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

LINE-1低甲基化结直肠癌的分子分析及其在癌症诊断和治疗中的应用

• 批准号: 23390321
• 负责人: KAWAKAMI KAZUYUKI
• 金额: $ 12.15万
• 依托单位: Tokyo Women's Medical University (2013)Kanazawa University (2011-2012)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23390321/
• 关键词: 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

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.

我们研究了5-FU对LINE-1低甲基化肿瘤有效的机制。LINE-1表达状态与肿瘤对5-FU的敏感性无关。LINE-1低甲基化的肿瘤中染色质结构松散。染色质疏松的结直肠癌细胞对5-FU的敏感性高于染色质浓缩的结直肠癌细胞。结果表明，LINE-1低甲基化和染色质结构之间的关联是5-FU抗癌活性机制的基础。LINE-1表达的敲低导致癌症生长的抑制。许多抗癌药物抑制LINE-1的表达，提示抑制LINE-1可能是5-FU与其他抗癌药物协同作用的机制之一。这些发现对于实现个性化化疗和开发使用5-FU的新策略具有重要意义。

项目成果

Knockdown of LINE-1 enhances sensitivity to 5-FU in LINE-1-hypomethylated colorectal cancer cell

LINE-1 的敲低增强了 LINE-1 低甲基化结直肠癌细胞对 5-FU 的敏感性

• 发表时间: 2012
• 作者: Kawakami K;Matsunoki A;Kotake M;Kaneko M;Kitamura H;Watanabe G;Minamoto T
• 通讯作者: Minamoto T

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

糖原合成酶激酶（GSK）3β作为胰腺癌的新治疗靶点：化疗策略的新进展

• 发表时间: 2011
• 作者: Adachi K;Furuta K;Aimi M;Fukazawa K;Shimura S;Ohara S;Nakata S;Inoue Y;Ryuko K;Ishine J;Katoh K;Hirata T;Ohhata S;Katoh S;Moriyama M;Sumikawa M;Sanpei M;Kinoshita Y;島崎猛夫
• 通讯作者: 島崎猛夫

AP1B plays an important role in intestinal tumorigenesis with the truncating mutation of an APC gene

AP1B通过APC基因的截短突变在肠道肿瘤发生中发挥重要作用

• DOI: 10.1002/ijc.26131
• 发表时间: 2011
• 期刊: Int.J.Cancer
• 作者: Mimura;M.;et al
• 通讯作者: et al

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

多重荧光MethyLight分析LINE-1甲基化及其在结直肠癌中的临床意义

• 发表时间: 2011
• 作者: 松之木愛香;川上和之;小竹優範;金子真美;源 利成
• 通讯作者: 源 利成

Isolation and molecular profiling of a circulating tumor cell by using a novel single cell picking system

使用新型单细胞挑选系统对循环肿瘤细胞进行分离和分子分析

• 发表时间: 2013
• 作者: Kondo Y;Hayashi H;Watabe T;Miwa Y;Kinoshita S;Higashimoto H;Sugisaki H;Nakajima G;Kawakami K;Hayashi K;Yamamoto M
• 通讯作者: Yamamoto M