OSANAI Makoto

写真a

Affiliation

School of Medicine, Department of Pathology (2)

Job title

Professor
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Education 【 display / non-display 】

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    -
    1997

    Asahikawa Medical University   医学研究科  

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    1997

    Asahikawa Medical College  

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    1993

    Asahikawa Medical University   School of Medicine   Medical Course  

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Degree 【 display / non-display 】

  • MD, PhD

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Professional Memberships 【 display / non-display 】

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    Japanese Society of Pathology

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    日本癌学会

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    日本病理学会

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    Japanese Cancer Association

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Research Areas 【 display / non-display 】

  • Life sciences   Cell biology  

  • Life sciences   Experimental pathology  

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Affiliation 【 display / non-display 】

  • Sapporo Medical University School of Medicine   DEpartment of Pathology   Professor  

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Research Interests 【 display / non-display 】

  • 細胞接着

  • アポトーシス

  • タイト結合

  • 細胞極性

  • ビタミンＤ

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Papers 【 display / non-display 】

  • Multilayered proteomics reveals that JAM-A promotes breast cancer progression via regulation of amino acid transporter LAT1.

    Kazufumi Magara, Akira Takasawa, Kumi Takasawa, Tomoyuki Aoyama, Misaki Ota, Daisuke Kyuno, Yusuke Ono, Taro Murakami, Soh Yamamoto, Yuna Nakamori, Naoya Nakahashi, Goro Kutomi, Ichiro Takemasa, Tadashi Hasegawa, Makoto Osanai

    Cancer science    2024.06  [International journal]

    　View Summary

    Recent studies have shown that transmembrane-type tight junction proteins are upregulated in various cancers compared with their levels in normal tissues and are involved in cancer progression, suggesting that they are potential therapeutic targets. Here, we demonstrated the expression profile and a novel role of junctional adhesion molecule-A (JAM-A) in breast cancer. Immunohistochemistry of surgical specimens showed that JAM-A was highly expressed from carcinoma in situ lesions, as in other adenocarcinomas, with higher expression in invasive carcinomas. High expression of JAM-A contributed to malignant aspects such as lymph node metastasis and lymphatic involvement positivity. In breast cancer cells, JAM-A expression status affects malignant potentials including proliferation and migration. Multilayered proteomics revealed that JAM-A interacts with the amino acid transporter LAT1 in breast cancer cells. JAM-A regulates the expression of LAT1 and interacts with it on the whole cell membrane, leading to enhanced amino acid uptake to promote tumor growth. Double high expression of JAM-A and LAT1 predicts poor prognosis in patients with breast cancer. Of note, an antibody against an extracellular domain of JAM-A suppressed the proliferation of breast cancer cells. Our findings indicate the possibility of JAM-A-targeted therapy ideally combined with LAT1-targeted therapy as a new therapeutic strategy against breast cancer.

    DOI PubMed

  • Vitamin D-metabolizing enzyme CYP24A1 affects oncogenic behaviors of oral squamous cell carcinoma and its prognostic implication.

    Yuna Nakamori, Akira Takasawa, Kumi Takasawa, Daisuke Kyuno, Yusuke Ono, Kazufumi Magara, Naoya Nakahashi, Shohei Sekiguchi, Kei Tsuchihashi, Akihiro Miyazaki, Makoto Osanai

    Medical molecular morphology    2024.05  [Domestic journal]

    　View Summary

    Vitamin D is an essential molecule for cellular homeostasis, playing a critical role in cell fate decisions including cell proliferation, differentiation, and viability. Accumulating evidence has revealed that expression of the vitamin D-metabolizing enzyme CYP24A1 is dysregulated in different types of human malignancy. CYP24A1 has been shown to be involved in the oncogenic property of a variety of carcinoma cells. However, the pathological relevance of CYP24A1 expression level in human oral malignancy remains to be clarified. In the present study, suppression of CYP24A1 expression in oral squamous cell carcinoma (OSCC) cells increased cell proliferation, invasive activity, colony formation efficacy, and tumor growth in vivo. In addition, knockout of CYP24A1 expression inhibited cell death induced by two different types of anticancer drugs, i.e., fluorouracil and cisplatin. Gene clustering by RNA-sequence analysis revealed that several signaling molecules associated with MYC are involved in CYP24A1-mediated oncogenic behaviors. Furthermore, decreased expression level of CYP24A1 was observed in 124/204 cases (61%) of OSCC and was shown to be associated with short relapse-free and overall survival periods. The results showed that a low expression level of CYP24A1 promotes the oncogenic activity of OSCC and is significantly associated with poor prognosis in patients with this malignancy.

    DOI PubMed

  • MPNSTで異常発現するPVRはがん悪性化に寄与し,治療標的となりうる

    中橋 尚也, 江森 誠人, 高澤 久美, 太田 未咲, 真柄 和史, 小野 祐輔, 及能 大輔, 杉田 真太朗, 長谷川 匡, 小山内 誠, 高澤 啓

    日本整形外科学会雑誌 ( (公社)日本整形外科学会 )  98 ( 2 ) S194 - S194  2024.03

  • 膵癌の進展におけるClaudin-1の機能(The role of Claudin-1 in Pancreatic Cancer)

    浅野 日南英, 及能 大輔, 奥村 礼央菜, 真柄 和史, 小野 佑輔, 高澤 久美, 高澤 啓, 小山内 誠

    日本病理学会会誌 ( (一社)日本病理学会 )  113 ( 1 ) 474 - 474  2024.02

  • 乳癌患者における癌幹細胞マーカーに対する血中自己抗体価と術後予後の相関(Autoantibodies against breast cancer stem cells are associated with a poor prognosis in patients)

    奥村 礼央菜, 及能 大輔, 水江 由佳, 廣橋 良彦, 浅野 日南英, 真柄 和史, 小野 佑輔, 小山内 誠

    日本病理学会会誌 ( (一社)日本病理学会 )  113 ( 1 ) 475 - 475  2024.02

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Books and Other Publications 【 display / non-display 】

  • The tight junction, intercellular seal as a cell-signaling player; Protocols for examination for its status.

    Elsevier  2010

  • Tight junctions and cancer development, Encyclopedia of Cancer. M. Schwab Osanai M

    Springer  2008

  • Expression of carbohydrate antigens in pancreatic cancer: Handbook of immunohistochemistry and in situ hybridization of human carcinomas. MA. Hayat. Osanai M

    Elsevier  2006

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Misc 【 display / non-display 】

  • 膵癌患者の予後と癌進展におけるJAM-Aの役割(Junctional Adhesion Molecule-A may play a role in the progression of pancreatic cancer)

    及能 大輔, 高澤 啓, 高澤 久美, 真柄 和史, 小山内 誠

    日本癌学会総会記事 ( (一社)日本癌学会 )  81回   J - 2053  2022.09

  • タイト結合分子JAM-Aの異常高発現が乳がんの悪性化に関与する(Elevated expression of JAM-A contributes malignant progression of breast cancer)

    真柄 和史, 高澤 啓, 高澤 久美, 及能 大輔, 小山内 誠

    日本癌学会総会記事 ( (一社)日本癌学会 )  81回   P - 3247  2022.09

  • 舌扁平上皮癌におけるPVR発現とその意義

    永井 佐和, 高澤 啓, 永井 美佐, 仲盛 優菜, 小野 佑輔, 真柄 和史, 及能 大輔, 高澤 久美, 村田 雅樹, 小山内 誠

    日本病理学会会誌 ( (一社)日本病理学会 )  111 ( 1 ) 354 - 354  2022.03

  • 子宮頸部腺癌におけるJAM-A高発現はPVR/CD155と関連して癌悪性化に寄与する

    村上 太郎, 高澤 啓, 青山 智志, 小野 佑輔, 高澤 久美, 村田 雅樹, 小山内 誠

    日本病理学会会誌 ( (一社)日本病理学会 )  111 ( 1 ) 250 - 250  2022.03

  • 免疫チェックポイント阻害薬による偽増悪および免疫関連有害事象を併発した肺多形癌の一剖検例

    多田 聡法, 真柄 和史, 高澤 啓, 久保田 雄策, 小野 佑輔, 及能 大輔, 高澤 久美, 廣橋 良彦, 小山内 誠

    日本病理学会会誌 ( (一社)日本病理学会 )  111 ( 1 ) 357 - 358  2022.03

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Industrial Property Rights 【 display / non-display 】

  • 糖尿病網膜症の予防治療薬. 澤田典均、小山内誠、錦織奈美

    Patent

    　View Summary

    2005-280166

  • 白内障の予防及び/又は治療のための医薬. 澤田典均、小山内誠、錦織奈美

    Patent

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    2006-258252

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Research Projects 【 display / non-display 】

  • レチノイン酸特異的代謝酵素CYP26のレチノイン酸非依存性がん悪性化機構の解明

    基盤研究(C)

    Project Year :

    2022.04
    -
    2025.03
     

    小野 佑輔, 高澤 啓, 小山内 誠

  • Retinoic acid-deficient renal mesangial cells are responsible for the development of diabetic nephropathy

    Grant-in-Aid for Scientific Research (C)

    Project Year :

    2017.04
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    2020.03
     

    Osanai Makoto

    　View Summary

    Diabetic nephropathy is the greatest single cause of hemodialysis due to renal failure. Here we propose that glomerular endothelial tight junctions (TJs) are plausible therapeutic targets for diabetic nephropathy because TJs primarily determine the vascular permeability. Indeed, mesangial cell-derived cytokines limit vascular leakiness of capillaries and eventually attenuate the breakdown of vascular integrity in diabetic angiopathy. We found that CYP26A1, an enzyme specifically involved in metabolic inactivation of retinoic acid (RA), is highly expressed in diabetic glomeruli. We also found that the state of reduced RA bioavailability caused by enhanced expression of CYP26A1 is sufficient to increase vascular permeability and causally leads to glomerular fibrosis and sclerosis. Our observations provide substantial evidence for deteriorating factor of CYP26A1 in diabetic angiopathy, and suggest mechanisms whereby RA deficient-mesangial cells might promote diabetic nephropathy.

  • Nuclear receptors as molecular regulator and chemopreventive targets of colon cancer stem cells.

    Grant-in-Aid for Scientific Research (C)

    Project Year :

    2011
    -
    2013
     

    MASUDA Sonoko, TANAKA Takuji, OSANAI Makoto, TERASAKI Masaru

    　View Summary

    Increasing evidence suggests that colon cancer stem cells (CCSC) have responsible for carcinogenesis, cancer development and recurrence. To establish signaling pathways in CCSC, which are implicated in the initiation and progression of colon cancer, we examined nuclear receptor signaling in colonospheres that are enriched in CCSC from established cell lines. We found that colonospheres formed by colon cancer cell lines are highly enriched in CCSC and that Wnt/b-catenin pathway plays a critical role in growth and maintenance of colonospheres. We also found that the combination of Fucoxanthinol and 1a,25-dihydroxyvitamin D3 acts on the CCSC cell growth through down-regulation of PPARg and NFkB p52, and as an intrinsic factor for the prevention of colon cancer. These findings establish a critical role for PPARg and vitamin D receptor (VDR) in growth regulation in colon cancer cells via functionally relevant cross-talk between these nuclear signaling pathways.

  • Retinoic acid metabolizing enzyme CYP26A1 is a candidate oncogene, and a possible therapeutic target for cancers.

    Grant-in-Aid for Scientific Research (C)

    Project Year :

    2008
    -
    2010
     

    OSANAI Makoto, LEE Gang-Hong

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    Vitamin A deficiency (VAD) is associated with increased susceptibility to carcinogenesis in animal models and elevated risk for a number of human cancers. We found that the CYP26A1, the gene encoding a cytochrome P450 enzyme specifically involved in metabolic inactivation of retinoic acid (RA), the most active vitamin A derivative, is highly expressed in a number of variety types of cancer, including primary breast carcinomas. We also found that the state of reduced RA bioavailability caused by enhanced expression of CYP26A1 is sufficient to markedly increase tumorigenic and metastatic potential. Our observations provide strong evidence for oncogenic and cell survival properties of CYP26A1 in carcinogenesis, and suggest mechanisms whereby VAD might promote cancer development. We believe that specific drug-mediated inactivation of CYP26A1 may have a notable impact on malignant potential of human tumors, and these results show its potential feasibility of CYP26A1-inhibitory cancer therapies.

  • Biological barrier and human diseases

    Grant-in-Aid for Scientific Research (B)

    Project Year :

    2005
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    2007
     

    KOJIMA Takashi, CHIBA Hideki, TOBIOKA Hrotoshi, MURATA Masaki

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    In this project, we have been trying to expand understanding of molecular regulation of tight junctions to human diseases, as follows. 1. Orphan nuclear receptor HNF-4alpha is shown to induce various kinds of tight junction proteins including claudins and microvilli component EBP-50, resulted in formation of microvilli as well as tight junctions. 2. Permeability of blood-retinal barrier is well known to increase with advance of diabetic retinopathy. We showed that retinoic acid, in particular RAR-alpha ligand, prevent the increase of the permeability by production of GDNF in astrocytes. 3. The epithelial barrier of the upper respiratory tract, which is the first site of exposure to inhaled antigens, plays a crucial role in host defense in terms of innate immunity. The epithelium of the nasal mucosa forms a continuous barrier against a wide variety of exogenous antigens by tight junctions. We first found that expression of dendritic cell activator TSLP is significantly increased in patients with nasal allergy. Thus to study the mechanisms involved in nasal allergy, we first established a culture method to passage human nasal epithelial cells using hTERT. These cultures express claudin-1, -4, -7, like the cells in vivo. Using these cultures, we demonstrate that TLR-2 ligand induces TSLP production. On the other hand, we found that TSLP induced expression of claudin-7. These results suggest dendritic cells tightly contact with nasal epithelium. 4. Ca^<2+> is considered to be absorbed across intestinal epithelial monolayers via transcellular and paracellular pathways. We show, by using vitamin V receptor knockout mice, RNA interference and overexpression strategies, that claudin-2 and claudin-12 contribute to paracellular Ca^<2+> absorption in intestinal epithelial cells. We also provide evidence showing that expression of claudins 2 and 12 is upregulated in enterocytes in vitro and in vivo by 1α,25 (OH)_2D_3 through its receptor VDR.

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