Identification and analysis of functional RNAs regulated by p53 family members in gastrointestinal tumorigenesis

• Project/Area Number: 23590920
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Sapporo Medical University
• Principal Investigator: SASAKI Yasushi 札幌医科大学, 医学部, 准教授 (70322328)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: p53 / p73 / p63 / 機能性RNA / miRNA / 消化器癌 / バイオマーカー

Research Abstract

The miR-200 family includes two clusters: miR-200b-200a-429 located on chromosome 1; and miR-200c-141 located on chromosome 12. We identified response elements located around both clusters that are responsive to p53 family. Here, in silico miRNA target prediction identified the v-crk sarcoma virus CT10 oncogene homolog-like (CRKL) as a potential miR-200b/200c/429 target. MiR-200b/200c/429 inhibits the expression of CRKL by directly targeting its 3'-UTR region. Importantly, CRKL expression was decreased in cancer cells with introduction of wild-type p53 and TAp63. Oncomine database shows that CRKL levels are significantly overexpressed in multiple cancer types compared with the corresponding normal tissues. We also found that CRKL was overexpressed in primary breast cancer tissues harboring mutant p53 genes. Our results indicate that a p53-inducible miRNA, 200b/200c/429 is a negative regulator of the CRKL oncoprotein and suggest a new p53-miR-200-CRKL pathway in carcinogenesis.

Research Products

• [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] 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] 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] The effect of IGF-I receptor blockade for human esophageal squamous cell carcinoma and adenocarcinoma (2014)
  • Author(s): Adachi Y, Ohashi H, Imsumran A, Yamamoto H, Matsunaga Y, Taniguchi H, Nosho K, Suzuki H, Sasaki Y, Arimura Y, Carbone DP, Imai K, Shinomura Y
  • Journal Title: Tumour Biol Volume: 35 Issue: 2 Pages: 973-985
  • DOI: 10.1007/s13277-013-1131-2
  • Peer Reviewed
• [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] CHFR regulates the mitotic checkpoint by targeting PARP-1 for ubiquitination and degradation (2012)
  • Author(s): Kashima, L., Idogawa, M., Mita, H., Shitashige, M., Yamada, T., Ogi, K., Suzuki, H., Toyota, M., Ariga, H., Sasaki, Y., Tokino, T.
  • Journal Title: J. Biol. Chem Volume: 287 Issue: 16 Pages: 12975-12984
  • DOI: 10.1074/jbc.m111.321828
  • Peer Reviewed
• [Journal Article] A novel approach to cancer treatment using structural hybrids of the p53 gene family. (2012)
  • Author(s): Sasaki Y, Oshima Y, Koyama R, Tamura M, Kashima L, Idogawa M, Yamashita T, Toyota M, Imai K, Shinomura Y, Tokino T.
  • Journal Title: Cancer Gene Ther Volume: 19 Issue: 11 Pages: 749-56
  • DOI: 10.1038/cgt.2012.51
  • Peer Reviewed
• [Journal Article] Heat shock enhances the expression of cytotoxic granule proteins and augments the activities of tumor-associated antigen-specific cytotoxic T lymphocytes (2012)
  • Author(s): Takahashi A, Torigoe T, Tamura Y, Kanaseki T, Tsukahara T, Sasaki Y, Kameshima H, Tsuruma T, Hirata K, Tokino T, Hirohashi Y, Sato N
  • Journal Title: Cell Stress Chaperones Volume: 17 Issue: 6 Pages: 757-763
  • DOI: 10.1007/s12192-012-0348-0
  • Peer Reviewed
• [Journal Article] CLCA2, a target of the p53 family, negatively regulates cancer cell migration and invasion (2012)
  • Author(s): Sasaki Y, Sugisaka J, Maruyama R, Sugisaka J, Tamura M, Sugisaka J, Suzuki H, Idogawa M, Shinomura Y, Tokino T
  • Journal Title: Cancer Biol Ther Volume: 13 Issue: 14 Pages: 1512-1521
  • DOI: 10.4161/cbt.22280
  • Peer Reviewed
• [Journal Article] Molecular Dissection of Premalignant Colorectal Lesions Reveals Early Onset of the CpG Island Methylator Phenotype. (2012)
  • Author(s): Yamamoto E, Suzuki H, Yamano HO
  • Journal Title: Am J Pathol Volume: 181(5) Issue: 5 Pages: 1847-61
  • DOI: 10.1016/j.ajpath.2012.08.007
  • Peer Reviewed
• [Journal Article] Myogenic lineage differentiated mesenchymal stem cells enhance recovery from dextran sulfate sodium-induced colitis in the rat (2011)
  • Author(s): Tanaka H, Arimura Y, Yabana T, Goto A, Hosokawa M, Nagaishi K, Yamashita K, Yamamoto H, Sasaki Y, Fujimiya M, Imai K, Shinomura Y
  • Journal Title: J Gastr oenter ol Volume: 46 Issue: 2 Pages: 143-152
  • DOI: 10.1007/s00535-010-0320-7
  • NAID: 10029027000
  • Peer Reviewed
• [Journal Article] Epigenetic alteration of DNA in mucosal wash fluid predicts invasiveness of colorectal tumors (2011)
  • Author(s): Seiko Kamimae
  • Journal Title: Cancer prevention research Volume: 4 Issue: 5 Pages: 674-83
  • DOI: 10.1158/1940-6207.capr-10-0214
  • Peer Reviewed
• [Journal Article] Genome-wide profiling of chromatin signatures reveals epigenetic regulation of microRNA genes in colorectal cancer (2011)
  • Author(s): Suzuki H
  • Journal Title: Cancer Res Volume: 71 Issue: 17 Pages: 5646-5658
  • DOI: 10.1158/0008-5472.can-11-1076
  • Peer Reviewed
• [Journal Article] p53 negatively regulates the hepatoma growth factor HDGF (2011)
  • Author(s): Sasaki Y, Negishi H, Idogawa M, Yokota I, Koyama R, Kusano M, Suzuki H, Fujita M, Maruyama R, Toyota M, Saito T, Tokino T
  • Journal Title: Cancer Res Volume: 71 Issue: 22 Pages: 7038-47
  • DOI: 10.1158/0008-5472.can-11-1053
  • Peer Reviewed
• [Presentation] p53 regulates negatively the expression of the nuclear export protein XPO1, establishing a positive feedback loop (2014)
  • Author(s): Sasaki Y, Tamura M, Kobayashi T, Idogawa M, Suzuki H, Shinomura Y, Tokino T
  • Organizer: 41st Congress of the International Society of Oncology and BioMarkers
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-03-17
• [Presentation] p53 negatively regulates the expression of the nuclear export protein XPO1, establishing a positive feedback loop (2014)
  • Author(s): Sasaki Y, Tamura M, Kobayashi T, Idogawa M, Suzuki H, Shinomura Y, Tokino T
  • Organizer: 41st Congress of the International Society of Oncology and BioMarkers
  • Place of Presentation: Barcelona, Spain
• [Presentation] p53によるXPO1の抑制機構とその意義 (2013)
  • Author(s): 佐々木泰史, 小橋健太, 鈴木信太郎, 田村みゆき, 竹田康祐, 井戸川雅史, 篠村恭久, 時野隆至
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2013-12-05
• [Presentation] p53によるXPO1の抑制機構とその意義 (2013)
  • Author(s): 佐々木泰史, 田村みゆき, 竹田康佑, 井戸川雅史, 丸山玲緒, 鈴木拓, 篠村恭久, 時野隆至
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-04
• [Presentation] Forkhead transcription factor FOXF1 is a novel target gene of the p53 family and regulates cancer cell migration and invasiveness (2013)
  • Author(s): Sasaki Y, Tamura M, Koyama R, Takeda K, Idogawa M, Tokino T
  • Organizer: 6th International p63/p73 Workshop
  • Place of Presentation: Kisarazu, Chiba, Japan
  • Year and Date: 2013-07-10
• [Presentation] CLCA2, a target of the p53 family, negatively regulates cancer cell migration and invasion (2013)
  • Author(s): Sasaki Y, Koyama R, Maruyama R, Tamura M, Ohashi T, Idogawa M, Suzuki H, Shinomura Y, Tokino T
  • Organizer: 9th AACR-JCA Joint International Conference
  • Place of Presentation: Maui, Hawaii
  • Year and Date: 2013-02-24
• [Presentation] p53 によるXPO1 の抑制機構とその意義 (2013)
  • Author(s): 佐々木泰史，田村みゆき，竹田康佑，井戸川雅史，丸山玲緒，鈴木拓，篠村恭久，時野隆至
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Identification of novel p53 target genes by ChIP-Seq and mRNA expression analysis combined with genome-wide p53-binding motif analysis in silico (2013)
  • Author(s): Idogawa M, Ohashi T, Sasaki Y, Tokino T
  • Organizer: 9th AACR-JCA Joint International Conference
  • Place of Presentation: Maui, Hawaii
• [Presentation] Forkhead transcription factor FOXF1 is a novel target gene of the p53 family and regulates cancer cell migration and invasiveness (2013)
  • Author(s): Tamura M, Sasaki Y, Koyama R, Yokota I, Ohashi T, Idogawa M, Tokino T
  • Organizer: 9th AACR-JCA Joint International Conference
  • Place of Presentation: Maui, Hawaii
• [Presentation] Apoptosis induction in p53-mutated cancer cells by shRNAs based on the screening of genome-wide shRNA library (2013)
  • Author(s): Ohashi T, Idogawa M, Sugisaka J, Tamura M, Yokota I, Sasaki Y, Tokino T
  • Organizer: 9th AACR-JCA Joint International Conference
  • Place of Presentation: Maui, Hawaii
• [Presentation] p53ファミリーを用いた人工ハイブリッド遺伝子の作成とアポトーシス誘導活性 (2012)
  • Author(s): 佐々木泰史, 大島雄一郎, 小山良太, 田村みゆき, 井戸川雅史, 篠村恭久, 時野隆至
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-12
• [Presentation] p53 family network and tumor suppression (2012)
  • Author(s): 佐々木泰史, 井戸川雅史, 時野隆至
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌(シンポジウム)
  • Year and Date: 2012-09-19
• [Presentation] p53により発現抑制される分泌性増殖因子HDGFの同定とがん組織における発現解析 (2012)
  • Author(s): 佐々木泰史, 根岸秀明, 小山良太, 井戸川雅史, 鈴木拓, 今井浩三, 篠村恭久, 時野隆至
  • Organizer: 第49回日本臨床分子医学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2012-04-12
• [Presentation] Identification of novel p53 target genes by ChIP-Seq and mRNA expression analysis combined with genome-wide p53-binding motif analysis in silico. (2012)
  • Author(s): Idogawa M, Sasaki Y, Shinomura Y, Imai K, Tokino T
  • Organizer: American Association of Cancer Research (AACR) annual meeting
  • Place of Presentation: Chicago
• [Presentation] p53 family network and tumor suppression (2012)
  • Author(s): 佐々木泰史，井戸川雅史，時野隆至
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] ゲノム網羅的p53応答配列解析とクロマチン免疫沈降シーケンシング（ChIP-seq）を組み合わせた新規p53標的遺伝子の同定 (2012)
  • Author(s): 井戸川雅史，大箸智子，佐々木泰史，篠村恭久，今井浩三，時野隆至
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] p53ファミリーの新規標的FOXF1の同定と機能解析:がん細胞の浸潤・遊走能への関与 (2012)
  • Author(s): 田村みゆき，佐々木泰史，井戸川雅史，時野隆至
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] ゲノム網羅的shRNAライブラリースクリーニングによるp53誘導アポトーシス阻害遺伝子の同定 (2012)
  • Author(s): 大箸智子，井戸川雅史，佐々木泰史，時野隆至
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] p53 ファミリーを用いた人工ハイブリッド遺伝子の作成とアポトーシス誘導活性 (2012)
  • Author(s): 佐々木泰史，大島雄一郎，小山良太，田村みゆき，井戸川雅史，篠村恭久，時野隆至
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] hCLCA2, a p53 inducible transmembrane protein regulates cancer cell migration and invasion (2011)
  • Author(s): Sasaki Y, Koyama R, Kobayashi T, Suzuki H, Shinomura Y, Tokino T
  • Organizer: 39th Congress of the International Society of Oncology and BioMarkers
  • Place of Presentation: Firenze, Italy
  • Year and Date: 2011-10-17
• [Presentation] p53により発現抑制される分泌性増殖因子HDGFの同定がんの浸潤・遊走への関与 (2011)
  • Author(s): 佐々木泰史、根岸秀明、横田育子、鹿島理沙、井戸川雅史、丸山玲緒, 鈴木拓、豊田実、今井浩三、篠村恭久、時野隆至
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-03
• [Presentation] がん抑制遺伝子p53研究の新展開 (2011)
  • Author(s): 佐々木泰史
  • Organizer: 第2回道南分子病態研究会
  • Place of Presentation: 函館
  • Year and Date: 2011-06-30
• [Presentation] hCLCA2, a p53 inducible transmembrane protein regulates cancer cell migration and invasion (2011)
  • Author(s): Sasaki Y, Koyama R, Kobayashi T, Suzuki H, Shinomura Y, Tokino T
  • Organizer: 39th Congress of the International Society of Oncology and BioMarkers.
  • Place of Presentation: Firenze, Italy
• [Presentation] ゲノム網羅的shRNAライブラリースクリーニングに基づく人工miRNA /p53共発現による癌治療 (2011)
  • Author(s): 井戸川雅史、佐々木泰史、鹿島理沙、篠村恭久、今井浩三、時野隆至
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] p53ファミリーの新規標的遺伝子FOXF1の同定と機能解析 (2011)
  • Author(s): 田村みゆき，佐々木泰史、横田育子、鹿島理沙、井戸川雅史、時野隆至
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] p53ファミリーの新規標的ICAM2の同定：がん細胞の接着・遊走能への関与 (2011)
  • Author(s): 横田育子、佐々木泰史、田村みゆき、鹿島理沙、井戸川雅史、時野隆至
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] hCLCA2, a p53 inducible transmembrane protein regulates cancer cell migration and invasion (2011)
  • Author(s): 平野雄大，佐々木泰史，小山良太，鈴木拓，杉坂淳，井戸川雅史，時野隆至
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
• [Presentation] Apoptosis induction in cancer cells by the simultaneous transduction of p53 and artificial miRNAs based on the screening of genome-wide shRNA library (2011)
  • Author(s): 杉坂淳，井戸川雅史，大箸智子，平野雄大，佐々木泰史，時野隆至
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
• [Presentation] がん抑制遺伝子p53研究の新展開 (2011)
  • Author(s): 佐々木泰史
  • Organizer: 第2回 道南分子病態研究会(招待講演)
  • Place of Presentation: 函館
• [Remarks]
  • URL: http://web.sapmed.ac.jp/canmol/index.html
• [Patent(Industrial Property Rights)] p53ファミリーキメラ分子およびその使用 (2012)
  • Inventor(s): 時野隆至，井戸川雅史，佐々木泰史
  • Industrial Property Rights Holder: 北海道公立大学法人 札幌医科大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2012-08-27