Maternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomas.
We have performed cDNA microarray analyses to identify gene expression differences between highly invasive glioblastoma multiforme (GBM) and typically benign pilocytic astrocytomas (PA). Despite the significant clinical and pathological differences between the 2 tumor types, only 63 genes were found to exhibit 2-fold or greater overexpression in GBM as compared to PA. Forty percent of these genes are related to the regulation of the cell cycle and mitosis. QT-PCR validation of 6 overexpressed genes: MELK, AUKB, ASPM, PRC1, IL13RA2 and KIAA0101 confirmed at least a 5-fold increase in the average expression levels in GBM. Maternal embryonic leucine zipper kinase (MELK) exhibited the most statistically significant difference. A more detailed investigation of MELK expression was undertaken to study its oncogenic relevance. In the examination of more than 100 tumors of the central nervous system, we found progressively higher expression of MELK with astrocytoma grade and a noteworthy uniformity of high level expression in GBM. Similar level of overexpression was also observed in medulloblastoma. We found neither gene promoter hypomethylation nor amplification to be a factor in MELK expression, but were able to demonstrate that MELK knockdown in malignant astrocytoma cell lines caused a reduction in proliferation and anchorage-independent growth in in vitro assays. Our results indicate that GBM and PA differ by the expression of surprisingly few genes. Among them, MELK correlated with malignancy grade in astrocytomas and represents a therapeutic target for the management of the most frequent brain tumors in adult and children.
Marie
Suely K N
SK
Department of Neurology, School of Medicine, University of São Paulo, São Paulo, Brazil. sknmarie@usp.br
Okamoto
Oswaldo K
OK
Uno
Miyuki
M
Hasegawa
Ana Paula G
AP
Oba-Shinjo
Sueli M
SM
Cohen
Tzeela
T
Camargo
Anamaria A
AA
Kosoy
Ana
A
Carlotti
Carlos G
CG
Toledo
Silvia
S
Moreira-Filho
Carlos A
CA
Zago
Marco A
MA
Simpson
Andrew J
AJ
Caballero
Otavia L
OL
D000328:Adult; D017209:Apoptosis; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D002648:Child; D019175:DNA Methylation; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D034741:RNA, Small Interfering; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases