腦膠質瘤是由腦中最多的細胞—神經膠細胞所產生的惡性腫瘤，而其中多型性腦膠母細胞瘤(glioblastoma multiforme, GBM)是第四期的星狀細胞瘤，不但是最常見、也是最惡性的腦內腫瘤。得到多型性腦膠母細胞瘤的病患其預後通常極差，平均餘命只有約一年左右。多型性腦膠母細胞瘤很少轉移至中樞神經系統以外的地方，但在顱內因惡性細胞極易浸潤及侵犯至其他正常的細胞，造成手術完全切除及治癒的困難。基質Gla蛋白(matrix gla protein, MGP)是一種維生素K依賴的分泌蛋白，主要由血管平滑肌及軟骨細胞生合成。近年來已有多篇報導指出其在腫瘤中占有重要的角色，而其中包含了腦膠質瘤。此研究的目的為釐清MGP在腦膠質瘤中所扮演的角色。我們在實驗中使用了兩種常用的大鼠腦膠質瘤細胞株—C6-1和C6-2，在本實驗室先前利用細胞培養和動物實驗研究結果發現C6-1具有較強的增生及腫瘤生成的能力。cDNA微陣列(microarray)的結果顯示MGP在C6-1的表現量顯著低於C6-2。我們使用了cell scratch assay及transwell cell invasion assay，發現有較高MGP表現量的C6-2擁有較強的細胞遷移(migration)及侵犯(invasion)的能力。利用lentivirus載體方式將MGP-shRNA表現於C6-2細胞導致細胞內的MGP表現量下降，其細胞的增生、遷移、及侵犯能力都顯著的被抑制。另一方面，若將MGP在C6-1中高度表現，其細胞增生未受影響，但是細胞遷移及侵犯的能力也有顯著地增強。此外，當把高度表現MGP的C6-1細胞種在塗有纖維蛋白的培養環境中，細胞會變為類似間葉細胞的型態。Slit2是另一種與細胞遷移相關的分子，且與MGP不同的是，它在C6-1的表現量較高。在C6-1中降低Slit2表現量會讓MGP表現量增高、細胞的遷移能力亦會增強。Slit2與MGP之間在腫瘤細胞行為上的相互關聯仍需進一步的探討。以目前的研究結果推測腦膠質瘤內高度表現MGP的腦膠質腫瘤細胞其遷移及侵犯能力是高於MGP表現量低的細胞，意即MGP在此腫瘤的遷移及侵犯能力中，扮演著舉足輕重的角色。

Gliomas are a group of tumors derived from glial cells, the most abundant cells in the brain. Among them, glioblastoma multiforme (GBM), also known as grade IV astrocytoma, is the most common and aggressive subtype. The prognosis of patients with GBM is usually poor with the average life expectancy less than one year. Metastasis of GBM beyond the central nervous system is rare, and its malignant presentation is attributed to the highly infiltration trait. Matrix gla protein (MGP) is a vitamin K-dependent small secretory protein, mainly synthesized by vascular smooth muscle cells and chondrocytes. Mounting evidence has reported its link with tumors, including glioma. Our recent study has demonstrated that a rat glioma cell line C6-1 exhibited higher tumorigenicity both in vitro and in vivo compared to another rat glioma cell line C6-2 that rarely formed tumor in rat brain. Moreover, cDNA microarray showed that MGP expression was much lower in C6-1 cells than C6-2 cells. Thus, the aim of this study is to elucidate the role of MGP in the cell dynamics of C6 cells. Through different assays, C6-2 cells expressing a higher level of MGP displayed better migration and invasion ability than C6-1 cells. The downregulation of MGP in C6-2 cells reduced their proliferation, migration, and invasion abilities. On the other hand, the overexpression of MGP in C6-1 cells enhanced their cell migration and invasion. Moreover, the cell shape of C6-1 cells after MGP overexpression become mesenchymal-like, when those cells were seeded onto fibronectin-coated culture environment. Slit2 is another factor responsible for cell migration, and in contrast to MGP, its expression is increased in C6-1 cells. Slit2 gene knockdown in C6-1 cells increased the gene expression of MGP, and the cell migration was enhanced. The crosstalk between MGP and Slit2 in tumor cell behavior needs to be delineated. In summary, our findings indicate that MGP plays critical part in the glioma migration and invasion.

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