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

2013 Fiscal Year Final Research Report

• 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
• Keywords: 大腸がん / レトロポゾン / メチル化 / 抗がん剤

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] Can population differences in chemotherapy outcomes be inferred from differences in pharmacogenetic frequencies? (2013)
  • Author(s): Loh M, Chua D, Yao Y, Soo RA, Garrett K, Zeps N, Platell C, Minamoto T, Kawakami K, Iacopetta B, Soong R
  • Journal Title: Pharmacogenomics J Volume: 13 Pages: 423-429
  • DOI: 10.1038/tpj.2012.26
  • Peer Reviewed
• [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 Pages: 2206-2217
  • DOI: 10.1093/carcin/bgt182
  • 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, Shimasaki T, Chikano Y, Nakada M, Hirose M, Higashi T, Ishigaki Y, Endo Y, Takino T, Sato H, Sai Y, Miyamoto K, Motoo Y, Kawakami K, Minamoto T
  • Journal Title: PLoS One Volume: 8 Pages: e55289
  • DOI: 10.1371/journal.pone.0055289
  • 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, Kotake M, Kaneko M, Kitamura H, Ooi A, Watanabe G, Minamoto T
  • Journal Title: BMC Cancer Volume: 12 Pages: 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, Ishigaki Y, Nakamura Y, Takata T, Nakaya N, Nakajima H, Sato I, Zhao X, Kitano A, Kawakami K, Tanaka T, Takegami T, Tomosugi N, Minamoto T, Motoo Y
  • Journal Title: J Gastroenterol Volume: 47 Pages: 321-333
  • DOI: 10.1007/s00535-011-0484-9
  • Peer Reviewed
• [Journal Article] AP1B plays an important role in intestinal tumorigenesis with the truncating mutation of an APC gene (2012)
  • Author(s): Mimura M, Masuda A, Nishiumi S, Kawakami K, Fujishima Y, Yoshie T, Mizuno S, Miki I, Ohno H, Hase K, Minamoto T, Azuma T, Yoshida M
  • Journal Title: Int J Cancer Volume: 130 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] 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] 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] 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