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Table 2. Summary of miRNAs significantly associated with NAFLD, NASH and HCC patients
Disease Upregulated miRNAs Downregulated miRNAs References
NAFLD miR-21, miR-34a, miR-122 (serum), miR-146b-5p miR-29a, miR-139-5p, miR-30b-5p, miR-122-5p (tissue), [49-56]
(tisuue), miR-181b, miR-451 miR-155, miR-422a, miR-181d, miR-99a, miR-197, miR-146b
(serum)
NASH miR-21, miR-33a, miR-34a, miR-122, miR-144, miR-125b, miR-451 [50,51,57-60]
miR-192, pri-miR-7-1, pri-miR-26a-1/2
HCC miR-10a, miR-21 (tissue), miR23a, miR-31, let-7f, miR-16, miR-21 (serum), miR-24, miR-30e, miR-99a, [50,61-67]
miR-34a-5p, miR-93-5p, miR-122, miR-155, miR-106b, miR-125b, miR-145, miR-146a, miR-148a, miR-155,
miR-183, miR-221-3p, miR-222-3p, miR-375, miR-183, miR-199a, miR-199a3p, miR-200c, miR-215,
miR-423 miR-223, miR-229, miR-7706
HCC: hepatocellular carcinoma; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis

NAFLD-related comorbidities, such as insulin resistance, diabetes, and cardiovascular disease. Accordingly,
[38]
NASH is a recognized cause of cirrhosis and is associated with development of HCC .
In this context, it is worth mentioning that multiple additional mechanisms may be implicated in the pro-
gression from NAFLD to NASH and HCC. In fact, keeping in mind that there are a growing number of
patients who can progress from NAFLD to advanced fibrosis in the absence of significant inflammation, the
alterations in immunologic, endocrine and metabolic pathways have a key role in the progression of NASH
toward HCC.

Accordingly, despite the few data on NAFLD-related hepatocarcinogenesis, it has been highlighted that the
phosphoinositide 3-kinase (PI3K)-AKT-mTOR pathway, implicated in the control of cellular energetic ho-
[39]
meostasis, is deregulated in over 50% of NAFLD-related HCCs .
The β-catenin/WNT signaling, that has a crucial role in cell proliferation, stem cell self-renewal and cell mi-
[39]
gration, was found affected by somatic mutation in > 37% of NAFLD-related HCC .

Below we reported a detailed description of some factors involved in HCC development in patients with
NAFLD.

Regarding the genetic factors involved in the progression from NAFLD to HCC, recent genome-wide studies
have highlighted genetic heterogeneity of liver cancers. Of note, some SNPs, such as Patatin-like phospholi-
pase domain-containing 3 (PNPLA3) gene variant I148M, have been related to the development and progres-
sion of NAFLD, NASH and NAFLD-related HCC, whereas others, such as the transmembrane 6 superfamily
member 2 (TM6SF2) gene variant E167K, have been mainly correlated with the development of cardiovascu-
lar diseases [5,40,41] . In this context, the most recent findings from genomic profiling let us better understand
[42]
that different pathways are involved in the initiation and progression of liver cancer , as shown in Figure 1.

In addition, altered transcriptional gene expression might be linked to inappropriate microRNAs (miRNAs)-
[43]
guided transcriptional control. The human genome is envisaged to encode approximately 1000 miRNAs ,
[44]
which are a perfect class of blood-based biomarkers for cancer detection . MiRNAs are endogenous 19-24
nucleotides noncoding single-stranded RNAs, which control, at post-transcriptional level, many comple-
mentary target mRNAs implicated in several pathophysiological processes, such as cell proliferation, differ-
[45]
entiation, metabolism, apoptosis and cancer . Lack of miRNA processing enzymes in cancer cells promotes
tumor invasiveness and more aggressive phenotypes, revealing their main role in controlling tumor- and
metastasis-initiating events [46-48] . Accordingly, different sets of miRNAs have been specifically correlated
with NAFLD, NASH and HCC [Table 2] [49-67] . Among the miRNAs recently identified in NAFLD patients,
it is worth mentioning the up-regulation of miR-146b-5p, miR-181b and miR-375, and the down-regulation
of miR-29a, miR30b-5p, miR-122-5p, miR-139-5p, miR-155 and miR-422a [49,53-56] . In addition, in NASH it has