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Page 4 of 6 Bellentani. Hepatoma Res 2020;6:29 I http://dx.doi.org/10.20517/2394-5079.2020.10
[20]
could be the one discovered recently by Loo et al. involving lipoteichoic acid, a gram-positive gut
microbial component that seems to promote HCC development by creating a tumor-promoting
microenvironment. Lipoteichoic acid enhances the senescence-associated secretory phenotype of hepatic
stellate cells (HSC) collaboratively with the obesity-induced gut microbial metabolite deoxycholic acid to
upregulate the expression of senescence-associated secretory phenotype factors and COX2 through Toll-
like receptor 2. Interestingly, COX2-mediated prostaglandin E2 (PGE2) production suppresses antitumor
immunity through a PTGER4 receptor, thereby contributing to HCC progression.

Moreover, COX2 overexpression and excess PGE2 production have been detected in HSCs in patients with
NASH-HCC. The gut microbiota-driven COX2 pathway produces the lipid mediator PGE2 in senescent
HSCs, which plays a pivotal role in suppressing antitumor immunity, suggesting that also PGE2 and its
[18]
receptor may be novel therapeutic targets for noncirrhotic HCC-NASH .
All these new experimental findings discovering links between lipid metabolism, inflammation, insulin
resistance, gut microbiome and HCC-NASH are still to be confirmed in humans, but they demonstrate that
the pathogenetic pathway of NASH-HCC is multifactorial, very complex and still far away from leading to
an efficacious treatment for this increasingly prevalent cancer.

T2DM AND NASH-HCC
T2DM was also found to be an independent factor associated with HCC among patients with cryptogenic
[21]
NASH-cirrhosis since 2002 . However, the association between diabetes and the risk of HCC in NASH
patients with cirrhosis is not well quantified and completely understood. Diabetes increases the risk of
[22]
liver disease progression to cirrhosis in patients with NASH. Only recently, Yang et al. investigated the
association between diabetes and HCC in patients with NASH cirrhosis in an large cohort with a longer
follow-up and were able to demonstrate, even also in humans, that T2DM is associated with an increased
risk of HCC in patients with NASH cirrhosis. Their secondary aim was to investigate the association
between other metabolic risk factors (body mass index, hypertension, and hyperlipidemia) and HCC.
[22]
However, the above metabolic risk factors were not associated with HCC risk .
Unfortunately there are not many other studies in humans that help to elucidate the molecular mechanisms
underlying the pathogenesis of NASH-HCC related to T2DM. Progress in this field depends on the
availability of reliable preclinical models amenable to genetic and functional analyses and exhibiting robust
NASH-to-HCC progression.

GENETIC, LIVER METABOLIC DISEASE AND NASH-HCC
Only recently was the association between NASH and genetic predisposition investigated, especially in
young adults with NASH without any metabolic diseases. The most recent and important study is the one
by Unalp-Arida and Ruhl . They examined the relationships of liver disease markers, including patatin-
[21]
like phospholipase domain-containing protein 3 (PNPLA3) I148M,w ith mortality in a very large series
(13,298 viral hepatitis-negative adults) belonging to the United States National Health and Nutrition
Examination Survey, 1988-1994, with 27 years of linked mortality data. They found that PNPLA3 I148M
was associated with increased liver disease mortality, and they suggested that the genetic variant PNPLA3
I148M may be used as a marker in patients with NAFLD/NASH for HCC surveillance.

SCREENING AND SURVEILLANCE OF HCC IN PATIENTS WITH NASH-CIRRHOSIS OR
METABOLIC DISEASES
There is now substantial evidence that NAFLD/NASH-associated HCC may arise either in the presence
or absence of cirrhosis [3,4,13,14,22-24] . Limited data are available to address the clinician’s need to know who is