Transcriptional Analysis of JAK/STAT Signaling in Glioblastoma Multiforme

Rekha      Jain; Asmita      Dasgupta; Aliasgar      Moiyadi; Sanjeeva      Srivastava

Abstract

Janus Kinases (JAKs) and Signal Transducer and Activator of Transcription proteins (STATs) are central mediators of cytokine and growth factor signaling pathways that are constitutively active in several cancers and play an important role in cancer progression. Glioblastoma multiforme (GBM; WHO grade IV) is the most commonly occurring brain tumor with very poor prognosis, limited options of treatment and a median survival of 12 to 16 months. The objective of this study was to investigate the transcriptional expression of JAK/STAT candidate genes, their regulators and interactors in post-surgical GBM tissue specimens and normal/non-neoplastic brain, using the global expression data in gliomas from two data series (GSE10878 and GSE19728) obtained from GEO datasets. The raw dataset was analyzed using GeneSpring GX11 software and expression data were obtained for JAK/STAT and other pertinent functionally related genes in GBM and normal tissue. Prior to the microarray data analysis, we built a comprehensive JAK/STAT interactome that brought into perspective all of the associated molecules in relation to cancer pathophysiology. This report represents for the first time, to the best of our knowledge, the transcriptional analysis for almost all the candidate genes, regulators as well as potential interactors of JAK/STAT pathway in GBM from two GEO datasets. Several key genes of the interactome, namely- STAT3, STAT4, STAT5A, STAT5B, TYK2, AKT2, SOCS1, SOCS3, SOCS6, PIAS1, PIAS2, PTPN6 and HIF1A were determined to be differentially expressed in GBM tumor tissues as compared to normal/nonneoplastic brain. Expression of STAT3, STAT4, SOCS3 and PDK1 in GBM tumor tissues with respect to normal brain was validated by qRT-PCR analysis of RNA preparations from tumor biopsies. We found an association of the transcript levels of a few of these genes with favorable prognosis of glioblastoma patients, which may potentially form a basis for future application of JAK/STAT interactome as a target of personalized medicine.

Keywords: Cancer, gene expression analysis, glioblastoma multiforme, human, JAK, JAK/STAT signaling, STAT

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