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

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，我们通过在裸鼠体内重复接种的方法建立了两个高转移的人肺腺癌细胞系，并利用基因芯片、微阵列和宏阵列比较了高转移潜能的人肺腺癌细胞系的两个亚群与亲本细胞的表达谱。基因芯片检测发现5个基因在高转移亚群中的表达显著增强或降低。其中一个过度表达的基因编码β-半乳糖苷结合蛋白Galectin 3。在所研究的非小细胞肺癌中，有一组(10/30)的Galectin 3基因过度表达，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新靶点。基质金属蛋白酶-2、纤溶酶原激活物抑制物-1、癌胚抗原等在高转移亚群中表达上调或下调。这些基因表达的改变似乎促进了这些功能中的高转移表型。为探讨p16INK4甲基化状态和hBUB1、hMAD2、胰岛素样生长因子2受体基因8p、3p在肺癌转移过程中的改变，我们还分析了30例晚期肺癌远处转移的原发和转移癌组织及正常肺组织标本。本研究结果表明，p16INK4基因启动子区高甲基化失活的肿瘤细胞在非小细胞肺癌的转移中可能具有优势。我们将评估基质金属蛋白酶-2、纤溶酶原激活物-1、癌胚抗原、半乳糖凝集素3的临床意义，并确定未知克隆。

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.