Abstract
The diffusely infiltrative nature of glioblastoma (GBM) makes them highly recurrent. IGF2 mRNA-binding protein 3 (IMP3), a GBM upregulated RNA binding protein, promotes glioma cell migration. An integrative bioinformatics analysis identified p65 (RELA), a subunit of NF-κB heterodimer as a target and an important mediator of IMP3 promoted glioma cell migration. IMP3 increased p65 protein levels without any change in p65 transcript levels, but promoted its polysome association. RIP-PCR demonstrated the binding of IMP3 to p65 transcript. UV crosslinking experiments with in vitro transcribed RNA confirmed the specific and direct binding of IMP3 to sites on p65 3′UTR. Further, IMP3 induced luciferase activity from p65 3′UTR reporter carrying wild type sites but not mutated sites. Exogenous overexpression of p65 from a 3′UTR-less construct rescued the reduced migration of glioma cells in IMP3 silenced condition. In addition, IMP3 silencing inhibited glioma stem-like cell maintenance and migration. The exogenous overexpression of 3′UTR-less p65 significantly alleviated the inhibition of neurosphere formation observed in IMP3 silenced glioma stem-like cells. Further, we show that IMP3 is transcriptionally activated by NF-κB pathway indicating the presence of a positive feedback loop between IMP3 and p65. This study establishes p65 as a novel target of IMP3 in increasing glioma cell migration and underscores the significance of IMP3-p65 feedback loop for therapeutic targeting in GBM.
Highlights
Glioblastoma (GBM) is one of the leading causes of death caused due to brain tumors
Many RNA binding proteins regulate their targets at mRNA translation level, and few of the identified IGF2 mRNA-binding protein 3 (IMP3) targets were regulated at this level [17, 18]
Our integrated bioinformatics approach identified p65, a transcription factor in NF-κB pathway to be a putative target of IMP3
Summary
Glioblastoma (GBM) is one of the leading causes of death caused due to brain tumors. Despite the technical advances in diagnostics and the present treatment modalities the median overall survival of the patients remains 14.6 months [1, 2]. Many authors have demonstrated the existence of a small population of glioma stem-like cells (GSCs) in the tumors which in multiple ways contribute to this heterogeneity and the belligerence of the disease [3,4,5]. They have been demonstrated to be resistant to the current treatment modalities and are ascertained to be the culprits for the high rates of GBM recurrence [4]. Inhibition of such molecules will diminish the tumor load and resistance to existing therapies which may result in lower recurrence rate
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