A, Hara A, Asai N, Kobayashi T, Horinouchi A, Maruyama S, Ishikawa Y, Nishiyama T, Kiyoi H, Kato T, Ando K, Weng L, Mii S, Asai M, Mizutani Y, Watanabe O, Hirooka Y, Goto H, Takahashi M.

    Sci Rep.   Vol. 6   page: 22288   2016

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    Language:English  

  42. Low-grade cribriform cystadenocarcinoma arising from a minor salivary gland: A case report. Reviewed

    Kimura M, Mii S, Sugimoto S, Saida K, Morinaga S, Umemura M.

    J Oral Sci.   Vol. 58   page: 145 - 149   2016

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  43. Potential involvement of kinesin-1 in the regulation of subcellular localization of Girdin. Reviewed

    Muramatsu A, Enomoto A, Kato T, Weng L, Kuroda K, Asai N, Asai M, Mii S, Takahashi M.

    Biochem Biophys Res Commun.   Vol. 463   page: 999 - 1005   2015

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    Language:English  

  44. Akt-Girdin signaling in cancer-associated fibroblasts contributes to tumor progression. Reviewed

    Yamamura Y, Asai N, Enomoto A, Kato T, Mii S, Kondo Y, Ushida K, Niimi K, Tsunoda N, Nagino M, Ichihara S, Furukawa K, Maeda K, Murohara T, Takahashi M.

    Cancer Res.   Vol. 75   page: 813 - 823   2015

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    Language:English  

  45. Girdin is phosphorylated on tyrosine 1798 when associated with structures required for migration. Reviewed

    Omori K, Asai M, Kuga D, Ushida K, Izuchi T, Mii S, Enomoto A, Asai N, Nagino M, Takahashi M.

    Biochem Biophys Res Commun.   Vol. 458   page: 934 - 940   2015

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  46. CD109 attenuates TGF-β1 signaling and enhances EGF signaling in SK-MG-1 human glioblastoma cells. Reviewed

    Zhang JM, Murakumo Y, Hagiwara S, Jiang P, Mii S, Kalyoncu E, Saito S, Suzuki C, Sakurai Y, Numata Y, Yamamoto T, Takahashi M.

    Biochem Biophys Res Commun.   Vol. 459   page: 252 - 258   2015

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  47. TRIM27/MRTF-B-dependent integrin β1 expression defines leading cells in cancer cell collectives. Reviewed

    Kato T, Enomoto A, Watanabe T, Haga H, Ishida S, Kondo Y, Furukawa K, Urano T, Mii S, Weng L, Ishida-Takagishi M, Asai M, Asai N, Kaibuchi K, Murakumo Y, Takahashi M.

    Cell Rep.   Vol. 7   page: 1156 - 1167   2014

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    Language:English  

  48. Detection of a soluble form of CD109 in serum of CD109 transgenic and tumor xenografted mice. Reviewed

    Sakakura H, Murakumo Y, Mii S, Hagiwara S, Kato T, Asai M, Hoshino A, Yamamoto N, Sobue S, Ichihara M, Ueda M, Takahashi M.

    PLoS One.   Vol. 9   page: e83385   2014

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  49. Mycobacterium tuberculosis escapes from the phagosomes of infected human osteoclasts reprograms osteoclast development via dysregulation of cytokines and chemokines. Reviewed

    Hoshino A, Hanada S, Yamada H, Mii S, Takahashi M, Mitarai S, Yamamoto K, Manome Y.

    Pathog Dis.   Vol. 70   page: 28 - 39   2014

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  50. Suppression of REV7 enhances cisplatin sensitivity in ovarian clear cell carcinoma cells. Reviewed

    Niimi K, Murakumo Y, Watanabe N, Kato T, Mii S, Enomoto A, Asai M, Asai N, Yamamoto E, Kajiyama H, Shibata K, Kikkawa F, Takahashi M.

    Cancer Sci.   Vol. 105   page: 545 - 552   2014

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  51. Similar phenotypes of Girdin germ-line and conditional knockout mice indicate a crucial role for Girdin in the nestin lineage. Reviewed

    Asai M, Asai N, Murata A, Yokota H, Ohmori K, Mii S, Enomoto A, Murakumo Y, Takahashi M.

    Biochem Biophys Res Commun.   Vol. 426   page: 533 - 538   2012

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  52. RET finger protein expression is associated with prognosis in lung cancer with epidermal growth factor receptor mutations. Reviewed

    Iwakoshi A, Murakumo Y, Kato T, Kitamura A, Mii S, Saito S, Yatabe Y, Takahashi M.

    Pathol Int.   Vol. 62   page: 324 - 330   2012

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  53. Expression of RET finger protein predicts chemoresistance in epithelial ovarian cancer. Reviewed

    Horio M, Kato T, Mii S, Enomoto A, Asai M, Asai N, Murakumo Y, Shibata K, Kikkawa F, Takahashi M.

    Cancer Med.   Vol. 1   page: 218 - 229   2012

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  54. Dedifferentiation and progression of an intracranial solitary fibrous tumor: autopsy case of a Japanese woman with a history of radiation therapy of the head during infancy. Reviewed

    Moritani S, Ichihara S, Hasegawa M, Takada S, Takahashi T, Kato E, Mii S, Iwakoshi A.

    Pathol Int.   Vol. 61   page: 143 - 149   2011

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  55. Loss of Sprouty2 partially rescues renal hypoplasia and stomach hypoganglionosis but not intestinal aganglionosis in Ret Y1062F mutant mice. Reviewed

    Miyamoto R, Jijiwa M, Asai M, Kawai K, Ishida-Takagishi M, Mii S, Asai N, Enomoto A, Murakumo Y, Yoshimura A, Takahashi M.

    Dev Biol.   Vol. 349   page: 160 - 168   2011

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  56. Protective role of Gipie, a Girdin family protein, in endoplasmic reticulum stress responses in endothelial cells. Reviewed

    Matsushita E, Asai N, Enomoto A, Kawamoto Y, Kato T, Mii S, Maeda K, Shibata R, Hattori S, Hagikura M, Takahashi K, Sokabe M, Murakumo Y, Murohara T, Takahashi M.

    Mol Biol Cell.   Vol. 22   page: 736 - 747   2011

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  57. Correlation of pathological grade and tumor stage of urothelial carcinomas with CD109 expression. Reviewed

    Hagikura M, Murakumo Y, Hasegawa M, Jijiwa M, Hagiwara S, Mii S, Hagikura S, Matsukawa Y, Yoshino Y, Hattori R, Wakai K, Nakamura S, Gotoh M, Takahashi M.

    Pathol Int.   Vol. 60   page: 735 - 743   2010

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  58. Processing of CD109 by furin and its role in the regulation of TGF-β signaling. Reviewed

    Hagiwara S, Murakumo Y, Mii S, Shigetomi T, Yamamoto N, Furue H, Ueda M, Takahashi M.

    Oncogene.   Vol. 29   page: 2181 - 2191   2010

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  59. CD109 expression in basal-like breast carcinoma. Reviewed

    Hasegawa M, Moritani S, Murakumo Y, Sato T, Hagiwara S, Suzuki C, Mii S, Jijiwa M, Enomoto A, Asai N, Ichihara S, Takahashi M.

    Pathol Int.   Vol. 58   page: 288 - 294   2008

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  60. Sprouty2 regulates growth and differentiation of human neuroblastoma cells through RET tyrosine kinase. Reviewed

    Ishida M, Ichihara M, Mii S, Jijiwa M, Asai N, Enomoto A, Kato T, Majima A, Ping J, Murakumo Y, Takahashi M.

    Cancer Sci.   Vol. 98   page: 815 - 821   2007

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  61. Sensory nerve-dominant nerve degeneration and remodeling in the mutant mice lacking complex gangliosides. Reviewed

    Sugiura Y, Furukawa K, Tajima O, Mii S, Honda T, Furukawa K.

    Neuroscience.   Vol. 135   page: 1167 - 1178   2005

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▼display all

MISC 3

  1. ASO Visual Abstract: Downregulation of ROBO4 in Pancreatic Cancer Serves as a Biomarker of Poor Prognosis and Indicates Increased Cell Motility and Proliferation Through Activation of MMP-9. International journal

    Masaya Yamanaka, Masamichi Hayashi, Fuminori Sonohara, Suguru Yamada, Haruyoshi Tanaka, Akihiro Sakai, Shinji Mii, Daigo Kobayashi, Keisuke Kurimoto, Nobutake Tanaka, Yoshikuni Inokawa, Hideki Takami, Norifumi Hattori, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera

    Annals of surgical oncology   Vol. 29 ( 11 ) page: 7192 - 7193   2022.10

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  2. Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics (Apr, 10.1038/s41388-022-02288-9, 2022)

    Iida, T; Mizutani, Y; Esaki, N; Ponik, SM; Burkel, BM; Weng, L; Kuwata, K; Masamune, A; Ishihara, S; Haga, H; Kataoka, K; Mii, S; Shiraki, Y; Ishikawa, T; Ohno, E; Kawashima, H; Hirooka, Y; Fujishiro, M; Takahashi, M; Enomoto, A

    ONCOGENE   Vol. 41 ( 23 ) page: 3302 - 3302   2022.6

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  3. [Corrigendum] Increased expression levels of ppGalNAc-T13 in lung cancers: Significance in the prognostic diagnosis

    Nogimori K, Hori T, Kawaguchi K, Fukui T, Mii S, Nakada H, Matsumoto Y, Yamauchi Y, Takahashi M, Furukawa K, Tetsuya O, Yokoi K, Hasegawa Y, Furukawa K.

        2017.2

Presentations 76

  1. Meflinは尿路上皮癌における免疫チェックポイント阻害剤治療の効果予測バイオマーカーである(Meflin is a good predictive biomarker for ICI in urothelial carcinoma)

    大脇 貴之, 宮井 雄基, 飯田 忠, 江崎 寛季, 白木 之浩, 三井 伸二, 榎本 篤

    日本癌学会総会記事  2022.9  (一社)日本癌学会

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    Event date: 2022.9

    Language:English  

  2. 骨肉腫におけるMeflin陽性細胞を標的とした抗体薬物複合体の研究開発(An Effective Therapy that Antibody-Drug Conjugates Targeting Meflin(+) Cells for Osteosarcoma)

    迫田 朋佳, 江崎 寛季, 安藤 良太, 宮井 雄基, 飯田 忠, 松山 誠, 白木 之浩, 三井 伸二, 西田 佳弘, 高橋 雅英, 榎本 篤

    日本癌学会総会記事  2022.9  (一社)日本癌学会

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    Event date: 2022.9

    Language:English  

  3. CD109 on Dendritic Cells Regulates Airway Hyperreactivity and Eosinophilic Airway Inflammation

    Aono Y, Suzuki Y, Horiguchi R, Inoue Y, Karayama M, Hozumi H, Furuhashi K, Enomoto N, Fujisawa T, Inui N, Mii S, Ichihara M, Takahashi M, Suda T.

    American Thoracic Society International Conference 2022  2022.5.18 

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    Event date: 2022.5

  4. CD109 on Dendritic Cells Regulates Airway Hyperreactivity and Eosinophilic Airway Inflammation

    Aono, Y; Suzuki, Y; Horiguchi, R; Inoue, Y; Karayama, M; Hozumi, H; Furuhashi, K; Enomoto, N; Fujisawa, T; Inui, N; Mii, S; Ichihara, M; Takahashi, M; Suda, T

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE  2022.5.1 

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    Event date: 2022.5

  5. 骨肉腫におけるGPIアンカー型膜タンパク質CD109の発現とその機能解析

    三井 伸二, 森田 悠聖, 大河内 凱翔, 下山 芳江, 高橋 雅英, 榎本 篤

    日本病理学会会誌  2022.3  (一社)日本病理学会

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    Event date: 2022.3

    Language:Japanese  

  6. 大腸がん間質のがん関連線維芽細胞の多様性によるBMPシグナルとがん進展の制御機構

    榎本 篤, 小林 大貴, 市原 亮介, 安藤 良太, 森 奈津美, 浅井 直也, 白木 之浩, 三井 伸二, 高橋 雅英

    日本病理学会会誌  2021.3  (一社)日本病理学会

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    Event date: 2021.3

    Language:Japanese  

  7. CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-β signaling

    Mii, S; Taki, T; Shiraki, Y; Enomoto, A; Takahashi, M

    CANCER SCIENCE  2021.2 

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    Event date: 2021.2

  8. Stromal imbalance of bone morphogenetic protein signaling drives colorectal carcinogenesis

    Kobayashi H, Gieniec K, Wright J, Wang T, Asai N, Mizutani Y, Iida T, Ando R, Suzuki N, Lannagan T, Ng J, Hara A, Shiraki Y, Mii S, Ichinose M, Vrbanac L, Lawrence M, Sammour T, Uehara K, Davies G, Lisowski L, Alexander I, Hayakawa Y, Butler L, Zannettino A, Din MO, Hasty J, Burt A, Leedham S, Rustgi A, Mukherjee S, Wang TC, Enomoto A, Takahashi M, Worthley D, Woods S.

    Gastroenterological Society of Australia (GESA) Australian Gastroenterology Week (AGW) 2020  2020.11 

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    Event date: 2020.11 - 2022.11

    Language:Japanese  

  9. CD109タンパク質はTGF-βシグナルを介して肺腺癌の浸潤を制御する

    三井 伸二, 滝 哲郎, 白木 之浩, 榎本 篤, 高橋 雅英

    日本癌学会総会記事  2020.10  (一社)日本癌学会

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    Event date: 2020.10

    Language:English  

  10. 悪性腫瘍におけるGPIアンカー型膜タンパク質CD109の発現と臨床的意義

    三井 伸二, 白木 之浩, 滝 哲郎, 榎本 篤, 高橋 雅英

    日本病理学会会誌  2020.3  (一社)日本病理学会

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    Event date: 2020.3

    Language:Japanese  

  11. 肺腺癌における癌関連タンパク質CD109の機能解析

    滝 哲郎, 三井 伸二, 白木 之浩, 榎本 篤, 高橋 雅英

    日本病理学会会誌  2020.3  (一社)日本病理学会

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    Event date: 2020.3

    Language:Japanese  

  12. 肺腺癌におけるGPIアンカー型膜タンパク質CD109の機能解析(Dissection of the function of CD109 in lung adenocarcinoma)

    滝 哲郎, 三井 伸二, 白木 之浩, 榎本 篤, 高橋 雅英

    日本癌学会総会記事  2019.9  (一社)日本癌学会

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    Event date: 2019.9

    Language:English  

  13. 肺腺癌における癌関連タンパク質CD109の機能解析

    滝 哲郎, 三井 伸二, 白木 之浩, 榎本 篤, 高橋 雅英

    日本病理学会会誌  2019.4  (一社)日本病理学会

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    Event date: 2019.4

    Language:Japanese  

  14. 骨組織および骨肉腫におけるGPIアンカー型膜タンパク質CD109の発現とその意義

    三井 伸二, 白木 之浩, 下山 芳江, 榎本 篤, 高橋 雅英

    日本病理学会会誌  2019.4  (一社)日本病理学会

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    Event date: 2019.4

    Language:Japanese  

  15. 非扁平上皮系悪性腫瘍におけるGPIアンカー型膜タンパク質CD109の発現と臨床的意義

    三井 伸二, 白木 之浩, 滝 哲郎, 榎本 篤, 浅井 直也, 高橋 雅英

    日本病理学会会誌  2018.10  (一社)日本病理学会

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    Event date: 2018.10

    Language:Japanese  

  16. 肺腺癌におけるGPIアンカー型膜タンパク質CD109の機能解析(Dissection of the function of CD109 in lung adenocarcinoma)

    滝 哲郎, 三井 伸二, 白木 之浩, 榎本 篤, 高橋 雅英

    日本癌学会総会記事  2018.9  (一社)日本癌学会

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    Event date: 2018.9

    Language:English  

  17. CD109タンパク質の欠損により骨粗鬆症様の骨減少症が生じる(CD109 deficiency induces osteopenia showing an osteoporosis-like phenotype in vivo)

    三井 伸二, 星野 昭芳, 山口 朗, 高橋 雅英

    日本病理学会会誌  2018.4  (一社)日本病理学会

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    Event date: 2018.4

    Language:English  

  18. 肺腺癌における癌関連タンパク質CD109の機能解析

    滝 哲郎, 三井 伸二, 榎本 篤, 高橋 雅英

    日本病理学会会誌  2018.4  (一社)日本病理学会

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    Event date: 2018.4

    Language:Japanese  

  19. 腫瘍幹細胞におけるCD109の機能解析(The role of CD109 in Brain tumor stem cells derived from PDGFB-induced glioma mouse model)

    白木 之浩, 三井 伸二, 浅井 直也, 榎本 篤, 高橋 雅英

    日本病理学会会誌  2018.4  (一社)日本病理学会

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    Event date: 2018.4

    Language:English  

  20. 脳腫瘍マウスモデルにおけるテモゾロミド感受性に対するCD109の機能解析

    白木 之浩, 三井 伸二, 浅井 直也, 榎本 篤, 百田 洋之, 夏目 敦至, 若林 俊彦, 高橋 雅英

    日本癌学会総会記事  2017.9  (一社)日本癌学会

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    Event date: 2017.9

    Language:English  

  21. ヒトgliiomaにおけるCD109の発現(Significance of Perivascular Tumor Cells Defined by CD109 Expression)

    白木 之浩, 三井 伸二, 榎本 篤, 高橋 雅英

    日本病理学会会誌  2017.3  (一社)日本病理学会

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    Event date: 2017.3

    Language:English  

  22. 慢性皮膚炎症を伴うCD109ノックアウトマウスにおいて皮膚腫瘍形成は抑制される(Suppression of skin tumorigenesis in CD109-deficient mice with chronic skin inflammation)

    三井 伸二, 砂川 真輝, 榎本 篤, 村雲 芳樹, 梛野 正人, 高橋 雅英

    日本病理学会会誌  2017.3  (一社)日本病理学会

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    Event date: 2017.3

    Language:English  

  23. Lower grade gliomaにおける免疫組織化学染色でのCD109の発現は、予後と相関する

    白木 之浩, 砂川 真輝, 三井 伸二, 浅井 直也, 榎本 篤, 百田 洋之, 夏目 敦至, 若林 俊彦, 高橋 雅英

    日本癌学会総会記事  2016.10  (一社)日本癌学会

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    Event date: 2016.10

    Language:English  

  24. 慢性皮膚炎症を伴うCD109ノックアウトマウスにおいて皮膚腫瘍形成は抑制される

    三井 伸二, 砂川 真輝, 榎本 篤, 村雲 芳樹, 梛野 正人, 高橋 雅英

    日本癌学会総会記事  2016.10  (一社)日本癌学会

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    Event date: 2016.10

    Language:English  

  25. The C3-like molecule CD109 controls Th1 versus Th17 induction in CD4(+) T cells

    Martin Kolev, Estefania Nova-Lamperti, Simon Freeley, Dorota Smolarek, Shinjini Chakraborthy, Shinji Mii, Masahide Takahashi, Richard A. Smith, Behdad Afzali, Claudia Kemper

    IMMUNOBIOLOGY  2016.10  ELSEVIER GMBH, URBAN & FISCHER VERLAG

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    Event date: 2016.9

    Language:English  

  26. 脳腫瘍幹細胞におけるmTORC1活性制御とその分子機構の解析

    榎本 篤, 翁 良, 韓 一梵, 浅井 直也, 三井 伸二, 高橋 雅英

    日本病理学会会誌  2016.9  (一社)日本病理学会

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    Event date: 2016.9

    Language:Japanese  

  27. 皮膚腫瘍形成におけるCD109の役割の検討(CD109-deficiency suppresses chemically induced H-ras mutation and tumorigenesis in mouse skin)

    砂川 真輝, 三井 伸二, 梛野 正人, 高橋 雅英

    日本病理学会会誌  2016.4  (一社)日本病理学会

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    Event date: 2016.4

    Language:English  

  28. 骨肉腫における新規免疫組織化学的マーカーとしてのCD109の可能性

    三井 伸二, 白木 之浩, 下山 芳江, 榎本 篤, 浅井 直也, 高橋 雅英

    日本病理学会会誌  2016.4  (一社)日本病理学会

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    Event date: 2016.4

    Language:Japanese  

  29. 間葉系幹細胞およびペリサイトの新規マーカーMeflinの同定と機能解析

    榎本 篤, 前田 啓子, 浅井 直也, 三井 伸二, 高橋 雅英

    日本病理学会会誌  2016.4  (一社)日本病理学会

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    Event date: 2016.4

    Language:Japanese  

  30. 脳腫瘍モデルマウスを用いた神経膠腫におけるCD109の機能解析(Analysis of PDGFB-inducedglioma in CD109-deficient mice)

    白木 之浩, 加藤 琢哉, 砂川 真輝, 三井 伸二, 浅井 直也, 榎本 篤, 百田 洋之, 夏目 敦至, 若林 俊彦, 高橋 雅英

    日本病理学会会誌  2016.4  (一社)日本病理学会

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    Event date: 2016.4

    Language:English  

  31. 皮膚腫瘍形成におけるCD109の役割の検討

    砂川 真輝, 三井 伸二, 梛野 正人, 高橋 雅英

    日本癌学会総会記事  2015.10  (一社)日本癌学会

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    Event date: 2015.10

    Language:English  

  32. 脳腫瘍モデルマウスを用いた神経膠腫におけるCD109の機能解析

    白木 之浩, 加藤 琢哉, 砂川 真輝, 三井 伸二, 浅井 直也, 百田 洋之, 高橋 雅英

    日本癌学会総会記事  2015.10  (一社)日本癌学会

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    Event date: 2015.10

    Language:English  

  33. CD109タンパク質の欠損により骨芽細胞および破骨細胞の異常を伴う骨減少症が生じる

    三井 伸二, 星野 昭芳, 山口 朗, 高橋 雅英

    日本病理学会会誌  2015.3  (一社)日本病理学会

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    Event date: 2015.3

    Language:Japanese  

  34. REV7の発現抑制は卵巣明細胞癌のシスプラチン感受性を増強する

    村雲 芳樹, 加藤 琢哉, 三井 伸二, 榎本 篤, 浅井 真人, 浅井 直也, 高橋 雅英

    日本病理学会会誌  2015.3  (一社)日本病理学会

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    Event date: 2015.3

    Language:Japanese  

  35. 皮膚腫瘍形成におけるCD109の役割の検討(CD109 deficiency inhibited tumorigenesis in mouse skin)

    砂川 真輝, 三井 伸二, 梛野 正人, 高橋 雅英

    日本病理学会会誌  2015.3  (一社)日本病理学会

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    Event date: 2015.3

    Language:English  

  36. 腫瘍微小環境におけるAkt結合蛋白Girdinの関与の検討

    山村 由美子, 浅井 直也, 榎本 篤, 三井 伸二, 高橋 雅英

    日本病理学会会誌  2015.3  (一社)日本病理学会

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    Event date: 2015.3

    Language:Japanese  

  37. 脳腫瘍モデルマウスを用いた神経膠腫におけるTRIM27の機能解析

    白木 之浩, 加藤 琢哉, 三井 伸二, 浅井 直也, 榎本 篤, 高橋 雅英

    日本病理学会会誌  2015.3  (一社)日本病理学会

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    Event date: 2015.3

    Language:Japanese  

  38. DNA repair protein Rev7 is required for primordial germ cell maintenance in the mouse

    Yoshiki Murakumo, Naoki Watanabe, Shinji Mii, Masato Asai, Naoya Asai, Kaoru Niimi, Takuya Kato, Atsushi Enomoto, Masahide Takahashi

    CANCER RESEARCH  2014.10  AMER ASSOC CANCER RESEARCH

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    Event date: 2014.10

    Language:English  

  39. CD109は神経膠芽腫細胞株において細胞依存的にTGF-β1、EGFシグナルを制御する(Cell-type dependent effect of CD109 on TGF-beta1 and EGF signaling in human glioblastoma cells)

    村雲 芳樹, 三井 伸二, 高橋 雅英

    日本癌学会総会記事  2014.9  (一社)日本癌学会

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    Event date: 2014.9

    Language:English  

  40. 癌関連線維芽細胞においてAktシグナルの下流にあるGirdinがリン酸化されることにより腫瘍増大を引き起こす(Akt signaling in cancer-associated fibroblasts contributes to tumor progression via Girdin phosphorylation)

    山村 由美子, 浅井 直也, 榎本 篤, 加藤 琢哉, 三井 伸二, 近藤 裕史, 前田 健吾, 室原 豊明, 高橋 雅英

    日本癌学会総会記事  2014.9  (一社)日本癌学会

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    Event date: 2014.9

    Language:English  

  41. 皮膚腫瘍形成におけるCD109の役割の検討(CD109 deficiency inhibited tumorigenesis in mouse skin)

    砂川 真輝, 三井 伸二, 梛野 正人, 高橋 雅英

    日本癌学会総会記事  2014.9  (一社)日本癌学会

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    Event date: 2014.9

    Language:English  

  42. CD109は神経膠芽腫細胞株SK-MG-1にてTGF-β1シグナル抑制的、EGFシグナル促進的に働く

    村雲 芳樹, 三井 伸二, 高橋 雅英

    日本病理学会会誌  2014.3  (一社)日本病理学会

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    Event date: 2014.3

    Language:Japanese  

  43. TRIM27-USP7によるp53制御機構の解明

    加藤 琢哉, 榎本 篤, 三井 伸二, 浅井 真人, 浅井 直也, 高橋 雅英

    日本病理学会会誌  2014.3  (一社)日本病理学会

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    Event date: 2014.3

    Language:Japanese  

  44. 遺伝子改変マウスを用いた癌関連タンパク質CD109の機能解析および新規腫瘍マーカーへの応用可能性

    三井 伸二, 村雲 芳樹, 坂倉 寛紀, 浅井 真人, 浅井 直也, 市原 正智, 高橋 雅英

    日本病理学会会誌  2014.3  (一社)日本病理学会

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    Event date: 2014.3

    Language:Japanese  

  45. 肺に著明なpanmyelosisが認められ、呼吸不全によって死亡したatypical CMLの1剖検例

    白木 之浩, 市原 正智, 三井 伸二, 浅井 直也, 榎本 篤, 岩田 洋介, 伊藤 雅文, 高橋 雅英

    日本病理学会会誌  2014.3  (一社)日本病理学会

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    Event date: 2014.3

    Language:Japanese  

  46. CD109は培養細胞においてその培養上清中のExosome上に発現する(CD109 is a component of exosomes secreted from cultured cells)

    坂倉 寛紀, 村雲 芳樹, 三井 伸二, 萩原 純孝, 山本 憲幸, 上田 実, 高橋 雅英

    日本癌学会総会記事  2013.10  (一社)日本癌学会

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    Event date: 2013.10

    Language:English  

  47. DNA修復蛋白Rev7はマウスの始原生殖細胞の維持のために必須である(DNA repair protein Rev7 Is required for Primordial Germ Cell Maintenance in the Mouse)

    村雲 芳樹, 三井 伸二, 浅井 直也, 新美 薫, 加藤 琢哉, 榎本 篤, 高橋 雅英

    日本癌学会総会記事  2013.10  (一社)日本癌学会

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    Event date: 2013.10

    Language:English  

  48. CD109は培養細胞においてその培養上清中のExosome上に発現する

    坂倉 寛紀, 村雲 芳樹, 三井 伸二, 萩原 純孝, 山本 憲幸, 上田 実, 高橋 雅英

    日本細胞生物学会大会講演要旨集  2013.5  (一社)日本細胞生物学会

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    Event date: 2013.5

    Language:Japanese  

  49. マウス生殖細胞の維持におけるRev7の重要性

    村雲 芳樹, 渡辺 直樹, 三井 伸二, 浅井 直也, 浅井 真人, 加藤 琢哉, 榎本 篤, 高橋 雅英

    日本病理学会会誌  2013.4  (一社)日本病理学会

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    Event date: 2013.4

    Language:Japanese  

  50. 癌関連タンパク質CD109の新規血清腫瘍マーカーとしての可能性の検討

    三井 伸二, 坂倉 寛紀, 村雲 芳樹, 市原 正智, 高橋 雅英

    日本病理学会会誌  2013.4  (一社)日本病理学会

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    Event date: 2013.4

    Language:Japanese  

  51. リン酸化Girdin特異的抗体の作製とマウス脳における組織学的検討

    浅井 真人, 浅井 直也, 三井 伸二, 榎本 篤, 高橋 雅英

    日本病理学会会誌  2013.4  (一社)日本病理学会

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    Event date: 2013.4

    Language:Japanese  

  52. Atelocollagen-Delivered Small Interfering RNA Targeting Girdin Attenuates Intimal Hyperplasia Vein Grafts in vivo

    Hiroki Miyachi, Shinji Mii, Atsushi Enomoto, Masahide Takahashi, Kimihiro Komori

    CIRCULATION  2012.11  LIPPINCOTT WILLIAMS & WILKINS

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    Event date: 2012.11

    Language:English  

  53. AktによるGirdinのリン酸化は腫瘍進展時の血管形成に関与する可能性がある(A possible role of Akt-mediated Girdin phosphorylation in the development of tumor blood vessel during tumor orogression)

    山村 由美子, 浅井 直也, 榎本 篤, 前田 健吾, 加藤 琢哉, 三井 伸二, 室原 豊明, 高橋 雅英

    日本癌学会総会記事  2012.8  (一社)日本癌学会

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    Event date: 2012.8

    Language:English  

  54. CD109ノックアウト/lacZノックインマウスにおける皮膚表現型の解析(Epidermal hyperplasia and appendage abnormalities in mice lacking CD109, a negative regulator of TGF-beta signaling)

    三井 伸二, 村雲 芳樹, 浅井 直也, 高橋 雅英

    日本癌学会総会記事  2012.8  (一社)日本癌学会

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    Event date: 2012.8

    Language:English  

  55. TGF-β関連タンパク質CD109の新規腫瘍マーカーへの応用(Application for the novel tumor marker of TGF-beta associated protein 'CD109')

    坂倉 寛紀, 村雲 芳樹, 三井 伸二, 萩原 純孝, 山本 憲幸, 上田 実, 高橋 雅英

    日本癌学会総会記事  2012.8  (一社)日本癌学会

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    Event date: 2012.8

    Language:English  

  56. Deficiency of CD109, a negative regulator of TGF-beta signaling, leads epidermal hyperplasia and appendage abnormalities in mice

    Shinji Mii, Yoshiki Murakumo, Naoya Asai, Masato Asai, Masahide Takahashi

    CANCER RESEARCH  2012.4  AMER ASSOC CANCER RESEARCH

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    Event date: 2012.4

    Language:English  

  57. CD109ノックアウト/lacZノックインマウスにおける皮膚表現型の病理学的解析

    三井 伸二, 村雲 芳樹, 浅井 真人, 浅井 直也, 高橋 雅英

    日本病理学会会誌  2012.3  (一社)日本病理学会

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    Event date: 2012.3

    Language:Japanese  

  58. Rev7は胎生期の始原生殖細胞の維持に必須である

    渡辺 直樹, 村雲 芳樹, 三井 伸二, 浅井 真人, 浅井 直也, 高橋 雅英

    日本病理学会会誌  2012.3  (一社)日本病理学会

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    Event date: 2012.3

    Language:Japanese  

  59. ネスチン細胞系統はGirdinストレートノックアウトマウスの致死的表現型の原因となる(The Nestin cell lineage is responsible for the lethal phenotypes of Girdin straight knockout mice)

    浅井 真人, 浅井 直也, 三井 伸二, 榎本 篤, 村雲 芳樹, 高橋 雅英

    日本病理学会会誌  2012.3  (一社)日本病理学会

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    Event date: 2012.3

    Language:English  

  60. 肺癌におけるRET finger protein発現と予後に関する免疫組織学的検討

    岩越 朱里, 村雲 芳樹, 加藤 琢哉, 北村 彩, 三井 伸二, 谷田部 恭, 高橋 雅英

    日本病理学会会誌  2012.3  (一社)日本病理学会

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    Event date: 2012.3

    Language:Japanese  

  61. CD109ノックアウト/lacZノックインマウスにおける皮膚表現型の解析(CD109 Knockout/lacZ Knock-in Mice show Epidermal Abnormality)

    三井 伸二, 村雲 芳樹, 浅井 直也, 高橋 雅英

    日本癌学会総会記事  2011.9  (一社)日本癌学会

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    Event date: 2011.9

    Language:English  

  62. CD109ノックアウト/LacZノックインマウスにおける皮膚表現型の病理学的解析

    三井 伸二, 村雲 芳樹, 浅井 直也, 浅井 真人, 高橋 雅英

    日本病理学会会誌  2011.3  (一社)日本病理学会

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    Event date: 2011.3

    Language:Japanese  

  63. REV7の欠損は精巣生殖細胞の形成不全をもたらす

    渡辺 直樹, 村雲 芳樹, 三井 伸二, 浅井 真人, 浅井 直也, 高橋 雅英

    日本病理学会会誌  2011.3  (一社)日本病理学会

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    Event date: 2011.3

    Language:Japanese  

  64. Ret Y1062FマウスにおいてSprouty2の部分的消失は腎低形成と胃神経節細胞減少を救済する(Loss of Sprouty2 partially rescues renal hypoplasia and stomach hypoganglionosis in Ret Y1062F mice)

    浅井 真人, 宮本 理恵子, 時々輪 真由美, 川井 久美, 三井 伸二, 浅井 直也, 榎本 篤, 村雲 芳樹, 高橋 雅英

    日本病理学会会誌  2011.3  (一社)日本病理学会

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    Event date: 2011.3

    Language:English  

  65. TGF-βシグナル制御のパラダイム TGF-βシグナルの制御におけるCD109の役割(Paradigm on Regulation of TGF-beta Signals Role of CD109 in the regulation of TGF-beta signaling)

    村雲 芳樹, 萩原 純孝, 三井 伸二, 萩倉 美奈子, 高橋 雅英

    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  2010.12  (公社)日本生化学会

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    Event date: 2010.12

    Language:English  

  66. CD109-LacZノックインマウスにおける皮膚表現型の解析(CD109 knockout/LacZ knock-in mice show epidermal abnormality)

    三井 伸二, 村雲 芳樹, 浅井 直也, 高橋 雅英

    日本癌学会総会記事  2010.8  (一社)日本癌学会

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    Event date: 2010.8

    Language:English  

  67. CD109ノックアウトマウスにおける毛周期の変化

    三井 伸二, 村雲 芳樹, 浅井 直也, 高橋 雅英

    日本病理学会会誌  2010.3  (一社)日本病理学会

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    Event date: 2010.3

    Language:Japanese  

  68. 膀胱癌におけるCD109発現の臨床病理学的特徴との関連性の検討

    萩倉 美奈子, 村雲 芳樹, 三井 伸二, 浅井 真人, 服部 良平, 後藤 百万, 高橋 雅英

    日本病理学会会誌  2010.3  (一社)日本病理学会

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    Event date: 2010.3

    Language:Japanese  

  69. CD109の高発現は扁平上皮の癌化に関係する

    萩原 純孝, 村雲 芳樹, 佐藤 朋子, 三井 伸二, 高橋 雅英

    日本病理学会会誌  2009.3  (一社)日本病理学会

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    Event date: 2009.3

    Language:Japanese  

  70. Sauropus androgynus(アマメシバ)による閉塞性細気管支炎の一剖検例

    三井 伸二, 島田 聡子, 橋本 克訓, 榎本 篤, 鈴木 智景, 浅井 直也, 村雲 芳樹, 中村 栄男, 横井 豊治, 高橋 雅英

    日本病理学会会誌  2009.3  (一社)日本病理学会

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    Event date: 2009.3

    Language:Japanese  

  71. 腎のmucinous tubular and spindle cell carcinomaの1症例

    鈴木 智景, 岩田 洋介, 都築 豊徳, 榎本 篤, 前田 永子, 三井 伸二, 時々輪 真由美, 村雲 芳樹, 高橋 雅英

    日本病理学会会誌  2009.3  (一社)日本病理学会

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    Event date: 2009.3

    Language:Japanese  

  72. Choroid plexus papillary carcinomaの一例

    鈴木 智景, 岩田 洋介, 村雲 芳樹, 榎本 篤, 三井 伸二, 下山 芳江, 長坂 徹郎, 高橋 雅英

    日本病理学会会誌  2008.3  (一社)日本病理学会

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    Event date: 2008.3

    Language:Japanese  

  73. 乳腺腺筋上皮腫(adenomyoepithelioma)の1例

    時々輪 真由美, 市原 周, 長谷川 正規, 佐藤 朋子, 鈴木 智景, 三井 伸二, 榎本 篤, 森谷 鈴子, 浅井 直也, 村雲 芳樹, 高橋 雅英

    日本病理学会会誌  2008.3  (一社)日本病理学会

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    Event date: 2008.3

    Language:Japanese  

  74. 基底細胞型乳癌の新しいマーカーとしてのCD109

    長谷川 正規, 森谷 鈴子, 三井 伸二, 佐藤 朋子, 時々輪 真由美, 村雲 芳樹, 市原 周, 高橋 雅英

    日本病理学会会誌  2008.3  (一社)日本病理学会

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    Event date: 2008.3

    Language:Japanese  

  75. Sprouty2はRETチロシンキナーゼ下流シグナルによる神経芽細胞種の増殖と分化を調節する(Sprouty2 mediates growth and differentiation of human neuroblastoma cells through RET tyrosine kinase)

    石田 麻紀, 市原 正智, 三井 伸二, 時々輪 真由美, 浅井 直也, 榎本 篤, 加藤 琢哉, 村雲 芳樹, 高橋 雅英

    日本癌学会総会記事  2007.8  (一社)日本癌学会

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    Event date: 2007.8

    Language:English  

  76. Sprouty-related protein with EVH-1 domain(Spred)のGDNF/RETシグナル伝達系に及ぼす影響の検討

    三井 伸二, 市原 正智, 吉村 昭彦, 高橋 雅英

    日本癌学会総会記事  2002.10  (一社)日本癌学会

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    Event date: 2002.10

    Language:Japanese  

▼display all

KAKENHI (Grants-in-Aid for Scientific Research) 5

  1. Analysis of mechanism of tumor stroma formation and stromal invasion in lung cancer

    Grant number:22K07000  2022.4 - 2026.3

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

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    Authorship:Principal investigator 

    Grant amount:\4030000 ( Direct Cost: \3100000 、 Indirect Cost:\930000 )

  2. サルコペニアモデル動物の確立を目標とした疾患モデル動物の病態解析

    Grant number:19K11780  2019.4 - 2024.3

    科学研究費助成事業  基盤研究(C)

    祖父江 沙矢加, 市原 正智, 後藤 亜由美, 三井 伸二

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    Authorship:Coinvestigator(s) 

    様々な哺乳動物において加齢により筋力低下や筋萎縮が起きることが知られており、この筋の老化をサルコペニアと呼ぶ。進行する高齢社会への対応策としてサルコペニアに関心が集まっているが、サルコペニアの発症メカニズムは極めて複雑であり研究発展が期待されている。本研究では老化や筋萎縮における核-細胞質間輸送因子の役割について検討し、新たなサルコペニアモデル動物の確立およびサルコペニア特異的筋萎縮発症メカニズムの解明に向けた研究を行う。
    本研究の目的は、筋萎縮症の発症メカニズムを筋萎縮モデル動物を通じて解明し、これを高齢時のサルコペニア性筋萎縮と比較することでサルコペニアモデルの確立可能性を探求することである。サルコペニアは加齢に伴う筋量減少や筋力低下を指す用語で、高齢化の進行と共に発症者数が増えると予想されている。しかし、サルコペニアの発症メカニズムや分子機序がまだ特定されていないため、そのキーとなる分子や機序の解明が急務となっている。我々は、筋萎縮症モデルラットの次世代シーケンシング解析を通じて、核-細胞質間輸送因子の遺伝子変異が筋萎縮症の発症に関連すると推察される結果を得た。この結果を基に、この遺伝子変異が引き起こす筋萎縮がサルコペニアにおける筋萎縮と同じ表現型を示すかどうかを評価するため、該当遺伝子に一塩基置換を有するノックインマウスを作製し、検証を行った。
    2022年度には、2020年度に確立したノックインマウスを使用して表現型の確認を行った。後肢筋肉では、野生型と比較してノックインマウスにおいて有意な筋重量の低下が観察された。ホモ接合体およびヘテロ接合体の一塩基置換変異を持つ系統をそれぞれ野生型と比較したところ、どちらの場合でも筋重量の低下が認められた。さらに、後肢筋肉の骨格筋線維の萎縮状態について蛍光免疫染色を用いて評価したところ、速筋線維であるType IIb線維で萎縮が見られる傾向が認められた。また、ノックインマウスで筋萎縮が認められた時期にRNA-seq解析を用いて遺伝子発現の解析を行い、ノックインにより発現量が変動する遺伝子や影響を受ける経路を推察した。これらの結果は、遺伝子変異による筋萎縮のメカニズムを理解するための重要な手がかりを提供し、同時にサルコペニアの分子機序の解明へと繋がる可能性を示している。今後の研究では、これらの結果をさらに深堀りし、サルコペニアの治療法開発に貢献できる知見を得ることを目指す。
    2019年度と2021年度に産休・育休取得のため一時的に研究を中断したことと新型コロナウイルス感染拡大の影響で実験動物の繁殖・飼育に制限が出たことにより研究に遅れが生じている。
    引き続きノックインマウスを用いて表現型の確認を行う。まずは未実施の筋線維数の計測を行い、ノックインマウスで認められた筋重量低下が筋線維数の減少によるものかを検討する。次に中心核の出現頻度、速筋線維と遅筋線維の分布と面積比率の算出を行う。ロータロッド試験による運動機能解析、握力測定による筋力評価も実施する。

  3. Functional analysis of CD109 in tumor progression using osteosarcoma cells and tissue

    Grant number:19K07503  2019.4 - 2022.3

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

    Mii Shinji

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    Authorship:Principal investigator 

    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

    In this study, we investigated the role of CD109 using osteosarcoma cell lines and human osteosarcoma tissue. We performed immunohistochemical analysis on human osteosarcoma tissue and found that patients with CD109-high osteosarcoma had a significantly worse prognosis than those with CD109-low one.
    Although no significant difference was found in TGF-β1 signaling between CD109-knockdown osteosarcoma cells and control cells, we observed that CD109 suppressed SMAD1/5/9 phosphorylation by BMP-2, which is one of the member of TGF-β superfamily.
    These results suggest that CD109 is involved in the exacerbation of osteosarcoma via not TGF-β but BMP singlaing.

  4. 乾癬モデルマウスを用いた慢性炎症と皮膚発癌の連関解明

    Grant number:16K19104  2016.4 - 2018.3

    科学研究費補助金   若手研究(B)

    三井 伸二

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3900000 ( Direct Cost: \3000000 、 Indirect Cost:\900000 )

    本研究では,我々の作製したCD109欠損マウスを用いて皮膚腫瘍形成実験を行い,癌関連遺伝子CD109の欠損により皮膚腫瘍の発生率が低下することを示した.
    また,その原因を探るためにマウス皮膚より得た初代培養ケラチノサイトを用いて検討したところ,CD109が欠損することでTGF-β/SMAD/NRF2経路が活性化することで皮膚腫瘍の発生が抑えられている可能性が示唆された.
    以上のように,CD109が腫瘍発生において果たす役割について,本研究によりその一端が明らかとなった.

  5. 細胞融合の制御機構と腫瘍性多核巨細胞の形成メカニズムの解明

    Grant number:25860293  2013.4 - 2016.3

    科学研究費補助金  若手研究(B)

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    Authorship:Principal investigator 

 

Teaching Experience (On-campus) 4

  1. 病理学各論

    2023

  2. 病理学各論

    2022

  3. 病理学各論

    2021

  4. 病理学各論

    2020

 

Academic Activities 1

  1. 日本病理学会 Pathology International 刊行委員会 委員

    Role(s):Peer review