Department of Anatomy, University of Kiel, Kiel, Germany.
J Neuropathol Exp Neurol. 2010 Mar;69(3):215-23. doi: 10.1097/NEN.0b013e3181ce9f67.
Glial tumors exhibit a high morbidity and mortality because of their invasive nature. Matrix metalloproteinase 19 (MMP19) is a secreted protease that together with epilysin (MMP28) forms a structural subgroup of MMPs. We analyzed their expression by quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry in tumor and normal control brain tissues and in glioblastoma (GB) cells and performed MMP19 silencing functional assays. Matrix metalloproteinase 28 was transcribed to the same extent in normal brain samples and gliomas but was undetectable in GB cell lines. In contrast, MMP19 was detected by immunohistochemistry in normal brain samples only in endothelial cells but was found at high levels in astrocytomas of different World Health Organization grades in situ and in GB cells in vitro. Matrix metalloproteinase 19 was upregulated in GB cells after exposure to proinflammatory cytokines. In Transwell invasion assays, MMP19-silenced cells migrated more slowly through laminin-, basal lamina-, and brevican-coated membranes than controls. Matrix metalloproteinase 19-silenced GB cells also migrated into brain tissue slices compared with control cells. Brevican, a brain-specific proteoglycan and major component of brain extracellular matrix, was degraded by recombinant human MMP19. Taken together, these results indicate that MMP19 is highly expressed in proliferating astrocytoma/glioma cells, and that its expression may facilitate their invasion through brain extracellular matrix components.
神经胶质肿瘤具有侵袭性，因此发病率和死亡率都很高。基质金属蛋白酶 19（MMP19）是一种分泌型蛋白酶，与表皮素（MMP28）一起构成了 MMPs 的一个结构亚群。我们通过定量逆转录聚合酶链反应、Western blot 和免疫组织化学分析了肿瘤和正常对照脑组织以及神经胶质瘤（GB）细胞中它们的表达情况，并进行了 MMP19 沉默功能测定。基质金属蛋白酶 28 在正常脑组织样本和神经胶质瘤中的转录程度相同，但在 GB 细胞系中无法检测到。相比之下，免疫组织化学检测到 MMP19 仅在正常脑组织样本中的血管内皮细胞中表达，但在不同世界卫生组织分级的星形细胞瘤原位和体外 GB 细胞中均高表达。GB 细胞暴露于促炎细胞因子后 MMP19 上调。在 Transwell 侵袭测定中，沉默 MMP19 的细胞穿过层粘连蛋白、基底膜和 brevican 涂层膜的迁移速度比对照细胞慢。与对照细胞相比，沉默 MMP19 的 GB 细胞也迁移到脑组织切片中。Brevican 是一种大脑特异性蛋白聚糖，也是大脑细胞外基质的主要成分，可被重组人 MMP19 降解。综上所述，这些结果表明 MMP19 在增殖性星形细胞瘤/神经胶质瘤细胞中高表达，其表达可能有助于它们穿过脑细胞外基质成分的侵袭。
