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Page 6 of 15 Chen et al. Hepatoma Res 2018;4:29 I http://dx.doi.org/10.20517/2394-5079.2018.18

P38 is mainly involved in cell inflammation and proliferation with four phenotypes of p38α, p38β, p38γ and
p38δ. P38α. The most important factor in the p38 MAPK pathway, regulates the release of inflammatory
cytokines such as IL-1β, IL-6 and TNF-α, and also increases ROS activity inducing hepatocyte apoptosis .
[74]
The p38 pathway can down-regulate the expression of cyclin D1 and block the cell cycle in G1-S and G2-M,
and can also affect the downstream gene GADD45A of the ringing tumor suppressor gene p53 to regulate the
development of early HCC . An interesting mouse study suggested that inhibiting p38 MAPK (MAPK14)
[75]
could help treat the sorafenib resistant liver cancers. In a mouse model of sorafenib-resistant HCC, it was
discovered through in vivo screening of a shRNA library that p38 MAPK knockdown contributed sensitivity
to sorafenib. In other mouse models of HCC, sorafenib and a p38 MAPK shRNA or a small molecule
MAPK14 inhibitor skepinone-L increased survival of mice with HCC compared with sorafenib alone .
[76]
NF-κB pathway
NF-κB activation induces several pro-inflammatory cytokines which are prominent in supporting the
progression of cancer [77,78] . Chronic infection and inflammatory response are closely related to tumorigenesis.
HCC is the result of chronic inflammatory response induced by hepatitis B/C . IKK/NF-κB pathway
[79]
plays an important role in hepatitis, liver fibrosis and HCC. NF-κB is a class of nucleoprotein factors with
multidirectional transcriptional regulation. The main endogenous inhibitory factor of NF-κB is IκB, which
makes NF-κB remain in the cytoplasm and inhibits its nuclear translocation. NF-κB is phosphorylated by
the IκB protein kinase complex, which is then ubiquitinated and degraded. The released NF-κB is transferred
from the cytoplasm to the nucleus, and then regulates Inhibition of apoptosis proteins (IAPs), Bcl-2 family,
TNFR-associated factor (TRAF-1, TRAF-2) and JNK in the cell [80-82] .

Continued abnormal activation of NF-κB in hepatocytes results in the development of cholestatic hepatitis
and HCC. Inhibition of NF-κB can affect the normal apoptosis of hepatocytes . Blocking IKK/NF-κB
[82]
signal transduction pathway may reduce hepatic inflammation from chronic inflammation . It is possible
[80]
to prevent the development of HCC by blocking the abnormal JNK pathway activation and scavenging ROS
products and other ways to maintain the normal physiological level of NF-κB in the liver [83,84] . However,
NF-κB is often of over-abundant activation in liver cells to facilitate HCC transformation. Therefore, how
to remove overactive NF-κB and maintain it at normal physiological levels is the key to prevention and
treatment of HCC.

VEGF pathway
VEGF is a multifunctional cytokine that promotes endothelial cell division, proliferation and angiogenesis,
monocyte migration, and induction of inflammatory cytokines [85,86] . Liver VEGF is mainly present in
hepatocytes and endothelial cells with the VEGF receptors. Chronic liver disease includes hepatocyte atypical
hyperplasia, adenoid hyperplasia, nodules and other regenerative processes. The expression of VEGF in
cancer tissue initiates the neovascularization. In the early stage of liver disease, VEGF overexpression can
cause the increase of blood VEGF. VEGF levels in HCC patients are higher than in patients with chronic
hepatitis and cirrhosis. The increase of VEGF is negatively correlated with the prognosis of liver cancer [87,88] .
The current only FDA approved first line therapeutic drug for advanced HCC, sorafenib, is also a tyrosine
kinase inhibitor (TKI) directed against the VEGF family. The ALICE-1 study suggested that the analysis of
VEGF and VEGFR SNPs may represent a potential clinical tool for better selection of HCC patients who
are more likely to benefit from sorafenib treatment. Currently, apatinib (YN968D1), a TKI that selectively
inhibits the VEGFR2, is actively studied in advanced HCC alone or combination with TACE (NCT03046979,
NCT03398122).

JAK/STAT pathway
In 1994, Darnell et al. found JAK-STAT pathway. It was a new extremely fast signaling pathway, which
[89]
can transmit extracellular signals to the nucleus and through tyrosine kinase signaling and transcription