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, 13 (6), 4533-4539

Differential Expression of the Notch1 Receptor, and Its Ligands Dll1, Dll3 and Dll4 in Distinct Human Pituitary Adenoma Subtypes

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Differential Expression of the Notch1 Receptor, and Its Ligands Dll1, Dll3 and Dll4 in Distinct Human Pituitary Adenoma Subtypes

Jianfu Zhang et al. Oncol Lett.

Abstract

Pituitary adenoma (PA) is a common type of benign tumor of the pituitary gland that is characterized by specific signs and symptoms, primarily associated with hypersecretion of pituitary glycoprotein hormones (thyroid-stimulating, growth and adrenocorticotrophic hormones, and prolactin). Surgery is the first-line treatment, although postoperative residual tissues/cells and subsequent recurrence remain notable complications. Gene therapy is an effective approach for treatment, as previous studies have demonstrated that the Notch signaling pathway participates in the pathogenesis of PA. The focus of the present study was on the associations between the expression of the Notch1 receptor and its ligands δ-like canonical Notch ligand (Dll) 1, Dll3 and Dll4 in patients with PA. Using reverse transcription-quantitative polymerase chain reaction and western blot analyses, to the best of our knowledge, this is the first study to provide a description of the differential expression of the Notch1 receptor and its ligands Dll1, Dll3, and Dll4 in various types of human PA at the mRNA and protein levels. The results of the present study demonstrated that Notch1 protein expression was positively correlated with Dll4 protein expression, but negatively correlated with Dll3 protein expression, indicating synergistic effects between the Notch1 receptor and Dll4 ligand. Furthermore, the Dll3 ligand may be an inhibitor of the Notch1 receptor, indicating an antagonistic association between Notch1 and the Dll3 ligand. These results have identified a potential target for the treatment of patients with PA.

Keywords: Notch signaling pathway; notch1; pathogenesis; pituitary adenoma; δ-like canonical Notch ligand-1; δ-like canonical Notch ligand-3; δ-like canonical Notch ligand-4.

Figures

Figure 1.
Figure 1.
Western blot analysis of tissue samples from patients with pituitary adenoma. (A) Representative western blot analysis of Notch1, Dll1, Dll3 and Dll4 protein expression. Quantification of (B) Notch1, (C) Dll1, (D) Dll3 and (E) Dll4 protein expression in null cell adenoma (n=4), GA (n=4), GH-secreting (n=4) and PRL-secreting adenoma (n=4). β-actin was used for normalization. Western blot analysis revealed increased Notch1 expression in GA and GH-secreting adenoma (P=0.023). Increased Dll1 expression was demonstrated in GH-secreting and PRL-secreting adenoma (P=0.036). Increased Dll3 expression was demonstrated in null cell adenoma (P=0.041). Decreased Dll3 expression was evident in PRL-secreting adenoma (P=0.037). Increased Dll4 expression was detected in GH-secreting and PRL-secreting adenoma (P=0.030). Decreased Dll4 expression was evident in null cell adenoma (P=0.016). Dll, δ-like canonical Notch ligand; GH, growth hormone; PRL, prolactin; GA, gonadotroph adenoma. *Comparison between null cell and the other groups; #comparison between the three groups except null cell.
Figure 2.
Figure 2.
qPCR analysis results of tissue samples from patients with pituitary adenoma. (A) qPCR analysis of relative Notch1 mRNA expression in null cell adenoma (n=4), GA (n=4), GH-secreting (n=4) and PRL-secreting adenoma (n=4). Increased Notch1 expression was demonstrated in GA (P=0.048). (B) qPCR analysis of relative Dll1 mRNA expression in null cell adenoma, GA, GH-secreting and PRL-secreting adenoma samples. Dll1 expression was lowest in GH-secreting adenoma (P=0.036). (C) qPCR analysis of relative Dll3 mRNA expression in null cell adenoma, GA, GH-secreting and PRL-secreting adenoma. Increased Dll3 expression was demonstrated in GA (P=0.028). Decreased Dll3 expression was evident in GH-secreting adenoma (P=0.045). (D) qPCR analysis of relative Dll4 mRNA expression in null cell adenoma, GA, GH-secreting and PRL-secreting adenoma. Decreased Dll4 expression was evident in GA (P=0.047). qPCR, quantitative polymerase chain reaction; Dll, δ-like canonical Notch ligand; GH, growth hormone; PRL, prolactin; GA, gonadotroph adenoma. *Comparison between null cell and the other groups; #comparison between the three groups except null cell.
Figure 3.
Figure 3.
Scatter diagrams demonstrating the associations between (A) Notch1 and DLL4, and between (B) Notch1 and DLL3 following the analysis of tissue samples from patients with pituitary adenoma. Dll, δ-like canonical Notch ligand.

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