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Study of mechanisms of the highly metastatic feature using human lung cancer sublines with highly metastatic property established

利用具有高转移特性的人肺癌亚系研究高转移特性的机制

基本信息

批准号：
11670598
负责人：
GEMMA Akihiko
金额：
$ 1.86万
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：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670598/
关键词：
Lung Cancer Metastasis Microarray Macroarray Gene Expression

项目摘要

A better understanding of the key factors of metastasis may be useful for designing new molecular targets of 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. The genomic structure of these genes will be detrmined. The expression of matrix metalloproteinase-2 (MMP-2), plasminogen activator inhibitor-1 (PAI-1), carcinoembryonic antigen (CEA), Fas ligand and etc.were upregulated or downregulated in the highly metastatic subpopulations. The differential expression of these genes was confirmed by Northern blot analysis or reverse transcription-polymerase chain reaction (RT-PCR). Altered expression of these genes seems to promote 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 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. The differential expression of the gene was not detected among subpopulations with high metastatic potential of the cell line and the parent line. The expression of the p16INK4 gene did not seem to be involved in the highly metastatic phenotype in this cell line.

更好地了解转移的关键因素可能有助于设计新的治疗分子靶点。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。这些基因的基因组结构将被确定。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物1（派-1）、癌胚抗原（CEA）、Fas配体等表达上调或下调。通过北方印迹分析或逆转录-聚合酶链反应（RT-PCR）证实这些基因的差异表达。这些基因的表达改变似乎促进了这些功能中的高转移表型。为探讨p16 INK 4甲基化状态和hBUB 1、hMAD 2、胰岛素样生长因子2受体基因的基因组状态在肺癌转移过程中是否发生改变，我们还分析了30例晚期肺癌远处转移患者的原发灶、转移灶和正常肺组织。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。该基因在高转移潜能细胞系和亲本细胞系的亚群中未检测到差异表达。p16 INK 4基因的表达似乎不参与该细胞系的高转移表型。