New insights into p53 signaling regulation to cure cancer

• Project/Area Number: 25430115
• 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): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: p53 / がん抑制遺伝子 / マイクロRNA / FOXF1 / 転移・浸潤

Outline of Final Research Achievements

We found that forkhead transcription factor FOXF1 and intercellular adhesion molecule-2 (ICAM2) are novel target genes of p53. The ectopic expression of FOXF1 and ICAM2 inhibited cancer cell invasion and migration, whereas the inactivation of FOXF1 and ICAM2 stimulated cell invasion and migration. Our findings suggest that FOXF1 and ICAM2 induction by p53 are on key pathways in inhibiting cancer cell migration and invasion.
We also found CRKL oncogene is downregulated by p53 through miR-200s. First, we identified that miR-200s are direct transcriptional targets of p53 and then miR-200b/200c/429 inhibited CRKL mRNA and protein expression by directly targeting its 3’-UTR region. The CRKL oncogene encodes an adaptor protein containing Src homology 2 and 3 (SH2/SH3) domains and is reported to be overexpressed in a subset of cancer types. Our results demonstrate that the p53 target miR-200b/200c/429 miRNAs are negative regulators of the CRKL oncogene.

Research Products

• [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] 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] 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] CRKL oncogene is downregulated by p53 through miR-200s (2015)
  • Author(s): Tamura M, Sasaki Y, Kobashi K, Takeda K, Nakagaki T, Idogawa M, Tokino T.
  • Journal Title: CANCER SCIENCE Volume: 106 Issue: 8 Pages: 1033-1040
  • DOI: 10.1111/cas.12713
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Molecular diagnostics of a single drug-resistant multiple myeloma case using targeted next-generation sequencing (2015)
  • Author(s): Ikeda H, Ishiguro K, Igarashi T, Aoki Y, Hayashi T, Ishida T, Sasaki Y, Tokino T, Shinomura Y.
  • Journal Title: ONCOTARGETS AND THERAPY Volume: 8 Pages: 2805-2815
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Epigenetic silencing of NTSR1 is associated with lateral and noninvasive growth of colorectal tumors (2015)
  • Author(s): Kamimae S, Yamamoto E, Kai M, Niinuma T, Yamano HO, Nojima M, Yoshikawa K, Kimura T, Takagi R, Harada E, Harada T, Maruyama R, Sasaki Y, Tokino T, Shinomura Y, Sugai T, Imai K, Suzuki H
  • Journal Title: Oncotarget Volume: 6 Issue: 30 Pages: 29975-90
  • DOI: 10.18632/oncotarget.5034
  • NAID: 130005161526
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Analysis of the molecular features of rectal carcinoid tumors to identify new biomarkers that predict biological malignancy (2015)
  • Author(s): Mitsuhashi K, Yamamoto I, Kurihara H, Kanno S, Ito M, Igarashi H, Ishigami K, Sukawa Y, Tachibana M, Takahashi H, Tokino T, Maruyama R, Suzuki H, Imai K, Shinomura Y, Yamamoto H, Nosho K
  • Journal Title: ONCOTARGET Volume: 6 Issue: 26 Pages: 22114-22125
  • DOI: 10.18632/oncotarget.4294
  • Peer Reviewed / Open Access
• [Journal Article] One-dimensional sliding of p53 along DNA is accelerated in the presence of Ca(2+) or Mg(2+) at millimolar concentrations (2015)
  • Author(s): Murata A, Ito Y, Kashima R, Kanbayashi S, Nanatani K, Igarashi C, Okumura M, Inaba K, Tokino T, Takahashi S, Kamagata K
  • Journal Title: JOURNAL OF MOLECULAR BIOLOGY Volume: 427 Issue: 16 Pages: 2663-2678
  • DOI: 10.1016/j.jmb.2015.06.016
  • Peer Reviewed / Open Access
• [Journal Article] A Screen for Epigenetically Silenced microRNA Genes in Gastrointestinal Stromal Tumors. (2015)
  • Author(s): Isosaka M, Niinuma T, Nojima M, Kai M, Yamamoto E, Maruyama R, Nobuoka T, Nishida T, Kanda T, Taguchi T, Hasegawa T, Tokino T, Hirata K, Suzuki H, Shinomura Y
  • Journal Title: PLoS One Volume: 10 Issue: 7 Pages: e0133754-e0133754
  • DOI: 10.1371/journal.pone.0133754
  • Peer Reviewed / Open Access
• [Journal Article] Relation between Ku80 and microRNA-99a expression and late rectal bleeding after radiotherapy. (2015)
  • Author(s): Someya M, Yamamoto H, Nojima M, Hori M, Tateoka K, Nakata K, Takagi M, Saitoh M, Hirokawa N, Tokino T, Sakata K
  • Journal Title: Radiotherapy and Oncology Volume: in press Issue: 2 Pages: 235-239
  • DOI: 10.1016/j.radonc.2015.04.008
  • Peer Reviewed
• [Journal Article] Array-based genome-wide RNAi screening to identify shRNAs that enhance p53-related apoptosis in human cancer cells. (2014)
  • Author(s): Idogawa M, Ohashi T, Sugisaka J, Sasaki Y, Suzuki H, Tokino T
  • Journal Title: Oncotarget Volume: 5 Pages: 7540-7548
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Forkhead transcription factor FOXF1 is a novel target gene of the p53 family and regulates cancer cell migration and invasiveness (2014)
  • Author(s): Tamura M, Sasaki Y, Koyama R, Takeda K, Idogawa M, Tokino T
  • Journal Title: Oncogene Volume: (in press) Issue: 40 Pages: 4837-4846
  • DOI: 10.1038/onc.2013.427
  • Peer Reviewed / Open Access
• [Journal Article] Identification and analysis of large intergenic non-coding RNAs regulated by p53 family members through a genome-wide analysis of p53-binding sites (2014)
  • Author(s): Idogawa M, Ohashi T, Sasaki Y, Maruyama R, Kashima L, Suzuki H, Tokino T
  • Journal Title: Hum Mol Genet Volume: 23 Issue: 11 Pages: 2847-2857
  • DOI: 10.1093/hmg/ddt673
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-31 expression in relation to BRAF mutation, CpG island methylation and colorectal continuum in serrated lesions (2014)
  • Author(s): Ito M, Mitsuhashi K, Igarashi H, Nosho K, Yamamoto H
  • Journal Title: Int J Cancer Volume: (Epub ahead of print) Issue: 11 Pages: 2507-2515
  • DOI: 10.1002/ijc.28920
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Genomicsを目指した半導体NGSによるがんゲノム解析 (2014)
  • Author(s): 丸喜明，佐々木泰史，中村友紀，横井左奈，大平美紀，時野隆至，永瀬浩喜
  • Journal Title: 羊土社 Volume: 32 Pages: 1781-1788
• [Journal Article] AKR1B10, a transcriptional target of p53, is Downregulated in Colorectal Cancers Associated with Poor Prognosis (2013)
  • Author(s): Ohashi T et al.
  • Journal Title: Mol Cancer Res Volume: 11 Issue: 12 Pages: 1554-1163
  • DOI: 10.1158/1541-7786.mcr-13-0330-t
  • Peer Reviewed
• [Journal Article] Methylation of a panel of microRNA genes is a novel biomarker for detection of bladder cancer (2013)
  • Author(s): Shimizu T, Suzuki H, Nojima M, Kitamura H, Yamamoto E, Maruyama R, Ashida M, Hatahira T, Kai M, Masumori N, Tokino T, Imai K, Tsukamoto T, Toyota M
  • Journal Title: Eur Urol Volume: 63 Issue: 6 Pages: 1091-1100
  • DOI: 10.1016/j.eururo.2012.11.030
  • Peer Reviewed
• [Journal Article] DNA methyltransferase 1 is essential for initiation of the colon cancers (2013)
  • Author(s): Morita R,Hirohashi Y,Suzuki H, et al
  • Journal Title: Experimental and Molecular Pathology Volume: 94 Issue: 2 Pages: 322-329
  • DOI: 10.1016/j.yexmp.2012.10.004
  • Peer Reviewed
• [Presentation] p53経路と発がん (2016)
  • Author(s): 時野隆至
  • Organizer: 日本癌学会
  • Place of Presentation: パシフィコ横浜，神奈川県横浜市
  • Year and Date: 2016-10-06
  • Invited
• [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) annuak meeting.
  • Place of Presentation: New Orleans Convention Center, USA
  • Year and Date: 2016-04-19
  • Int'l Joint Research
• [Presentation] p53ネットワークとがん：最近の話題 (2015)
  • Author(s): 時野隆至
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
  • Invited
• [Presentation] Genome-wide RNAi screening to identify shRNA that enhance p53-related apoptosis in human cancer cells (2015)
  • Author(s): Tokino T
  • Organizer: SNUCRI Cancer Symposium
  • Place of Presentation: Hwasun, Korea
  • Year and Date: 2015-04-01
  • Int'l Joint Research / Invited
• [Presentation] Identification and analysis of large intergenic non-coding RNAs regulated by p53 family members through a genome-wide analysis of p53 binding sites. (2014)
  • Author(s): Idogawa M, Ohashi T, Sasaki Y, Tokio T
  • Organizer: 16th International p53 Workshop.
  • Place of Presentation: Stockholm, Sweden.
  • Year and Date: 2014-06-17
• [Presentation] Genome-based personalized medicine in oncology. (2014)
  • Author(s): Tokino T
  • Organizer: The 18th International Congress of Personalized Medicine.
  • Place of Presentation: 札幌
  • Year and Date: 2014-06-14
  • Invited
• [Presentation] p53 family network and tumor suppression. (2014)
  • Author(s): Sasaki Y, Tamura, M, Takeda K, Idogawa M, Maruyama R, Suzuki H, Shinomura Y, Tokino T
  • Organizer: The 3rd International Symposium on Genetic Regulation and Targeted Therapy of Cancer and 5th Symposium of A3 Foresight Program
  • Place of Presentation: Zhangjiajie, China.
  • Year and Date: 2014-06-13
• [Presentation] Forkhead transcription factor FOXF1 is a novel target gene of the p53 family and regulates cancer cell migration and invasiveness. (2014)
  • Author(s): Tokino T, Tamura M, Idogawa M, Sasaki Y
  • Organizer: American Association of Cancer Research (AACR) Annual Meeting.
  • Place of Presentation: San Diego, USA.
  • Year and Date: 2014-04-06
• [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/
• [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ホームページ
  • 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 業績
  • URL: http://web.sapmed.ac.jp/canmol/paper.html
• [Remarks] 札幌医大フロンティア研ゲノム医科学部門
  • URL: http://web.sapmed.ac.jp/canmol/