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

1.为了构建一个实用的肺腺癌侵袭性评价指标体系，利用基因表达谱芯片对候选基因进行了筛选，重点分析了肺癌侵袭前沿微环境中的基因网络，特别是在1)肿瘤血管生成，2)微乳头成分(新近提出的一种新的侵袭性指标)，以及3)原位腺癌和侵袭性腺癌之间的差异基因表达。在1)肿瘤血管生成方面，除CD105标记的新生血管数量外，VEGF121、Ang-2、HIF1α、HIF2α基因的表达与肺癌患者的肿瘤侵袭性和预后有关。2)在微乳头状腺癌中，微乳头状腺癌的基因表达谱与常规乳头状腺癌的基因表达谱有显著差异。CXCL14和S100P基因被提名为微乳头状腺癌侵袭性生物学行为的候选基因。3)原位腺癌和浸润性腺癌中，HDAC-1、Twist-1、CEACAM-1基因表达上调，MMP28、VEGF-D基因表达下调，与肺腺癌的侵袭性相关。利用这些基因和前期研究中筛选出的9个基因，包括MMP14、MMP3、p21RAC1、Notch-4/Jagge1、Jagge2、c-fos相关抗原、Ezrin、MIC-1，构建了评价肺腺癌侵袭性的小组。目前正在对该小组的临床应用进行评估。一项使用HT1080肿瘤细胞在裸鼠体内不同接种方式的实验方法揭示了蛋白球蛋白(Gamma-Catenin)是一种新的转移抑制基因，这一点在对高度恶性的人类肉瘤病例的分析中得到了证实。

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.