Multidisciplinary research for molecular mechanism of cancer progression and development of diagnostic and therapeutic tool

癌症进展分子机制的多学科研究及诊断和治疗工具的开发

• 批准号: 18209043
• 负责人: ARII Shigeki
• 金额: $ 32.03万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-18209043/
• 关键词: Hepatocellular carcinoma; Pancreas cancer; Recurrence; Molecular target; Aurora kinase B; Conexin 43; Grb7; Iκkinase B; オミックス解析; cDNA Microarray; Array-CGH; 肝癌; ミラノ基準; 分子標的剤

This research project yielded the following results.1) Predictive factors for aggressive recurrence of hepatocellular carcinoma (HCC) and identification of a novel molecular target: A prognosis of HCC patients was found to depend on the mode of recurrence, and prognostic indicators were tumor differentiation, tumor size, and aurora kinase B (ARKB) which plays a key role in genome instability. ARKB is considered to be a promising molecular target for HCC treatment.2) Clinical implication of Gap junctional intercellular communication, Conexin (Cg) 43:3) Cx 43 was found to facilitate the growth of HCC, and to be a possible molecular target, and also Vitamin K 2 was found to suppress HCC growth through upregulation of Cx32 and downregulation of Cx43.4) Identification of genes responsible for carcinogenesis and development of HCC : We identified CREB3L4, INTS3, SNAPAP located at 1q 21.5) Identification of genes responsible for pancreatic cancer metastasis : We identified Gr7 which is phospholylated with FAK, thereby inducing cell invasion. We synthesized a peptide, G7-18NATE-P which inhibits phospholylation of Grb7, thereby clarifying the inhibitory effect on the peritoneal dissemination model of pancreas cancer.6) Effect of Iκ B kinase (IKKB) inhibition on pancreas cancer: SiRNA and synthesized compound, IMD-0354 for IKKB inhibitor were found to suppress the growth of pancreas cancer in the xenograft model.

1)肝细胞癌侵袭性复发的预测因素和新分子靶点的确定：肝癌患者的预后取决于复发模式，预后指标是肿瘤分化、肿瘤大小和极光激酶B(ARKB)，后者在基因组不稳定中起关键作用。2)细胞间缝隙连接通讯的临床意义，Conexin(CG)43：3)Cx43被发现促进肝癌的生长，并可能是一个分子靶点，维生素K2还被发现通过上调Cx32和下调Cx43.4)抑制肝癌的生长。3)发现与肝癌发生和发展相关的基因：我们发现CREB3L4、INTS3、SNAPAP位于1Q21.5)胰腺癌转移相关基因的鉴定：我们鉴定了与FAK磷酸化的GR7，从而诱导细胞侵袭。我们合成了一种抑制GRB7磷酸化的多肽G7-18NatE-P，从而阐明了其对胰腺癌腹膜转移模型的抑制作用。6)抑制IκB激酶对胰腺癌的作用：在异种移植瘤模型中，发现siRNA和合成的化合物IMD-0354抑制了胰腺癌的生长。

项目成果

Vitamin K2 suppresses malignancy of HuH7 hepatoma cells via inhibition of connexin 43

• DOI: 10.1016/j.canlet.2007.12.019
• 发表时间: 2008-05-08
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Kaneda, Makoto;Zhang, Dan;Morita, Ikuo
• 通讯作者: Morita, Ikuo

BAMCA (BAC-arraybased MCA)法による肝癌DNAメチル化遺伝子の網羅的控索

利用BAMCA（BAC-arraybased MCA）方法全面寻找肝癌DNA甲基化基因

• 发表时间: 2007
• 作者: 趙 晨;井本逸勢;井上 純田中真二;有井滋樹;田中 博;稲澤譲治.
• 通讯作者: 稲澤譲治.

高密度オリゴヌクレオチド・アレイを用いた肝細胞癌における1p32-p31遺伝子増幅領域の標的遺伝子の同定

利用高密度寡核苷酸芯片鉴定肝细胞癌1p32-p31基因扩增区的靶基因

• 发表时间: 2006
• 作者: 中島知明;安居幸一郎;稲垣恭和;全圭夏;伊藤義人;谷脇雅史;有井滋樹;岡上 武.
• 通讯作者: 岡上 武.

Analysis of Angiopoietin-2/Tie2 Signaling; Novel Molecular-Targeting The rapy of Hepatocellular Carcinoma.

血管生成素-2/Tie2 信号转导分析；

• 发表时间: 2006
• 作者: S. Tanaka;T. Ochiai;M. Yasen;A. Kudo;N. Nakamura;K. Ito;K. Teramoto;S. Arii.
• 通讯作者: S. Arii.

肝細胞癌における新規18qホモ欠失領域-高密度オリゴヌクレオチド・アレイによる解析

肝细胞癌中新型 18q 纯合缺失区域 - 使用高密度寡核苷酸阵列进行分析

• 发表时间: 2006
• 作者: 安居幸一郎;中島知明;稲垣恭和;全圭夏;伊藤義人;谷脇雅史;有井滋樹;岡上 武.
• 通讯作者: 岡上 武.