Decreased TAp63 and ΔNp63 mRNA Levels in Most Human Pituitary Adenomas Are Correlated with Notch3/Jagged1 Relative Expression

Abstract

Despite recent advances in molecular genetics, the pituitary adenoma initiation, development, progress, and the molecular basis of their unique features are still poorly understood. In this sense, it is proposed that stem cell could be involved in pituitary adenoma tumorigenesis. It is suggested that TP63 has important functions in stem cells, and it may have interplay of TP63 and Notch and its ligand Jagged in this process. This study aimed to evaluate the distinct expression of TP63 isoforms (TAp63 and ΔNp63), as well as its correlation with Notch3 receptor and its ligand Jagged1 in human pituitary adenomas at the messenger RNA (mRNA) level. We included 77 pituitary adenoma tumor samples from patients who underwent surgical resection. The expression levels of TP63 isoforms (TAp63 and ΔNp63) and Notch3 and its ligand Jagged1 were evaluated by qRT-PCR using isoform-specific primers. We also evaluated proliferation index immunohistochemically using KI-67 antibody. The expression levels were associated with clinical outcomes, as age, gender, tumor size, and tumor subtype. In summary, we found that mRNA expression of both TP63 isoforms decreased in pituitary adenomas compared with normal pituitary control. On the other hand, there was an increase of relative Notch3 and Jagged1 mRNA expression in the majority of examined samples. The mRNA expression of three genes evaluated was correlated and statistically significantly. There was no significant association between gene expression and the analyzed clinical data. The current study has provided the first time evidence that Tap63 and ΔNp63 isoforms are underexpressed in most pituitary adenomas. These results are correlated with Notch3 and its ligand Jagged1 overexpression, corroborating previous studies pointing its antagonistic interactions.

p63-related signaling at a glance

“…ΔNp63 affects Notch signaling by regulating the expression of multiple genes encoding Notch pathway components, including Notch1, Notch3, Jag1, Jag2 and Hes1 (Kent et al, 2011;Mezzomo et al, 2017;Ravindran and Devaraj, 2012;Yalcin-Ozuysal et al, 2010). ΔNp63α is directly involved in transactivation of Notch by binding to the Notch1 promoter; this increases mRNA and protein levels of Notch1 and leads to increased accumulation of the Notch1 intracellular domain.…”

JAG1, Regulated by microRNA-424-3p, Involved in Tumorigenesis and Epithelial–Mesenchymal Transition of High Proliferative Potential-Pituitary Adenomas

“…Up-regulated Notch3 and JAG1 have been observed in human non-functional PAs, but not in human pituitary glands or hormone-secreting adenomas. In the majority of examined PA samples, an increase has been found in the expression of relative Notch3 and JAG1 mRNA, which may be a crucial factor in the initiation and proliferation of human nonfunctional adenomas (15,16).…”

Análise da expressão da filamina A nos tumores hipofisários e suas implicações clínicas e terapêuticas

“…Ainda que a definição dessas características não seja uniforme (20,24) , muitos autores consideram os sinais de invasão parasselar e infrasselar, nos exames de imagem e achados intra-operatórios, como invasividade e a presença de múltiplos tratamentos, necessidade de radioterapia e índice de proliferação celular Ki-67 acima de 3% como características de agressividade tumorais (26) . Notch, que regula o "destino" das células, através da inibição lateral, permitindo a formação de "barreiras" entre células de um mesmo tipo ou não (178) , participa do processo de tumorigênese dos tumores hipofisários (179)(180)(181) , inclusive em corticotropinomas (182) . Há evidências de que a FLNA forme um complexo com Notch e outras proteínas (183) , portanto, o aumento da expressão de FLNA nos corticotropinomas invasivos poderia estar relacionado a maior ativação dos sitema Notch.…”