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NAIKI Aya

    Graduate School of Medical Sciences Department of Experimental Pathology and Tumor Biology　Associate Professor
Last Updated :2024/10/30

Researcher Information

Alias Name

    ITO Aya

URL

Research funding number

  • 20509236

J-Global ID

Research Interests

  • 肝線維化   前立腺癌   酸化ストレス   細胞間コミュニケーション   

Research Areas

  • Life sciences / Experimental pathology

Academic & Professional Experience

  • 2019/10 - Today  Nagoya City UniversityGraduate School of Medical Sciences准教授
  • 2018/04 - 2019/09  Nagoya City UniversityGraduate School of Medical Sciences, Education and Research Center for Advanced Medicine講師
  • 2017/10 - 2019/09  名古屋市立東部医療センター病理診断科診療科部長
  • 2016/04 - 2017/09  Nagoya City UniversityGraduate School of Medical Sciences講師
  • 2008/04 - 2016/03  Nagoya City UniversityGraduate School of Medical Sciences助教

Association Memberships

  • 日本臨床細胞学会（細胞診専門医）   日本がん予防学会（評議員・認定がん予防エキスパート）   日本毒性病理学会（評議員）   日本癌学会（評議員）   日本病理学会（評議員、病理専門医、病理専門医研修指導医、分子病理専門医）   

Published Papers

MISC

Industrial Property Rights

Awards & Honors

  • 2024/09 日本がん予防学会 奨励賞
     
    受賞者: 内木 綾
  • 2020/12 高松宮妃癌研究基金研究助成金
     
    受賞者: 内木 綾
  • 2020/11 日本病理学会学術研究賞（Ａ演説）
     
    受賞者: 内木 綾
  • 2019/02 International Academy of Toxicologic Pathology The IATP/JSTP Food Safety Scientific Award
     
    受賞者: NAIKI-ITO Aya
  • 2018/06 日本病理学会 英国病理学会派遣
     
    受賞者: 内木 綾
  • 2017/04 日本病理学会 学術奨励賞
     細胞間相互連絡による肝障害調節機構の分子病理学的解析と肝発癌遺伝子の同定 
    受賞者: 内木 綾
  • 2016/10 名古屋市立大学 学長表彰
     
    受賞者: 内木 綾
  • 2014/06 名古屋市立大学医学部同窓会 学術部門賞
     
    受賞者: 内木 綾
  • 2014/01 日本毒性病理学会 会長賞最優秀賞
     
    受賞者: 内木 綾
  • 2013/12 日本膵臓病研究財団 膵臓病研究奨励賞
     膵管癌モデル動物を用いたアディポネクチン誘導物質による発がん抑制効果
  • 2010/01 日本毒性病理学会 会長賞 優秀賞
     JPN
  • 2008/12 名古屋市立大学 医学会賞
     JPN
  • 2008/03 名古屋市立大学大学院医学研究科 優秀論文賞
  • 2007/01 日本毒性病理学会 会長賞 優秀賞
     JPN

Research Grants & Projects

  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2022/04 -2025/03 
    Author : 内木 綾; 惠谷 俊紀; 内木 拓; 高橋 智
  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    Date (from‐to) : 2021/04 -2024/03 
    Author : 内木 拓; 河合 憲康; 内木 綾; 永井 隆; 惠谷 俊紀; 飯田 啓太郎; 安井 孝周; 野崎 哲史
     
    私たちは、ラットのプロバシン遺伝子プロモーターの下流に、SV40ラージT抗原の遺伝子を結合して得られるPBSVTジーンを、Sprague-Dawley (SD)系ラットの受精卵に導入し、前立腺癌動物モデル(TRAP)を確立した。またTRAPから得られた癌組織を、去勢したヌードマウス皮下に移植し長期に継代することで、アンドロゲンの枯渇した状態でも、安定して増殖するCRPCモデルを樹立した。私たちはこのCRPCモデルの解析によって、酸化ストレスの制御機構がCRPCの増殖・進展に促進的に働いていることを解明した。また抗酸化剤によって、AR-V7の発現低下を介してCRPCの増殖抑制が起こる事を解明し、さらにAR-V7を制御する新たなマイクロRNAであるmiR-8080を、世界に先駆けて発見した。そして今回、CRPC転移モデルにおいて去勢抵抗性を獲得する前後でcDNAマイクロアレイを行った結果、CRPCにおいてこれまで文献上報告のない遺伝子Cx43の発現低下を、新たに発見することができた。さらに、TCGAの癌ゲノムデータベースを用いた解析でも、ヒト前立腺組織におけるCx43タンパクの低発現は、予後不良因子となりうることを証明した。
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2020/04 -2023/03 
    Author : 惠谷 俊紀; 河合 憲康; 内木 綾; 永井 隆; 安藤 亮介; 飯田 啓太郎; 安井 孝周; 内木 拓; 野崎 哲史
     
    (1)LSD1の発現プロファイルの検討：前立腺癌患者における臨床検体を用いて、悪性度（Gleason score）ごとのLSD1発現の変化について検討した。Gleason score 3,4,5の各群でLSD1発現を免疫染色で定量化し比較したところ、悪性度の高い癌においてLSD1が高発現していることが確認された。Gleason scoreの高い癌は臨床においても治療抵抗性になりやすく、かつ転移をきたしやすいため、悪性度が高く癌性疼痛の原因になりやすい癌ほどLSD1の発現が高いことから、LSD1の癌性疼痛の標的としての可能性が示唆された。 (2)in vivoにおいて去勢がLSD1発現に与える影響の検討：本学において樹立した、ラット由来前立腺癌細胞株PCai1を用いて検討した。PCai1をCharcoal stripped mediumで長期間培養し、去勢抵抗性前立腺癌細胞株PCai1-CSを作成した。ウェスタンブロットを用いてPCai1とPCai1-CSにおけるLSD1発現を検討したところ、去勢によるLSD1発現の大きな変化は認めなかった。これは昨年度の臨床検体を用いた検討の結果とも一致しており、LSD1は去勢抵抗性の獲得の段階にかかわらず癌性疼痛の治療標的となりうる可能性が示唆された。 (3) 液体高速クロマトグラフ質量分析器（LC-MS）を用いたホルムアルデヒド検出の検討：前年度の蛍光を用いた検出方法よりさらに低濃度のホルムアルデヒドを高精度に検出する方法を確立するために、本学に導入されたLC-MSシステム（LC-MS8030 島津製作所）を用いて、ホルムアルデヒドの計測を試みた。除タンパクや誘導体化につき条件設定を行い、in vitroの条件でホルムアルデヒド試薬を用いてホルムアルデヒドが検出可能なことを確認できた。
  • ナノマテリアルの物理化学的性状を考慮した肺、胸腔及び全身臓器における有害性の評価ならびに新規in vitro予測手法の開発
    厚生労働省：厚生労働科学研究費補助金
    Date (from‐to) : 2020/04 -2023/03 
    Author : 内木綾、戸塚ゆ加里、梯アンナ、津田洋幸
  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    Date (from‐to) : 2019/04 -2022/03 
    Author : 高橋 智; 内木 綾; 加藤 寛之
     
    正常免疫を有するラットにおいても生着可能なラット前立腺細胞PLS10からmRNAを抽出し、作成したcDNA群をエントリーベクターに組み込みcDNAライブラリーを作成した。さらにcDNAライブラリーをレンチウイルスベクターに組み替え、cDNA発現ライブラリーを作成した。この発現ライブラリーをレンチウイルスにパッケージングし、PLS30に感染させた。セレクションマーカーであるブラストサイジン存在下で細胞を培養したところ細胞増殖がみられなかった。 PLS10、PLS20、PLS30のマイクロアレイ解析からPLS10のみ高発現がみられた遺伝子を9種類（Cd81、Ccl2、Cx3cl1、Ifi44、Pycard、Nradd、Tmem9、Ubxd8、Tmem252）見いだし、qRT-PCR法を用いて検討したところ、Cd81、Ccl2、Cx3cl1、Nradd、Tmem252の5遺伝子はmRNA量がPLS10のみ増加していることを確認した。この5遺伝子の中からCd81についてさらに検討した。PLS10、PLS30のCd81タンパク発現量を比較し、PLS10のみで高発現していることを確認した。これらを踏まえ、Cd81発現ベクターを作成し、PLS30に遺伝子導入した。PCR法によりFLAG-Cd81融合タンパク質を作成し、レンチウイルスベクターに組み込み、PLS30に導入してCd81発現安定株を樹立した。Cd81を導入したPLS30は優位に細胞増殖速度が増加していた。Cd81-PLS30および対照であるlacZ-PLS30をそれぞれ2×106個をF344ラット前立腺腹葉に移植した。20週以上経過しても前立腺内に腫瘍形成は見られず、Cd81は細胞増殖には寄与しているものの免疫回避機構には関与していないことが明らかとなった。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2019/04 -2022/03 
    Author : Naiki-Ito Aya
     
    Transgenic rats with dominant negative mutant of connexin 32, a hepatocyte gap junction protein, and dysfunction of gap-junctional intercellular communication, were treated with a high fat diet and dimethylnitrosamine to establish a model for induction of NASH, fibrosis, as well as insulin resistance. TNFα, Tgfβ1, NF-κB and JNK signaling was involved in the activation of hepatic stellate cells and NASH progression. Intake of chemicals inhibiting those signaling was found to have an inhibitory effect on NASH and fibrosis.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2018/04 -2021/03 
    Author : Nakagawa Motoo
     
    Dual energy CT was performed on patients with bladder cancer, and monoenergetic images equivalent to 40 keV were reconstructed from the data of the images. These image data were compared with the image data of normal tube voltage 120 kVp imaging to examine whether there is a difference in the detection ability of bladder cancer. A comparison of the contrast effect of bladder cancer showed that the 40 keV images showed stronger contrast than the conventional 120 kVp images (P<0.01). The 40 keV images were also significantly more sensitive in detecting bladder cancer in subjective diagnostic imaging. These results were published in an English journal (Jpn J Radiol. 2022;40:177-183).
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2017/04 -2020/03 
    Author : Akita Hidetoshi
     
    LSD1, the first histone demethylase to be discovered, is a novel target in prostate cancer therapy. NCL1 and NCD38, novel selective cell-active inhibitors of LSD1, were discovered at our university. We analyzed the efficacy of LSD1 inhibitors in germ cell tumors. The WST assay revealed a reduction in the number of viable cells in a dose-dependent manner after NCL1 or NCD38 treatment. In western blotting, NCL1 or NCD38 treatment induced caspase-dependent apoptosis, while Oct4 and SOX2 expression was decreased. In flow cytometry analysis, NCL1 or NCD38 significantly induced apoptosis in a dose-dependent manner. Subcutaneous tumor volumes and serum AFP levels were significantly lower in mice treated with NCL1 or NCD38 than in controls. TUNEL analysis showed that NCL1 and NCD38 treatment induced apoptosis in NTERA2 subcutaneous tumors. Tissue array analysis showed that LSD1 expression in human seminoma specimens was significantly higher than that in noncancerous specimens.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2017/04 -2020/03 
    Author : NAGATA DAISUKE
     
    Recent report described that apparent diffusion coefficient (ADC) levels in magnetic resonance imaging (MRI) correlate the malignant levels in bladder carcinoma. However, those could not analyze including the prognosis. Therefore, the purpose of this study is to investigate the prognostic value of ADC levels in localized bladder cancer patient. From 2007 to 2012, total of eligible 141 patients who were performed TURB were enrolled.The median age was 71 years old. The T stage was 38 cases in pTa, 62 cases in pT1, and 41 cases in T2 or more, with 35 cases in low grade and 116 cases in high grade. The more T stage was worsened, ADC levels significantly decreased. Particular in pT1 cases, cases in low level of ADC group were significantly poor PFS compared with in high level group. Furthermore, multivariate analysis revealed that ADC levels was independent prognostic factor in pT1 patients. In pT1 bladder carcinoma patients, the ADC levels could be good prognostic biomarker.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2017/04 -2020/03 
    Author : Naiki Taku
     
    Prostate cancer growth is androgen sensitive, therefore, the first-line therapy of prostate cancer is androgen deprivation therapy like castration. However, the therapeutic efficacy is limited and lead to castration resistant prostate cancer (CRPC). Previous study, we established the new CRPC model, and by analyzing them, we newly explored that oxidative stress induced mechanism was highly activated in CRPC. Therefore, in this study, we investigated the therapeutic efficacy of luteolin, which is one of natural flavonoids, in CRPC. As a result, luteolin suppressed CRPC growth both in vitro and in vivo, and the main mechanism of growth suppression was apoptosis regulated by ROS caused by the changes of molecular network. In conclusion, luteolin is promising chemotherapeutic agent for CRPC.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2016/04 -2019/03 
    Author : ETANI TOSHIKI; TAKAHASHI satoru; SUZUKI takayoshi
     
    The CRPC cell lines, 22Rv1, PC3, and PCai1CS, were treated with NCL1, and LSD1 expression and cell viability were assessed. CRPC cells showed strong LSD1 expression, and cell viability was decreased by NCL1 in a dose-dependent manner. In western blotting and flow cytometry, NCL1 also dose-dependently induced caspase-dependent apoptosis. In addition, stimulation of autophagy was observed in NCL1-treated 22Rv1 cells by transmission electron microscopy and LysoTracker analysis. In ex vivo analysis, castrated nude mice were injected subcutaneously with PCai1 cells and intraperitoneally with NCL1. Tumor volume was found to be reduced with no adverse effects in NCL1-treated mice compared with controls. Finally, immunohistochemical analysis using consecutive human specimens in pre- and post-androgen deprivation therapy demonstrated that LSD1 expression levels in CRPC were very high, and identical to levels observed in previously examined prostate biopsy specimens.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2017/03 
    Author : NAIKI-ITO Aya
     
    NASH has the potential to lead to the development of cirrhosis and hepatocellular carcinoma (HCC). To clarify the role of hepatocyte gap junction protein, Cx32 and luteolin on the progression of NASH and hepatocarcinogenesis, Cx32 dominant negative transgenic (Tg) were used. Steatohepatitis, fibrosis, inflammatory cytokine expression, reactive oxygen species and number of preneoplastic foci were greater in Tg as compared with Wt rats, and significantly suppressed by luteolin in both genotypes. Microarray analysis identified Bex1 as an up-regulated gene in Tg rat liver. in situ hybridization revealed that increased Bex1 mRNA was localized in preneoplastic foci in Tg rats. Moreover, Bex1 increased cell proliferation through activation of NF-κB signaling in rat hepatocyte and HCC cell lines. These results show that Cx32 and luteolin have suppressive roles in inflammation, fibrosis and hepatocarcinogenesis during NASH progression, suggesting a potential therapeutic application for NASH.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2017/03 
    Author : NAIKI Taku
     
    Prostate cancer growth is androgen sensitive, therefore, the first-line therapy of prostate cancer is androgen deprivation therapy like castration. However, the therapeutic efficacy is limited. Chemotherapy including taxane derivatives is next strategy in castration resistant prostate cancer (CRPC), however, the distribution of derivatives is various. Connexin 43 (Cx43) is a major gap junction (GJ) protein, and intracellular communication by using low molecular substances is normally performed through GJ. We previously established new CRPC animal models, and present study, cDNA microarray analyses revealed that Cx43 was suppressed in CRPC. Moreover, Cx43 regulates apoptotic signaling in castrated condition in new established Cx43 overexpressed prostate cancer cells. Therefore, GJ may play important roles in preventing castration resistant growth.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2011 -2012 
    Author : NAIKI Aya
     
    Connexin 32 (Cx32) is a major gap junction protein in the liver. We established Cx32 dominant negative transgenic rats and Cx32 transfected rat hepatocellular carcinoma cells. The present study by using them indicated that caspase 3 dependent apoptosis was an important mechanism of acetaminophen-induced hepatotoxicity. Moreover, Cx32 regulates apoptotic signaling in both normal liver tissue and hepatocellular carcinoma cells, may play important roles in preventing carcinogenesis by inducing apoptosis in genetically damaged cells with cancer initiation.
  • 発がん感受性に関与する因子の解析
  • 肝発がんメカニズムの解析

Social Contribution

  • 内閣府食品安全委員会器具・容器包装専門調査会
    Date (from-to) : 2023/10-Today
    Role : Others
  • 内閣府食品安全委員会動物用医薬品専門調査会専門委員
    Date (from-to) : 2021/10/01-Today
    Role : Others
    Category : Investigation
  • オープンカレッジ
    Date (from-to) : 2023/11/24
    Role : Lecturer
    Sponser, Organizer, Publisher  : 名古屋市立大学医学研究科

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