Analysis of epigenome and functional RNA in colorectal cancer cells and cancer stem cells

• Project/Area Number: 23501261
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Carcinogenesis
• Research Institution: Sapporo Medical University
• Principal Investigator: SUZUKI Hiromu 札幌医科大学, 医学部, 教授 (20381254)
• 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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 大腸癌 / 癌幹細胞 / エピジェネティクス / DNAメチル化 / microRNA / メチル化 / noncoding RNA

Research Abstract

By analyzing epigenome and microRNA expression profiling in colorectal cancer (CRC) cells, we identified a series of epigenetically silenced microRNA genes. We found that DNA methyltransferase 1 (DNMT1) is essential for the maintenance of cancer stem-like cells (CSC)/ cancer initiating cells (CIC), and we also identified microRNA genes which are differentially expressed in CSC/CIC. We carried out genome and epigenome analysis in precursor and malignant lesions in colorectum, and identified aberrant DNA methylation patterns in the premalignant stage. Finally, by performing integrative analysis of molecular, pathological and endoscopic findings of premalignant colorectal lesions, we identified a novel surface microstructure which is specific to the precursor lesions of CpG island methylator phenotype (CIMP)-positive CRC.

Research Products

• [Journal Article] Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators (2014)
  • Author(s): Tahara T, Yamamoto E, Madireddi P, Suzuki H, Maruyama R, Chung W, Garriga J, Jelinek J, Yamano HO, Sugai T, Kondo Y, Toyota M, Issa JP, Estecio MR
  • Journal Title: Gastroenterology Volume: 146 Issue: 5 Pages: 530-538
  • DOI: 10.1158/0008-5472.can-13-1865
  • Peer Reviewed
• [Journal Article] Association of microRNA-31 with BRAF mutation, colorectal cancer survival, and serrated pathway (2014)
  • Author(s): Nosho K (他18名), Igarashi H, Ito M, Nojima M, Yamamoto H, Shinomura Y
  • Journal Title: Carcinogenesis Volume: 35 Issue: 4 Pages: 776-783
  • DOI: 10.1093/carcin/bgt374
  • 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
• [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] Association between genomic alterations and metastatic behavior of colorectal cancer identified by array-based comparative genomic hybridization. (2013)
  • Author(s): Sawada T, Yamamoto E, Suzuki H
  • Journal Title: Genes Chromosomes Cancer Volume: 52(2) Issue: 2 Pages: 140-9
  • DOI: 10.1002/gcc.22013
  • Peer Reviewed
• [Journal Article] Spontaneous rupture of an advanced pancreatoblastoma : aberrant RASSF1A methylation and CTNNB1 mutation as molecular genetic markers (2013)
  • Author(s): Honda S, Okada T, Miyagi H, Minato M, Suzuki H, Taketomi A
  • Journal Title: J Pediatr Surg Volume: 48 Issue: 4 Pages: e29-e32
  • DOI: 10.1016/j.jpedsurg.2013.02.038
  • 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] Upregulation of miR-196a and HOTAIR drive malignant character in gastrointestinal stromal tumors (2012)
  • Author(s): Takeshi Niinuma
  • Journal Title: Cancer research Volume: 72 Issue: 5 Pages: 1126-36
  • DOI: 10.1158/0008-5472.can-11-1803
  • Peer Reviewed
• [Journal Article] A novel pit pattern identifies the precursor of colorectal cancer derived from sessile serrated adenoma. (2012)
  • Author(s): Kimura T, Yamamoto E, Yamano HO.
  • Journal Title: Am J Gastroenterol. Volume: 107(3) Issue: 3 Pages: 460-9
  • DOI: 10.1038/ajg.2011.457
  • Peer Reviewed
• [Journal Article] DNA methylation and microRNA dysregulation in cancer. (2012)
  • Author(s): Suzuki Hiromu
  • Journal Title: Mol Oncol Volume: 6 Issue: 6 Pages: 567-78
  • DOI: 10.1016/j.molonc.2012.07.007
  • Peer Reviewed
• [Journal Article] Emerging links between epigenetic alterations and dysregulation of noncoding RNAs in cancer (2012)
  • Author(s): Maruyama R, Suzuki H, Yamamoto E, Imai K, Shinomura Y
  • Journal Title: Tumour Biol Volume: 33 Issue: 2 Pages: 277-85
  • DOI: 10.1007/s13277-011-0308-9
  • Peer Reviewed
• [Journal Article] Aberrant Methylation of RASGRF1 Is Associated with an Epigenetic Field Defect and Increased Risk of Gastric Cancer. (2012)
  • Author(s): Takamaru H, Yamamoto E, Suzuki H.
  • Journal Title: Cancer Prev Res (Phila) Volume: 5(10) Issue: 10 Pages: 2012-2012
  • DOI: 10.1158/1940-6207.capr-12-0056
  • Peer Reviewed
• [Journal Article] Genomic vulnerability to LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma (2012)
  • Author(s): Aoki Y, Nojima M, Suzuki H, Yasui H, Maruyama R, Yamamoto E, Ashida M, Itagaki M, Asaoku H, Ikeda H, Hayashi T, Imai K, Mori M, Tokino T, Ishida T, Toyota M, Shinomura Y
  • Journal Title: Genome Med Volume: 4 Pages: 101-101
  • URL: http://genomemedicine.com/content/4/12/101
  • 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] 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] Genome-wide analysis of DNA methylation identifies novel cancer-related genes in hepatocellular carcinoma (2012)
  • Author(s): Shitani M, Sasaki S, Akutsu N, Takagi H, Suzuki H, Nojima M, Yamamoto H, Tokino T, Hirata K, Imai K, Toyota M, Shinomura Y
  • Journal Title: Tumour Biol Volume: 33 Issue: 5 Pages: 1307-1317
  • DOI: 10.1007/s13277-012-0378-3
  • Peer Reviewed
• [Journal Article] Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumour (2012)
  • Author(s): Okamoto Y
  • Journal Title: Gut Volume: 61 Issue: 3 Pages: 392-401
  • DOI: 10.1136/gut.2011.241034
  • 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] 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] Clinicopathological and molecular features of colorectal serrated neoplasias with different mucosal crypt patterns (2011)
  • Author(s): Yano Y, Konishi K, Yamochi T, Katagiri A, Nozawa H, Suzuki H, Toyota M, Kubota Y, Muramoto T, Kobayashi Y, Tojo M, Konda K, Makino R, Kaneko K, Yoshikawa N, Ota H, Imawari M
  • Journal Title: Am J Gastroenterol Volume: 106 Issue: 7 Pages: 1351-1358
  • DOI: 10.1038/ajg.2011.76
  • 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] 腸管洗浄液のメチル化検出による大腸癌診断法の開発 (2013)
  • Author(s): 原田拓,山本英一郎,野島正寛,丸山玲緒,佐藤亜紀子,甲斐正広,山野泰穂,鈴木拓
  • Organizer: 第33回日本分子腫瘍マーカー研究会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-02
• [Presentation] 消化器癌の発生や進展に関与する長鎖ncRNA の量的・質的異常の探索と臨床応用への試み (2013)
  • Author(s): 丸山玲緒,山本英一郎,粂川昂平,津矢田明泰,鈴木亮,芦田仁己,甲斐正広,佐藤亜紀子,新沼猛,山野泰穂,菅井有,篠村恭久,時野隆至,鈴木拓
  • Organizer: 第33回日本分子腫瘍マーカー研究会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-02
• [Presentation] がんエピゲノム解析による病態解明と診断応用 (2013)
  • Author(s): 鈴木拓
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] マイクロRNA 遺伝子のエピジェネティクス異常と臨床応用 (2013)
  • Author(s): 鈴木拓,山本英一郎,丸山玲緒,鈴木 亮,清水崇,原田拓,山野泰穂,野島正寛,高塚伸太朗,新沼猛、甲斐正広,篠村恭久,今井浩三
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] 消化器癌において重要な役割を果たす長鎖ncRNA の網羅的同定の試み (2013)
  • Author(s): 丸山玲緒,山本英一郎,粂川昂平,津矢田明泰,鈴木亮,芦田仁己,佐藤亜紀子,甲斐正広,山野泰穂,菅井有,篠村恭久,時野隆至,鈴木拓
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] マイクロRNA遺伝子のエピジェネティクス異常と臨床応用 (2013)
  • Author(s): 鈴木 拓
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] microRNA遺伝子のメチル化を用いた膀胱癌新規バイオマーカーの開発 (2013)
  • Author(s): 鈴木 拓
  • Organizer: 第64回日本電気泳動学会総会
  • Place of Presentation: 仙台
• [Presentation] Epigenetic silencing of neurotensin receptor type 1 (NTSR1) in colorectal tumor (2013)
  • Author(s): Hiromu Suzuki
  • Organizer: AACR International Conference on Frontiers in Basic Cancer Research
  • Place of Presentation: National Harbor, MD, USA
• [Presentation] 大腸腫瘍におけるニューロテンシン受容体1型遺伝子のメチル化と臨床的意義 (2013)
  • Author(s): 鈴木 拓
  • Organizer: 第9回日本消化管学会総会学術総会
  • Place of Presentation: 東京
• [Presentation] 消化管腫瘍のエピゲノムおよびnon-coding RNA 解析による分子マーカー探索 (2012)
  • Author(s): 鈴木拓
  • Organizer: 第32回日本分子腫瘍マーカー研究会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-18
• [Presentation] microRNA-196a とHOTAIRの過剰発現は消化管間質腫瘍の悪性度と相関する (2012)
  • Author(s): 鈴木拓,新沼猛,野島正寛,丸山玲緒,山本英一郎,甲斐正広,能正勝彦,山本博幸,時野隆至,今井浩三,篠村恭久
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] 大腸癌においてエピジェネティックに抑制されている長鎖ncRNA の網羅的同定の試み (2012)
  • Author(s): 丸山玲緒,粂川昇平,山本英一郎,井戸川雅史,野島正寛,甲斐正広,能正勝彦,佐々木泰史,山野泰穂,菅井有,篠村恭久,時野隆至,鈴木拓
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] 大腸腫瘍におけるニューロテンシン受容体1 型遺伝子のメチル化と臨床的意義 (2012)
  • Author(s): 山本英一郎,鈴木拓,神前正幸,丸山玲緒,山野泰穂,澤田武,能正勝彦,山本博幸,甲斐正広,時野隆至,菅井有,今井浩三,篠村恭久
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] 大腸腫瘍におけるニューロテンシン受容体1 型遺伝子のメチル化と臨床的意義 (2012)
  • Author(s): 鈴木拓,山本英一郎,丸山玲緒,山野泰穂,甲斐正広,山本博幸,篠村恭久
  • Organizer: 第23回日本消化器癌発生学会総会
  • Place of Presentation: 徳島
• [Presentation] miR-196aおよびHOTAIR の過剰発現は消化管間質腫瘍の悪性度を促進する (2012)
  • Author(s): 鈴木拓,野島正寛,丸山玲緒,山本英一郎,津矢田明泰,篠村恭久
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] Upregulation of miR-196a and HOTAIR drive malignant character in gastrointestinal stromal tumor (2012)
  • Author(s): 鈴木 拓
  • Organizer: 第71回日本癌学会学術集会
  • Place of Presentation: 札幌
• [Presentation] 大腸腫瘍におけるニューロテンシン受容体１型遺伝子のメチル化と臨床的意義 (2012)
  • Author(s): 鈴木 拓
  • Organizer: 第20回日本消化器病関連学会週間(JDDW)
  • Place of Presentation: 神戸
• [Presentation] 大腸腫瘍におけるニューロテンシン受容体１型遺伝子のメチル化と臨床的意義 (2012)
  • Author(s): 鈴木 拓
  • Organizer: 第23回日本消化器癌発生学会総会
  • Place of Presentation: 徳島
• [Presentation] 大腸がんのエピゲノム解析によるがん関連miRNA遺伝子の同定 (2012)
  • Author(s): 鈴木 拓
  • Organizer: 日本食品化学工学学会第59回大会
  • Place of Presentation: 札幌
  • Invited
• [Presentation] 大腸癌のエピゲノム解析による癌関連miRNA 遺伝子の同定 (2011)
  • Author(s): 鈴木拓,山本英一郎,丸山玲緒,篠村恭久,今井浩三,豊田実
  • Organizer: 第31回日本分子腫瘍マーカー研究会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-02
• [Presentation] 消化管癌におけるmicroRNA 遺伝子のエピジェネティックな不活化の網羅的解析 (2011)
  • Author(s): 鈴木拓,山本英一郎,篠村恭久
  • Organizer: 第97回日本消化器病学会総会
  • Place of Presentation: 東京
• [Presentation] エピゲノム解析による造血器腫瘍の新たな分子標的の同定 (2011)
  • Author(s): 豊田実,野島正寛,鈴木拓,丸山玲緒,山本英一郎,甲斐正広,時野隆至,篠村恭久,今井浩三
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] 大腸癌のエピゲノム解析からアプローチする癌関連miRNA の探索 (2011)
  • Author(s): 鈴木拓,山本英一郎,野島正寛,丸山玲緒,高丸博之,甲斐正広,時野隆至,今井浩三,豊田実,篠村恭久
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] 大腸癌におけるmicroRNA 遺伝子のエピジェネティックな制御の網羅的解析 (2011)
  • Author(s): 鈴木拓,山本英一郎,丸山玲緒,野島正寛,今井浩三,篠村恭久,豊田実
  • Organizer: 第22回日本消化器癌発生学会総会
  • Place of Presentation: 佐賀
• [Presentation] microRNA遺伝子のエピジェネティクス異常によるがん診断
  • Author(s): 鈴木 拓
  • Organizer: 日本がん分子標的治療学会第9回トランスレーショナルリサーチワークショップ
  • Place of Presentation: 東京
  • Invited
• [Presentation] 大腸癌におけるmiRNA遺伝子のエピジェネティックな制御の解析
  • Author(s): 鈴木 拓
  • Organizer: 第5回日本エピジェネティクス研究会年会
  • Place of Presentation: 熊本
• [Presentation] Genome-wide profiling of chromatin signatures reveals epigenetic regulation of microRNA genes in colorectal cancer
  • Author(s): 鈴木 拓
  • Organizer: 第70回日本癌学会総会
  • Place of Presentation: 名古屋
• [Presentation] The origin of colorectal cancer with CpG island methylator phenotype
  • Author(s): 鈴木 拓
  • Organizer: International Society of Oncology and Biomarker (ISOBM) 2011
  • Place of Presentation: イタリア・フィレンツェ