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Page 2 of 8 Fu et al. Hepatoma Res 2018;4:39 I http://dx.doi.org/10.20517/2394-5079.2018.29

teomics, microRNA and liquid biopsy [14-20] . We want to highlight that promutagenic DNA adducts is a new
field which need further investigations in the search of biomarkers for HCC.

HEPATATOCARCINOGENESIS AND OXIDATIVE STRESS
More than 90% of HCCs arise in the context of hepatic inflammation [21-29] . Chronic liver inflammation leads
to oxidative/nitrosative stress and lipid peroxidation (LPO), generating excess reactive oxygen species (ROS)
and reactive nitrogen species (RNS), together with aldehydes which can react with DNA bases to form
[30]
promutagenic DNA adducts through either endogenous or exogenous insults . Oxidative stress has been
demonstrated as an important factor to carcinogenesis since the first experiment on ROS-induced transfor-
[31]
mation of mouse fibroblast cells in the 1980s . It has emerged as an important player in the development
[32]
and progression of liver carcinogenesis for different etiologies (e.g., HBV- and HCV- induced liver diseases) .
HCC incidences in the USA are largely associated with HCV-related cirrhosis, but changes observed by
[33]
epidemiological studies have attributed obesity and diabetes as risk factors as well . The increased oxida-
tive stress in obesity and diabetes may play a crucial role in hepatatocarcinogenesis [34,35] . Because oxidative
stress drives genomic damage and genetic instability to cause mutations, and mutations play a crucial role
in carcinogeneisis. This notion is supported by the chemopreventive effect demonstrated in a large number
of epidemiology studies on the relationship of high fruit and, vegetable consumption with low cancer inci-
dences, among which, antioxidants effects and maintenance of normal DNA repair capacity are indicated to
be two crucial mechanisms of actions [36,37] . The same concept was illustrated when knocking out antioxidant
defenses significantly increased the rate of liver cancer, e.g., knock-out mice lacking CuZuSOD (copper-
[38]
zinc superoxide dismutase) are found to increase liver carcinogenesis . Another mouse model showed that
knocking out nuclear respiratory factor-1 (Nrf1), an essential transcription for mediating oxidative stress,
[39]
induces steatosis, fibrosis and liver cancer, eventually .
The notion that oxidative stress induces HCC is also supported by studies on hemochromatosis. A positive
correlation between mild/excess iron deposition and HCC in patients with hemochromatosis suggests a pos-
sible carcinogenic role for oxidative stress induced by iron through Fenton reactions [40,41] . In the iron-nitrilo-
triacetic acid rat model of hemochromatosis, elevated genotoxic products from oxidative stress, 4-hydroxyl-2-
[42]
nonenal (HNE) and malondialdehyde (MDA), are found . This increase is also accompanied by damaged
cellular defense system, for instance, vitamin E level, GSH/GSSG ratio and superoxide dismutase are all
decreased. HNE has the potential to damage genomic DNA and cause mutations, e.g., HNE adduct has been
[43]
demonstrated to cause p53 mutations which are associated with more than 50% of HCC incidences . A
more important link was discovered in patients with hemochromatosis who suffered iron overload and p53
mutations following HCC development [41,44-46] ; it suggests that oxidative stress is an underlying mechanism
[44]
of HCC carcinogenesis . The role of oxidative stress in liver carcinogenesis is also supported by the result
of a multicenter study: using tissue microarray screening, cytochrome P450 1A2 (CYP1A2) oxidase in non-
[47]
cancerous tissue is found and validated as the only predictive factor for HCC recurrence .

Oxidative stress is a crucial factor in the initiation and progression of HCC under various pathological con-
[48]
ditions . Oxidative stress can be induced by ROS produced in the mitochondria in non-alcoholic fatty liver
disease, which damages hepatocytes, promotes pathologic polyploidization, triggers inflammation, and con-
tributes to insulin resistance [49-53] . Additionally, oxidative stress is also involved in migration, invasion, and
metastasis of HCC [54-56] . In that, biomarkers of oxidative stress can predict HCC risk and also the recurrence
of HCC. Quantitative methods for the evaluation of oxidative stress can be divided into three categories:
(1) determination of compounds modified by oxidative stress; (2) determination of the activity of antioxi-
dant enzymes; and (3) determination of oxidative stress indicators containing transcription factors. Serum
quantification of derivatives of reactive oxygen metabolites (d-ROM) level, a simple method for measuring
hydrogen peroxide, is found to predict the risk of HCC recurrence after surgical resection or radiofrequency