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Chen et al. Hepatoma Res 2018;4:29 I http://dx.doi.org/10.20517/2394-5079.2018.18 Page 3 of 15

develop HCC . The development of HCC is a multistep process. There is a common situation that HCC are
[11]
originating from liver chronic injuries and inflammation, subsequent fibrosis and/or cirrhosis. When patients
get liver injury or inflammation, the liver parenchymal cells will die and release signaling molecules of death,
or cause inflammatory reaction. During chronic inflammatory hepatitis, the host's immune response to
HBV or HCV is usually not strong enough to eradicate the infection and damage, eventually leading to the
body's continued over-activation [12-14] . Cirrhosis is a chronic, progressive diffuse change in the liver caused
by a variety of factors. Long-term damage to liver cells will lead to degeneration and necrosis of liver cells.
After a wide range of liver cell degeneration and necrosis, intrahepatic connective tissue is regenerating,
then fibrous tissue is diffusing proliferation. This process helps promote the development and progression of
liver cancer. The process involved many mechanisms such as oxidative stress, endoplasmic reticulum stress
and mitochondrial damage, which will activate and promote the synthesis and secretion of tumor-related
transcription factors and cytokines, resulting in DNA damage and further promoting tumorigenesis [15-18] .

INFLAMMATORY SIGNALING PATHWAYS OF HCC
The relationship between liver inflammation and HCC is strongly suggested by recent studies. A lot of
evidences about inflammatory mediators and signaling pathways are reported in HCC [4,9,19] . However, there
is a lack of adequate clinical evidence to support the routine use of anti-inflammatory drugs to improve
the prognosis of patients with liver cancer. So it is an interesting strategy to further investigate the anti-
inflammatory treatment for liver cancer. A large number of studies indicated that chemokines and cytokines
are candidates linking molecules between inflammation and cancer. The following parts will describe a few of
the key cytokines and chemokines and signaling pathways which are involved in the inflammation and HCC.

Cytokines and chemokines
Inflammatory cytokines are critically important in the liver injury development. When liver tissue or cells
stimulate with stimulants like alcohol and fatty acid, liver tissue synthesizes various types of cytokines
to defend that [20-25] . The well-studied cytokines include tumor necrosis factor-α (TNF-α) [26,27] , interleukin
family (IL-6, IL-1β) [7,28,29] , chemokines (VCAM-1, ICAM-1 and MCP-1) [30-33] , etc. TNF-α and IL-6 are two
multifunctional cytokines in chronic hepatic inflammation. Kuffer cells will be activated during chronic
hepatitis, including NASH, alcoholic hepatitis, and hepatic infections with HBV and HCV, and inflammatory
cytokines. Following that, TNF-α and IL-6 will be synthesized and secreted in abundance. Elevated serum
levels of TNF-α and IL-6 have been found in patients with chronic hepatitis B [34,35] . Higher serum levels of
TNF-α and IL-6 have been reported as the high risk factors for cirrhosis and HCC development in patients,
especially with HBV and HCV infection. Several studies have shown that the hepatic tissue of DEN-treated
rats or mice has increased IL-6 and TNF-α production levels compared with the control group . It has
[36]
been certified that TNF-α causes DNA damage through the induction of reactive oxygen species (ROS) [19,37] .
IL-6 and IL-1β can potentially promote autophagy in liver tumor cells [25,38] . IL-1β has been linked with
[39]
inflammasome NLRP3 to promote the occurrence and development of chronic liver disease . Both IL-1β
and TNF-α are related to stimulate cancer cell proliferation during chronic inflammation situation .
[40]
Chemokines induce chemotactic migration of targeting cells through their interaction with their receptors.
A large number of studies have shown that chemokines are up-regulated in various liver injuries. In chronic
liver inflammation, inflammatory factors, growth factors, oxygen stress and their products stimulate the
expression of chemokines. High expression of chemokines can activate hepatic stellate cells (HSC) involved
in the formation of liver fibrosis and even cirrhosis. It should been noted that IL-1β and TNF-α can activate
quiescent HSC to produce MCP-1, IL-8, indicating that inflammatory cytokines further accelerate the
conversion of inflammation to cancer through chemokines [41-43] . The CXC family is a family of chemokines
that have attracted the most attention during the metastasis of cancer and this family can promote the
migration of neutrophils, which often promote the development of inflammation. CXCL1, CXCL2, CXCL3
and CXCL have been reported to be highly expressed in hepatoma cells [44,45] . It has been shown that CXCL12