BMP4在胶质母细胞瘤的多药耐药中的作用及机制研究

The Effect of BMP4 on Multidrug Resistance in Glioblastoma and the Mechanism Study

背景与目的:近年来的一系列实验证实,骨形成发生蛋白4(bone morphogenetic proteins 4,BMP4)在体内外可以抑制肿瘤的生长,但其机制还不清楚。本研究旨在探讨BMP4在胶质母细胞瘤多药耐药中的作用及机制。方法:检测人脑胶质母细胞瘤和正常脑组织标本中BMP4的表达量;构建多药耐药细胞株并进行鉴定,检测在多药耐药细胞株和正常胶质母细胞瘤细胞株内BMP4的表达量;通过在多药耐药细胞株中高表达BMP4,检测BMP4逆转多药耐药的可能性;通过检测高表达BMP4后耐药相关基因的表达变化,初步筛选出BMP4调节胶质母细胞瘤多药耐药的可能机制。结果:在胶质母细胞瘤内,BMP4表达量降低;多药耐药细胞株构建成功,且与对照组相比,多药耐药细胞株的BMP4表达量明显降低,高表达BMP4可以逆转多药耐药;高表达BMP4后,多药耐药相关的基因中,BCL-2和GDNF表达量明显降低。结论:BMP4可以逆转胶质母细胞瘤多药耐药,其可能机制是通过调节BCL-2和GDNF的表达。

BACKGROUND ＆ OBJECTIVE： Recent data suggest that bone morphogenetic proteins 4 （BMP4） inhibit the proliferation of cancer cells. In this study, we aimed to detect the effect of BMP4 in multidrug resistance （MDR） in glioblastoma and the underlying mechanism. METHODS： The expression of BMP4 in glioblastoma and normal brain tissues was detected by western blot and realtime PCR. Multidrug resistance cell line was established and the expression of BMP4 was detected. BMP4 was transfected into multidrug resistance cells and the chemosensitivity was detected. Multidrug resistance genes were detected when BMP4 was over expressed. chemosensitivity was detected when B-cell lymphoma 2 （BCL-2） or glial cell derived neurotrophic factor （GDNF） was knocked down. RESULTS： The expression level of BMP4 was lower in glioblastoma compared to normal brain tissues, and BMP4 expression decreased in multidrug resistance cell line U251/TMZ compared to U251 cells. Our research demonstrated that over expression of BMP4 can reverse the multidrug resistance. BCL-2 and GDNF were inhibited when BMP4 was over-expressed, and this data was consistent with the negative relationship in human samples, analysis of 40 patient＇s glioblastoma and brain samples revealed a significant negative correlationbetween BMP4 and BCL-2 and GDNF. CONCLUSION： BMP4 can reverse MDR in glioblastoma, which involved negative regulation of BCL-2 and GDNF.