Notch system is differentially expressed in tumoral and normal pituitaries

CRISTINA, CAROLINA; BACCARINI, LETICIA; PERRONE, SOFIA; GAZZA, ELIAS; BECU-VILLALOBOS, DAMASIA; LUQUE, GUILLERMINA; BARICALLA, AGUSTIN; DEMARCHI, GIANINA

ONCOTARGET

Impact Journals

Lugar: New York; Año: 2017 vol. 8 p. 57072 - 57088

Pituitary adenomas are among the most frequent intracranial neoplasms, whose treatments depend on tumor subtype, size and mass compression. Unfortunately, non responder cases occur for which new molecular targets are needed. Notch system component expression and activation data are scarce in pituitary tumorigenesis. We therefore aimed to characterize Notch signaling in pituitary tumors. In human pituitary adenomas we showed NOTCH1-4 receptors, JAGGED1 ligand and HES1 target gene expression with positive correlations between NOTCH1,2,4 and HES1, and NOTCH3 and JAGGED1, denoting Notch system activation in specific tumors. In addition, Notch activation was found in AtT20 tumor corticotrope cells with high expression of NOTCH1-3 active domains and higher Jagged1 and Hes1 mRNA levels compared to normal pituitaries. Comparing rat prolactinoma models: GH3 and MMQ cells, and in vivo GH3 tumors in Nude mice, with normal glands we found increased active domains of NOTCH2 in MMQ cells and NOTCH1 in GH3 tumors. Furthermore, high levels of Jagged1 and Dll1 were detected in GH3 but not in MMQ cells, while Hes1, Hey1 and Hey2 target genes were expressed in specific patterns depending on the model. Finally, in prolactinomas harbored by lacDrd2KO female mice Notch receptors were increased when compared to Drd2loxP/loxP control mice. Our study provides evidence of differential and specific expression of Notch system components in tumoral and normal pituitaries. This information is paramount in tailoring targeted therapy in pituitary tumors of different histotypes.