Notch3 and Hey-1 as Prognostic Biomarkers in Pancreatic Adenocarcinoma

Abstract

In order to achieve a better outcome for pancreatic cancer patients, reliable biomarkers are required which allow for improved diagnosis. These may emanate from a more detailed molecular understanding of the aggressive nature of this disease. Having previously reported that Notch3 activation appeared to be associated with more aggressive disease, we have now examined components of this pathway (Notch1, Notch3, Notch4, HES-1, HEY-1) in more detail in resectable (n = 42) and non-resectable (n = 50) tumours compared to uninvolved pancreas. All three Notch family members were significantly elevated in tumour tissue, compared to uninvolved pancreas, with expression maintained within matched lymph node metastases. Furthermore, significantly higher nuclear expression of Notch1, -3 and -4, HES-1, and HEY-1 (all p≤0.001) was noted in locally advanced and metastatic tumours compared to resectable cancers. In survival analyses, nuclear Notch3 and HEY-1 expression were significantly associated with reduced overall and disease-free survival following tumour resection with curative intent, with nuclear HEY-1 maintaining independent prognostic significance for both outcomes on multivariate analysis. These data further support a central role for Notch signalling in pancreatic cancer and suggest that nuclear expression of Notch3 and its target gene, HEY-1, merit validation in biomarker panels for diagnosis, prognosis and treatment efficacy. A peptide fragment of Notch3 was detected in plasma from patients with inoperable pancreatic cancer, but due to wide inter-individual variation, mean levels were not significantly different compared to age-matched controls.

Notch signaling molecules as prognostic biomarkers for non-small cell lung cancer

“…However, the present data demonstrated that Notch 3 is (8,9,13). The mechanism of this phenomenon and how Notch 3 exerts its function in NSCLC remain unclear and require further research.…”

“…The activation of Notch 1 signaling appears to sustain the motility, migration and invasion of tumor cells in esophagus squamous cell carcinomas, lingual squamous cell carcinoma, endometrial carcinoma and breast cancer (11)(12)(13)(14)(15). Almost all cases of T cell acute lymphoblastic leukemia (T-ALL), and colorectal, pancreatic and ovarian cancer have been reported to exhibit aberrant Notch 3 expression (6,8,16,17). Our previous study also reported that Notch 3 overexpression was associated with a poor prognosis in NSCLC patients (18).…”

“…In hematological malignancies, the role for Notch is well established, while more recent studies have demonstrated the significance of Notch activity in the initiation and progression of solid tumors (5)(6)(7)(8)(9). The mammalian Notch receptor family consists of four type I transmembrane receptors (known as Notch 1-4), all of which have been implicated in human cancer.…”

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

“…Increased Notch3 protein levels have been identified as a prognostic marker for patients with PDAC (Mann et al ., 2012), and lead to increased tumor invasion, metastasis, and shortened patient survival (Zhou et al ., 2016). Because of this, Notch3 has become a target for novel cancer therapies.…”

Notch4 inhibition reduces migration and invasion and enhances sensitivity to docetaxel by inhibiting Akt/fascin in pancreatic cancer cells

“…In addition, our previous findings revealed that the activation of Notch4 promoted GC cell growth in vitro and in vivo, while the inactivation of Notch4 by siRNA had the opposite effects (6). In the present study, it was demonstrated Notch expression in PC was correlated with serosal invasion, lymph node metastasis, histopathological grading, tumor-node-metastasis stage and recurrence (21)(22)(23)(24). Enhanced Notch4 expression in salivary adenoid cystic carcinoma may stand as a novel mechanism for promoting metastasis (25).…”