Molecular mechanisms of aberrant DNA methylation during multistage carcinogenesis

• Project/Area Number: 21790371
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Human pathology
• Research Institution: National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
• Principal Investigator: ARAI Eri 独立行政法人国立がん研究センター, 研究所, 研究員 (40446547)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2009: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 分子病理学 / 腫瘍 / DNAメチル化 / DNMT1 / 発がんリスク評価 / 分子病理

Research Abstract

The aim of this study is to detect the molecules which associate with DNA methyltransferase (DNMT)1 and contribute to induce aberrant DNA methylation profiles during human carcinogenesis. We used HepG2 cell line which was derived from human liver cancer and showed high expression levels of DNMT1. We performed immunoprecipitation of DNMT1 using optimum antibody in HepG2 nuclear extract, and separated immunoprecipitant by SDS-PAGE. Co-precipitated proteins were analyzed by 2 Dimensional Image Converted Analysis of LCMS (2D-ICAL method), and the candidate molecule which may associate DNMT1 and may contribute aberrant DNA methylation was identified. Direct association between the candidate molecule and DNMT1 is being evaluated. Mechanisms how the candidate molecule participates in aberrant distribution of DNMT1 resulting in aberrant DNA methylation profiles will be examined.

Research Products

• [Journal Article] Copy number alterations in urothelial carcinomas : Their clinicopathological significance and correlation with DNA methylation alterations. (2011)
  • Author(s): Nishiyama N, Arai E, Nagashio R, Fujimoto H, Hosoda F, Shibata T, Tsukamoto T, Kanai Y.
  • Journal Title: Carcinogenesis 32 Pages: 462-469
• [Journal Article] Genome-wide DNA methylation profiles in renal tumors of various histological subtypes and non-tumorous renal tissues. (2011)
  • Author(s): Arai E., Wakai-Ushijima S., Fujimoto H., Hosoda F., Shibata T., Kondo T., Yokoi S., Imoto I., Inazawa J., Hirohashi S., Kanai Y.
  • Journal Title: Pathobiology 78 Pages: 1-9
• [Journal Article] Diagnosis and prognostication of ductal adenocarcinomas of the pancreas based on genome-wide DNA methylation profiling by bacterial artificial chromosome array-based methylated CpG island amplification. (2011)
  • Author(s): Gotoh M, Arai E, Wakai-Ushijima S, Hiraoka N, Kosuge T, Hosoda F, Shibata T, Kondo T, Yokoi S, Imoto I, Inazawa J, Kanai Y.
  • Journal Title: J Biomed Biotech
• [Journal Article] Carcinogenetic risk estimation based on quantification of DNA methylation levels in liver tissue at the precancerous stage. (2011)
  • Author(s): Nagashio R, Arai E, Ojima H, Kosuge T, Kondo Y, Kanai Y.
  • Journal Title: Int J Cancer (in press.)
• [Journal Article] Genome-wide DNA methylation profiles in renal tumors of various histological subtypes and non-tumorous renal tissues (2011)
  • Author(s): Arai E, et al.
  • Journal Title: Pathobiology Volume: 78 Pages: 1-9
  • Peer Reviewed
• [Journal Article] Copy number alterations in urothelial carcinomas : their clinicopathological significance and correlation with DNA methylation alterations. (2011)
  • Author(s): Nishiyama N, et al.
  • Journal Title: Carcinogenesis Volume: 32 Pages: 462-469
  • Peer Reviewed
• [Journal Article] Diagnosis and prognostication of ductal adenocarcinomas of the pancreas based on genome-wide DNA methylation profiling by bacterial artificial chromosome array-based methylated CpG island amplification. (2011)
  • Author(s): Gotoh M, et al.
  • Journal Title: J Biomed Biotechnol Volume: 2011
  • Peer Reviewed
• [Journal Article] Carcinogenetic risk estimation based on quantification of DNA methylation levels in liver tissue at the precancerous stage. (2011)
  • Author(s): Nagashio R, et al.
  • Journal Title: Int J Cancer Volume: (in print)
  • Peer Reviewed
• [Journal Article] Genetic and epigenetic alterations during renal carcinogenesis (review). (2010)
  • Author(s): Arai E, Kanai Y.
  • Journal Title: Int J Clin Exp Pathol 4 Pages: 58-73
• [Journal Article] DNA methylation profiles in precancerous tissue and cancers : Carcinogenetic risk estimation and prognostication based on DNA methylation status (review). (2010)
  • Author(s): Arai E, Kanai Y.
  • Journal Title: Epigenomics 2 Pages: 467-481
• [Journal Article] Genetic and epigenetic alterations during renal carcinogenesis. (2010)
  • Author(s): Arai E, et al.
  • Journal Title: Int J Clin Exp Pathol Volume: 4 Pages: 58-73
  • Peer Reviewed
• [Journal Article] Genome-wide DNA methylation profiles in urothelial carcinomas and urothelia at the precancerous stage (2010)
  • Author(s): Nishiyama N, et al.
  • Journal Title: Cancer Science Volume: 101 Pages: 231-240
  • Peer Reviewed
• [Journal Article] Genome-wide DNA methylation profiles in urothelial carcinomas and urothelia at the precancerous stage (2010)
  • Author(s): Nishiyama N, et al.
  • Journal Title: Cancer Science 101 Pages: 231-240
  • Peer Reviewed
• [Journal Article] 上皮内癌 (2010)
  • Author(s): 新井恵吏, 他
  • Journal Title: 病理と臨床 28巻臨時増刊号 Pages: 218-219
• [Journal Article] フィールド効果 (2010)
  • Author(s): 中川徹, 他
  • Journal Title: 病理と臨床 28巻臨時増刊号 Pages: 214-215
• [Journal Article] Genome-wide DNA methylation profiles in urothelial carcinomas and urothelia at the precancerous stage. (2009)
  • Author(s): Nishiyama N, Arai E, Chihara Y, Fujimoto H, Hosoda F, Shibata T, Kondo T, Tsukamoto T, Yokoi S, Imoto I, Inazawa J, Hirohashi S, Kanai Y.
  • Journal Title: Cancer Sci 101 Pages: 231-240
  • NAID: 10027200383
• [Journal Article] Genome-wide DNA methylation profiles in liver tissue at the precancerous stage and in hepatocellular carcinoma. (2009)
  • Author(s): Arai E, Ushijima S, Gotoh M, Ojima H, Kosuge T, Hosoda F, Shibata T, Kondo T, Yokoi S, Imoto I, Inazawa J, Hirohashi S, Kanai Y.
  • Journal Title: Int J Cancer 125 Pages: 2854-2862
• [Journal Article] Genome-wide DNA methylation profiles in both precancerous conditions and clear cell renal cell carcinomas are correlated with malignant potential and patient outcome. (2009)
  • Author(s): Arai E, Ushijima S, Fujimoto H, Hosoda F, Shibata T, Kondo T, Yokoi S, Imoto I, Inazawa J, Hirohashi S, Kanai Y.
  • Journal Title: Carcinogenesis 30 Pages: 214-221
• [Journal Article] Genome-wide DNA methylation profiles in liver tissue at the precancerous stage and in hepatocellular carcinoma (2009)
  • Author(s): Arai E, et al.
  • Journal Title: International Journal of Cancer 125 Pages: 2854-2862
  • Peer Reviewed
• [Journal Article] ゲノム網羅的DNAメチル化解析に基づく発がんリスク評価とがんの個性診断 (2009)
  • Author(s): 新井恵吏
  • Journal Title: 病理と臨床 27 Pages: 641-647
• [Journal Article] DNAメチル化異常の分子病理診断への展開 (2009)
  • Author(s): 新井恵吏, 他
  • Journal Title: 医学のあゆみ 229 Pages: 8231-8236
• [Presentation] 腎細胞がん発生過程におけるDNAメチル化異常の網羅的解析 (2011)
  • Author(s): 新井恵吏, 森泰昌, 知久季倫, 後藤政広, 中川徹, 藤元博行, 金井弥栄
  • Organizer: 日本エピジェネティクス研究会第5回年会
  • Place of Presentation: 熊本
• [Presentation] 慢性障害肝におけるDNAメチル化状態を指標とした発がんリスク評価の肝生検検体を用いた臨床応用 (2011)
  • Author(s): 長塩亮, 新井恵吏, 尾島英, 小菅智男, 金井弥栄
  • Organizer: 日本エピジェネティクス研究会第5回年会
  • Place of Presentation: 熊本
• [Presentation] 泌尿器系腫瘍及びその背景組織のメチル化解析 (2011)
  • Author(s): 新井恵吏, 金井弥栄
  • Organizer: 日本病理学会第100回総会
  • Place of Presentation: 横浜
• [Presentation] 酸化ストレス誘発ラット腎癌は高度な染色体不安定性を示す (2011)
  • Author(s): 赤塚慎也, 山下依子, 岡崎泰昌, 蒋麗, 永井裕崇, 新井恵吏, 金井弥栄, 豊國伸哉
  • Organizer: 日本病理学会第100回総会
  • Place of Presentation: 横浜
• [Presentation] Copy number alterations in urothelial carcinomas : Their clinicopathological significance and correlation with DNA methylation alterations. (2011)
  • Author(s): Nishiyama N, Arai E, Nagashio R, Fujimoto H, Hosoda F, Shibata T, Tsukamoto T, Yokoi S, Imoto I, Inazawa J, Kanai Y.
  • Organizer: AACR 102^<nd> annual meeting 2011
  • Place of Presentation: Orlando, FL.
• [Presentation] (2011)
  • Author(s): Nishiyama N, et al.
  • Organizer: AACR 102^<nd> annual meeting 2011
  • Place of Presentation: Orlando, FL
• [Presentation] Focal DNA methyltransferase 3B expression is associated with poor outcome of stage I testicular seminoma (2010)
  • Author(s): Arai E, et al.
  • Organizer: Epigenetics and Stem Cells
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2010-08-25
• [Presentation] Genome-wide DNA methylation profiles in renal tumors of various histological subtypes and non-tumorous renal tissues (2010)
  • Author(s): Arai E, et al.
  • Organizer: AACR special conference, Cancer epigenetics
  • Place of Presentation: San Juan, Puerto Rico
  • Year and Date: 2010-01-22
• [Presentation] Stage I精巣セミノーマにおけるDNMT3B巣状発現は再発予測指標となる (2010)
  • Author(s): 新井恵吏, 若井-牛島抄織, 中川徹, 藤元博行, 金井弥栄
  • Organizer: 日本癌学会第69回学術総会
  • Place of Presentation: 大阪
• [Presentation] DNAメチル化を指標とする慢性肝障害患者における発がんリスク評価法の開発 (2010)
  • Author(s): 長塩亮, 新井恵吏, 尾島英知, 小菅智男, 近藤豊, 金井弥栄
  • Organizer: 日本癌学会第69回学術総会
  • Place of Presentation: 大阪
• [Presentation] DNAメチル化プロファイルに基づいた膵がんの存在診断・病態診断指標の確立 (2010)
  • Author(s): 後藤政広, 新井恵吏, 若井-牛島抄織, 平岡伸介, 小菅智男, 細田文恵, 柴田龍弘, 近藤格, 横井左奈, 井本逸勢, 稲澤譲治, 金井弥栄
  • Organizer: 日本癌学会第69回学術総会
  • Place of Presentation: 大阪
• [Presentation] Focal DNA methyltransferase 3B expression is associated with poor outcome of stage I testicular seminoma. (2010)
  • Author(s): Arai E, Ushijima-Wakai S, Nakagawa T, Fujimoto H, Kanai Y.
  • Organizer: Epigenetics and Stem Cells Conference
  • Place of Presentation: Copenhagen, Denmark.
• [Presentation] Focal DNA methyltransferase 3B expression is associated with poor outcome of stage I testicular seminoma. (2010)
  • Author(s): 新井恵吏, 若井-牛島抄織, 中川徹, 藤元博行, 金井弥栄
  • Organizer: 日本エピジェネティクス研究会第4回年会
  • Place of Presentation: 米子
• [Presentation] DNAメチル化を指標とする慢性肝障害患者における発がんリスク評価法の開発 (2010)
  • Author(s): 長塩亮, 新井恵吏, 尾島英知, 小菅智男, 近藤豊, 金井弥栄
  • Organizer: 日本エピジェネティクス研究会第4回年会
  • Place of Presentation: 米子
• [Presentation] DNAメチル化プロファイルに基づいた膵がんの存在診断・病態診断指標の確立 (2010)
  • Author(s): 後藤政広, 新井恵吏, 平岡伸介, 小菅智男, 細田文恵, 柴田龍弘, 近藤格, 横井左奈,井本逸勢, 稲澤譲治, 金井弥栄
  • Organizer: 日本エピジェネティクス研究会第4回年会
  • Place of Presentation: 米子
• [Presentation] Genome-wide DNA methylation profiles in renal tumors of various histological subtypes and non-tumorous renal tissues. (2010)
  • Author(s): Arai E, Ushijima-Wakai S, Fujimoto H, Hosoda F, Shibata T, Kondo T, Yokoi S, Imoto I, Inazawa J, Hirohashi S, Kanai Y.
  • Organizer: AACR special conference, Cancer epigenetics
  • Place of Presentation: San Juan, Puerto Rico.
• [Presentation] DNAメチル化状態を指標とする慢性肝障害患者における発がんリスク評価法の開発 (2010)
  • Author(s): 長塩亮, 他
  • Organizer: 日本癌学会第69回学術総会
  • Place of Presentation: 大阪
• [Presentation] 精巣Stage IセミノーマにおけるDNMT3B巣状発現は腫瘍再発予測指標となる (2010)
  • Author(s): 新井恵吏, 他
  • Organizer: 日本エピジェネティクス研究会第4回年会
  • Place of Presentation: 米子, 鳥取
• [Presentation] DNAメチル化プロファイルに基づいた膵がんの存在診断・病態診断指標の確立 (2010)
  • Author(s): 後藤政広, 他
  • Organizer: 日本エピジェネティクス研究会第4回年会
  • Place of Presentation: 米子, 鳥取
• [Presentation] DNAメチル化状態を指標とする慢性肝障害患者における発がんリスク評価法の開発 (2010)
  • Author(s): 長塩亮, 他
  • Organizer: 日本エピジェネティクス研究会第4回年会
  • Place of Presentation: 米子, 鳥取
• [Presentation] DNAメチル化異常を指標とした肝細胞がんのリスク評価と予後予測 (2009)
  • Author(s): 新井恵吏, 他
  • Organizer: 日本癌学会第68回学術総会
  • Place of Presentation: 横浜,神奈川
  • Year and Date: 2009-10-02
• [Presentation] 尿路上皮がんならびに前がん段階にある尿路上皮におけるDNAメチル化プロファイルー発がんリスク評価と予後予測 (2009)
  • Author(s): 西山直隆, 他
  • Organizer: 日本癌学会第68回学術総会
  • Place of Presentation: 横浜,神奈川
  • Year and Date: 2009-10-02
• [Presentation] 定量的DNAメチル化解析に基づく尿路上皮がん診断示標 (2009)
  • Author(s): 千原良友, 他
  • Organizer: 日本癌学会第68回学術総会
  • Place of Presentation: 横浜,神奈川
  • Year and Date: 2009-10-01
• [Presentation] 鉄ニトリロ三酢酸誘発ラット腎癌に見られる高度の染色体不安定性 (2009)
  • Author(s): 赤塚慎也, 他
  • Organizer: 日本癌学会第68回学術総会
  • Place of Presentation: 横浜,神奈川
  • Year and Date: 2009-10-01
• [Presentation] 種々の組織亜型の腎腫瘍におけるDNAメチル化プロファイル (2009)
  • Author(s): 新井恵吏, 他
  • Organizer: 日本エピジェネティクス研究会第3回年会
  • Place of Presentation: 千代田区,東京
  • Year and Date: 2009-05-22
• [Presentation] Regional DNA hypermethylation and copy number alterations during renal carcinogenesis (2009)
  • Author(s): Arai E, et al.
  • Organizer: AACR 100^<th> annual meeting 2009
  • Place of Presentation: Denver,CO
  • Year and Date: 2009-04-22
• [Presentation] DNAメチル化の変化を指標とした肝細胞がんのリスク評価と予後予測 (2009)
  • Author(s): 新井恵吏, 牛島抄織, 後藤政広, 尾島英知, 小菅智男, 細田文恵, 柴田龍弘, 近藤格, 横井左奈, 井本逸勢, 稲澤譲治, 廣橋説雄, 金井弥栄
  • Organizer: 日本癌学会第68回学術総会
  • Place of Presentation: 横浜
• [Presentation] 尿路上皮がんならびに前がん状態にある尿路上皮におけるDNAメチル化プロファイル-発がんリスク評価と予後予測 (2009)
  • Author(s): 西山直隆, 新井恵吏, 藤元博行, 細田文恵, 柴田龍弘, 近藤格, 塚本泰司, 横井左奈, 井本逸勢, 稲澤譲治, 廣橋説雄, 金井弥栄
  • Organizer: 日本癌学会第68回学術総会
  • Place of Presentation: 横浜
• [Presentation] 定量的DNAメチル化解析に基づく尿路上皮がん診断示標 (2009)
  • Author(s): 千原良友, Gangning Liang, Peter Jones, 新井恵吏, 藤元博行, 菅野康吉, 藤本清秀, 平尾佳彦, 金井弥栄
  • Organizer: 日本癌学会第68回学術総会
  • Place of Presentation: 横浜
• [Presentation] 鉄ニトリロ三酢酸誘発ラット腎癌に見られる高度の染色体不安定性 (2009)
  • Author(s): 赤塚慎也, 山下依子, 蒋麗, 大原浩貴, 泉谷昌志, 阿部浩一郎, 中釜斉, 村上秀樹, 関戸好孝, 新井恵吏, 金井弥栄, 樋野興夫, 豊國伸哉
  • Organizer: 日本癌学会第68回学術総会
  • Place of Presentation: 横浜
• [Presentation] 種々の組織亜型の腎腫瘍におけるDNAメチル化プロファイル (2009)
  • Author(s): 新井恵吏, 牛島抄織, 藤元博行, 細田文恵, 柴田龍弘, 近藤格, 横井左奈, 井本逸勢, 稲澤譲治, 廣橋説雄, 金井弥栄
  • Organizer: 日本エピジェネティクス研究会第3回年会
  • Place of Presentation: 東京
• [Presentation] Genome-wide DNA methylation alterations and copy number alterations during renal carcinogenesis. (2009)
  • Author(s): Arai E, Ushijima S, Fujimoto H, Hosoda F, Shibata T, Kondo T, Yokoi S, Imoto I, Inazawa J, Hirohashi S, Kanai Y.
  • Organizer: AACR 100th annual meeting
  • Place of Presentation: Denver, CO.
• [Book] DNA methylation status in chronic liver disease and hepatocellular carcinoma (review).(Grisham JW, Thorgeirsson S, Springer) (2010)
  • Author(s): Kanai Y, Arai E.
  • Publisher: In : Molecular Genetics of Liver Neoplasia. ed.
• [Patent(Industrial Property Rights)] Pyrosequencing技術を用いてDNAメチル化状態を定量評価し肝細胞がんの発生リスクを評価する方法 (2011)
  • Inventor(s): 金井弥栄、新井恵吏、長塩亮
  • Industrial Property Rights Holder: 金井弥栄、新井恵吏、長塩亮
  • Industrial Property Number: 2011-016695
  • Filing Date: 2011-01-28