The Role of Notch Signaling Pathway in the Progression of Pancreatic Cancer

Introduction

Pancreatic cancer (PC) is a highly aggressive malignancy and ranks as the fourth leading cause of cancer-related death in the United States . This high mortality is partly due to the absence of specific symptoms and signs, and the lack of early detection tests for PC, as well as the lack of effective chemotherapies . Although the molecular mechanisms of PC development remain largely unclear, many factors have been reported to be associated with increased incidence of PC . For example, a history of diabetes or chronic pancreatitis, chronic cirrhosis, a family history of PC, a high-fat and high-cholesterol diet, tobacco smoking, alcohol and coffee intake, and specific blood type have been found to contribute to PC development . Accumulated evidence has demonstrated that many key genes and cell signaling pathways also play critical roles in pancreatic tumorigenesis . Recently, some studies have demonstrated that the Notch signaling pathway contributes to PC development and progression . Therefore, in the following sections, we will discuss the roles of the Notch signaling pathway in the regulation of cell proliferation, apoptosis, migration, invasion, metastasis, angiogenesis, drug resistance, epithelial-to-mesenchymal transition (EMT), and cancer stem cell (CSC) functions in PC.

Notch Signaling Pathway

It has been well documented that the Notch signaling pathway plays critical mechanistic roles in the development of organs, tissue proliferation, differentiation, and apoptosis . It is known that mammals express four transmembrane Notch receptors (Notch-1, Notch-2, Notch-3, and Notch-4) and five canonical transmembrane ligands (Delta-like 1, Delta-like 3, Delta-like 4, Jagged-1, and Jagged-2) . All four Notch receptors are very similar, although they have subtle differences in their extracellular and cytoplasmic domains ( Figure 4.1 ). The extracellular domains of the Notch proteins possess multiple repeats that are related to epidermal growth factor (EGF) and are thought to participate in ligand binding. The amino-terminal EGF-like repeats are followed by a cysteine-rich region termed the LNR (LIN-12/Notch-related region), which prevents signaling when a ligand is absent . The cytoplasmic region of the Notch conveys the signal to the nucleus; it contains a recombination signal-binding protein 1 for J-kappa (RBP-J)-association molecule (RAM) domain, ankyrin (ANK) repeats, nuclear localization signals (NLS), a transactivation domain (TAD), and a region rich in proline, glutamine, serine, and threonine residues (PEST) sequences . Notch ligands have multiple EGF-like repeats in their extracellular domain and a cysteine-rich region (CR) in serrate which are absent in delta .

The Notch signaling pathway is activated after Notch-ligand binding followed by three consecutive proteolytic cleavages by multiple enzyme complexes including γ-secretase complex . This produces an active fragment, the Notch intracellular domain (NICD), which enters the nucleus and binds to CSL, displaces corepressors from CSL, and subsequently recruits a coactivator complex containing mastermind, p300, and other coactivators, leading to the activation of Notch target genes . So far, many Notch target genes have been identified such as hairy enhance of split (Hes) family, Hey family, Akt, cyclin D1, c-myc, cyclooxygenase-2 (COX-2), extracellular signal-regulated kinase (ERK), matrix metalloproteinase-9 (MMP-9), mammalian target of rapamycin (mTOR), nuclear factor-kappa B (NF-κB), p21, p27, p53, and vascular endothelial growth factor (VEGF) . Since these target genes are critically involved in tumorigenesis, the Notch signaling pathway plays a pivotal role in the development and progression of human cancers including PC via regulating its target genes .

The Role of Notch in PC

It is worth mentioning that the function of Notch signaling in tumorigenesis can be either oncogenic or oncosuppressive, suggesting that its function is context dependent to some extent . For example, one study has shown that Notch-1 has an oncosuppressive function in skin cancer . In contrast, most studies have revealed that Notch activation is oncogenic in a variety of human cancers including PC . In the following paragraphs, we will discuss how the Notch signaling pathway is involved in the development and progression of PC.