Expression of nuclear notch3 in pancreatic adenocarcinomas is associated with adverse clinical features, and correlates with the expression of STAT3 and phosphorylated Akt

Abstract

Background and Objectives: Reactivation of the Notch signalling pathway occurs in a range of human malignancies. Previous research suggests that Notch3 is expressed in pancreatic adenocarcinomas, but neither cellular location nor association with clinical parameters has been described. The relationship between Notch3, clinical endpoints, and other proteins with potential to interact with Notch was therefore examined. Methods: An immunohistochemical study was performed on human pancreatic adenocarcinoma (n ¼ 23) and normal pancreas (n ¼ 12), to assess expression of Notch3, cyclin D1, pAkt, STAT3 and pSTAT3. Immunohistochemical data were then correlated with clinicopathological characteristics. Results: Notch3 was significantly overexpressed in the cytoplasm of 73.9% of tumours. Nuclear expression was not observed in normal pancreatic ductal tissue, but was noted in 43.5% of tumours. No tumour expressing nuclear Notch3 was resectable. There were significant correlations between expression and intracellular location of Notch3 and each of STAT3, pSTAT3 and pAkt, but not cyclin D1. Conclusion:The presence of Notch3 in tumour nuclei is likely to represent functional activation of the protein, and is clearly linked to a more aggressive tumour phenotype. The correlation with STAT3, pSTAT3 and pAkt expression has not previously been described and the concurrent intracellular localisation of these proteins suggests a functional relationship between them.

NKL homeobox genes in leukemia

“…Different pathways that are targeted by NKX2-5 have been proposed to have a role in leukemogenesis. NKX2-5 activates NOTCH3, 67 which can enhance survival 68,69 and NKX2-5 causes upregulation of miR-17-92, which may lead to increased proliferation. 70 In addition, NKX2-5 binds the promoter of MEF2C and activates MEF2C transcription in T-ALL cell lines.…”

Inhibition of γ-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells

“…By providing an internally hydrophilic environment within the plasma membrane (Lazarov et al, 2006), g-secretase is responsible for cleaving more than 30 substrates, including amyloid precursor protein (APP), Notch (Mumm et al, 2000), ErbB4 (Ni et al, 2001), E-cadherin (Marambaud et al, 2002), CD44 (Lammich et al, 2002) and p75 (Schluesener et al, 1992), which regulate vital cell functions such as proliferation, cell cycle, cell adhesion and apoptosis. Interestingly, increased expression of Notch ligands, receptors, and/or downstream targets are highly associated in the pathogenesis of breast (Jones et al, 2004;Stylianou et al, 2006;Yamaguchi et al, 2008), brain (Purow et al, 2005), colon (Akiyoshi et al, 2008), cervical (Liu et al, 2007) pancreatic (Doucas et al, 2008) and skin cancers (Dang et al, 2006). Thus, the g-secretase complex may be a potential therapeutic target in a wide array of carcinomas.…”

Targeting Notch Signaling with a Notch2/Notch3 Antagonist (Tarextumab) Inhibits Tumor Growth and Decreases Tumor-Initiating Cell Frequency

“…In NOTCH3 high tumors, OMP-59R5 treatment induced a significant decrease in both Notch3 ECD and Notch3 ICD protein levels, suggesting that NOTCH3 gene expression is an important determinant of Notch3 signaling-mediated growth of these tumors. Indeed, Notch3 expression has been associated with disease stage, poorer overall survival, and resistance to chemotherapy in solid tumors (5,7,9). The low sensitivity to OMP-59R5 in nonresponsive tumors is not likely due to loss-of-function mutations in ligand-binding domain/other functional regions of NOTCH2/3 or due to OMP-59R5-induced Notch1 activation in nonresponsive tumors, as whole-exome sequencing of our PDX tumors showed no mutations in either NOTCH2 or NOTCH3 that result in amino acid substitutions in EGF repeats involved in ligand binding, and Notch1 ICD level was not increased by the combination therapy in either responsive and nonresponsive tumors.…”

“…In particular, dysregulated Notch2 and/or Notch3 activity has been associated with several human tumor types, including lung (2), ovarian (3), breast (4), pancreatic (5,6), and colon cancers (7). In addition to its role in developmental biology and cancer, Notch signaling also plays a key role in tumor vasculature and pericytes (8).…”