p53 family target ncRNAs and gastrointestinal tumorigenesis

2017 Fiscal Year Annual Research Report

• Project/Area Number: 26460944
• Research Institution: Sapporo Medical University
• Principal Investigator: 佐々木 泰史 札幌医科大学, 医療人育成センター, 教授 (70322328)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Keywords: p53 / p63 / p73 / miRNA / 非コードRNA / 消化器癌

Outline of Annual Research Achievements

平成26, 27年度は，p53誘導性miRNA，miR-200b/200c/429の新規標的遺伝子としてCRKL， およびp53ファミリーに直接転写制御される新規標的遺伝子としてICAM2を同定した．それぞれ消化器癌の予後と相関することを明らかにし，学術誌に掲載された．平成28年度はp53ファミリーに転写調節される誘導性lncRNA（long non-coding RNA）としてNEAT1を報告し，p53の転写活性化能，抗腫瘍活性を増強することを明らかにした．また，NEAT1発現低下が大腸癌の予後不良因子であることを発見し，Int J Cancer誌に掲載された(Int J Cancer. 140: 2785-91, 2017)．最終年度はさらに，p53の新規標的遺伝子としてBreast cancer metastasis suppressor 1-like (BRMS1L) を同定し，転写制御機構およびその機能解析として癌細胞における浸潤能に与える影響を検討した．BRMS1Lは外因性，内在性のp53発現上昇に伴いともに発現が誘導され，BRMS1L遺伝子内にp53結合配列を2か所同定し，p53により直接制御される遺伝子であることを示した．機能解析においては， BRMS1Lがp53の転写活性を増強する補助因子であることが示唆された．さらに，種々のヒト腫瘍において，正常組織と比較し癌組織でのBRMS1L発現が有意に低下しており，癌患者においてBRMS1L低発現群で有意に生存率が低下していることから，BRMS1L低発現が予後不良因子と考えられた（Cancer Sci. 108: 2413-21, 2017）．
以上，p53によって制御される新規非コードRNA，蛋白コード遺伝子を同定し，がん組織における発現異常，遺伝子変異・構造異常の解析，浸潤・転移および悪性度や予後との関連性を解析した．今後は消化器癌の新しい診断・治療システムの構築を目指したい．

Research Products

• [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 Y, Ohnishi H, Tokino T, Zembutsu H
  • Journal Title: Exp Ther Med Volume: 15 Pages: 1339-1359
  • DOI: 10.3892/etm.2017.5533
  • Peer Reviewed
• [Journal Article] p53 mediates the suppression of cancer cell invasion by inducing LIMA1/EPLIN (2017)
  • Author(s): Ohashi T, Idogawa M, Sasaki Y, Tokino T
  • Journal Title: Cancer Lett Volume: 390 Pages: 58-66
  • DOI: 10.1016/j.canlet.2016.12.034
  • Peer Reviewed
• [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): Idogawa M, Ohashi T, Sasaki Y, Nakase H, Tokino T.
  • Journal Title: Int J Cancer Volume: 140 Pages: 2785-2791
  • DOI: 10.1002/ijc.30689
  • 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, Sasaki Y, Tokino T, Esumi M.
  • Journal Title: PLoS One Volume: 12 Pages: e0176280
  • DOI: 10.1371/journal.pone.0176280
  • 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 Pages: 55768-55769
  • DOI: 10.18632/oncotarget.19229
  • 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 Pages: 59113-59122
  • DOI: 10.18632/oncotarget.19262
  • 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 Sci Volume: 108 Pages: 2413-2421
  • DOI: 10.1111/cas.13420
  • Peer Reviewed / Open Access
• [Presentation] Targeted exome sequences of cancer-related genes in human cancers using amplicon sequencing (2017)
  • Author(s): Sasaki Y, Nakagaki T, Tamura M, Fukushima F, Ikeda H, Koyama R, Idogawa M, Tokino T
  • Organizer: American Association of Cancer Research (AACR) annual meeting 2017
  • Int'l Joint Research
• [Presentation] Mutation detection by target sequence analyses using tissue-specific panels in esophageal squamous cell carcinoma. (2017)
  • Author(s): Iwaya T, Endo F, Kume K, Sasaki Y, Tokino T, Nishizuka S
  • Organizer: American Association of Cancer Research (AACR) annual meeting 2017
  • Int'l Joint Research
• [Presentation] Exome sequencing of cancer-related genes to identify genetic markers for sensitivity to cytotoxic anticancer drugs (2017)
  • Author(s): Idogawa C, Sasaki Y, Suemizu H, Ohnishi Y, Ohnishi H, Tokino T, Zembutsu H
  • Organizer: American Association of Cancer Research (AACR) annual meeting 2017
  • Int'l Joint Research
• [Presentation] Profiling cancer-related gene mutations in oral squamous cell carcinoma from Japanese patients by targeted amplicon sequencing (2017)
  • Author(s): Sasaki Y, Nakagaki T, Tamura M, Kobashi K, Koyama R, Fukushima F, Idogawa M, Ogi K, Hiratsuka H, Tokino T
  • Organizer: The 12th International Workshop on Advanced Genomics
  • Int'l Joint Research
• [Presentation] p53標的遺伝子BRMS1Lの同定と機能解析 (2017)
  • Author(s): 佐々木泰史，小山良太，田村みゆき，中垣貴文，大箸智子，井戸川雅史，時野隆至
  • Organizer: 第76回日本癌学会学術総会
• [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/index.html