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Chen et al. Hepatoma Res 2018;4:29 I http://dx.doi.org/10.20517/2394-5079.2018.18 Page 7 of 15

activator targets. The activation eventually leads to biological effects. JAKs family belongs to the non-
receptor tyrosine kinase, so far there are 4 members of family: JAK1, JAK2, JAK3 and TYK2, with diverse
sizes, molecular weight between 120-140 kDa and evolution degree conservative . STATs are a kind of
[90]
cytoplasmic proteins, associating with target genes binding. STATs are downstream substrates for JAKs. After
abnormal activation of JAK/STAT3 signaling pathway, p-STAT3 can bind to specific DNA in the nucleus and
directly or indirectly up-regulate the expression of apoptotic genes and thus regulate cell proliferation and
apoptosis . STAT is highly expressed in many human malignant tumor tissues and cell lines, especially
[91]
STAT3, which is currently considered as an oncogene and may promote the occurrence and development of
liver cancer by influencing cell growth, differentiation and apoptosis [92,93] . Many evidence suggest possible
interactions between STAT3 and NF-κB signaling pathways. STAT3 can promote p65 into the nucleus,
resulting in NF-κB activation. JAK/STAT signaling pathway also play a part in pancreatic elastase-induced
secretion of interleukin-18 . Injection of JAK2 inhibitor AG490 significantly inhibited the activation of
[94]
JAK2-STAT3 after hepatic ischemia, and decreased the activation of NF-κB and TNF . A phase I/Ib study
[95]
has been completed to assess the safety and anti-tumour activity of AZD9150 in patients with advanced/
metastatic HCC (NCT01839604).

EGFR signaling pathway
The EGFR is a tyrosine kinase that contributes to the regulation of cellular homeostasis. It is a 170-KDa
membrane protein that stimulates downstream cell proliferation, survival, and tumorigenesis .
[96]
Members of the human ErbB/HER receptor family include EGFR (ErbB1/HER1), ErbB2 (HER2/neu),
ErbB3 (HER3) and ErbB4 (HER4). EGFR encoded by the proto-oncogene erbB1 with EGFR ligand
family members of 10, such as EGF, transforming growth factor-α (TGF-α), amphiregulin, b cytokines,
heparin-binding EGF and epidermal regulatory elements . EGFR activation can activate extracellular
[97]
downstream signaling transduction pathways such as ERKs-MAPK and PI3K. It is involved in the
regulation of cell division, differentiation and proliferation and promotes the repair of tissue injury. It
is also closely related to tumor cell cycle progression, apoptosis inhibition, tumor angiogenesis and cell motility
and invasion [98,99] . EGFR is highly expressed in hepatoma cells stimulated by TGF-α or EGF. In vitro and in vivo
experiments show that EGFR blockade can inhibit HCC proliferation and metastasis through the EGFR
pathway, and have synergistic effect of HGF treatment with other growth factor signaling pathways [100] .
Currently, a pilot clinical trial studies the best dose of EGFR inhibitor erlotinib hydrochloride for
preventing liver cancer in patients with scarring (cirrhosis) of the liver undergoing surgery. Erlotinib
hydrochloride may help to prevent the development of fibrosis/cirrhosis and liver cancer in patients liver
cirrhosis (NCT02273362).

TLR signaling pathway
TLR is a transmembrane protein present on the surface of human cells. TLR plays an important role in
the innate immune response in the body as a major pattern recognition receptor. Currently, more than
a dozen TLR have been found in the human body and they are widely distributed in various tissues with
the specificity of cells and tissue distribution. TLR4, a natural receptor for LPS, plays an important role
in the regulation of acute inflammatory responses, transduction of cell signals and apoptosis . During
[101]
liver fibrosis in rats, the expression of TLR4 protein in liver showed that compared with the normal control
group, the level of hydroxyproline in liver tissue began to increase significantly , and the level of plasma
[102]
endotoxin in model group increased gradually with a significant positive correlation between the content of
hydroxyproline after CCl4 treatment . In HCV patients, the severity of the disease is associated with the
[103]
expression of TLR2/4 mRNA . Compared with the normal group, TLR2/4 mRNA expression of chronic
[104]
hepatitis C patients were elevated. The study found that TLR4-MyD88-NF-κB signaling pathway plays an
important regulatory role in abnormal liver immune response, inflammatory response-triggered liver injury,
activation of hepatic stellate cells and the progression of hepatic fibrosis .
[105]