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Chen et al. Hepatoma Res 2018;4:29 I http://dx.doi.org/10.20517/2394-5079.2018.18 Page 5 of 15

CTNNB1 or inactivating mutations of AXIN1 and APC, which caused the activation of the WNT/β-catenin
pathway. The activating mutations of CTNNB1 results in the mutated β-catenin accumulation and migration
into the nucleus to activate transcription from target genes, which will promote HCC cell proliferation and
stemness. HBV-related HCCs showed less frequent activating mutations of CTNNB1 and more frequent
inactivation mutation of AXIN1 compared to HCCs related to HCV infection, alcohol consumption, or
NASH, which suggested that the mechanism of the WNT/β-catenin signaling activation may be different
in HCCs with different etiology . A recent interesting study showed that deletion of endogenous β-catenin
[63]
in hepatocytes of mice aggravated HCC development driven by an oncogenic version of β-catenin together
with MET. This hepatocarcinogenesis featured up-regulation of Erk, Akt and WNT/β-catenin signaling and
cyclin D1 expression. The transcriptomics analysis of these mice tumors showed similar transcriptomes
to human HCCs with concomitant CTNNB1 mutations and MET overexpression. The β-catenin-deficient
livers displayed many changes including increased DNA damage response, expanded Sox9+ cells, and
up-regulation of pro-tumorigenic cytokines like IL-6 and TGF-β1. This study together with previous
studies suggested that both activating and inactivating mutations in CTNNB1, encoding β-catenin and
[64]
activation of WNT-β-catenin pathway, play important roles in liver tumorigenesis in humans and mice .
Recent researches show that abnormal expression of wnt signaling pathway is involved in the intrahepatic
inflammation, abnormal lipid metabolism and oxidative stress, with resulting in the occurrence of chronic
liver diseases such as non-alcoholic fatty liver disease and liver fibrosis [65,66] .

MAPK pathway
Ras/Raf/MEK/MAPK is one of the key signal transduction pathways in the HCC. Many growth factors
could activate residual tyrosine of Ras/Raf/MEK/MAPK to phosphorylate itself including EGF, IGF, VEGF,
PDGF, FGFs and HGF. MAPK signal transduction is a three-step kinase cascade way, first of all MAP-
KKK is activated and phosphorylated by mitogen on the basis of the stimulation, the phosphorylated MAP-
KKK turns to activate MAP-KK, after which, the activated MAP-KK is able to phosphorylate MAPK and
finally translocate into the nucleus. The main pathways of MAPK signaling pathway are Ras-Raf-ERK, c-Jun
N-terminal kinase (JNK), and p38- MAPK pathway .
[67]
The Ras mutation on the oncogene activates Raf activation. The activated Raf activates it by phosphorylating the
serine residues on the mitogen activated kinase kinase (MEK) loop, then MEK activates extracellular signal-
regulated kinases (ERKs). ERK can also be activated by decreasing the level of dual specificity phosphatase
(DUSP), when the Ras mutation rate is low in HCC patients. Activated ERK in turn phosphorylates a
number of substrates that are linked to the cytoplasm and membrane, while also rapidly translocated into the
nucleus to dephosphorylate and activate transcriptional molecules involved in proliferative responses such as
ELK-1, AP-1, TCF, and the others, which regulate the expression of ETS, c-Jun, c-Fos, c-Myc, and cyclin D
in HCC and affect the prognosis of HCC . In addition, activated ERK can regulate the phosphorylation of
[68]
histone, the pro-apoptotic protein Bad and the transcription factor CREB by ribosomal S6 protein kinase-2
phosphorylation . Continuous activation of ERK results in the increase of phosphorylated ERK, which is
[69]
the basis of hepatoma cell proliferation and invasion .
[70]
JNK pathway maintains cell cycle continuity mainly through activation of JNK activating transcription factor
c-Jun synergistic with ERK pathway . Activated JNK is not only bound to transcription factors ATF2 and
[69]
c-Jun amino-terminal domain, phosphorylation of the active region of the transcription factor, activation of
the transcription factor AP-1, up-regulating the expression of apoptotic precursors CD95 and TNF-α , but
[71]
also regulates phosphorylation of Bcl-2 indirectly after being activated, through the mitochondrial pathway
to diminish its anti-apoptotic ability. Studies have shown that JNK pathway can affect the invasion and
metastasis of HCC cell line MHCC97H, and that JNK inhibitor can affect human HCC xenografts and
increase chemically inducing murine liver cancer [72,73] .