Malignant glioma is the most common brain tumor with
16,000 individuals diagnosed annually in the United
States. We performed a systematic large-scale
transcriptomics data mining study of 9,783 Affymetrix
samples from the GeneSapiens database
(www.genesapiens.org) to systematically identify genes
that are most glioma-specific. We searched for genes that
were highly expressed in 322 glioblastoma multiforme
tissue samples and 66 anaplastic astrocytomas as compared
to 425 samples from histologically normal central nervous
system. Transcription cofactor HES6 (Hairy and Enhancer
of Split 6) emerged as one of the most glioma-specific
genes. Immunostaining of a tissue microarray showed HES6
expression in 335 (98.8%) out of the 339 glioma samples.
HES6 was also expressed in endothelial cells in normal
and glioma tissues. Recurrent grade 2 astrocytomas and
grade 2-3 oligodendrogliomas showed higher levels of HES6
immunoreactivity than the corresponding primary tumors.
Functional studies implied a critical role for HES6 in
supporting survival of glioma cells, as evidenced by
reduction of cancer cell proliferation and induction of
Caspase 3/7 activity after HES6 silencing in A172 and
LN405 cells. The biological role and consequences of HES6
silencing and overexpression was explored with
genome-wide analyses, which implicated a role for HES6 in
p53, c-myc, and NF-?B transcriptional networks. We
conclude that HES6 has a critical role in sustaining
glioma cell growth, survival, migration and possibly
angiogenesis. HES6 is a potential therapeutic target and
biomarker for glioma.
This work was supported by funding under the 6th FP of
the European Union, Project RIGHT (LSHB-CT-2004-005276),
and the Academy of Finland.