PRAJA is overexpressed in glioblastoma and contributes to neural precursor development.

Joshua Shin,Chu-Xia Deng,Lopa Mishra,Amee A Kapadia,Kazufumi Ohshiro,Eric Glasgow,Bhargava Chitti,Viveka Mishra,Bibhuti Mishra,Neha Rana,Shuyun Rao,Sobia Zaidi

doi:10.18632/genesandcancer.151

Abstract

PRAJA, a RING-H2 E3 ligase, is abundantly expressed in brain tissues such as the cerebellum and frontal cortex, amongst others, and more specifically in neural progenitor cells as well as in multiple cancers that include glioblastomas. However, the specific role that Praja plays in neural development and gliomas remains unclear. In this investigation, we performed bioinformatic analyses to examine Praja1 and Praja2 expression across 29 cancer types, and observed raised levels of Praja1 and Praja2 in gliomas with an inverse relationship between Praja1 and apoptotic genes and Praja substrates such as Smad3. We analyzed the role of Praja in the developing brain through loss of function studies, using morpholinos targeting Praja1 in embryonic zebrafish, and observed that Praja1 is expressed prominently in regions enriched with neural precursor cell subtypes. Antisense Praja morpholinos resulted in multiple embryonic defects including delayed neural development likely through increased apoptosis. Further studies revealed high levels of Cdk1 with loss of Praja1 in TGF-β or insulin treated cells, supporting the link between Praja1 and cell cycle regulation. In summary, these studies underscore Praja's role in mammalian brain development and Praja1 deregulation may lead to gliomas possibly through the regulation of cell cycle and/or apoptosis.

Highlights

Glioblastoma multiforme (GBM) is the most common primary malignancy of the brain as it is highly infiltrative and has a poor prognosis among cancers
One of the most striking observations was that the greatest amplitude in expression of PJA1 and PJA2 occurred in glioblastomas [8], and correlated with a concomitant and significant decrease in expression levels of Smad3, which we have identified as a PJA1 substrate [6, 7], and as a key receptor that regulates Transforming Growth Factor-β (TGF-β) signaling molecules [9, 10]
To better understand their roles in brain development and malignancies, we performed bioinformatic analyses of the expression of PJA1 and PJA2 across 29 cancers in the The Cancer Genome Atlas (TCGA) databases and found that both PJA1 and PJA2 are highly expressed in brain malignancies including Glioblastoma (GBM) and Gliomas (Figure 1A) [8]

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common primary malignancy of the brain as it is highly infiltrative and has a poor prognosis among cancers. We identified a RING E3 ligase, PRAJA that is highly expressed in brain tissues including the cerebellum, cerebral cortex, occipital pole, frontal lobe, amongst others [4]. We have previously demonstrated that PJA1 is involved in regulating tumor suppressors in the Transforming Growth Factor-β (TGF-β) signaling pathway [5,6,7]. In this investigation, to explore a potential role for PRAJA in tumorigenesis, we conducted a genomic analysis of Praja (PJA1), Praja (PJA2) and Smad across 29 tumor types. One of the most striking observations was that the greatest amplitude in expression of PJA1 and PJA2 occurred in glioblastomas [8], and correlated with a concomitant and significant decrease in expression levels of Smad, which we have identified as a PJA1 substrate [6, 7], and as a key receptor that regulates TGF-β signaling molecules [9, 10]

Methods

Results

Conclusion