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Several signaling pathways are of interest due to their cleavage cascade of the Notch intracellular domain (NICD) via
specific oncogenic and/or tumor suppressor characteristics. -secretase with NICD translocated to the nucleus. NICD
[31]
For instance, the ras/raf pathway provides the only current then binds with the RBP-J family activating the complex
approved therapeutic approach in advanced HCC through as well as recruiting co-activator MAML1 that initiates
the use of sorafenib. [13,14] Other traditional pathways transcription of Notch downstream targets including hairy
such as PI3k/Akt/mammalian target of rapamycin, [15-17] enhancer of split, hairy enhancer of split with YRPW motif
Wnt/-catenin, as well as Notch signaling [19-21] have been families, p21, and Sox-9. [32-36] Deactivation of the Notch signal
[18]
investigated. Further delineation into the manipulation of is rapidly induced by phosphorylation and degradation. NICD
these pathways is critical for future alternative strategies is phosphorylated within the PEST domain by the CDK8
for HCC. One of these pathways of interest is Notch kinase and targeted for proteasomal degradation by E3
signaling. As a functionally conserved pathway, it is involved ubiquitin ligases that include Sel10/Fbw7. [37,38] Transcription
in the regulation of several cellular properties including activation of the ternary complex is disassembled and reset
differentiation, proliferation, homeostasis and survival. for the next round of signaling. With no second messenger to
First studied in Drosophila, Notch was linked to neural amplify its signal, deactivation is acute and tightly regulated.
development. Future studies were able to identify the
homology between species as well as accurately describe the Noncanonical Notch signaling involves a multiple of parallel
Notch transmembrane receptor and provide evidence in its pathways as cross-talk between these pathways dominates
role as cellular regulator of differentiation, proliferation, and the influence of Notch through paracrine regulation. [31,39]
survival. [22-28] Continued work in the field of Notch signaling One particular, well documented, example is the signaling of
would inevitably showcase its role in a myriad of cellular Notch and the Wnt/-catenin pathways. Both pathways can
processes centered on the development. act in synergistic concert through traditional Notch signaling
or opposing interactions. Conversely, antagonistic signaling
[40]
NOTCH SIGNALING is through noncanonical effects. A second crucial aspect
particular to Notch signaling is the counteracting effects.
The Notch signaling pathway consists of Notch receptors, Notch signals involve either the promotion or suppression of
ligands, negative and positive modifiers, and transcription cell proliferation, cell death, and activation of differentiation
factors. In mammals, these efficient modules have several programs. This happens in cells throughout development of
members and the interplay between these molecules is not the organism and during the maintenance of self-renewing
yet fully understood, but its role in several processes is being adult tissues. Therefore, gain or loss of Notch signaling
teased out including regulation of metabolism, inflammation, mechanisms has been directly linked to multiple human
liver regeneration and repair. Notch signaling is important disorders. Even more conflicting in nature, opposing actions
[29]
from other conserved signaling pathways because its role in of Notch has been linked to similar disease processes in the
the mechanism of signal transduction is crucial. Compare to liver. [41,42]
other intercellular signaling pathways such as Wnt, Hedgehog,
and transforming growth factor-, Notch is distinctive in NOTCH SIGNALING IN THE LIVER
several traits. First, the signaling of Notch is unique. It is
comprised of both canonical and noncanonical signaling. The The role of Notch signaling in the liver remained relatively
traditional canonical pathway occurs in a juxtacrine process unknown until the discovery and investigation of Alagille
that is unique to Notch. Cell-to-cell interaction is required syndrome (AGS). As an autosomal dominant disease, AGS
for subsequent signaling. A transmitter cell releases one is characterized by ductopenia and cholestasis. Diminished
of the five major Notch ligands (Jagged 1, 2, and Delta-like development of intrahepatic bile ducts is the hallmark of
1, 3, 4) and binds to one of the four transmembrane Notch AGS. Through genetic testing, near the turn of the century,
receptors (Notch 1-4) on the associate cell. Signaling is it was demonstrated that mutations in the Jagged 1 gene
through several cleavage steps. The Notch receptor is cleaved and to a lesser extent Notch-2 led to AGS. [43-46] Therefore, it
by furin-like convertases in the trans-Golgi network, which evidenced the role of Notch signaling in hepatogenesis, more
results in two subunits of the mature/functional receptor. specifically hepatic duct morphogenesis. Further research
The extracellular Notch receptor subunit consists of a into the role of Notch in liver development focused on liver
ligand-binding domain that is composed of epidermal growth regeneration following injury. During injury and subsequent
[30]
factor-like repeats. In addition, mammalian Notch-1, -2 liver regeneration (i.e., partial liver resection) hepatocyte and
and -3 receptors contain cytokine response regions and cholangiocyte proliferative properties are often inhibited;
transcriptional activation domains. Successful binding therefore, precursor hepatic progenitor cells (HPCs) are
[30]
of the ligand to the representative receptor triggers a activated in response to massive liver injury. [47-49] HPCs

12 Hepatoma Research | Volume 1 | Issue 1 | April 15, 2015