Molecular analysis of colorectal cancer with LINE-1 hypomethylation and its application to cancer diagnosis and therapy

• Project/Area Number: 23390321
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Tokyo Women's Medical University (2013); Kanazawa University (2011-2012)
• Principal Investigator: KAWAKAMI KAZUYUKI 東京女子医科大学, 医学部, 准教授 (00293358)
• Co-Investigator(Kenkyū-buntansha): MINAMOTO Toshinari 金沢大学, がん研究所, 教授 (50239323)
• Co-Investigator(Renkei-kenkyūsha): SOGA Tomoyoshi 慶應義塾大学, 環境情報学部, 教授 (60338217)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000); Fiscal Year 2013: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2012: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2011: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 大腸がん / レトロポゾン / メチル化 / 抗がん剤 / LINE-1 / DNAメチル化 / 5-FU

Research Abstract

We investigated the mechanism by which 5-FU is effective on the tumor with LINE-1 hypomethylation. LINE-1 expression status is not associated with tumor sensitivity to 5-FU. Chromatin structure looses in the tumor with LINE-1 hypomethylation. Colorectal cancer cell with loosed chromatin is more sensitive to 5-FU compared to one with condensed chromatin. The results suggest that the association between LINE-1 hypomethylation and chromatin structure underlies mechanism of anticancer activity of 5-FU. Knockdown of LINE-1 expression results in suppression of cancer growth. Many anticancer drugs inhibit LINE-1 expression, suggesting that suppression of LINE-1 might be one of mechanism by which 5-FU and other anticancer drugs shows synergistic effect. These findings could be important for achieving personalized chemotherapy and developing novel strategy using 5-FU.

Research Products

• [Journal Article] Glycogen synthase kinase 3β inhibition sensitizes human glioblastoma cells to temozolomide by affecting O6-methylguanine DNA methyltransferase promoter methylation via c-Myc signaling (2013)
  • Author(s): Pyko IV, Nakada M, Sabit H, Teng L, Furuyama N, Hayashi Y, Kawakami K, Minamoto T, Fedulau AS, Hamada J
  • Journal Title: Carcinogenesis Volume: 34 Issue: 10 Pages: 2206-2217
  • DOI: 10.1093/carcin/bgt182
  • URL: http://www.kanazawa-u.ac.jp/~ganken/shuyoseigyo/
  • Peer Reviewed
• [Journal Article] Aberrant glycogen synthase kinase 3β is involved in pancreatic cancer cell invasion and resistance to therapy (2013)
  • Author(s): Kitano A
  • Journal Title: PLoS One Volume: 8 Issue: 2 Pages: 15-15
  • DOI: 10.1371/journal.pone.0055289
  • URL: http://www.kanazawa-u.ac.jp/~ganken/shuyoseigyo/
  • Peer Reviewed
• [Journal Article] Can population differences in chemotherapy outcomes be inferred from differences in pharmacogenetic frequencies? (2012)
  • Author(s): Loh M, Kawakami K, Minamoto T, et al
  • Journal Title: Pharmacogenomics J Volume: (in press) Issue: 5 Pages: 423-429
  • DOI: 10.1038/tpj.2012.26
  • Peer Reviewed
• [Journal Article] LINE-1 methylation shows little intra-patient heterogeneity in primary and synchronous metastatic colorectal cancer (2012)
  • Author(s): Matsunoki A, Kawakami K, et al, Minamoto T
  • Journal Title: BMC Cancer Volume: 12 Issue: 1 Pages: 574-574
  • DOI: 10.1186/1471-2407-12-574
  • Peer Reviewed
• [Journal Article] Glycogen synthase kinase 3β inhibition sensitizes pancreatic cancer cells to gemcitabine (2012)
  • Author(s): Shimasaki T, Kawakami K, Minamoto T, et al
  • Journal Title: J Gastroenterol Volume: 47 (3) Issue: 3 Pages: 321-33
  • DOI: 10.1007/s00535-011-0484-9
  • NAID: 10030560208
  • URL: http://www.kanazawa-u.ac.jp/~ganken/shuyoseigyo/
  • Peer Reviewed
• [Journal Article] AP1B plays an important role in intestinal tumorigenesis with the truncating mutation of an APC gene (2011)
  • Author(s): Mimura, M., et al
  • Journal Title: Int.J.Cancer Volume: 130 Issue: 5 Pages: 1011-1020
  • DOI: 10.1002/ijc.26131
  • Peer Reviewed
• [Presentation] Isolation and molecular profiling of a circulating tumor cell by using a novel single cell picking system (2013)
  • Author(s): Kondo Y, Hayashi H, Watabe T, Miwa Y, Kinoshita S, Higashimoto H, Sugisaki H, Nakajima G, Kawakami K, Hayashi K, Yamamoto M
  • Organizer: 9th International Symposium on Minimal Residual Cancer
  • Place of Presentation: Pullman Paris Bercy (France)
  • Year and Date: 2013-09-25
• [Presentation] Isolation and molecular profiling of a circulating tumor cell by using a novel single cell picking system (2013)
  • Author(s): Kondo Y, Kawakami K, et al.
  • Organizer: 9th International Symposium on Minimal Residual Cancer
  • Place of Presentation: Paris, France
• [Presentation] LINE-1 methylation level is a potential marker of the sensitivity to 5-FU plus oxaliplatin in colorectal cancer cells (2012)
  • Author(s): Kaneko M, Kawakami K, Kotake M, Kitamura H, Watanabe G, Minamoto T
  • Organizer: 71st Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: ホテルロイトン札幌(北海道)
  • Year and Date: 2012-09-20
• [Presentation] Knockdown of LINE-1 enhances sensitivity to 5-FU in LINE-1-hypomethylated colorectal cancer cell (2012)
  • Author(s): Kawakami K, Matsunoki A, Kotake M, Kaneko M, Kitamura H, Watanabe G, Minamoto T
  • Organizer: 22nd Biennial Congress of the European Association for Cancer Research
  • Place of Presentation: Centre Convencions International Barcelona, Spain
  • Year and Date: 2012-07-08
• [Presentation] LINE-1 methylation level is a molecular marker with little intra-patient heterogeneity in primary and synchronous metastatic colorectal cancer (2012)
  • Author(s): Matsunoki A, Kawakami K, Kotake M, Kaneko M, Watanabe G, Minamoto T
  • Organizer: 103rd Annual Meeting of American Association for Cancer Research
  • Place of Presentation: McCormick Place in Chicago (USA)
  • Year and Date: 2012-04-02
• [Presentation] Knockdown of LINE-1 enhances sensitivity to 5-FU in LINE-1-hypomethylated colorectal cancer cell (2012)
  • Author(s): Kawakami K, et al.
  • Organizer: 22nd Biennial Congress of the European Association for Cancer Research
  • Place of Presentation: Barcelona, Spain
• [Presentation] LINE-1 methylation level is a molecular marker with little intra-patient heterogeneity in primary and synchronous metastatic colorectal cancer (2012)
  • Author(s): Matsunoki A, Kawakami K, et al.
  • Organizer: 103rd Annual Meeting of American Association for Cancer Research
  • Place of Presentation: Chicago, U.S.A.
• [Presentation] LINE-1 methylation level is a potential marker of the sensitivity to 5-FU plus oxaliplatin in colorectal cancer cells (2012)
  • Author(s): Kaneko M, Kawakami K, et al.
  • Organizer: 71st Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Sapporo, Japan
• [Presentation] 多重蛍光 MethyLight による LINE-1 のメチル化解析と大腸がんにおけるその臨床的意義 (2011)
  • Author(s): 松之木愛香, 川上和之, 小竹優範, 金子真美, 源 利成
  • Organizer: 第22回日本消化器癌発生学会
  • Place of Presentation: ホテルニューオータニ佐賀(佐賀県)
  • Year and Date: 2011-11-26
• [Presentation] 多重蛍光MethyLightによるLINE-1のメチル化解析と大腸がんにおけるその臨床的意義 (2011)
  • Author(s): 松之木愛香, 川上和之, ほか, 源利成
  • Organizer: 第22回日本消化器癌発生学会
  • Place of Presentation: ホテルニューオータニ佐賀(佐賀県)
  • Year and Date: 2011-11-26
• [Presentation] リンパ節および遠隔転移を伴う大腸がんにおける高頻度の LINE-1 低メチル化 (2011)
  • Author(s): 小竹優範, 川上和之, (他4名) , 源 利成
  • Organizer: 第70回日本癌学会学術集会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-05
• [Presentation] リンパ節および遠隔転移を伴う大腸がんにおける高頻度のLINE-1低メチル化 (2011)
  • Author(s): 小竹優範, 川上和之, ほか, 源利成
  • Organizer: 第70回日本癌学会学術集会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-05
• [Presentation] 膵癌の新規治療標的としてのglycogen synthase kinase (GSK) 3β:化学療法戦略の新展開 (2011)
  • Author(s): 島崎猛夫, 川上和之, ほか, 源利成
  • Organizer: 第70回日本癌学会学術集会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-03
• [Remarks]
  • URL: http://www.kanazawa-u.ac.jp/~ganken/shuyoseigyo/index.html