CHARACTERIZATION OF HNRNP A2/B1 AS A NEW ONCOGEN IN GLIOBLASTOMA AND ITS INHIBITION AS A NEW THERAPY
Led by Rotem Karni at Hadassah Medical School
Even though major advances in basic and clinical research revealed many important biological pathways that are involved in brain cancer development, the molecular basis for brain cancer is not fully understood. Thus, a better understanding of the molecular basis for brain tumor development and the concurrent identification of specific targets for brain cancer therapy, are greatly needed.
Our bioinformatics and experimental analysis of brain tumor samples shows that a protein called hnRNPA2/B1 is over-produced in glioblastoma compared to normal brain samples. Moreover, patients with extra copies of the gene HNRNPA2B1 in their tumors show poor prognosis, while patients in whom the NRNPA2B1 gene is deleted, show better prognosis than the average. Silencing of hnRNP A2/B1 in glioblastoma cells inhibited their cancerous capabilities including tumor formation in mice, suggesting that hnRNP A2/B1 is a putative cancercausing gene (oncogene) in glioblastoma development. Because hnRNP A2/B1 is a broad regulator of the fundamental step in gene expression called RNA alternative splicing, we hypothesize that hnRNP A2/B1
overexpression will change the splicing program of a large set of target genes which probably involved in survival, motility, invasiveness and other cancerous properties of glioblastoma tumor cells. We aim to reveal the full spectrum of hnRNP A2/B1 splicing targets using RNA deep sequencing. We propose to study the functional
role of hnRNPA2/B1 in glioblastoma development and tumor maintenance and to identify its splicing targets relevant to the cancerous properties of glioblastoma tumors. In addition, we are developing new tools to silence hnRNP A2/B1 in glioblastoma tumors as a new therapeutic approach and we propose to validate this approach in this study.
We believe that this study has the potential of discovering new biomarkers for diagnosis and prognosis of glioblastoma patients, to uncover new molecular aspects of brain cancer, and to provide new opportunities for glioblastoma therapy.
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