Analysis of activated gene network in the microenvironment of lung cancer-invasion front.

1. 为了构建一个实用的评估肺腺癌侵袭性的面板，利用cDNA芯片进行基因表达谱分析，寻找候选基因，重点研究肺癌侵袭前沿微环境中的基因网络，特别是1)肿瘤血管生成，2)微乳头成分（最近被提出作为侵袭性的新指标）。3)原位腺癌与浸润性腺癌基因表达差异。1)肿瘤血管生成中，除cd105标记的新生血管数量外，VEGF 121、Ang-2、HIF 1α、HIF 2α基因的表达与肺癌患者的肿瘤侵袭性和预后相关。2)在微乳头状成分中，微乳头状腺癌在无监督聚类分析中表现出与传统乳头状腺癌显著不同的基因表达谱。CXCL14和S100P基因被提名为微乳头状腺癌侵袭性生物学行为决定因素的候选基因。3)原位和侵袭性腺癌中，HDAC 1、Twist 1、CEACAM 1基因的上调以及MMP 28、VEGF-D的下调与肺腺癌的侵袭性相关。利用这些基因以及前期研究中选择的MMP-14、MMP-3、p21-Rac 1、Notch-4 / Jagged-1、Jagged-2、c-fos相关抗原、ezrin、MIC-1等9个基因构建肺腺癌侵袭性评价小组。目前正在评估该小组的临床用途。利用不同接种方式的HT1080肿瘤细胞在裸鼠体内的实验方法揭示了血小板红蛋白（γ -连环蛋白）是一种新的转移抑制基因，这在高度恶性的人肉瘤病例分析中得到了证实。

1. In order to construct a practical panel for evaluation of the invasiveness of pulmonary adenocarcinoma, candidate genes were searched by gene expression profiling analysis using cDNA microarray, emphasizing gene network in the microenvironment of lung cancer-invasion front, especially in 1) tumor angiogenesis, 2) micropapillary component (which have been recently proposed as a novel indicator of the aggressiveness), and 3) different gene expression between in situ adenocarcinoma and invasive one.2. In 1) tumor angiogenesis, in addition to the number of CD105-labelled neovasculatures, expressions of VEGF 121, Ang-2, HIF 1α, HIF 2α genes were disclosed to correlate with both tumor invasiveness and prognoses of lung cancer patients.3. In 2) micropapillary component, micropapillary adenocarcinoma showed a significantly different gene expression profile from that of conventional papillary adenocarcinoma in the unsupervised cluster analysis. CXCL14 and S100P genes were nominated as candidates for determinant of aggressive biological behavior of micropapillary adenocarcinoma.4. In 3) In situ and invasive adenocarcinoma, up-regulation of HDAC 1, Twist 1, CEACAM 1 genes and down-regulation of MMP 28 and VEGF-D were demonstrated to correlate with invasiveness of pulmonary adenocarcinomas.5. A panel for the evaluation of invasiveness of pulmonary adenocarcinoma was constructed using those genes as well as nine genes which had been selected in the previous study, including MMP-14, MMP-3, p21-Rac 1, Notch-4 / Jagged-1, Jagged-2, c-fos related antigen, ezrin, MIC-1. Clinical usefulness of the panel is now being evaluated.6. An experimental approach using HT1080 tumor cells inoculated differently in nude mice disclosed plakoglobin (gamma-catenin) is a novel metastasis-supressor gene, which was confirmed in the analysis of highly malignant human sarcoma cases.