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Figure 1. Pathogenic mechanisms involved in the development of HCC. HCC: hepatocellular carcinoma; NAFLD: nonalcoholic fatty liver
disease; NASH: nonalcoholic steatohepatitis; IGF: insulin-like growth factor; ROS: reactive oxygen species; PAMPs: pathogen-associated
molecular patterns

been reported the up-regulation of miR-33a and miR-144 and the down-regulation of miR-451 [58,60] . Finally,
in NAFLD-related HCC the up-regulation of miR-10a, miR-33a, miR-144, miR-155, miR-183, miR-375 and
miR-423 and the down-regulation of miR-229 and miR-7706 were found [65-67] .

MiRNA analyses, in combination with other clinical parameters and standard liver examinations, may
be extremely useful to predict the possible progression of NAFLD toward HCC, and for monitoring the
[50]
response to treatments . However, despite the association between definite miRNA signatures and patho-
genesis of NAFLD-related HCC, the expression levels of specific hepatic miRNAs during liver tissue trans-
formation are still controversial. Further studies are needed to shed light on their function in the context of
NAFLD-related HCC.

Regarding oxidative stress, reactive oxygen species (ROS) have a central role in HCC onset. ROS, in fact,
are noticeable factors playing an essential role in regulating cell homeostasis. In this regard, our group has
recently highlighted the role of altered systemic biometals distribution in NAFL/NASH patients and the as-
[68]
sociated increasing levels of ROS . Accordingly, toxic biometal accumulation is a common feature in many
cancers. Moreover, perturbations of mechanisms that control transcripts encoding proteins that regulate
biometals have been described in cancer cells, including differences in epigenetic control (methylation and
acetylation), miRNAs expression and protein activities [68,69] .