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Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma

Somasundaram, Kumaravel and Reddy, Sreekanth P and Vinnakota, Katyayni and Britto, Ramona and Subbarayan, Madhavan and Nambiar, Sandeep and Hebbar, Aparna and Samuel, Cini and Shetty, Mitesh and Sreepathi, Hari Kishore and Santosh, Vani and Hegde, Alangar Sathyaranjandas and Hegde, Sridevi and Kondaiah, Paturu and Rao, MRS (2005) Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma. In: Oncogene, 24 (47). pp. 7073-7083.

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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-like1(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 over expressed 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 up regulation 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.

Item Type: Journal Article
Additional Information: Copyright for this article belongs to Nature Publishing Group.
Keywords: glioma;astrocytoma;ASCL1;Notch signaling;glioblastoma multiforme;microarray
Department/Centre: Division of Biological Sciences > Molecular Reproduction, Development & Genetics (formed by the merger of DBGL and CRBME)
Division of Biological Sciences > Biochemistry
Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited: 22 Nov 2005
Last Modified: 27 Aug 2008 11:34
URI: http://eprints.iisc.ernet.in/id/eprint/4087

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