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Page 14 of 22 Nevola et al. Hepatoma Res 2018;4:55 I http://dx.doi.org/10.20517/2394-5079.2018.38

of transcription 3 (STAT3) and extracellular signal-regulated kinases (ERK) [169,198,199] . Such leptin-induced
pathways represent early events in the promotion of the survival and proliferation of pre-neoplastic cell
clones, thus favoring the development of HCC and its invasion and metastasis [198,199] . Furthermore, higher
levels of leptin are closely related to an increased risk of recurrent HCC after curative treatment [200] . On the
other hand, IR inhibits the production of adiponectin, an adipokin with anti-inflammatory functions, as
[169]
well as anti-atherogenic, anti-proliferative, pro-apoptotic, insulin-sensitizing and anti-angiogenic factors .
[201]
In fact, this cytokine is able to stimulate the activation of JNK and induce cell apoptosis . Reductions in
adiponectin levels appear to be closely associated with the risk of carcinogenesis [202] .

Similar to what is observed in ALD, deficiency in the autophagy mechanism is also observable in NAFLD,
causing reticuloendothelial damage and cellular oxidative stress and contributing to the formation of an
environment suitable for the development of HCC [203] .

The immune system may also participate in the complex multifactorial mechanisms of hepatocarcinogenesis.
In fact, the metabolic stress promotes the migration of immune cells in the liver, while the T cells CD8 +
and Natural Killer (NK), stimulated by the cell damage caused by NAFLD, interact with the hepatocytes
activating the signaling cascades that feed the pre-existing state inflammatory [204] . In this way, they can
establish a further vicious circle that worsens hepatocyte damage, promoting the progression of NAFLD
towards the development of HCC.

DECLARATIONS
Authors’ contributions
Designed the study: Adinolfi LE
Contributed equally to the search for literature and the writing of the text: Nevola R, Rinaldi L, Giordano M,
Marrone A
Reviewed the manuscript: Adinolfi LE, Nevola R
Approved the final version: all authors

Availability of data and materials
Not applicable.

Financial support and sponsorship
There was no financial support or sponsorship for this study.

Conflicts of interest
All authors declare that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2018.

REFERENCES
1. Global Burden of Disease Liver Cancer Collaboration. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at
the global, regional, and national level: results from the Global Burden of Disease Study 2015. JAMA Oncol 2017;3:1683-91.