Molecular mechanisms of epigenetic alterations in gastrointestinal cancer and application to diagnosis and therapy

2009 Fiscal Year Final Research Report

• Project/Area Number: 17109008
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Sapporo Medical University
• Principal Investigator: IMAI Kohzoh Sapporo Medical University, 学長 (60117603)
• Co-Investigator(Kenkyū-buntansha): SHINOMURA Yasuhisa 札幌医科大学, 医学部, 教授 (90162619) ; TOYOTA Minoru 札幌医科大学, 医学部, 教授 (70270676) ; YAMAMOTO Hiroyuki 札幌医科大学, 医学部, 講師 (40332910) ; ARIMURA Yoshiaki 札幌医科大学, 医学部, 講師 (80305218) ; SUZUKI Hiromu 札幌医科大学, 医学部, 助教 (20381254)
• Project Period (FY): 2005 – 2009
• Keywords: DNAメチル化 / エピジェネティクス / ヒストン修飾 / 個別化医療

Research Abstract

Molecular mechanisms how this epigenetic alterations contribute to development of tumors remains to be determined. DNA methylation also leads to silencing of genes involved in cell signaling, which in turn leads to dysregulation of the oncogenic signaling such as Ras, WNT, and microRNA. We found that epigenetic inactivation of IGFBP7 plays a critical role in escaping senescence in CIMP positive colorectal cancers. We also found that epigenetic information can be used to detect cancer cells from colorectal mucosal solution.

Research Products

• [Journal Article] IGFBP7 is p53 responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype. (2010)
  • Author(s): Suzuki H, Igarashi S, Nojima M, Maruyama R, Yamamoto E, Kai M, Akashi H, Watanabe Y, Yamamoto H, Sasaki Y, Itoh F, Imai K, Sugai T, Shen L, Issa JPJ, Shinomura Y, Tokino T, Toyota M
  • Journal Title: Carcinogenesis 31 Pages: 342-349
  • Peer Reviewed
• [Journal Article] Epigenetic inactivation of the circadian clock gene BMAL1 in hematological malignancies. (2009)
  • Author(s): Taniguchi H, Fernandez AF, Setien F, Ropero S, Ballestar E, Villanueva A, Yamamoto H, Imai K, Shinomura Y, Esteller M
  • Journal Title: Cancer Res 69 Pages: 8447-8454
  • Peer Reviewed
• [Journal Article] Genomic Screening for Genes Silenced by DNA Methylation Revealed an Association between RASD1 Inactivation and Dexamethasone Resistance in Multiple Myeloma. (2009)
  • Author(s): Nojima M, Maruyama R, Yasui H, Suzuki H, Maruyama Y, Tarasawa I, Sasaki Y, Asaoku H, Sakai H, Hayashi T, Mori M, Imai K, Tokino T, Ishida T, Toyota M, Shinomura Y
  • Journal Title: Clin Cancer Res 15 Pages: 4356-4364
  • Peer Reviewed
• [Journal Article] p53 family members regulate the expression of the apolipoprotein D gene. (2009)
  • Author(s): Sasaki Y, Negishi H, Koyama R, Anbo N, Ohori K, Idogawa M, Mita H, Toyota M, Imai K, Shinomura Y, Tokino T
  • Journal Title: J Biol Chem 284 Pages: 872-883
  • Peer Reviewed
• [Journal Article] Cancer Epigenomics : Implications of DNA methylation in personalized therapy. (2009)
  • Author(s): Toyota M, Suzuki H, Yamashita T, Hirata K, Shinomura Y, Tokino T, Imai K
  • Journal Title: Cancer Sci 100 Pages: 787-791
  • Peer Reviewed
• [Journal Article] Integrated analysis of genetic and epigenetic alterations in cancer. (2009)
  • Author(s): Toyota M, Suzuki H, Yamamoto E, Yamano H, Imai K, Shinomura Y
  • Journal Title: Epigenomics 1 Pages: 291-299
  • Peer Reviewed
• [Journal Article] Epigenetic silencing of microRNA-34b/c and BTG4 is associated with CpG island methylation in colorectal cancer. (2008)
  • Author(s): Toyota M, Suzuki H, Sasaki Y, Maruyama R, Imai K, Shinomura Y, Tokino T
  • Journal Title: Cancer Res 68 Pages: 4123-4132
  • Peer Reviewed
• [Journal Article] DNA hypermethylation contributes incomplete synthesis of carbohydrate determinants in gastrointestinal cancer. (2008)
  • Author(s): Kawamura YI, Toyota M, Kawashima R, Hagiwara T, Suzuki H, Imai K, Shinomura Y, Tokino T, Kannagi R, Dohi T
  • Journal Title: Gastroenterol 135 Pages: 142-151
  • Peer Reviewed
• [Journal Article] A requirement for DICER to maintain full promoter CpG Island hypermethylation in human cancer cells. (2008)
  • Author(s): Ting A, Suzuki H, Cope L, Schuebel K, Lee B, Toyota M, Imai K, Shinomura Y, Tokino T, Baylin SB
  • Journal Title: Cancer Res 68 Pages: 2570-2575
  • Peer Reviewed
• [Journal Article] Identification of flotillin-2, a major protein on lipid rafths, as a novel target of the p53 family members. (2008)
  • Author(s): Sasaki Y, Ohshima Y, Koyama R, Maruyama R, Akashi H, Mita H, Toyota M, Shinomura Y, Imai K, Tokino T
  • Journal Title: Mol Cancer Res 6 Pages: 395-406
  • Peer Reviewed
• [Journal Article] Epigenetic inactivation of RASSF2 in oral squamous cell carcinoma. (2008)
  • Author(s): Imai T, Toyota M, Suzuki H, Akino K, Ogi K, Sogabe Y, Kashima L, Maruyama R, Nojima M, Mita H, Sasaki Y, Itoh F, Imai K, Shinomura Y, Hiratsuka H, Tokino T
  • Journal Title: Cancer Sci 99 Pages: 958-966
  • Peer Reviewed
• [Journal Article] Cytoplasmic RASSF2A is a proapoptotic mediator whose expression is epigenetically silenced in gastric cancer. (2008)
  • Author(s): Maruyama R, Akino K, Toyota M, Suzuki H, Imai T, Ohe-Toyota M, Yamamoto E, Nojima M, Fujikane T, Sasaki Y, Yamashita T, Watanabe Y, Hiratsuka Y, Hirata K, Itoh F, Imai K, Shinomura Y, Tokino T
  • Journal Title: Carcinogenesis 29 Pages: 1312-1318
  • Peer Reviewed
• [Journal Article] The hsitone deacetylase inhibitor FK288 enhances adenovirus-mediated p53 family gene therapy in cancer models. (2008)
  • Author(s): Sasaki Y, Negishi H, Idogawa M, Suzuki H, Mita H, Toyota M, Shinomura Y, Imai K, Tokino T
  • Journal Title: Mol Cancer Ther 7 Pages: 779-787
  • Peer Reviewed
• [Journal Article] Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma. (2008)
  • Author(s): Takagi H, Sasaki S, Suzuki H, Toyota M, Maruyama R, Nojima M, Yamamoto H, Omata M, Tokino T, Imai K, Shinomura Y
  • Journal Title: J. Gastroenterol 43 Pages: 378-389
  • Peer Reviewed
• [Journal Article] LINE-1 hypomethylation is associated with increased CpG island methylation in helicobactor pylori-related enlarged fold gastritis. (2008)
  • Author(s): Yamamoto E, Toyota M, Suzuki H, Kondo Y, Imai K, Sanomura T, Murayama Y, Ohe-Toyota M, Maruyama R, Nojima M, Ashida M, Fujii K, Sasaki Y, Hayashi N, Mori M, Imai K, Tokino T, Shinomura Y
  • Journal Title: Cancer Epidemiol Biomarkers Prev 17 Pages: 2555-2564
  • Peer Reviewed
• [Journal Article] DNA methylation and cancer pathways in gastrointestinal tumors. (2008)
  • Author(s): Suzuki H, Tokino T, Shinomura Y, Imai K, Toyota M
  • Journal Title: Pharmacogenomics 9 Pages: 1917-1928
  • Peer Reviewed
• [Journal Article] Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer. (2008)
  • Author(s): Suzuki H, Toyota M, Caraway H, Gabrielson E, Ohmura T, Fujikane T, Nishikawa N, Sogabe Y, Nojima M, Sonoda T, Mori M, Hirata K, Imai K, Shinomura Y, Baylin SB, Tokino T
  • Journal Title: British J Cancer 98 Pages: 1147-1156
  • Peer Reviewed
• [Journal Article] Gene amplification and overexpression of PRDM14 in breast cancer (2007)
  • Author(s): Nishikawa N, Toyota M, Suzuki H, Homma T, Fujikane T, Ohmura T, Nishidate T, Ohe-Toyota M, Maruyama R, Sonoda T, Sasaki Y, Urano T, Imai K, Hirata K, Tokino T
  • Journal Title: Cancer Res 67 Pages: 9649-9657
  • Peer Reviewed
• [Journal Article] Comparing the DNA hypermethylation with gene mutations in human colorectal cancer. (2007)
  • Author(s): Schuebel KE, Chen E, Cope Lm Glockner SC, Suzuki H, Yi JM, Chan TA, Van Neste L, Van Criekinge W, van den Bosch S, van Engeland M, Ting AH, Jair K, Yu W, Toyota M, Imai K, Ahuja N, Herman JG, Baylin SB
  • Journal Title: Plos Genet 3 Pages: 1709-1723
  • Peer Reviewed
• [Journal Article] Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer. (2007)
  • Author(s): Akino K, Toyota M, Suzuki H, Imai T, Maruyama R, Kusano M, Nishikawa N, Watanabe Y, Sasaki Y, Abe T, Yamamoto E, Tarasawa I, Sonoda T, Mori M, Imai K, Shinomura Y, Tokino T
  • Journal Title: Cancer Sci 98 Pages: 88-95
  • Peer Reviewed
• [Journal Article] Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer. (2007)
  • Author(s): Nojima M, Suzuki H, Toyota M, Watanabe Y, Maruyama R, Sasaki S, Sasaki Y, Mita H, Nishikawa N, Yamaguchi K, Hirata K, Itoh F, Tokino T, Mori M, Imai K, Shinomura Y
  • Journal Title: Oncogene 26 Pages: 4699-4713
  • Peer Reviewed
• [Journal Article] Expression profiling of PRDM family genes identified PRDM5 as a target of epigenetic silencing in colorectal and gastric cancer. (2007)
  • Author(s): Watanabe Y, Toyota M, Kondo Y, Suzuki H, Imai T, Ohe-Toyota M, Maruyama R, Nojima M, Sasaki Y, Sekido Y, Hiratsuka H, Shinomura Y, Imai K, Itoh F, Tokino T
  • Journal Title: Clin Cancer Res 13 Pages: 4786-4794
  • Peer Reviewed
• [Journal Article] Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors. (2007)
  • Author(s): Sato H, Suzuki H, Toyota M, Nojima M, Maruyama R, Sasaki S, Takagi H, Sogabe Y, Sasaki Y, Idogawa M, Sonoda T, Mori M, Imai K, Tokino T, Shinomura Y
  • Journal Title: Carcinogenesis 28 Pages: 2459-2466
  • Peer Reviewed
• [Journal Article] Genetic, epigenetic and clinicopathological features of gastric cancers with CpG island methylator phenotype and an association with Epstein-Barr virus. (2006)
  • Author(s): Kusano M, Toyota M, Suzuki H, Akino K, Aoki F, Fujita M, Hosokawa M, Shinomura Y, Imai K, Tokino T
  • Journal Title: Cancer 106 Pages: 1467-1479
  • Peer Reviewed
• [Journal Article] Comparative genome analysis identified the vitamin D receptor gene as a direct target of p53-mediated transcriptional activation. (2006)
  • Author(s): Maruyama R, Aoki F, Toyota M, Sasaki Y, Akashi H, Mita H, Suzuki H, Akino K, Ohe-Toyota M, Maruyama Y, Tatsumi H, Imai K, Shinomura Y, Tokino T
  • Journal Title: Cancer Res 66 Pages: 4574-4583
  • Peer Reviewed
• [Journal Article] Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer. (2005)
  • Author(s): Murai M, Toyota M, Suzuki H, Satoh A, Akino K, Mita H, Tokino T, Imai K
  • Journal Title: Clin Cancer Res 11 Pages: 1021-1027
  • Peer Reviewed
• [Journal Article] Aberrant methylation and silencing of the BNIP3 gene in hematopietic tumors. (2005)
  • Author(s): Murai M, Toyota M, Satoh A, Suzuki H, Akino K, Mita H, Ishida T, Tokino T, Imai K
  • Journal Title: British J Cancer 92 Pages: 1165-1172
  • Peer Reviewed
• [Journal Article] The RAS effector RASSF2 is a novel tumor suppressor in colorectal cancer. (2005)
  • Author(s): Akino K, Toyota M, Suzuki H, Mita H, Sasaki Y, Ohe-Toyota M, Issa JP, Hinoda Y, Imai K, Tokino T
  • Journal Title: Gastroenterol 129 Pages: 156-169
  • Peer Reviewed
• [Journal Article] Epigenetic inactivation of interferon regulatory factor genes in gastric cancer.
  • Author(s): Yamashita M, Toyota M, Suzuki H, Nojima M, Yamamoto E, Kamimae S, Watanabe Y, Kai M, Akashi H, Maruyama R, Sasaki Y, Yamano H, Sugai T, Shinomura Y, Imai K, Tokino T, Itoh F
  • Journal Title: Cancer Sci (in press)
  • Peer Reviewed
• [Presentation] The role of epigenetic changes in cancer immunothelapy. (2009)
  • Author(s): Toyota M, Imai K
  • Organizer: US-Japan Workshop on Immunological Molecular Markers in Oncology
  • Place of Presentation: Hawaii, USA
  • Year and Date: 20090323-20090324
• [Presentation] Epigenetic gene silencing and microRNA in human colon cancer. Symposium (2008)
  • Author(s): Toyota M, Imai K
  • Organizer: 36th Congress of the International Society for Oncodevelopmental Biology and Medicine
  • Place of Presentation: Tokyo
  • Year and Date: 20081005-20081009
• [Presentation] The role of DNA methylation changes in signaling pathway. (2008)
  • Author(s): Toyota M, Imai K
  • Organizer: AACR Special Conference on Cancer Research: Cancer Epigenetics
  • Place of Presentation: Boston, USA
  • Year and Date: 20080528-20080531
• [Presentation] Epigenetic silencing of genes involved in signaling pathways in gastric cancer. Symposium (2007)
  • Author(s): Toyota M, Imai K
  • Organizer: 5th Congress of the International Society for Oncodevelopmental Biology and Medicine
  • Place of Presentation: Plaque, Czech Republic
  • Year and Date: 20070915-20070919
• [Presentation] Frequent epigenetic inactivation of DICKKOPF family genes in gastrointestinal tumors. (2007)
  • Author(s): Suzuki H, Toyota M, Maruyama R, Imai K, Shinomura Y
  • Organizer: 35th Congress of the International Society for Oncodevelopmental Biology and Medicine
  • Place of Presentation: Plaque, Czech Republic
  • Year and Date: 20070915-20070919
• [Presentation] Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer. (2007)
  • Author(s): Toyota M, Suzuki H, Maruyama R, Akino K, Watanabe Y, Sasaki Y, Imai K, Tokino T, Shinomura Y
  • Organizer: 98th Annual Meeting of American Association for Cancer Research.
  • Place of Presentation: Los Angeles
  • Year and Date: 20070414-20070418
• [Presentation] Epigenetic silencing of genes involved in signaling pathway. Symposium (2007)
  • Author(s): Toyota M, Suzuki H, Shinomura Y, Tokino T, Imai K
  • Organizer: The 7th Joint Conference of the American Association for Cancer Research and the Japanese Cancer Association
  • Place of Presentation: Hawaii, USA
  • Year and Date: 20070121-20070125
• [Presentation] DNA methylation changes in cancer: application to diagnosis and therapy. Symposium (2006)
  • Author(s): Toyota M, Suzuki H, Shinomura Y, Imai K
  • Organizer: 34th Congress of the International Society for Oncodevelopmental Biology and Medicine
  • Place of Presentation: Pasadena, USA
  • Year and Date: 20060916-20060920
• [Presentation] Epigenetic inactivation of TCF2 in human tumors (2006)
  • Author(s): Toyota M, Terasawa K, Sagae S, Ogi K, Suzuki H, Maruyama R, Shinomura Y, Saito T, Imai K, Tokino T
  • Organizer: 97th Annual Meeting of American Association for Cancer Research
  • Place of Presentation: Washington DC, USA
  • Year and Date: 20060401-20060405
• [Book] エピジェネティクス-メチル化とヒストン修飾. がんの分子標的治療 (2008)
  • Author(s): 今井浩三、豊田実, 鶴尾隆. (編集)
  • Total Pages: 145-149
  • Publisher: 南山堂
• [Book] 消化管と遺伝子異常. 消化管病理標本の読み方改訂2版 (2008)
  • Author(s): 豊田実、今井浩三、篠村恭久, 中村眞一. (編集)
  • Total Pages: 213-222
  • Publisher: 日本メディカルセンター
• [Book] The role and clinical implication of DNA methylation in gastrointestinal cancer. Recent Advances in Gastrointestinal Carcinogenesis. (2006)
  • Author(s): Toyota M, Suzuki H, Maruyama R, Tarasawa I, Yamamoto E, Tokino T, Imai K, Shinomura Y
  • Total Pages: 115-123
  • Publisher: Edited by Bamba H and Ota S, Transworld Research Network, Kerala, India
• [Patent(Industrial Property Rights)] 新規遺伝子ACMG1のメチル化を指標とする胃癌の診断方法 (2009)
  • Inventor(s): 豊田実、今井浩三、株式会社ジェネティックラボ
  • Industrial Property Rights Holder: 豊田実、株式会社ジェネティックラボ
  • Industrial Property Number: 特許・特許第4426549号
  • Acquisition Date: 2009-12-18
• [Patent(Industrial Property Rights)] 癌の検出方法および検出用キット、ならびに癌治療剤 (2008)
  • Inventor(s): 今井浩三
  • Industrial Property Rights Holder: 札幌医科大学
  • Industrial Property Number: 特許・特願2008-121671
  • Filing Date: 2008-05-07
• [Patent(Industrial Property Rights)] 胃粘膜洗浄液を利用した疾患関連マーカー検出法 (2006)
  • Inventor(s): 今井浩三
  • Industrial Property Rights Holder: 札幌医科大学
  • Industrial Property Number: 特許・特願2006-134878
  • Acquisition Date: 2006-05-12