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ARTICLE

Combined Expression of FOXO and Tribbles Proteins Predicts Survival of Glioma Patients

Bruno F. Santos1,2,3,4, Ana-Teresa Maia4,5, Inês Grenho1,2,4, André Besouro-Duarte5, Juan M. Sepúlveda-Sánchez6, Bibiana I. Ferreira1,2,4,*, Wolfgang Link7,*
1 Algarve Biomedical Center Research Institute—ABC-RI, Universidade do Algarve, Campus de Gambelas, Faro, Portugal
2 Algarve Biomedical Center (ABC), Campus de Gambelas, Faro, Portugal
3 Unidade Local de Saúde do Algarve (ULSAlg), Rua Leão Penedo, Faro, Portugal
4 Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve, Campus de Gambelas, Faro, Portugal
5 RISE-Health, University of Algarve, Campus de Gambelas, Faro, Portugal
6 Neuro-Oncology Unit, Hospital HM Sanchinarro (CUHMED), Instituto de Investigación 12 de Octubre (I+12), Madrid, Spain
7 Sols-Morreale Biomedical Research Institute (IIBM), Spanish National Research Council (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain
* Corresponding Author: Bibiana I. Ferreira. Email: email; Wolfgang Link. Email: email

Oncology Research https://doi.org/10.32604/or.2026.083560

Received 06 April 2026; Accepted 27 July 2026; Published online 28 August 2026

Abstract

Background: High-grade gliomas remain therapeutically challenging and are associated with poor survival outcomes. Current biomarkers inadequately stratify patients for therapy selection and fail to support early detection of disease progression. The FOXO transcription factors and Tribbles pseudokinases are key regulators of the PI3K/AKT pathway and have been implicated in cancer progression, however, their prognostic value in gliomas remains unclear. This study aimed to determine whether transcriptional profiles of FOXO and Tribbles family members predict survival in glioma patients. Methods: Using RNA-seq data from TCGA and CGGA, along with microarray datasets REMBRANDT and Gravendeel, we analyzed the association of FOXO1, FOXO3, FOXO4, FOXO6 and TRIB1, TRIB2, TRIB3 mRNA levels with overall survival and WHO classification. We also experimentally validated the functional role of FOXO1 and TRIB3 in glioblastoma cells through gene depletion assays. Results: Using the TCGA RNA-seq cohort, we identified a FOXO/Tribbles transcriptional signature characterized by ↑FOXO1, ↓FOXO3/4 and ↑TRIB1/2/3, which was subsequently evaluated in independent microarray cohorts that confirmed the prognostic relevance of coordinated FOXO/Tribbles family dysregulation despite cohort-specific differences in the optimal gene combinations. Grade 4 tumors exhibited elevated FOXO1 and TRIB1/TRIB2/TRIB3, but reduced FOXO3/FOXO4 levels compared to lower-grade gliomas. Experimental validation supported a potential role of FOXO1 and TRIB3 in promoting glioblastoma cell viability. Conclusion: The combined FOXO/Tribbles expression signature (↑FOXO1/↓FOXO3/FOXO4/↑TRIB1/TRIB2/TRIB3) may represent a candidate prognostic biomarker requiring further validation before clinical application, particularly involving emerging agents directed against TRIB2, TRIB3, and FOXO1, as well as small-molecule activators of FOXO3.

Keywords

FOXO; tribbles; glioblastoma; prognostic biomarker; patient stratification; therapeutic target

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