Felix Y. Narváez Irizarry, BA
Kevin A. Rosa Gonzalez, BA
Lilia Kucheryavykh, PhD

Department of Biochemistry, Universidad Central del Caribe, Bayamón, Puerto Rico

Introduction

Glioblastoma (GBM) is a highly aggressive brain tumor with an average survival time of about one year. Identifying specific biomarkers that can facilitate the development of targeted therapies and novel imaging techniques is one of the major challenges in cancer biology, including GBM research. Previously, we demonstrated the accumulation of amyloid-β in human GBM specimens and in a mouse GBM model. The mechanisms behind amyloid-β accumulation and its role in tumor development are yet to be elucidated. The purpose of this study was to identify key players in amyloid-β metabolism involved in GBM tumor development and progression.

Methods

Clinical data and expression values for the amyloid precursor protein (APP), key components of γ-secretase presenilin 1 (PSEN1) and presenilin enhancer (PSENEN), basigin (BSG), also known as extracellular matrix metalloproteinase inducer, β-secretase 1 (BACE1), the BACE1 inhibitor Peroxisome Proliferator-Activated Receptor Alpha (PPARA), disintegrin and metalloproteinase domain-containing proteins 9, 10, 17, and 19 (ADAM9, ADAM10, ADAM17, ADAM19), which belong to the α-secretase family, and adenylate cyclase-activating polypeptide (ADCYAP1), shown to activate α-secretase, were obtained from cBioPortal for Cancer Genomics. Survival probability and gene expression correlation analyses were conducted on GBM RNA-seq datasets containing 211 samples, with separate analyses for males and females.

Results

The study revealed significantly higher survival probability with high expression of PSENEN (17.64 months in the high-expression group vs. 8.87 months in the low-expression group) and low expression of BSG (19.7 months in the low-expression group vs. 8.76 months in the high-expression group) in females, but not in males. High expression of PPARA, an inhibitor of BACE1, correlated with higher survival probability in both males and females (26 months in the high-expression group vs. 14.6 months in the low-expression group). In males, high expression of ADAM10 correlated with better survival probability (28.9 months vs. 11 months in the low-expression group), but this correlation was not observed in females. Additionally, Pearson correlation analysis revealed a negative correlation between BACE1 and PSENEN expression in females (r = -0.64), with a less pronounced correlation in males (r = -0.35).

Conclusions

Sex-specific differences in gene expression and their impact on survival in GBM patients were identified. The study discovered that overexpression of PSENEN and PPARA in female GBM patients, and PPARA and ADAM10 in male GBM patients, is associated with improved survival, suggesting that PPARA may play a protective role in the progression of GBM. The negative correlation between BACE1 and PSENEN expression indicated potential interplay between these genes in the context of GBM. The findings provide insights into the mechanisms of amyloid-β regulation in GBM and identify key therapeutic targets.

Funding

This study was supported by NIH Grants 1R15CA287203 and 1R16GM153522.

IRB Approval Number

2024-31