Novel mutations of SRPX facilitate the stemness and malignant progression of glioma.

Abstract

Background: Explorations of genomic profiles are of great clinical significance for glioma due to the high tumor heterogeneity and stemness. High-depth sequencing enabled to identify driver genes and potential treatment targets in glioma.

Methods: A whole exome sequencing analysis of 27 Chinese patients was conducted and somatic mutation signatures were analyzed using validated computational methods. The biological roles of SRPX mutations and subsequent regulatory mechanisms were revealed by common experimental methods.

Results: We intriguingly found that SRPX drove glioma progression with two frequent in-frame deletion mutations of p.L14DEL and p.L23DEL. Mechanistically, both the two mutations of SRPX promoted binding with transcription factor AHR on its promoter, upregulated gene transcription of itself, then activated EGFR/ Akt/ Nestin pathway and contributed to aggressive tumor phenotypes and animal tumor growth. Further, knockdown of AHR or application of Akt inhibitor suppressed the oncogenic role of mutated SRPX.

Conclusions: Our study highlighted the landscape of glioma in revealing a non-distinctive mutation and signaling pathway profile between low and high grades. More importantly, we identified a novel role of SRPX mutations in acceleration to stemness and malignant progression, which could provide new targets in improving outcomes of glioma.