Elucidation of the microRNA-mediated RNA networks in castration resistant prostate cancer and development of innovative treatments

• Project/Area Number: 16H05462
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Chiba University
• Principal Investigator: Ichikawa Tomohiko 千葉大学, 大学院医学研究院, 教授 (20241953)
• Co-Investigator(Kenkyū-buntansha): 関 直彦 千葉大学, 大学院医学研究院, 准教授 (50345013) ; 坂本 信一 千葉大学, 医学部附属病院, 講師 (70422235)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 前立腺癌 / 癌抑制 / 転移抑制 / 去勢抵抗性 / マイクロＲＮＡ / 泌尿器癌 / microＲＮＡ / マイクロRNA / microRNA

Outline of Final Research Achievements

We constructed the microRNA (miRNA) expression signature of castration-resistant prostate cancer (CRPC) using clinical specimens, and investigated the functional significance of tumor-suppressive miRNAs. We further investigated oncogenes regulated by the tumor-suppressive miRNAs. We have revealed that miR-452, miR-320a, miR-26a/b, miR-29a/b/c, miR-218, miR-145-3p, miR-150-5p/3p, miR-205-5p, miR-99a-3p, miR-455-5p/3p, and miR-199a/b-3p function as tumor suppressors in prostate cancer. We have also identified the genes regulated by those miRNAs.

Academic Significance and Societal Importance of the Research Achievements

前立腺癌で発現異常を認めるマイクロRNAの機能性RNA分子ネットワークの解析を行うことにより、前立腺癌やCRPCの機能性RNA分子ネットワークの解析を進める事ができた。それらが制御する癌遺伝子は前立腺癌の予後を予測することが可能な分子マーカーであった。これにより、前立腺癌の診療、特に去勢抵抗性前立腺癌の診断や治療への道筋をつけることができた。今後の研究の展開により新規治療法を確立するための基盤を整えることができた。

Research Products

• [Journal Article] Micro-ribonucleic acid expression signature of metastatic castration-resistant prostate cancer: Regulation of NCAPH by antitumor miR-199a/b-3p. (2019)
  • Author(s): Arai T, Kojima S, Yamada Y, Sugawara S, Kato M, Yamazaki K, Naya Y, Ichikawa T, Seki N.
  • Journal Title: International journal of urology Volume: 26 Issue: 4 Pages: 506-520
  • DOI: 10.1111/iju.13911
  • Peer Reviewed / Open Access
• [Journal Article] Role of pre-miR-532 (miR-532-5p and miR-532-3p) in regulation of gene expression and molecular pathogenesis in renal cell carcinoma. (2019)
  • Author(s): Yamada Y, Arai T, Kato M, Kojima S, Sakamoto S, Komiya A, Naya Y, Ichikawa T, Seki N.
  • Journal Title: American Journal of Clinical and Experimental Urology Volume: 7 Pages: 11-30
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of NCAPG by miR-99a-3p (passenger strand) inhibits cancer cell aggressiveness and is involved in CRPC (2018)
  • Author(s): Arai, T. Okato, A. Yamada, Y. Sugawara, S. Kurozumi, A. Kojima, S. Yamazaki, K. Naya, Y. Ichikawa, T. Seki, N.
  • Journal Title: Cancer Med Volume: 7(5) Issue: 5 Pages: 1988-2002
  • DOI: 10.1002/cam4.1455
  • Peer Reviewed / Open Access
• [Journal Article] Pirin: a potential novel therapeutic target for castration-resistant prostate cancer regulated by miR-455-5p (2018)
  • Author(s): Arai Takayuki、Kojima Satoko、Yamada Yasutaka、Sugawara Sho、Kato Mayuko、Yamazaki Kazuto、Naya Yukio、Ichikawa Tomohiko、Seki Naohiko
  • Journal Title: Molecular Oncology Volume: 13 Issue: 2 Pages: 322-337
  • DOI: 10.1002/1878-0261.12405
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of bone scan index in the prognosis and effects of therapy on prostate cancer with bone metastasis: Study design and rationale for the multicenter Prostatic Cancer Registry of Standard Hormonal and Chemotherapy Using Bone Scan Index (PROSTAT-BSI) study (2018)
  • Author(s): Nakajima Kenichi、Kaneko Go、Takahashi Satoru、Matsuyama Hideyasu、Shiina Hiroaki、Ichikawa Tomohiko、Horikoshi Hiroyuki、Hashine Katsuyoshi、Sugiyama Yutaka、Miyao Takeshi、Kamiyama Manabu、Harada Kenichi、Ito Akito、Mizokami Atsushi、the PROSTAT-BSI Investigators
  • Journal Title: International Journal of Urology Volume: 25 Issue: 5 Pages: 492-499
  • DOI: 10.1111/iju.13556
  • NAID: 120006471063
  • Peer Reviewed
• [Journal Article] Treatment strategy for metastatic prostate cancer with extremely high PSA level: reconsidering the value of vintage therapy (2018)
  • Author(s): Sakamoto Shinichi、Yamada Yasutaka、Amiya Yoshiyasu、Sasaki Makoto、Shima Takayuki、Komiya Akira、Suzuki Noriyuki、Akakura Koichiro、Ichikawa Tomohiko、Nakatsu Hiroomi
  • Journal Title: Asian Journal of Andrology Volume: 20 Issue: 5 Pages: 432-432
  • DOI: 10.4103/aja.aja_24_18
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-tumor roles of both strands of the miR-455 duplex: their targets SKA1 and SKA3 are involved in the pathogenesis of renal cell carcinoma (2018)
  • Author(s): Yamada, Y. Arai, T. Kojima, S. Sugawara, S. Kato, M. Okato, A. Yamazaki, K. Naya, Y. Ichikawa, T. Seki, N.
  • Journal Title: Oncotarget Volume: 9 (42) Issue: 42 Pages: 26638-58
  • DOI: 10.18632/oncotarget.25410
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of antitumor miR-144-5p targets oncogenes: Direct regulation of syndecan-3 and its clinical significance (2018)
  • Author(s): Yamada, Y. Arai, T. Kojima, S. Sugawara, S. Kato, M. Okato, A. Yamazaki, K. Naya, Y. Ichikawa, T. Seki, N.
  • Journal Title: Cancer Sci Volume: 109 (9) Issue: 9 Pages: 2919-2936
  • DOI: 10.1111/cas.13722
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular pathogenesis of renal cell carcinoma: Impact of the anti-tumor miR-29 family on gene regulation (2018)
  • Author(s): Yamada, Y. Sugawara, S. Arai, T. Kojima, S. Kato, M. Okato, A. Yamazaki, K. Naya, Y. Ichikawa, T. Seki, N.
  • Journal Title: Int J Urol Volume: 25(11) Issue: 11 Pages: 953-965
  • DOI: 10.1111/iju.13783
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Duration of androgen deprivation therapy and nadir of testosterone at 20 ng/dL predict testosterone recovery to supracastrate level in prostate cancer patients who received external beam radiotherapy. (2018)
  • Author(s): Takei A, Sakamoto S, Wakai K, Tamura T, Imamura Y, Xu M, Maimaiti M, Kawamura K, Imamoto T, Komiya A, Akakura K, Ichikawa T.
  • Journal Title: Int J Urol. Volume: 25 Issue: 4 Pages: 352-358
  • DOI: 10.1111/iju.13521
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Biparametric Prostate Imaging, the Reporting and Data System, Version 2, and International Society of Urological Pathology Grade Predict for Biochemical Recurrence After Radical Prostatectomy. (2018)
  • Author(s): Takeuchi N, Sakamoto S, Nishiyama A, Horikoshi T, Yamada Y, Iizuka J, Maimaiti M, Imamura Y, Kawamura K, Imamoto T, Komiya A, Ikehara Y, Akakura K, Ichikawa T.
  • Journal Title: Clin Genitourin Cancer Volume: 「印刷中」 Issue: 4 Pages: e817-e829
  • DOI: 10.1016/j.clgc.2018.02.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Impact of novel oncogenic pathways regulated by antitumor miR-451a in renal cell carcinoma (2018)
  • Author(s): Yamada Yasutaka、Arai Takayuki、Sugawara Sho、Okato Atsushi、Kato Mayuko、Kojima Satoko、Yamazaki Kazuto、Naya Yukio、Ichikawa Tomohiko、Seki Naohiko
  • Journal Title: Cancer Sci Volume: 印刷中 Issue: 4 Pages: 1239-1253
  • DOI: 10.1111/cas.13526
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular pathogenesis of interstitial cystitis based on microRNA expression signature: miR-320 family-regulated molecular pathways and targets. (2018)
  • Author(s): Arai T, Fuse M, Goto Y, Kaga K, Kurozumi A, Yamada Y, Sugawara S, Okato A, Ichikawa T, Yamanishi T, Seki N.
  • Journal Title: Journal of Human Genetics Volume: 印刷中 Issue: 5 Pages: 543-554
  • DOI: 10.1038/s10038-018-0419-x
  • Peer Reviewed
• [Journal Article] Dual strands of the miR-223 duplex (miR-223-5p and miR-223-3p) inhibit cancer cell aggressiveness: targeted genes are involved in bladder cancer pathogenesis (2018)
  • Author(s): Sugawara Sho、Yamada Yasutaka、Arai Takayuki、Okato Atsushi、Idichi Tetsuya、Kato Mayuko、Koshizuka Keiichi、Ichikawa Tomohiko、Seki Naohiko
  • Journal Title: J Hum Genet Volume: 印刷中 Issue: 5 Pages: 657-668
  • DOI: 10.1038/s10038-018-0437-8
  • Peer Reviewed
• [Journal Article] Dual strands of pre-miR-150 (miR-150-5p and miR-150-3p) act as antitumor miRNAs targeting SPOCK1 in na?ve and castration-resistant prostate cancer (2017)
  • Author(s): Okato Atsushi、Arai Takayuki、Kojima Satoko、Koshizuka Keiichi、Osako Yusaku、Idichi Tetsuya、Kurozumi Akira、Goto Yusuke、Kato Mayuko、Naya Yukio、Ichikawa Tomohiko、Seki Naohiko
  • Journal Title: International Journal of Oncology Volume: 51 Issue: 1 Pages: 245-256
  • DOI: 10.3892/ijo.2017.4008
  • Peer Reviewed / Open Access
• [Journal Article] Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer (2017)
  • Author(s): Goto Yusuke、Kurozumi Akira、Arai Takayuki、Nohata Nijiro、Kojima Satoko、Okato Atsushi、Kato Mayuko、Yamazaki Kazuto、Ishida Yasuo、Naya Yukio、Ichikawa Tomohiko、Seki Naohiko
  • Journal Title: British Journal of Cancer Volume: 117 Issue: 3 Pages: 409-420
  • DOI: 10.1038/bjc.2017.191
  • Peer Reviewed
• [Journal Article] Regulation of HMGB3 by antitumor miR-205-5p inhibits cancer cell aggressiveness and is involved in prostate cancer pathogenesis (2017)
  • Author(s): Yamada Yasutaka、Nishikawa Rika、Kato Mayuko、Okato Atsushi、Arai Takayuki、Kojima Satoko、Yamazaki Kazuto、Naya Yukio、Ichikawa Tomohiko、Seki Naohiko
  • Journal Title: J Hum Genet Volume: 63 Issue: 2 Pages: 195-205
  • DOI: 10.1038/s10038-017-0371-1
  • Peer Reviewed / Open Access
• [Journal Article] Testosterone Reduction of 480 ng/dL Predicts Favorable Prognosis of Japanese Men With Advanced Prostate Cancer Treated With Androgen-Deprivation Therapy. (2017)
  • Author(s): Yamamoto S, Sakamoto S, Minhui X, Tamura T, Otsuka K, Sato K, Maimaiti M, Kamada S, Takei A, Fuse M, Kawamura K, Imamoto T, Komiya A, Akakura K, Ichikawa T.
  • Journal Title: Clin Genitourin Cancer Volume: 15 Issue: 6 Pages: e1107-e1115
  • DOI: 10.1016/j.clgc.2017.07.023
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cancer-specific mortality of high-risk prostate cancer after carbon-ion radiotherapy plus long-term androgen deprivation therapy (2017)
  • Author(s): Kasuya Goro、Ishikawa Hitoshi、Tsuji Hiroshi、Haruyama Yasuo、Kobashi Gen、Ebner Daniel K.、Akakura Koichiro、Suzuki Hiroyoshi、Ichikawa Tomohiko、Shimazaki Jun、Makishima Hirokazu、Nomiya Takuma、Kamada Tadashi、Tsujii Hirohiko、the Working Group for Genitourinary Tumors
  • Journal Title: Cancer Science Volume: 108 Issue: 12 Pages: 2422-2429
  • DOI: 10.1111/cas.13402
  • Peer Reviewed / Open Access
• [Journal Article] Significant prognostic difference between Grade Group 4 and 5 in the 2014 International Society of Urological Pathology Grading System for High Grade Prostate Cancer with Bone Metastasis (2017)
  • Author(s): Yamada Yasutaka、Sakamoto Shinichi、Shimazaki Jun、Sugiura Masahiro、Amiya Yoshiyasu、Sasaki Makoto、Shima Takayuki、Komiya Akira、Suzuki Noriyuki、Akakura Koichiro、Ichikawa Tomohiko、Nakatsu Hiroomi
  • Journal Title: Prostate Int Volume: 5 Issue: 4 Pages: 143-148
  • DOI: 10.1016/j.prnil.2017.03.001
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of spindle and kinetochore-associated protein 1 by antitumor miR-10a-5p in renal cell carcinoma (2017)
  • Author(s): Arai Takayuki、Okato Atsushi、Kojima Satoko、Idichi Tetsuya、Koshizuka Keiichi、Kurozumi Akira、Kato Mayuko、Yamazaki Kazuto、Ishida Yasuo、Naya Yukio、Ichikawa Tomohiko、Seki Naohiko
  • Journal Title: Cancer Science Volume: 108 Issue: 10 Pages: 2088-2101
  • DOI: 10.1111/cas.13331
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dual Strands of Pre-miR-149 Inhibit Cancer Cell Migration and Invasion through Targeting FOXM1 in Renal Cell Carcinoma (2017)
  • Author(s): Okato Atsushi、Arai Takayuki、Yamada Yasutaka、Sugawara Sho、Koshizuka Keiichi、Fujimura Lisa、Kurozumi Akira、Kato Mayuko、Kojima Satoko、Naya Yukio、Ichikawa Tomohiko、Seki Naohiko
  • Journal Title: International Journal of Molecular Sciences Volume: 18 Issue: 9 Pages: 1969-1969
  • DOI: 10.3390/ijms18091969
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of metastasis-promoting LOXL2 gene expression by antitumor microRNAs in prostate cancer. (2017)
  • Author(s): Kato M, Kurozumi A, Goto Y, Matsushita R, Okato A, Nishikawa R, Fukumoto I, Koshizuka K, Ichikawa T, Seki N.
  • Journal Title: J Hum Genet Volume: 62 Issue: 1 Pages: 123-132
  • DOI: 10.1038/jhg.2016.68
  • NAID: 40021036352
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Aberrantly expressed microRNAs in bladder cancer and renal cell carcinoma. (2017)
  • Author(s): Kurozumi A, Goto Y, Okato A, Ichikawa T, Seki N.
  • Journal Title: J Hum Genet Volume: 62 Issue: 1 Pages: 49-56
  • DOI: 10.1038/jhg.2016.84
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Regulation of E3 ubiquitin ligase-1 (WWP1) by microRNA-452 inhibits cancer cell migration and invasion in prostate cancer. (2016)
  • Author(s): Goto Y, Kojima S, Kurozumi A, Kato M, Okato A, Matsushita R, Ichikawa T, Seki N.
  • Journal Title: Br J Cancer Volume: 114 Issue: 10 Pages: 1135-1144
  • DOI: 10.1038/bjc.2016.95
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Direct regulation of LAMP1 by tumor-suppressive microRNA-320a in prostate cancer. (2016)
  • Author(s): Okato A, Goto Y, Kurozumi A, Kato M, Kojima S, Matsushita R, Yonemori M, Miyamoto K, Ichikawa T, Seki N.
  • Journal Title: Int J Oncol Volume: 49 Issue: 1 Pages: 111-122
  • DOI: 10.3892/ijo.2016.3522
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The microRNA signature of patients with sunitinib failure: regulation of UHRF1 pathways by microRNA-101 in renal cell carcinoma. (2016)
  • Author(s): Goto Y, Kurozumi A, Nohata N, Kojima S, Matsushita R, Yoshino H, Yamazaki K, Ishida Y, Ichikawa T, Naya Y, Seki N.
  • Journal Title: Oncotarget Volume: 7 Issue: 37 Pages: 59070-59086
  • DOI: 10.18632/oncotarget.10887
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Identification of dual tumor-suppressors (miR-222-5p/miR-222-3p) based on microRNA expression signature by deep sequencing of CRPC. (2016)
  • Author(s): Goto Y, Kojima S, Kurozumi A, Kato M, Okato A, Sakamoto S, Naya Y, Enokida H, Matsushita R, Nakagawa M, Ichikawa T, Seki N.
  • Organizer: AUA annual meeting 2016
  • Place of Presentation: San Diego Convention Center, San Diego, 米国 カリフォルニア州
  • Year and Date: 2016-05-06
  • Int'l Joint Research
• [Remarks] 千葉大学大学院医学研究院泌尿器科学
  • URL: http://www.m.chiba-u.ac.jp/class/urology/