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A better understanding of p53 network for cancer therapy

Research Project

Project/Area Number 16K07122
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Tumor biology
Research InstitutionSapporo Medical University

Principal Investigator

TOKINO Takashi  札幌医科大学, 医学部, 教授 (40202197)

Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsp53 / がん抑制遺伝子 / TP53
Outline of Final Research Achievements

p53 is one of the most important tumor suppressor genes. Thus, understanding p53 network is an important issue. In this study, we identified BRMS1L and ARVCF as novel p53-target genes. Functional analysis showed that ectopic expression of BRMS1L inhibited cancer cell invasion and migration; knockdown of BRMS1L by siRNA induced the opposite effects. Importantly, clinical databases revealed that reduced BRMS1L expression correlated with poor prognosis in patients with breast and brain cancer. We found that BRMS1L is one of the mediators downstream of the p53 pathway, such as p21 activation and survivin suppression. We also revealed the knockdown of ARVCF inhibited p53-induced apoptosis. Our results suggest that p53-induced ARVCF indirectly, but not directly, regulates p53 target selectivity through splicing alterations of specific genes. Our study indicates that BRMS1L and ARVCF are involved in tumor suppression, and could be therapeutic targets for human cancer.

Academic Significance and Societal Importance of the Research Achievements

新規p53標的としてBRMS1L,ARVCFを同定した.BRMS1Lは転移抑制遺伝子BRMS1, mSds3とファミリを形成しているが,その差異については不明な点が多かった.本研究で,BRMS1Lがp53経路とつながったことで,p53による腫瘍細胞の浸潤・遊走抑制におけるメカニズムの解明が進むことが期待できる.また,ARVCFの機能について,細胞接着・運動および選択的mRNAスプライシングへの関与が報告されていた.本研究において,ARVCFがp53誘導性細胞死およびp53変異をもつ患者の予後不良・生存率低下に関与していることが示された.ARVCFは新しいがん治療標的になる可能性がある.

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (35 results)

All 2020 2019 2018 2017 2016 Other

All Journal Article (31 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 31 results,  Open Access: 26 results,  Acknowledgement Compliant: 5 results) Presentation (1 results) (of which Int'l Joint Research: 1 results) Remarks (3 results)

  • [Journal Article] p53-induced ARVCF modulates the splicing landscape and supports the tumor suppressive function of p532020

    • Author(s)
      Suzuki, N. Idogawa, M. Tange, S. Ohashi, T. Sasaki, Y. Nakase, H. Tokino, T.
    • Journal Title

      Oncogene

      Volume: 39 Issue: 10 Pages: 2202-2211

    • DOI

      10.1038/s41388-019-1133-7

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chemotherapy after progression on nivolumab is essential for responders with genetic alterations of driver gene: Review of two recurrent/metastatic oral squamous cell carcinoma patients2020

    • Author(s)
      Ogi, K. Kobayashi, J. Nakagaki, T. Okamoto, J. Koike, K. Hirokawa, N. Someya, M. Sakamoto, H. Takada, K. Tokino, T. Sasaki, Y. Hiratsuka, H. Miyazaki, A.
    • Journal Title

      Oral Oncol

      Volume: 102 Pages: 104509-104509

    • DOI

      10.1016/j.oraloncology.2019.104509

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis2020

    • Author(s)
      Fujita, Y. Matsuda, S. Sasaki, Y. Masugi, Y. Kitago, M. Yagi, H. Abe, Y. Shinoda, M. Tokino, T. Sakamoto, M. Kitagawa, Y.
    • Journal Title

      Cancer Sci

      Volume: 111 Issue: 2 Pages: 739-748

    • DOI

      10.1111/cas.14268

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Prognostic Effect of Long Noncoding RNA NEAT1 Expression Depends on p53 Mutation Status in Cancer2019

    • Author(s)
      Idogawa, M. Nakase, H. Sasaki, Y. Tokino, T.
    • Journal Title

      J Oncol

      Volume: 1 Pages: 4368068-4368068

    • DOI

      10.1155/2019/4368068

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Renal angiomyolipoma (AML) harboring a missense mutation of TSC2 with copy-neutral loss of heterozygosity (CN-LOH)2019

    • Author(s)
      Idogawa Masashi、Hida Tokimasa、Tanaka Toshiaki、Ohira Noriaki、Tange Shoichiro、Sasaki Yasushi、Uhara Hisashi、Masumori Naoya、Tokino Takashi、Natori Hiroshi
    • Journal Title

      Cancer Biology & Therapy

      Volume: 21 Issue: 4 Pages: 315-319

    • DOI

      10.1080/15384047.2019.1702406

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] UHRF1 depletion and HDAC inhibition reactivate epigenetically silenced genes in colorectal cancer cells2019

    • Author(s)
      Niinuma Takeshi、Kitajima Hiroshi、Kai Masahiro、Yamamoto Eiichiro、Yorozu Akira、Ishiguro Kazuya、Sasaki Hajime、Sudo Gota、Toyota Mutsumi、Hatahira Tomo、Maruyama Reo、Tokino Takashi、Nakase Hiroshi、Sugai Tamotsu、Suzuki Hiromu
    • Journal Title

      Clinical Epigenetics

      Volume: 11 Issue: 1 Pages: 70-70

    • DOI

      10.1186/s13148-019-0668-3

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genomic characterization for familial cases with urothelial carcinoma2019

    • Author(s)
      Shindo T, Hirobe M, Adachi Y, Sasaki Y, Tokino T, Masumori N
    • Journal Title

      Int Cancer Conf J

      Volume: 8 Issue: 4 Pages: 185-189

    • DOI

      10.1007/s13691-019-00381-7

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy2019

    • Author(s)
      Darwis, N. D. M. Nachankar, A. Sasaki, Y. Matsui, T. Noda, S. E. Murata, K. Tamaki, T. Ando, K. Okonogi, N. Shiba, S. Irie, D. Kaminuma, T. Kumazawa, T. Anakura, M. Yamashita, S. Hirakawa, T. Kakoti, S. Hirota, Y. Tokino, T. Iwase, A. Ohno, T. Shibata, A. Oike, T. Nakano, T.
    • Journal Title

      Int J Mol Sci

      Volume: 20 Issue: 18 Pages: 4563-4563

    • DOI

      10.3390/ijms20184563

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors2019

    • Author(s)
      Fukamachi H、Kim SK、Koh J、Lee HS、Sasaki Y、Yamashita K、Nishikawaji T、Shimada S、Akiyama Y、Byeon SJ、Bae DH、Okuno K、Nakagawa M、Tanioka T、Inokuchi M、Kawachi H、Tsuchiya K、Kojima K、Tokino Takashi、Eishi Y、Kim YS、Kim WH、Yuasa Y、Tanaka S
    • Journal Title

      Journal of Experimental & Clinical Cancer Research

      Volume: 38 Issue: 1 Pages: 127-127

    • DOI

      10.1186/s13046-019-1121-3

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Targeted next-generation sequencing of 50 cancer-related genes in Japanese patients with oral squamous cell carcinoma2018

    • Author(s)
      Nakagaki Takafumi、Tamura Miyuki、Kobashi Kenta、Omori Akina、Koyama Ryota、Idogawa Masashi、Ogi Kazuhiro、Hiratsuka Hiroyoshi、Tokino Takashi、Sasaki Yasushi
    • Journal Title

      Tumor Biology

      Volume: 40 Issue: 9 Pages: 0-0

    • DOI

      10.1177/1010428318800180

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Target amplicon exome-sequencing identifies promising diagnosis and prognostic markers involved in RTK-RAS and PI3K-AKT signaling as central oncopathways in primary central nervous system lymphoma2018

    • Author(s)
      Takashima Yasuo、Sasaki Yasushi、Hayano Azusa、Homma Jumpei、Fukai Junya、Iwadate Yasuo、Kajiwara Koji、Ishizawa Shin、Hondoh Hiroaki、Tokino Takashi、Yamanaka Ryuya
    • Journal Title

      Oncotarget

      Volume: 9 Issue: 44 Pages: 27471-27486

    • DOI

      10.18632/oncotarget.25463

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer2018

    • Author(s)
      Shindo Tetsuya、Niinuma Takeshi、Nishiyama Naotaka、Shinkai Nobuo、Kitajima Hiroshi、Kai Masahiro、Maruyama Reo、Tokino Takashi、Masumori Naoya、Suzuki Hiromu
    • Journal Title

      Oncotarget

      Volume: 9 Issue: 36 Pages: 24457-24469

    • DOI

      10.18632/oncotarget.25326

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Screening for long noncoding RNAs associated with oral squamous cell carcinoma reveals the potentially oncogenic actions of DLEU12018

    • Author(s)
      Nishiyama K、Maruyama R、Niinuma T、Kai M、Kitajima H、Toyota M、Hatanaka Y、Igarashi T、Kobayashi J、Ogi K、Dehari H、Miyazaki A、Yorozu A、Yamamoto E、Idogawa M、Sasaki Y、Sugai T、Tokino Takashi、Hiratsuka H、Suzuki H
    • Journal Title

      Cell Death & Disease

      Volume: 9 Issue: 8 Pages: 826-826

    • DOI

      10.1038/s41419-018-0893-2

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling2018

    • Author(s)
      Ishiguro Kazuya、Kitajima Hiroshi、Niinuma Takeshi、Ishida Tadao、Maruyama Reo、Ikeda Hiroshi、Hayashi Toshiaki、Sasaki Hajime、Wakasugi Hideki、Nishiyama Koyo、Shindo Tetsuya、Yamamoto Eiichiro、Kai Masahiro、Sasaki Yasushi、Tokino Takashi、Nakase Hiroshi、Suzuki Hiromu
    • Journal Title

      Haematologica

      Volume: 104 Issue: 1 Pages: 155-165

    • DOI

      10.3324/haematol.2018.191262

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mutational analysis of uterine cervical cancer that survived multiple rounds of radiotherapy2018

    • Author(s)
      Nuryadi E、Sasaki Y、Hagiwara Y、Permata TBM、Sato H、Komatsu S、Yoshimoto Y、Murata K、Ando K、Kubo N、Okonogi N、Takakusagi Y、Adachi A、Iwanaga M、Tsuchida K、Tamaki T、Noda S、Hirota Y、Shibata A、Ohno T、Tokino Takashi、Oike T、Nakano T
    • Journal Title

      Oncotarget

      Volume: 9 Issue: 66 Pages: 32642-32652

    • DOI

      10.18632/oncotarget.25982

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Dysregulation of miRNA in chronic hepatitis B is associated with hepatocellular carcinoma risk after nucleos(t)ide analogue treatment2018

    • Author(s)
      Wakasugi H, Takahashi H, Niinuma T, Kitajima H, Oikawa R, Matsumoto N, Takeba Y, Otsubo T, Takagi M, Ariizumi Y, Suzuki M, Okuse C, Iwabuchi S, Nakano M, Akutsu N, Kang JH, Matsui T, Yamada N, Sasaki H, Yamamoto E, Kai M, Sasaki Y, Sasaki, Tanaka, Yotsuyanagi, Tsutsumi, Yamamoto, Tokino T , Nakase H, Suzuki H, Itoh F
    • Journal Title

      Cancer Letters

      Volume: 434 Pages: 91-100

    • DOI

      10.1016/j.canlet.2018.07.019

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Surface microstructures are associated with mutational intratumoral heterogeneity in colorectal tumors2018

    • Author(s)
      Harada T、Yamamoto E、Yamano HO、Aoki H、Matsushita HO、Yoshikawa K、Takagi R、Harada E、Tanaka Y、Yoshida Y、Eizuka M、Yorozu A、Sudo G、Kitajima H、Niinuma T、Kai M、Sasaki Y、Tokino Takashi、Sugai T、Nakase H、Suzuki H
    • Journal Title

      Journal of Gastroenterology

      Volume: 53 Issue: 12 Pages: 1241-1252

    • DOI

      10.1007/s00535-018-1481-z

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Targeted sequencing reveals genetic variants associated with sensitivity of 79 human cancer xenografts to anticancer drugs.2018

    • Author(s)
      Udagawa C, Sasaki Y, Suemizu H, Ohnishi H, Tokino T, Zembutsu H
    • Journal Title

      Experimental and Therapeutic Medicine

      Volume: 15 Pages: 1339-1359

    • DOI

      10.3892/etm.2017.5533

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification and characterization of a metastatic suppressor BRMS1L as a target gene of p53.2017

    • Author(s)
      Koyama R, Tamura M, Nakagaki T, Ohashi T, Idogawa M, Suzuki H, Tokino T, Sasaki Y
    • Journal Title

      Cancer Science

      Volume: 108 Issue: 12 Pages: 2413-2421

    • DOI

      10.1111/cas.13420

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Profiling cancer-related gene mutations in oral squamous cell carcinoma from Japanese patients by targeted amplicon sequencing.2017

    • Author(s)
      Nakagaki T, Tamura M, Kobashi K, Koyama R, Fukushima H, Ohashi T, Idogawa M, Ogi K, Hiratsuka H, Tokino T, Sasaki Y
    • Journal Title

      Oncotarget

      Volume: 8 Issue: 35 Pages: 59113-59122

    • DOI

      10.18632/oncotarget.19262

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fledglings in p53 signaling network.2017

    • Author(s)
      Tokino T, Idogawa M, Sasaki Y
    • Journal Title

      Oncotarget

      Volume: 8 Issue: 34 Pages: 55768-55769

    • DOI

      10.18632/oncotarget.19229

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Assessment of the quality of DNA from various formalin-fixed paraffin-embedded (FFPE) tissues and the use of this DNA for next-generation sequencing (NGS) with no artifactual mutation.2017

    • Author(s)
      Einaga N, Yoshida A, Noda H, Suemitsu M, Nakayama Y, Sakurada A, Kawaji Y, Yamaguchi H, Sasaski Y, Tokino T, Esumi M
    • Journal Title

      PLoS One

      Volume: 12 Issue: 5 Pages: e0176280-e0176280

    • DOI

      10.1371/journal.pone.0176280

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Downregulation of miR-186 is associated with metastatic recurrence of gastrointestinal stromal tumors.2017

    • Author(s)
      Niinuma T, Kai M, Kitajima H, Yamamoto E, Harada T, Maruyama R, Nobuoka T, Kanda T, Hasegawa T, Tokino T, Sugai T, Shimomura Y, Nakase H, Suzuki H
    • Journal Title

      Oncology Letters

      Volume: 14 Pages: 5703-5710

    • DOI

      10.3892/ol.2017.6911

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long non-coding RNA NEAT1 is a transcriptional target of p53 and modulates p53-induced transactivation and tumor-suppressor function.2017

    • Author(s)
      Masashi Idogawa, Tomoko Ohashi, Yasushi Sasaki, Hiroshi Nakase, Takashi Tokino
    • Journal Title

      International Joural of Cancer

      Volume: 印刷中 Issue: 12 Pages: 2785-2791

    • DOI

      10.1002/ijc.30689

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] p53 mediates the suppression of cancer cell invasion by inducing LIMA1/EPLIN.2017

    • Author(s)
      Tomoko Ohashi, Masashi Idogawa, Yasushi Sasaki, Takashi Tokino
    • Journal Title

      Cancer Letters

      Volume: 390 Pages: 58-66

    • DOI

      10.1016/j.canlet.2016.12.034

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] The effect of forced expression of mutated K-RAS gene on gastrointestinal cancer cell lines and the IGF-1R targeting therapy.2017

    • Author(s)
      Matsunaga Y, Adachi Y, Sasaki Y, Koide H, Motoya M, Nosho K, Takagi H, Yamamoto H, Sasaki S, Tokino T, Carbone DP, Imai K, Shinomura Y
    • Journal Title

      Molecular Carcinogenesis

      Volume: VOL. 56 Issue: 2 Pages: 515-526

    • DOI

      10.1002/mc.22513

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification and characterization of the intercellular adhesion molecule-2 gene as a novel p53 target.2016

    • Author(s)
      Sasaki Y, Tamura M, Takeda K, Ogi K, Nakagaki T, Koyama R, Idogawa M, Hiratsuka H, Tokino T
    • Journal Title

      Oncotarget

      Volume: VOL. 7 Issue: 38 Pages: 61426-61437

    • DOI

      10.18632/oncotarget.11366

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Genomic characterization of esophageal squamous cell carcinoma: Insights from next-generation sequencing2016

    • Author(s)
      Sasaki Y, Tamura M, Koyama R, Nakagaki T, Adachi Y, Tokino T.
    • Journal Title

      WORLD JOURNAL OF GASTROENTEROLOGY

      Volume: 22 Issue: 7 Pages: 2284-2293

    • DOI

      10.3748/wjg.v22.i7.2284

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] TET1 Depletion Induces Aberrant CpG Methylation in Colorectal Cancer Cells.2016

    • Author(s)
      Kai M, Niinuma T, Kitajima H, Yamamoto E, Harada T, Aoki H, Maruyama R, Toyota M, Sasaki Y, Sugai T, Tokino T, Nakase H, Suzuki H.
    • Journal Title

      PLoS One

      Volume: 11 Issue: 12 Pages: e0168281-e0168281

    • DOI

      10.1371/journal.pone.0168281

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Plasticity of lung cancer stem-like cells is regulated by the transcription factor HOXA5 that is induced by oxidative stress2016

    • Author(s)
      Hiroshi Saijo, Yoshihiko Hirohashi, et al.
    • Journal Title

      Oncotarget

      Volume: 2;7(31) Issue: 31 Pages: 50043-50056

    • DOI

      10.18632/oncotarget.10571

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] A genomic screen for long noncoding RNA genes epigenetically silenced by aberrant DNA methylation in colorectal cancer.2016

    • Author(s)
      Kumegawa K, Maruyama R, Yamamoto E, Ashida M, Kitajima H, Tsuyada A, Niinuma T, Kai M, Yamano HO, Sugai T, Tokino T, Shinomura Y, Imai K, Suzuki H.
    • Journal Title

      Sci Rep

      Volume: 6 Issue: 1 Pages: 26699-26699

    • DOI

      10.1038/srep26699

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] p53 downregulates CRKL oncogene through miR-200.2016

    • Author(s)
      Tokino T, Tamura M, Idogawa M, Sasaki Y
    • Organizer
      American Association of Cancer Research (AACR) annual meeting.
    • Place of Presentation
      New Orleans Convention Center, USA
    • Year and Date
      2016-04-19
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Remarks] 札幌医科大学医学部フロンティア医学研究所ゲノム医科学部門ホームページ

    • URL

      https://web.sapmed.ac.jp/canmol/

    • Related Report
      2019 Annual Research Report
  • [Remarks] 札幌医科大学フロンティア医学研究所ゲノム医科学部門

    • URL

      http://web.sapmed.ac.jp/canmol/

    • Related Report
      2018 Research-status Report 2017 Research-status Report
  • [Remarks] 札幌医科大学 医学部附属フロンティア医学研究所 ゲノム医科学部門

    • URL

      http://web.sapmed.ac.jp/canmol/

    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2021-02-19  

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