title: Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma.
abstract: Astrocytoma is the most common type of brain cancer constituting more than half of all brain tumors. With an aim to identify markers describing astrocytoma progression, we have carried out microarray analysis of astrocytoma samples of different grades using cDNA microarray containing 1152 cancer-specific genes. Data analysis identified several differentially regulated genes between normal brain tissue and astrocytoma as well as between grades II/III astrocytoma and glioblastoma multiforme (GBM; grade IV). We found several genes known to be involved in malignancy including Achaete-scute complex-like 1 (Drosophila) (ASCL1; Hash 1). As ASCL has been implicated in neuroendocrine, medullary thyroid and small-cell lung cancers, we chose to examine the role of ASCL1 in the astrocytoma development. Our data revealed that ASCL1 is overexpressed in progressive astrocytoma as evidenced by increased levels of ASCL1 transcripts in 85.71% (6/7) of grade II diffuse astrocytoma (DA), 90% (9/10) of grade III anaplastic astrocytoma (AA) and 87.5% (7/8) of secondary GBMs, while the majority of primary de novo GBMs expressed similar to or less than normal brain levels (66.67%; 8/12). ASCL1 upregulation in progressive astrocytoma is accompanied by inhibition of Notch signaling as seen by uninduced levels of HES1, a transcriptional target of Notch1, increased levels of HES6, a dominant-negative inhibitor of HES1-mediated repression of ASCL1, and increased levels of Notch ligand Delta1, which is capable of inhibiting Notch signaling by forming intracellular Notch ligand autonomous complexes. Our results imply that inhibition of Notch signaling may be an important early event in the development of grade II DA and subsequent progression to grade III AA and secondary GBM. Furthermore, ASCL1 appears to be a putative marker to distinguish primary GBM from secondary GBM.
authors.affiliation: 1Department of Microbiology and Cell Biology, Indian Institute of Science, Malleswaram, Bangalore 560012, India.
authors.forename: Kumaravel
authors.initials: K
authors.lastname: Somasundaram
authors.forename: Sreekanth P
authors.initials: SP
authors.lastname: Reddy
authors.forename: Katyayni
authors.initials: K
authors.lastname: Vinnakota
authors.forename: Ramona
authors.initials: R
authors.lastname: Britto
authors.forename: Madhavan
authors.initials: M
authors.lastname: Subbarayan
authors.forename: Sandeep
authors.initials: S
authors.lastname: Nambiar
authors.forename: Aparna
authors.initials: A
authors.lastname: Hebbar
authors.forename: Cini
authors.initials: C
authors.lastname: Samuel
authors.forename: Mitesh
authors.initials: M
authors.lastname: Shetty
authors.forename: Hari Kishore
authors.initials: HK
authors.lastname: Sreepathi
authors.forename: Vani
authors.initials: V
authors.lastname: Santosh
authors.forename: Alangar Sathyaranjandas
authors.initials: AS
authors.lastname: Hegde
authors.forename: Sridevi
authors.initials: S
authors.lastname: Hegde
authors.forename: Paturu
authors.initials: P
authors.lastname: Kondaiah
authors.forename: M R S
authors.initials: MR
authors.lastname: Rao
mesh_terms: D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D012334:RNA, Neoplasm; D051880:Receptors, Notch; D014157:Transcription Factors; C065500:ASCL1 protein, human