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Balsano et al. Hepatoma Res 2018;4:38 I http://dx.doi.org/10.20517/2394-5079.2018.51 Page 7 of 12

In particular, biometals have the ability to catalyze oxidation-reduction reactions, which can lead to the pro-
duction of ROS, thus their tight homeostatic regulation should be always present in the body. Accordingly,
although the mechanisms are at present still unclear, a contribution of iron (Fe), copper (Cu) and zinc (Zn),
in the development of HCC, has been often suggested [68,70-72] . In fact, dysregulation of Fe, Cu or Zn homeo-
stasis stimulate proliferation, modulate the expression of epithelial mesenchimal transition (EMT) related
proteins, glycolysis, and antioxidant molecules, such as SOD1 and 2, HIF1, GSH, in various cancer cells and
human tumors [68,69,73-75] .

Accordingly, NASH and NAFL patients display higher iron absorption after the administration of an oral
[76]
iron absorption test and its deposition has been related to HCC development in NAFLD-cirrhosis . The un-
[77]
derlying mechanisms are not already clear, but might be related to oxidative DNA damage . Interestingly,
a recent meta-analysis highlighted that HFE mutations C282Y and H63D, associated in homozygosity with
[78]
hemochromatosis, were characterized by a higher risk of HCC in NAFLD patients . In addition, our group
highlighted that a statistical significant enhancement of serum copper levels has been reported in NAFLD-
cirrhotic patients and the altered homeostasis of this biometal was even more evident in HCC patients. In
the presence of higher concentrations of extracellular copper liver cells are sensitized to transformation.
The pathogenic copper-related pro-oncogenic mechanism seems to be, at least in part, managed by MYC,
[68]
which is able to directly bind a specific region of the CTR1 promoter, regulating its transcription . In this
regard, it is really interesting the recent study reporting that Golgi protein 73 (GP73) is an effective and reli-
[79]
able serological marker for the diagnosis of advanced fibrosis and prediction of appearance of cirrhosis .
The awareness that copper serves as a limiting factor for multiple aspects of tumor progression, including
growth, angiogenesis and metastasis suggests more attention to be paid to the potential and undiscovered
role of copper-specific chelators as effective therapeutic agents against HCC.

The prevalence of obesity is increasing worldwide as well as the link between obesity and cancer, becom-
ing an important and accepted risk factor for the development of HCC. As reported above, it is currently
accepted that NAFLD is caused by an insulin resistance and often appears in the presence of obesity. The
relationship between obesity and HCC was supported by a cohort study in Italy. In this work the odds ratio
[80]
progressively increased in the patients who have associated metabolic syndrome factors . Obesity is char-
acterized by the excess of adipose tissue and the altered secretion of adipocytokines that correlate with the
[81]
occurrence of HCC and liver-related death in patients with cirrhosis . In the last decade, it has become
evident that obesity-related metabolic inflammation is involved in different aspects of HCC progression and
metastatic dissemination, among which: neural regulation, innate immune responses, intestinal immune
system and endocrinal regulation. Unfortunately, only few studies have been focusing on long-term mecha-
[82]
nisms involved in obesity related HCC development , thus prospective studies are needed.
Finally, alterations in intestinal microbiota (or dysbiosis, defined as any change in the composition of the
microbiota commonly found in healthy conditions), creating a pro-inflammatory microenvironment in the
[83]
liver, seem to play a main role in the development of NAFLD-related HCC . Dysbiosis, beyond the known
risk factors for NAFLD, promotes the development of chronic liver diseases and HCC, independent of body
mass index (BMI) and insulin resistance, producing a large amount of bioactive molecules, which deeply af-
[84]
fect physiological and pathological body status . Interestingly, in a mouse model, drugs able to modify the
microbiome (e.g., rifaximin) may prevent HCC development. Rifaximin may additionally improve portal hy-
[85]
pertension, spontaneous bacterial infection (SBP) risk, liver fibrosis and hepatic encephalopathy . Actually,
metabolic alterations have been associated with dysbiosis: ob-ob mice (homozygous for the obese mutation)
have an imbalance of the intestinal microbiota with a decrease of Bacteroides and an increase in Firmicutes.
[86]
This pattern of intestinal bacteria has the increased capacity to harvest energy from diet , as well as the
[57]
microbiota composition described in NAFLD . The altered microbioma (the genetic information genomes
of gut microbiota) is characterized by the ability to produce alcohol, which in turn will be increased in the