Expression analysis of the autosomal recessive primary microcephaly genes MCPH1 (microcephalin) and MCPH5 (ASPM,
Carsten Hagemann1, Jelena Anacker, Stefanie Gerngras
1Department of Neurosurgery, University of Würzburg, D-97080 Würzburg, Germany. hagemann_c@klinik.uni-wuerzburg.de
Abstract:
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 neuro-epithelial 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 II 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 mRNA 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.
Insights
ASPM, a gene linked to microcephaly, is overexpressed in malignant brain tumors called gliomas. Increased ASPM expression correlates with tumor grade, suggesting it could serve as a biomarker for glioma malignancy and a potential therapeutic target.
Area of Science:
- Neuroscience
- Oncology
- Cell Biology
Background:
- Autosomal recessive primary microcephaly is linked to mutations in Microcephalin and ASPM, centrosomal proteins regulating cell cycle.
- Both Microcephalin and ASPM play roles in tumor growth, with altered expression observed in various cancers.
- Glioblastomas, aggressive adult brain tumors, exhibit invasiveness and rapid growth.
Purpose of the Study:
- To analyze the expression of Microcephalin and ASPM mRNA and protein in glioblastomas and astrocytomas.
- To investigate the correlation between Microcephalin and ASPM expression and glioma tumor grade.
- To evaluate ASPM as a potential biomarker for glioma malignancy and a therapeutic target.
Main Methods:
- Semi-quantitative RT-PCR was used to analyze mRNA expression levels.
- Western blotting was employed to assess protein expression.
- Immunohistochemistry was performed to localize protein expression within tumor tissues.
Main Results:
- Microcephalin expression showed no significant alteration during glioma development.
- ASPM mRNA and protein expression were significantly increased in gliomas compared to normal brain tissue.
- ASPM expression levels positively correlated with the World Health Organization (WHO) tumor grade.
Conclusions:
- ASPM expression is upregulated in gliomas and increases with tumor malignancy.
- ASPM serves as a potential biomarker for glioma malignancy.
- ASPM represents a promising therapeutic target for brain tumors like glioblastoma.
