A better understanding of p53 network for cancer therapy

• Project/Area Number: 16K07122
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Sapporo 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: ¥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)
• Keywords: p53 / 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．

Research Products

• [Journal Article] p53-induced ARVCF modulates the splicing landscape and supports the tumor suppressive function of p53 (2020)
  • 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
  • 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 patients (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis (2020)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic Effect of Long Noncoding RNA NEAT1 Expression Depends on p53 Mutation Status in Cancer (2019)
  • Author(s): Idogawa, M. Nakase, H. Sasaki, Y. Tokino, T.
  • Journal Title: J Oncol Volume: 1 Pages: 4368068-4368068
  • DOI: 10.1155/2019/4368068
  • 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
  • Peer Reviewed
• [Journal Article] UHRF1 depletion and HDAC inhibition reactivate epigenetically silenced genes in colorectal cancer cells (2019)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Genomic characterization for familial cases with urothelial carcinoma (2019)
  • 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
  • Peer Reviewed
• [Journal Article] FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy (2019)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors (2019)
  • 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
  • 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 carcinoma (2018)
  • 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
  • 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 lymphoma (2018)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer (2018)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Screening for long noncoding RNAs associated with oral squamous cell carcinoma reveals the potentially oncogenic actions of DLEU1 (2018)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling (2018)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Mutational analysis of uterine cervical cancer that survived multiple rounds of radiotherapy (2018)
  • 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
  • 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 treatment (2018)
  • 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
  • Peer Reviewed
• [Journal Article] Surface microstructures are associated with mutational intratumoral heterogeneity in colorectal tumors (2018)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genomic characterization of esophageal squamous cell carcinoma: Insights from next-generation sequencing (2016)
  • 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
  • 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
  • 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 stress (2016)
  • 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
  • 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
  • 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
  • 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/
• [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/
• [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/