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can differentiate or give rise to hepatocytes as well as showed that the functional Notch-1 signaling inhibited
cholangiocytes through Notch activation thus further proliferation of OSCC cell lines. [61]
strengthening the role of Notch in hepatogenesis and
morphogenesis. [50-52] During repair and regeneration and Notch-1 dysregulation is not the only isoform involved in
at the height of concentrated HPC involvement, several carcinogenesis. Studies have demonstrated that up regulation
pathways are activated to assist in morphogenesis including of the Notch-3 isoform was required for induction of
the Notch pathway. In addition, activation of the Notch p21 expression in senescent cells. Inactivation of Notch-3
[62]
pathway (specifically Notch-1 and -2 isoforms) is in concert by -secretase inhibitor (GSI) or short interference RNA (siRNA)
with parallel pathways during regeneration. [40,53,54] These decreased cell proliferation and induced apoptosis in the
critical and emerging studies linking Notch activation to chemoresistant ovarian cancer cells. Finally, Lu et al. have
[63]
[64]
intrahepatic morphogenesis was a fundamental building showed that the Notch-3 was positively correlated with Jagged-1
block to the transition to reviewing the role of Notch in at the mRNA and protein levels. Therefore, they concluded that
carcinogenesis. Notch-3 and Jagged-1 may play an important role in the initiation
and proliferation of human nonfunctioning adenomas. [64]
NOTCH IN CARCINOGENESIS
Despite these early indications of Notch as a potential
As the expanding role of Notch signaling in the development of target for cancer therapy, the reality of Notch signaling in
organogenesis continued, the role of Notch in carcinogenesis carcinogenesis remains opaque. Although there is growing
was ongoing. Notch-1 identification as an oncogene evidence as to Notch acting as an oncogenic process, other
was first discovered through investigation into T-cell cancers exhibit Notch’s role as a tumor suppressor in nature.
acute lymphoblastic leukemia (T-ALL). T-ALL gain of For instance, in neuroendocrine tumors, Notch-1 acts as a
function mutations in Notch-1 led to overexpression and tumor suppressor with overexpression leading to a reduction
constitutive activation of Notch-1 receptor and thus enhanced in cellular proliferation and growth. [26,65-67] Furthermore,
proliferation. In addition, the oncogenic ability of Notch despite thorough studies involving either the activation
[55]
was also exhibited in colorectal cancer. According to or inhibition of the Notch pathway in the modulation
[56]
Ambros, most Notch-mediated processes require a transient of carcinogenesis, there is limited data surrounding the
pulse of activity that in some cases lasts only as long as a expression of Notch receptors and their link with cancer.
[57]
fraction of the cell cycle degradation of the NICD. This is Additionally, noncanonical pathway activation of Notch
of particular interest as Notch transduction has a 1:1 ratio of further confuses and complicates the underlying roles of this
input to output without the presence of second messengers. pathway during times of aberrant cellular growth.
Therefore, constitutive activation will provide constant
transduction and thus aberrant proliferation. In addition TARGETING NOTCH IN HEPATOCELLULAR CARCINOMA
to mutations in Notch-1 signaling leading to oncogenic
enhancement, alterations in Notch-1 signaling also has led Despite promising results of Notch mediation in multiple
to changes in angiogenesis. [58] organ-specific cancers, there is limited and conflicting data
on Notch signaling in HCC. In several studies, Notch-1 acts as
The enhanced discoveries of the Notch signaling pathway a tumor suppressor. [41,68] On the other hand, there is evidence
lead to further advancement in additional solid tumors. that Notch is oncogenic in nature. [69-71] As time passes, growing
Robinson et al. studied the overexpression of Notch-1 evidence may indicate that although individual HCC signatures
[59]
and -2 fusion proteins in benign breast epithelial cells. may include Notch as a tumor suppressor, the majority of HCC
Subsequent constitutive expression resulted in altered Notch mediation is through overexpression and oncogenic
growth characteristics while the inhibition of Notch signaling activation. For instance, Villanueva et al. revealed that the
[72]
reduced the growth of the Notch gene fusion-expressing conditional expression of NICD1 in a mouse model led to
breast cancer xenografts. Zender et al. [60] showed that HCC in all test subjects within the 1st year. Biopsied tumors
overexpression of the Notch signaling pathway modulates represented varying stages in the mice test group. Moreover,
the dysregulation of the oncogene cyclin E, resulting overexpression of Notch-1 was closely linked to insulin-like
in the development of cholangiocellular carcinoma. In growth factor 2 and Sox-9 expression levels and interestingly,
addition, inhibition of Notch activity blocks tumor cell the NICD1 conditionally active mice genetic signature was
[72]
proliferation and induces apoptosis in cholangiocellular evidenced in a subset of human patients with HCC. Further
carcinoma. A retrospective analysis in oral squamous cell studies have shifted the tide toward Notch acting as an
[60]
carcinoma (OSCC) showed that the Notch pathway was oncogene in liver carcinogenesis. Sox-9, a downstream target
defective in 66% of patients and the studies of mechanism of Notch signaling cascade, is linked to cellular proliferation

Hepatoma Research | Volume 1 | Issue 1 | April 15, 2015 13