Exploring MicroRNA-based Methods and Biomarkers for the Prevention of Prostate Cancer

• Project/Area Number: 22K06963
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Nagoya City University
• Principal Investigator: Naiki-Ito Aya 名古屋市立大学, 医薬学総合研究院(医学), 准教授 (20509236)
• Co-Investigator(Kenkyū-buntansha): 惠谷 俊紀 名古屋市立大学, 医薬学総合研究院(医学), 講師 (30600754) ; 内木 拓 名古屋市立大学, 医薬学総合研究院(医学), 准教授 (50551272) ; 高橋 智 名古屋市立大学, 医薬学総合研究院(医学), 教授 (60254281)
• Project Period (FY): 2022-04-01 – 2025-03-31
• Project Status: Completed (Fiscal Year 2024)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2024: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2023: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 前立腺癌 / microRNA / フラボノイド / ルテオリン / 去勢抵抗性前立腺癌

Outline of Research at the Start

本研究の最終目標は、ルテオリン投与によって生じるmiRNAの発現変化とCRPCへの進展予防機構を解明することにより、CRPCに対する先端的な予防・治療法の樹立に結びつくものである。
[1] 前立腺全摘症例において、ルテオリン誘導miRNA発現と病理・臨床的指標の関連を解析する。
[2] 前立腺癌症例を対象に、ルテオリンを半年間投与し、安全性を検証する。
[3] 長期投与による安全性が担保された後、前立腺癌症例を対象に投与研究を行い、miRNA発現変化と癌進展予防効果を検証する。

Outline of Final Research Achievements

Prostate cancer is the second most common malignant tumor in men worldwide. In this study, we examined the mechanisms of action of microRNAs (miRNAs) induced by luteolin using prostate cancer cell lines 22Rv1 and LNCaP. Luteolin induced the expression of miR-29 and miR-30, as well as the down-regulation of AR and NKX3.1 and cell proliferation. Additionally, the oral administration of 50 mg of luteolin for 24 weeks to five prostate cancer patients undergoing with prostate cancer receiving active surveillance (AS) revealed a tendency toward decreased AR/NKX3.1 expression in prostate tissue and increased miR-29 and miR-30 expression in the serum. No apparent adverse events occurred. These results suggest that luteolin may inhibit prostate cancer progression via miRNAs, which could lead to new therapeutic strategies and biomarkers.

Academic Significance and Societal Importance of the Research Achievements

本研究は、ルテオリンがmiR-29およびmiR-30を介して前立腺癌の進行に関与するARやNKX3.1の発現を抑制する新たな抑制機構を明らかにした点で学術的意義が高い。加えて、血中miRNAの変動を確認したことで、治療モニタリング用バイオマーカーとしての可能性も示された。さらに、ルテオリンは食品由来で安全性が高く、臨床試験により6ヶ月間の投与でも有害事象が認められなかったことから、前立腺癌の進行抑制を目指す機能性食品や補完医療としての応用が期待される。高齢化社会におけるQOL向上と医療経済への貢献も見込まれる。

Research Products

• [Journal Article] Preliminary Evidence on Safety and Clinical Efficacy of Luteolin for Patients With Prostate Cancer Under Active Surveillance (2025)
  • Author(s): Naiki T, Naiki-Ito A, Murakami A, Kato H, Sugiyama Y, Kawai T, Kato S, Etani T, Nagai T, Shimizu N, Morikawa T, Aoki M, Gonda M, Kuang X, Nagayasu Y, Hamamoto S, Yasui T, Takahashi S.
  • Journal Title: Prostate Cancer. 2025 Feb 25;2025:8165686. Volume: - Issue: 1 Pages: 8165686-8165686
  • DOI: 10.1155/proc/8165686
  • Peer Reviewed / Open Access
• [Journal Article] Exploring experimental models of prostate cancer in chemoprevention: Oxidative stress as a key pathway to translational research (2025)
  • Author(s): Naiki‐Ito Aya、Naiki Taku、Takahashi Satoru
  • Journal Title: Pathology International Volume: 75 Issue: 3 Pages: 131-144
  • DOI: 10.1111/pin.13509
  • Peer Reviewed / Open Access
• [Journal Article] Incidence of Pancreatic Injury and Pancreatitis in Patients Treated With Immune Checkpoint Inhibitors (2024)
  • Author(s): Hori Yasuki、Naitoh Itaru、Naiki-Ito Aya、Kawai Tatsuya、Yoshida Michihiro、Kato Akihisa、Kachi Kenta、Sahashi Hidenori、Adachi Akihisa、Toyohara Tadashi、Kito Yusuke、Yamamoto Tatsuhito、Takahashi Satoru、Kataoka Hiromi
  • Journal Title: Clinical and Translational Gastroenterology Volume: 15 Issue: 4 Pages: e00667-e00667
  • DOI: 10.14309/ctg.0000000000000667
  • Peer Reviewed / Open Access
• [Journal Article] Urothelial carcinoma occurring in a defunctionalized bladder after urinary diversion due to the bladder exstrophy‐epispadias complex (2023)
  • Author(s): Morikawa Toshiharu、Iwatsuki Shoichiro、Naiki‐Ito Aya、Gonda Masakazu、Taguchi Kazumi、Naiki Taku、Hamamoto Shuzo、Okada Atsushi、Yasui Takahiro
  • Journal Title: IJU Case Reports Volume: 7 Issue: 2 Pages: 101-104
  • DOI: 10.1002/iju5.12675
  • Peer Reviewed / Open Access
• [Journal Article] Successful treatment with enfortumab-vedotin of metastatic signet ring cell cancer expressing nectin-4 and originating from the bladder (2023)
  • Author(s): Aoki M, Naiki T, Naiki-Ito A, Morikawa T, Matsuyama N, Torii K, Kato T, Maruyama T, Inaguma S, Yasui T.
  • Journal Title: IJU Case Reports Volume: 7 Issue: 2 Pages: 110-114
  • DOI: 10.1002/iju5.12678
  • Peer Reviewed / Open Access
• [Journal Article] Role of HIKESHI on Hyperthermia for Castration-Resistant Prostate Cancer and Application of a Novel Magnetic Nanoparticle with Carbon Nanohorn for Magnetic Hyperthermia (2023)
  • Author(s): Nagai Takashi、Kawai Noriyasu、Gonda Masakazu、Iida Keitaro、Etani Toshiki、Kobayashi Daichi、Naiki Taku、Naiki-Ito Aya、Ando Ryosuke、Yamaguchi Sataro、Sugahara Yuto、Ueno Sakyo、Tsutsumiuchi Kaname、Imae Toyoko、Yasui Takahiro
  • Journal Title: Pharmaceutics Volume: 15 Issue: 2 Pages: 626-626
  • DOI: 10.3390/pharmaceutics15020626
  • Peer Reviewed / Open Access
• [Journal Article] High preoperative serum strontium levels increase the risk of acute kidney injury after cardiopulmonary bypass (2023)
  • Author(s): Tomita Natsumi、Hotta Yuji、Ito Hidekazu、Naiki-Ito Aya、Matsuta Karin、Yamamoto Yuko、Ohashi Kazuki、Hayakawa Tomoaki、Sanagawa Akimasa、Horita Yasuhiro、Kondo Masahiro、Kataoka Tomoya、Takahashi Satoru、Sobue Kazuya、Kimura Kazunori
  • Journal Title: Clinical and Experimental Nephrology Volume: 27 Issue: 4 Pages: 382-391
  • DOI: 10.1007/s10157-022-02314-w
  • Peer Reviewed
• [Journal Article] Changes in zinc and manganese concentrations in cisplatin-induced acute kidney injury (2023)
  • Author(s): Yamamoto Yuko、Hotta Yuji、Tomita Natsumi、Naiki-Ito Aya、Kitagawa Ayae、Kuboshiki Urara、Hagita Tamaki、Noda Misuzu、Sanagawa Akimasa、Kataoka Tomoya、Kondo Masahiro、Furukawa-Hibi Yoko、Takahashi Satoru、Kimura Kazunori
  • Journal Title: Biochemistry and Biophysics Reports Volume: 33 Pages: 101422-101422
  • DOI: 10.1016/j.bbrep.2023.101422
  • Peer Reviewed / Open Access
• [Journal Article] A case of metastatic treatment‐emergent small cell/neuroendocrine prostate cancer with BRCA2 mutation diagnosed by liver biopsy (2022)
  • Author(s): Naiki Taku、Naiki‐Ito Aya、Kawai Tatsuya、Komatsu Hirokazu、Nishikawa Ryutaro、Gonda Masakazu、Aoki Maria、Sugiyama Yosuke、Tasaki Yoshihiko、Yasui Takahiro
  • Journal Title: IJU Case Reports Volume: 5 Issue: 6 Pages: 431-435
  • DOI: 10.1002/iju5.12501
  • Peer Reviewed / Open Access
• [Journal Article] A rare case of long‐term survival from metachronous bilateral adrenal metastasis of lung adenocarcinoma after combined surgical removal and immunochemotherapy (2022)
  • Author(s): Tomiyama Nami, Naiki Taku, Naiki-Ito Aya, Kawai Tatsuya, Etani Toshiki, Gonda Masakazu, Aoki Maria, Morikawa Toshiharu, Sugiyama Yosuke, Yasui Takahiro
  • Journal Title: IJU Case Reports Volume: 5 Issue: 6 Pages: 474-478
  • DOI: 10.1002/iju5.12519
  • Peer Reviewed / Open Access
• [Journal Article] Survival outcome after reduced-port laparoscopic radical cystectomy for bladder cancer: long-term follow-up analysis (2022)
  • Author(s): Noda Yusuke, Naiki Taku, Sugiyama Yosuke, Nagai Takashi, Naiki-Ito Aya, Kawai Tatsuya, Hamamoto Shuzo, Etani Toshiki, Iida Keitaro, Tomiyama Nami, Aoki Maria, Shimizu Nobuhiko, Moritoki Yoshinobu, Akita Hidetoshi, Ando Ryosuke, Kawai Noriyasu, Yasui Takahiro
  • Journal Title: Oncology Volume: 100 Issue: 8 Pages: 429-438
  • DOI: 10.1159/000525554
  • Peer Reviewed / Open Access
• [Journal Article] Protective effects of tadalafil on damaged podocytes in an adriamycin-induced nephrotic syndrome model. (2022)
  • Author(s): Tomita N, Hotta Y, Naiki-Ito A, Sanagawa A, Kataoka T, Furukawa-Hibi Y, Takahashi S, Kimura K.
  • Journal Title: J Pharmacol Sci. Volume: 149 Issue: 2 Pages: 53-59
  • DOI: 10.1016/j.jphs.2022.03.003
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of the toxicity and carcinogenicity of double-walled carbon nanotubes in the rat lung after intratracheal instillation: a two-year study. (2022)
  • Author(s): Saleh, D.M., Luo, S., Ahmed, O.H.M., Alexander, D.B., Alexander, W.T., Gunasekaran, S., El-Gazzar, A.M., Abdelgied, M., Numano, T., Takase, H., Ohnishi, M., Tomono, S., El Hadi, R.H.A., Fukamachi, K., Kanno, J., Hirose, A., Xu, J., Suzuki, S., Naiki-Ito, A., Takahashi, S., Tsuda, H.
  • Journal Title: Particle abd Fibre Toxicology Volume: 19 Issue: 1 Pages: 1-21
  • DOI: 10.1186/s12989-022-00469-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combination therapy with radiation and hyperthermia‐induced clinical complete response of small cell carcinoma of prostate (2022)
  • Author(s): Kawai Noriyasu、Nagai Takashi、Naiki‐Ito Aya、Iida Keitaro、Etani Toshiki、Naiki Taku、Hamamoto Shuzo、Okada Atsushi、Murai Taro、Yasui Takahiro
  • Journal Title: IJU Case Reports Volume: 5 Issue: 2 Pages: 113-116
  • DOI: 10.1002/iju5.12413
  • Peer Reviewed / Open Access
• [Presentation] 多層および単層カーボンナノチューブの肺・胸膜発がん性の比較 (2025)
  • Author(s): 内木 綾、梯 アンナ、加藤 寛之、津田 洋幸、高橋 智
  • Organizer: 第41回日本毒性病理学会総会
• [Presentation] 前立腺癌に対するルテオリンの有効性と安全性に関する臨床的評価 (2024)
  • Author(s): 内木綾、内木拓、村上明寛、加藤寛之、髙橋智
  • Organizer: 第83回日本癌学会学術総会
• [Presentation] 前立腺癌の増殖に対するルテオリン誘導miRNAの役割 (2024)
  • Author(s): 村上明寛、内木綾、髙橋智
  • Organizer: 第83回日本癌学会学術総会
• [Presentation] 天然フラボノイドのサプリメントを用いた前立腺癌に対する進展予防研究 (2024)
  • Author(s): 内木拓、内木綾、青木マリア、清水伸彦、森川敏治、権田将一、梅本幸裕、髙橋智、安井孝周
  • Organizer: 第31回日本がん予防学会総会
• [Presentation] モデル動物と臨床検体を用いた前立腺・肝発がんメカニズムの解析と予防研究 (2024)
  • Author(s): 内木 綾、髙橋 智
  • Organizer: 第113回日本病理学会総会
  • Invited
• [Presentation] 非アルコール性脂肪肝炎および肝線維化に対するlactoferrinの抑制効果 (2024)
  • Author(s): 内木 綾、加藤 寛之、小村理行、高橋 智
  • Organizer: 第40回日本毒性病理学会
• [Presentation] 多層カーボンナノチューブとフラーレンウィスカーの肺発がん性の解析 (2023)
  • Author(s): 内木 綾、加藤 寛之、梯 アンナ、津田 洋幸、髙橋 智
  • Organizer: 第82回日本癌学会学術総会
• [Presentation] 非アルコール性脂肪肝炎および肝発がんに対するlactoferrinの化学予防効果の検討 (2023)
  • Author(s): 内木 綾、加藤 寛之、小村 理行、髙橋 智
  • Organizer: 第30回日本がん予防学会総会
• [Presentation] 非アルコール性脂肪肝炎および肝線維化に対する紫米抽出物の抑制効果 (2022)
  • Author(s): 内木綾、加藤寛之、小村理行、長野愛矢、稲熊真悟、高橋智
  • Organizer: 第111回日本病理学会総会
• [Presentation] Identification of factors inducing multi-walled carbon nanotube carcinogenesis (2022)
  • Author(s): 内木綾、津田洋幸、髙橋智
  • Organizer: 第81回日本癌学会学術総会
  • Invited
• [Presentation] ラット発がんモデルを基盤としたがんの発生と予防メカニズムの解析 (2022)
  • Author(s): 内木綾、加藤寛之、小村理行、髙橋智
  • Organizer: 第35回発癌病理研究会
  • Invited
• [Presentation] 多層カーボンナノチューブおよびフラーレンウィスカーの肺発がん性の比較 (2022)
  • Author(s): 内木綾、加藤寛之、梯アンナ、津田洋幸、高橋智
  • Organizer: 第39回日本毒性病理学会