Expression analysis of the autosomal recessive primary microcephaly genes MCPH1 (microcephalin) and MCPH5 (ASPM, abnormal spindle-like, microcephaly associated) in human malignant gliomas
Expression analysis of the autosomal recessive primary microcephaly genes MCPH1 (microcephalin) and MCPH5 (ASPM, abnormal spindle-like, microcephaly associated) in human malignant gliomas
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DOI：
10.3892/or_00000007
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发表时间：
2008-08-01
期刊：
影响因子：
4.2
通讯作者：
Vince, Giles Hamilton
中科院分区：
文献类型：
--
作者：
Hagemann, Carsten;Anacker, Jelena;Vince, Giles Hamilton
常染色体隐性遗传性原发性小头畸形患者的大脑较小，但结构正常，神经元数量减少。Microcephalin和ASPM是导致这种疾病的两个基因。两者都是参与细胞周期调控的中心体蛋白。而小脑肽是DNA损伤反应的一个组成部分和端粒酶功能的阻遏物，ASPM是需要一个中央有丝分裂纺锤体的正确形成，并确保对称，神经上皮细胞的增殖分裂。这两种蛋白质也参与调节肿瘤生长。在乳腺癌细胞系和卵巢及前列腺的人类肿瘤中，小脑磷脂的表达减少。小脑肽mRNA表达减少与染色体不稳定性增加相关。ASPM mRNA在转化的人细胞系和肿瘤中过表达，其表达增加与胶质母细胞瘤细胞的增殖正相关。胶质母细胞瘤是成人中最常见的恶性脑肿瘤，其特征在于侵袭性增加，侵袭性局部生长模式和患者生存期短。在这项研究中，我们分析了15个胶质母细胞瘤和15个星形细胞瘤WHO 11级的半定量RT-PCR，蛋白质印迹和免疫组化的microcephalin mRNA和ASPM mRNA和蛋白质的表达。而脑胶质瘤的发展过程中，似乎没有改变microcephalin的表达，有一个明确的增加ASPM mRNA和蛋白质的表达，符合WHO的肿瘤等级。我们的研究结果是有意义的，因为ASPM的表达可以用作胶质瘤恶性程度的标志物，并代表潜在的治疗靶点。
Patients with autosomal recessive primary microcephaly have a small but architecturally normal brain containing a reduced number of neurons. Microcephalin and ASPM are two of the genes causing this disease. Both are centrosomal proteins involved in cell cycle regulation. Whereas microcephalin is a component of the DNA damage response and a repressor of telomerase function, ASPM is required for the proper formation of a central mitotic spindle and ensures symmetric, proliferative divisions of neuroepithelial cells. Both proteins are also involved in the regulation of tumor growth. Microcephalin expression is reduced in breast cancer cell lines and human tumors of the ovary and prostate. Reduction in microcephalin mRNA expression correlates with increased chromosomal instability. ASPM mRNA is overexpressed in transformed human cell lines and tumors, and its increased expression is positively associated with proliferation of glioblastoma cells. Glioblastomas are the most prevalent malignant brain tumors in adults, characterized by increased invasiveness, an aggressive local growth pattern and short survival periods of patients. In this study, we analysed the expression of microcephalin mRNA and ASPM mRNA and protein in a panel of 15 glioblastomas and 15 astrocytoma WHO grade 11 by semi-quantitative RT-PCR, Western blotting and immunohistochemistry. Whereas microcephalin expression did not seem to be altered during glioma development, there was a clear increase in ASPM rnRNA and protein expression that corresponded with the WHO grade of the tumor. Our findings are significant as the expression of ASPM may be used as a marker for glioma malignancy and represents a potential therapeutic target.