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include the following. crosstalk between Notch and Ras, a cell survival pathway,
or the death receptor 5, an apoptotic pathway, may decide
Canonical Wnt/beta-catenin signaling pathway whether Notch functions as an oncogene or a tumor
Multiple Wnt/beta-catenin target genes are key suppressor, respectively.
regulators of cellular proliferation, anti-apoptosis and
angiogenesis. These include c-myc, cyclin D1, FRA-1, Hedgehog signaling pathway
matrix metalloproteinase-7, c-Jun, urokinase plasminogen Activation of Hedgehog signaling induces hepatic
activator receptor, immunoglobulin transcription factor 2, malignancies. Many signaling molecules of the
[41]
endothelial growth factor receptor and vascular endothelial Hedgehog pathway, Sonic Hedgehog, PTC, SMO and GLl-1,
growth factor (VEGF) receptor. [29-31] In the absence of Wnt are over expressed in HB. Specific blockade of Hedgehog
ligand, the Wnt/beta-catenin signaling pathway is turned signal transduction inhibits the growth of HB. [42]
off and beta-catenin undergoes ubiquitin-mediated
degradation. [32] ANTI-TUMOR PROPERTIES OF CURCUMIN IN LIVER
CANCER
Majority of HBs contain beta-catenin gene mutations that
prevent beta-catenin from being degraded. As a result, As an anti-tumor agent, curcumin has been reported to
[33]
beta-catenin accumulates aberrantly in the cytoplasm, and exhibit direct action by inhibiting proliferation of tumor
then translocates to the nucleus. Most HBs have cytoplasm cells as well as an indirect action by inhibiting angiogenesis
and nuclear beta-catenin levels. Nuclear localization [Figure1].
[34]
of beta-catenin is leads to uncontrolled hepatoblast
proliferation. Beta-catenin has been considered as a Curcumin stimulates apoptosis of cancer cells
[35]
highly sensitive tumor marker for HB. Apoptosis or programmed cell death can be triggered by
extrinsic and intrinsic pathways. Intrinsic pathway is
[43]
Some HBs without beta-catenin mutations may also stimulated by internal stimuli such as DNA abnormality,
display beta-catenin accumulation due to other aberrant hypoxia, viral infection, cellular distress, etc. Extrinsic
components. About 65% of sporadic HBs possess (receptor mediated) pathway is initiated by extracellular
[36]
adenomatous polyposis coli APC gene alterations. messenger proteins such as TNF. Intrinsic pathway is
In absence of beta-catenin mutations, HBs with over regulated by the members of the Bcl-2 family of proteins,
expression of a catalytic subunit of the enzyme telomerase, which can be divided into three groups: (1) pro-apoptotic
telomerase reverse transcriptase also demonstrate beta- members that promote apoptosis, e.g. Bax, Bak; (2) anti-
catenin accumulation. The Wnt/catenin signaling in HB apoptotic members that protect cell from apoptosis,
[37]
is dependent on the liver and may contribute more to the e.g. Bcl-2, Bcl-w; (3) BH-3, only protein that promote
genesis of the embryonal than the fetal component of HB. [38] apoptosis through indirect mechanism. Extrinsic pathway
of apoptosis is mediated by several caspases which
Hepatocyte growth factor/c-met signaling are proteases with specific cellular targets, caspase-8
pathway followed by caspase 3, 6 and 7. Cancer cells are resistant
Hepatocyte growth factor (HGF), the natural ligand for to apoptosis and this leads to their uncontrolled growth.
c-met receptors HGF/c-met signaling also leads to aberrant
beta-catenin accumulation in hepatoblasts. [34,39] After Curcumin affects the following pathways and promotes
binding to HGF, c-met undergoes autophosphorylation apoptosis of cancer cells.
on tyrosine residues and further downstream signaling.
Beta-catenin is a substrate for tyrosine kinase. Tyrosine EF24 is a synthetic compound and a potent curcumin
phosphorylation of beta-catenin shields beta-catenin analogue with enhanced bioavailability. Liu et al.
[44]
from serine/threonine phosphorylation and subsequent demonstrated that EF24 significantly suppressed HCC
degradation, and leads to beta-catenin accumulation in and induced apoptosis in mouse liver cancer cell line. The
the tumor cells. Though this process is independent of levels of cytochrome c, cleaved-PARP, Bax and activated
Wnt but the result is the same. caspase-3 were increased whereas the levels of PARP and
Bcl-2 were down-regulated as compared to control (non-
Notch signaling pathway EF24 treated) groups. Incubation of human hepatoma
The Notch signaling plays a critical role in stem cell renewal, SMMC-7721 cells with curcumin for 24 h resulted in
differentiation, angiogenesis and endothelial sprouting. decreased expression of bcl-2 protein whereas expression
It is relevant for both hepatocyte embryogenesis and of bax protein increased significantly and a higher
cholangiocyte differentiation. curcumin concentration showed potent cytotoxicity. [45]

Deregulation of Notch signaling in HB has been EF24 induces cell cycle arrest at G2/M phase in mouse
documented. Notch activation is associated more with liver cancer cells. Passage from G2 to M-phase requires
[40]
the subtype pure fetal HB. The role of Notch signaling in the activation of cdc2 by cyclin B1. With the use of
tumorigenesis is dependent on the cellular context. The curcumin, the levels of cyclin B1 and cdc2 in the cells

Hepatoma Research | Volume 2 | March 9, 2016 65