RESUMEN
Pediatric adrenocortical tumors (ACTs) are rare, highly heterogeneous neoplasms with limited therapeutic options, making the investigation of new targets with potential therapeutic or prognostic purposes urgent. The PRKAB2 gene produces one of the subunits of the AMP-activated protein kinase (AMPK) complex and has been associated with cancer. However, little is known about the role AMPK plays in ACTs. We have evaluated how PRKAB2 is associated with clinical and biological characteristics in 63 pediatric patients with ACTs and conducted in vitro studies on the human NCI-H295R ACC cell line. An analysis of our cohort and the public ACC pediatric dataset GSE76019 showed that lower PRKAB2 expression was associated with relapse, death, metastasis, and lower event-free and overall survival rates. Multivariate analysis showed that PRKAB2 expression was an independent prognostic factor when associated with age, tumor weight and volume, and metastasis. In vitro tests on NCI-H295R cells demonstrated that Rottlerin, a drug that can activate AMPK, modulated several pathways in NCI-H295R cells, including AMPK/mTOR, Wnt/ß-catenin, SKP2, HH, MAPK, NFKB, and TNF. Treatment with Rottlerin decreased cell proliferation and migration, clonogenic capacity, and steroid production. Together, these results suggest that PRKAB2 is a potential prognostic marker in pediatric ACTs, and that Rottlerin is promising for investigating drugs that can act against ACTs.
RESUMEN
Pediatric adrenocortical tumors (ACTs), rare conditions with uncertain prognoses, have high incidence in southern and southeastern Brazil. Pediatric ACTs are highly heterogeneous, so establishing prognostic markers for these tumors is challenging. We have conducted transcriptomic analysis on 14 pediatric ACT samples and compared cases with favorable and unfavorable clinical outcomes to identify prognostically significant genes. This comparison showed 1257 differentially expressed genes in favorable and unfavorable cases. Among these genes, 15 out of 60 hub genes were significantly associated with five-year event-free survival (EFS), and 10 had significant diagnostic value for predicting ACT outcomes in an independent microarray dataset of pediatric adrenocortical carcinomas (GSE76019). Overexpression of N4BP2, HSPB6, JUN, APBB1IP, STK17B, CSNK1D, and KDM3A was associated with poorer EFS, whereas lower expression of ISCU, PTPR, PRKAB2, CD48, PRF1, ITGAL, KLK15, and HIST1H3J was associated with worse outcomes. Collectively, these findings underscore the prognostic significance of these hub genes and suggest that they play a potential role in pediatric ACT progression and are useful predictors of clinical outcomes.