Identification of a novel tumor marker(s), based on the comprehensive analysis of genes expressed selectively in micometastais site.

基于对微转移位点选择性表达的基因的综合分析，鉴定新的肿瘤标志物。

• 批准号: 16390163
• 负责人: MUKAIDA Naofumi
• 金额: $ 9.41万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390163/
• 关键词: Pim-3; serine; threonine kinase; apoptosis; hepatocellular carcinoma (HCC); pancreatic cancer; colorectal cancer; liver metastasis; chemokine; CCL2; CCR1; CCL3; 肺転移; 腫瘍壊死因子; 血管内皮増殖因子; スレオニンキナーゼ

1)Aberrant expression of a proto-oncogene with serine/threonine kinase activity; Pim-3, in malignant lesions of endoderm-derived organs. We compared gene expression patterns in pre-malignant and malignant lesions in murine hepatocarinogenesis model, by using fluorescent differential display method. As a result, we observed that a proto-oncogene with serine/threonine kinase activity, Pim-3 was aberrantaly expressed in pre-malignant and malignant lesions, but not normal hepatic tissues. Similar observations were obtained also on human hepatocellular carcinoma (HCC) and normal liver tissues. Pim-3 was constitutively expressed in human HCC cell lines and the inhibition of Pim-3 expression by short interfering RNA induced the apoptosis of human HCC cell lines. Pim-3 was not detected in other endoderm-derived organs such as pancreas and colon, but its expression was enhanced in the pre-malignant lesions and malignant lesions of these organs. In both human pancreatic cancer and colorectal can … More cer cell lines, Pim-3 was constitutively expressed and a pro-apoptotic molecule, Bad was co-localized with Pim and was phosphorylated at 112-Ser, which represents its inactive form. The inhibition of Pim-3 expression by short interfering RNA reduced the phosphorylation of Bad at 112-Ser and the expression of an anti-apoptotic molecule, Bcl-XL and eventually enhanced the apoptosis. These observations suggest that aberrant expression of Pim-3 can contribute to carcinogenesis in endoderm-derived organs, including liver, pancreas, and colon, by inhibiting apoptosis and that Pim-3 can be a novel tumor marker to detect pre-malignant and malignant lesions of these organs.2)Roles of chemokines and hepatocarcinogenesis and liver metastasis We observed that a chemokine, CCL3 and its receptor, CCR1, can inhibit the carcinogenesis in the early phase of murine hepatocarcinogenesis induced by diethylnitrosamine administration but that the CCL3-CCR1 axis can promote carcinogenesis of the same hepatocarcinogenesis, by inducing angiogenesis. We further demonstrated that another chemokine, CCL2 and its receptor, CCR2, can promote liver metastasis by activating hepatic stellate cells (Ito cells) and eventually accelerating neovascularization. Less

1)具有丝氨酸/苏氨酸激酶活性的原癌基因Pim-3在内胚层来源器官恶性病变中的异常表达我们利用荧光差异显示技术比较了小鼠肝癌发生模型中癌前病变和癌变病变的基因表达谱。结果，我们观察到具有丝氨酸/苏氨酸激酶活性的原癌基因Pim-3在癌前病变和恶性病变中异常表达，而在正常肝组织中不表达。在人肝细胞癌（HCC）和正常肝组织中也获得了类似的观察结果。Pim-3在人肝癌细胞系中呈组成型表达，短干扰RNA抑制Pim-3表达可诱导人肝癌细胞系凋亡。Pim-3在胰腺、结肠等其他内胚层来源的器官中未检测到，但在这些器官的癌前病变和恶性病变中表达增强。在人类胰腺癌和结肠直肠癌中， ...更多信息 在cer细胞系中，Pim-3组成型表达，促凋亡分子Bad与Pim共定位，并在112-Ser处磷酸化，这代表其失活形式。短干扰RNA抑制Pim-3表达可降低Bad在112-Ser的磷酸化和抗凋亡分子Bcl-XL的表达，最终促进细胞凋亡。这些观察结果表明，Pim-3的异常表达可以通过抑制细胞凋亡而促进内胚层来源的器官（包括肝、胰腺和结肠）中的癌发生，并且Pim-3可以是检测这些器官的癌前病变和恶性病变的新的肿瘤标记物。2）趋化因子与肝癌发生和肝转移的作用我们观察到趋化因子CCL 3及其受体CCR 1，可以抑制二乙基亚硝胺诱导的小鼠肝癌发生的早期阶段的癌变，但是CCL 3-CCR 1轴可以通过诱导血管生成促进相同肝癌发生的癌变。我们进一步证明了另一种趋化因子CCL 2及其受体CCR 2可以通过激活肝星状细胞（Ito细胞）并最终加速新生血管形成来促进肝转移。少

项目成果

A proto-oncogene, Pim-3 with serine/threonine kinase activity, is aberrantly expressed in human colon cancer cells and can prevent Bad-mediated apoptosis.

原癌基因 Pim-3 具有丝氨酸/苏氨酸激酶活性，在人结肠癌细胞中异常表达，可以阻止 Bad 介导的细胞凋亡。

• 发表时间: 2007
• 期刊: Cancer Science 98(3)
• 作者: Popivanova BK;Li Y-Y;Zhen H;Omura K;Fujii C;Tsuneyama K;Mukaida N
• 通讯作者: Mukaida N

Essential contribution of a chemokine, CCL3, and its receptor, CCR1, to hepatocellular carcinoma progression

趋化因子 CCL3 及其受体 CCR1 对肝细胞癌进展的重要贡献

• DOI: 10.1002/ijc.21596
• 发表时间: 2006-04-15
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Yang, XQ;Lu, PR;Mukaida, N
• 通讯作者: Mukaida, N

Monocyte chemoattractant protein-1 gene delivery enhances antitumor effects of herpes simplex virus thymidine kinase/ganciclovir system in a model of colon cancer

• DOI: 10.1038/sj.cgt.7700908
• 发表时间: 2006-04-01
• 期刊: CANCER GENE THERAPY
• 影响因子: 6.4
• 作者: Kagaya, T;Nakamoto, Y;Kaneko, S
• 通讯作者: Kaneko, S

Spontaneous regression of lung metastasis in the absence of tumor necrosis factor receptor p55

• DOI: 10.1002/ijc.20493
• 发表时间: 2004-12
• 期刊: International Journal of Cancer
• 影响因子: 6.4
• 作者: Y. Tomita;Xiaoqin Yang;Y. Ishida;Y. Nemoto-Sasaki;T. Kondo;M. Oda;G. Watanabe;G. Chaldakov;C. Fujii;N. Mukaida

Intrahepatic interleukin-8 production during disease progression of chronic hepatitis C

• DOI: 10.1016/j.canlet.2006.10.028
• 发表时间: 2007-06-18
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Tachibana, Yoshiya;Nakamoto, Yasunari;Kaneko, Shuichi
• 通讯作者: Kaneko, Shuichi