5-Aza-2’-deoxycytidine對人類神經膠質瘤細胞中之分化及侵襲性所造成的影響

1. 5-Aza-2’-deoxycytidine對人類神經膠質瘤細胞中之分化及侵襲性所造成的影響5-Aza-2’-deoxycytidine對人類神經膠質瘤細胞中之分化及侵襲性所造成的影響 • 5’-Aza-2-deoxycytidine (5’-AzadC)是一種抗癌藥物(商品名)，現今已被用來治療骨髓再生不良症候群和急性骨髓性白血病，然而它對於人類神經膠質瘤抗侵襲性的療效及機轉仍不太清楚。本研究探討在人類神經膠質瘤細胞中5’-AzadC是否調節細胞侵襲性及其可能機轉。我們發現惡性人類神經膠質瘤細胞會持續的表現matrix metalloproteninases-2 (MMP-2)，而且MMP-2的活性和腫瘤細胞的惡性度有密切的關係。在低劑量長時間的處理下我們發現5’-AzadC會降低MMP-2的表現而不會引起細胞的死亡，在相同的情況下我們發現5’-AzadC會增加在U87MG細胞中glial fibrillary acidic protein (GFAP)的表現。GFAP的表現和MMP-2的表現呈相反的關係，5’-AzadC會引起細胞再分化的現象，接著會降低細胞的侵襲性。利用in vitro invasion assay我們證實了分化中的U87MG cells 有較低的侵襲性。另外我們發現5’-AzadC會增加TIMP-2的表現，顯示5’-AzadC不只會減少MMP-2的表現，而且也會抑制MMP-2的活化。綜合以上結果，5’-AzadC可抑制MMP-2的活化、並降低其侵襲性；因此5’-AzadC可能可以用來控制神經膠質瘤的侵襲性，並用於人類神經膠質瘤之治療。

2. Effects of 5-Aza-2’-deoxycytidine on cell differentiation and invasiveness of human glioma cells • 5-Aza-2’-deoxycytidine (5-AzadC) is an anti-cancer drug, currently used in the tumor therapy. However, the underneath mechanisms of the anti-invasiveness effect on human glioma are still unknown. In the present study, we investigated the possibility of whether 5-AzadC can be used to control the invasiveness of human glioma, and the mechanisms by which 5-AzadC regulate cell invasiveness in human glioma cells. We found that malignant human glioma cells constitutively expressed matrix metalloproteinase-2 (MMP-2), and the MMP-2 activities were correlated well with their malignancies. We demonstrated that 5-AzadC suppressed MMP-2 activity in U87MG astrocytoma cells and other primary astrocytoma cell lines. 5-AzadC decreased MMP-2 expression without causing cell death. At the same conditions, we found that 5-AzadC increased glial fibrillary acidic protein (GFAP) expression in U87MG cell suggesting that 5-AzadC induces cell redifferentiation, which was associated with decreased cell invasiveness. Using in vitro invasion assay, we demonstrated that differentiated U87MG cells exhibited lower invasiveness. In addition, we found that 5-AzadC increased TIMP-2 expression, suggesting that 5-AzadC not only reduced MMP-2 expression but also inhibited MMP-2 activation. Taken together, these findings support a safer strategy targeting glioma invasiveness in context of glioma therapy