The mechanisms of the highly metastatic property using human lung cancer sublines with highly metastatic potential established and the expolation of the molecular targets for lung cancer therapy

利用具有高转移潜力的人肺癌亚系建立高转移特性的机制并揭示肺癌治疗的分子靶点

• 批准号: 13670620
• 负责人: GEMMA Akihiko
• 金额: $ 2.62万
• 依托单位: Nippon Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670620/
• 关键词: Lung Cancer; Metastasis; Microarray; Macroarray; Gene Expression; CDNA array; 発現プロファイル; cDNA array; expression profile; マクロアレイ; EST クローン

A better understanding of the key factors of metastasis may be useful for designing new molecular targets of cancer therapy. In order to identify these factors, we established two highly metastatic human lung adenocarcinoma cell lines in an experimental metastasis model by repeated inoculation in nude mice and compared the expression profiles of two subpopulations of an adenocarcinoma cell line with high metastatic potential, with the parent cell line, using cDNA arrays; microarray and macroarray. The expression of 5 genes was found to be significantly enhanced or reduced in the highly metastatic subpopulations by microarray. One of the over-expressed genes that was identified encoded the β-galactoside-binding protein Galectin 3. A population (10/30) of the non-small-cell lung cancers examined was found to over-express the Galectin 3 gene at levels 3 times higher than normal epithelial cells. Galectin 3 may represent a novel target molecule in non-small-cell lung cancer therapy. The expression of matrix metalloproteinase-2 (MMP-2), plasminogen activator inhibitor-1 (PAI-1), carcinoembryonic antigen (CEA) and etc. were upregulated or downregulated in the highly metastatic subpopulations. Altered expression of these genes seems topromote the highly metastatic phenotype in these function. To determine whether the change in p16INK4 methylation status and the genomic status of hBUB1, hMAD2, Insulin-like growth factor 2 receptor genes, chromosome 8p and 3p occurs during metastasis of primary lung cancers, we also analyzed the primary and metastatic tumor tissues and normal lung samples from 30 cases of advanced lung cancer with distant metastasis. The results of this study indicate that tumor cells in which the p16INK4 gene has been inactivated by hypermethylation of the promoter region could have an advantage in metastasis in non-small cell lung cancers. We will evaluate the clinical significance of MMP-2, PAI-1, CEA, Galectin 3 and identified unknown clones.

更好地了解转移的关键因素可能有助于设计新的肿瘤治疗分子靶点。为了确定这些因素，我们建立了两个高转移的人肺腺癌细胞系的实验转移模型，通过重复接种在裸鼠和比较的表达谱的两个亚群的腺癌细胞系具有高转移潜力，与亲本细胞系，使用cDNA阵列;微阵列和宏阵列。基因芯片检测发现5个基因在高转移亚群中表达显著增强或降低。其中一个被鉴定的过表达基因编码β-半乳糖苷结合蛋白Galectin 3。在非小细胞肺癌中，有10例（10/30）过表达Galectin 3基因，其水平是正常上皮细胞的3倍。Galectin 3可能是非小细胞肺癌治疗的一个新靶分子。高转移亚群中基质金属蛋白酶-2（MMP-2）、纤溶酶原激活物抑制剂-1（派-1）、癌胚抗原（CEA）等表达上调或下调。这些基因表达的改变似乎促进了这些功能的高转移表型。为探讨原发性肺癌转移过程中p16 INK 4甲基化状态、hBUB 1、hMAD 2、胰岛素样生长因子2受体基因、染色体8 p和3 p的基因组状态是否发生改变，我们还分析了30例晚期肺癌远处转移患者的原发癌组织、转移癌组织和正常肺组织。这项研究的结果表明，肿瘤细胞中的p16 INK 4基因已被失活的启动子区域的超甲基化可能有一个优势，在非小细胞肺癌的转移。我们将评估MMP-2、派-1、CEA、Galectin 3和鉴定的未知克隆的临床意义。

项目成果

Seike M: "The promoter region of the human BUBR1 gene and its expression analysis in lung cancer."Lung Cancer. 38(3). 229-234 (2002)

Seike M：“人类 BUBR1 基因的启动子区域及其在肺癌中的表达分析。”肺癌。