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Page 4 of 16 Chávez-López et al. Hepatoma Res 2020;6:14 I http://dx.doi.org/10.20517/2394-5079.2019.023
[46]
channels participate in modulating the proliferation of some HCC cells . Because the expression levels of
these channels (ASICs, SOCE, and T-type) [44,45] are increased in HCC in comparison with the normal liver,
they may be used as markers of the disease.

In the following, we describe several findings associating ion channels with HCC, beginning with some
liver diseases representing important HCC etiological factors.

ION CHANNELS IN LIVER DISEASES
Several liver diseases have been identified as HCC etiological factors, and many ion channels have been
found to have a role in liver diseases. Table 1 summarizes the ion channel expression changes for the most
common liver diseases.

Viral hepatitis and ion channels
It is estimated that 350 million people are chronic hepatitis B virus (HBV) carriers in the world, and that
up to 30% of them develop progressive chronic liver disease appearing as hepatitis, fibrosis, cirrhosis, and
[47]
HCC . HBV infection produces chronic necro-inflammation with subsequent fibrosis and hepatocyte
proliferation. One of the viral factors potentially involved in HBV-related hepatocarcinogenesis is the HBx
protein, which promotes cell cycle progression and inactivates negative growth regulators. This protein also
binds to and inhibits the expression of p53, as well as other tumor suppressor genes and senescence-related
factors [3,48-50] . The HBx protein regulates calcium signaling through the activation of store-operated calcium
channels (SOCs), which stimulate HBV replication [51,52] . In addition, HBx can activate SOCs by binding
[53]
C-terminal of Orail protein channels . Interestingly, co-immunoprecipitation experiments and pull-down
assays demonstrated the interaction between HBx and the Orai1 protein; the C-terminus of the Orai1
protein was involved in such interaction. The authors concluded that the HBx protein binds to the STIM1-
[53]
Orai1 complexes regulating the activity of SOCs . In this same direction, the HBV PreS2-mutant large
surface antigen activates store-operated calcium entry and promotes chromosome instability .
[54]
On the other hand, miR-125b inhibits HBV expression in vitro by targeting the sodium channel SCNN1A
[55]
gene . It has also been observed that P2X7 function is necessary for the infection of human hepatocytes
by HBV. Because P2X7 activation is a major component of inflammatory responses, HBV may contribute
[56]
to liver inflammation .

In the case of hepatitis C virus (HCV) infections, it is estimated that 130 million people have chronic HCV
[47]
infection and most of them develop chronic liver disease . Continuous inflammation and hepatocyte
regeneration in the setting of chronic hepatitis and subsequent progression to cirrhosis are thought to
lead to chromosomal damage, and possibly to initiate hepatic carcinogenesis. HCV also induces steatosis;
oxidative stress causes steatohepatitis and these pathways lead to liver injury or HCC in chronic HCV
infection [3,57,58] . Interestingly, the HCV p7 protein forms a cation channel in vitro [59-61] , and p7 deletions and
point mutations markedly reduce the production of infectious virions in cell culture [61-63] . p7 is a proton
channel required for the production of infectious virions . There are some small molecules that block the
[64]
p7 channel function and virion production in culture, rendering it an attractive antiviral target [59,65-71] .

P2X4 receptors expression form part of the purinergic signaling complex in HCV-induced liver
pathogenesis [72,73] . Additionally, the modulation of the gamma-aminobutyric acid type A (GABA-A)
receptor activity was observed in several chronic hepatitis failures, including hepatitis C. Increased
expression of GABA-A α1 receptor subunit, and decreased expression of GABA-A β3 subunit have been
found in chronic hepatitis C patients. Thus, the expression of GABA-A receptor subunits may be associated
with either current or previous HCV infection .
[74]