Analysis of molecular mechanisms of basement membrane destruction in the process of lung cancer cell invasion

在肺癌侵袭邻近细胞外基质的过程中，基底膜经常被破坏。为了解释这一点，我们假设除了抑制癌细胞的侵袭外，基底膜还隔离了癌细胞分泌的细胞因子扩散，并刺激成纤维细胞的生长，从而促进了癌细胞的侵袭性。碱性成纤维细胞生长因子和血小板衍生生长因子是癌细胞条件培养液中的生长刺激因子之一。基底膜基质通过与硫酸肝素的亲和结合，显著地隔离了bFGF的扩散。碱性成纤维细胞生长因子以较高的浓度储存在基底膜基质中，并有可能在基底膜破坏后二次释放。另一方面，基底膜基质抑制了HGF依赖的侵袭性生长对A549细胞的侵袭。采用基因芯片技术，检测了A549细胞在基底膜基质存在时基因表达谱的变化。我们发现在基底膜基质的存在下，包括EF(延伸因子)1a1、EF1a2、EF1d在内的50个基因的表达被显著抑制。已知EF(延伸因子)1a1、EF1a2、EF1d与f-肌动蛋白结合，可能调节细胞膜的运动。我们的结果表明，基底膜通过抑制延伸因子基因来抑制癌细胞的侵袭性。

In the process of lung cancer invasion to the neighboring extracellular matrix, basement membrane is quite often disrupted. For the explanation of this, in addition to the inhibition of cancer cell invasion, we hypothesized that basement membrane sequester the cytokine diffusion secreted by the cancer cells and stimulating the growth of fibroblasts which promote the invasive natures of cancer cells.We showed that lung cancer cell lines stimulated growth of fetal lung fibroblasts. bFGF and PDGF were the one of the growth stimulators in the cancer cell conditioned media. Basement membrane matrix significantly sequestered the diffusion of bFGF by the affinity binding to the heparin sulfate. bFGF were stored in the basement membrane matrix at higher concentration and the possibility of its release secondary to the basement membrane destruction.In the other hand, basement membrane matrix inhibit the invasive growth of HGF-dependent invasion of A549 cells. By the cDNA array method, we examined the change of gene expression pattern of A549 cells in the existence of basement membrane matrix. We found that expression of 50 genes, including EF(elongation factor)1a1, EF1a2, EF1d,were significantly suppressed in the existence of basement membrane matrix. EF(elongation factor)1a1, EF1a2, EF1d were known to bind to f-actin and possibly regulate the celuular motility. Our results suggest that basement membrane inhibits the invasive nature of cancer cells via the suppression of elongation factor genes.