title: HES6 gene is selectively overexpressed in glioma and represents an important transcriptional regulator of glioma proliferation.
abstract: Malignant glioma is the most common brain tumor with 16,000 new cases diagnosed annually in the United States. We performed a systematic large-scale transcriptomics data mining study of 9783 tissue samples from the GeneSapiens database 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 with 425 samples from histologically normal central nervous system. Transcription cofactor HES6 (hairy and enhancer of split 6) emerged as the most glioma-specific gene. Immunostaining of a tissue microarray showed HES6 expression in 335 (98.8%) out of the 339 glioma samples. HES6 was expressed in endothelial cells of the normal brain and glioma tissue. Recurrent grade 2 astrocytomas and grade 2 or 3 oligodendrogliomas showed higher levels of HES6 immunoreactivity than the corresponding primary tumors. High HES6 mRNA expression correlated with the proneural subtype that generally has a favorable outcome but is prone to recur. Functional studies suggested an important role for HES6 in supporting survival of glioma cells, as evidenced by reduction of cancer cell proliferation and migration after HES6 silencing. 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 nuclear factor-κB transcriptional networks. We conclude that HES6 is important for glioma cell proliferation and migration, and may have a role in angiogenesis.
authors.affiliation: Department of Medical Biotechnology, VTT Technical Research Centre of Finland and Centre for Biotechnology, University of Turku, Turku, Finland. saija.haapa-paananen@vtt.fi
authors.forename: S
authors.initials: S
authors.lastname: Haapa-Paananen
authors.forename: S
authors.initials: S
authors.lastname: Kiviluoto
authors.forename: M
authors.initials: M
authors.lastname: Waltari
authors.forename: M
authors.initials: M
authors.lastname: Puputti
authors.forename: J P
authors.initials: JP
authors.lastname: Mpindi
authors.forename: P
authors.initials: P
authors.lastname: Kohonen
authors.forename: O
authors.initials: O
authors.lastname: Tynninen
authors.forename: H
authors.initials: H
authors.lastname: Haapasalo
authors.forename: H
authors.initials: H
authors.lastname: Joensuu
authors.forename: M
authors.initials: M
authors.lastname: Perälä
authors.forename: O
authors.initials: O
authors.lastname: Kallioniemi
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics; D018628:Gene Dosage; D016259:Genes, myc; D005910:Glioma / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D006801:Humans; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D012097:Repressor Proteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D020796:Receptor, Platelet-Derived Growth Factor alpha; D012097:Repressor Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2; C411859:HES6 protein, human