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Chávez-López et al. Hepatoma Res 2020;6:14 I http://dx.doi.org/10.20517/2394-5079.2019.023 Page 3 of 16
[20]
gated (Kligand) channels . Membrane hyperpolarization due to potassium channel activity is needed for
cell cycle progression from G1 to S phase. Potassium flux is also very important for apoptosis, cell volume
+
regulation, and cytokine release. Therefore, even though the precise molecular mechanism of K channel
participation in cancer remains elusive, these channels have a significant role in the cell proliferation,
migration, and angiogenesis of a variety of carcinoma cells [14,21,22] .

Different subtypes of voltage-gated sodium channels (VGSC) are differentially expressed throughout the
body, and they have essential roles in the generation and propagation of action potentials in electrically
[23]
excitable cells such as neurons and cardiac and skeletal muscle . Several carcinoma cells express
VGSC [14,24,25] . Interestingly, these channels are active in metastatic cells . Accordingly, sodium currents
[25]
[26]
through VGSC enhance migration, invasion, and metastasis in vivo .
Chloride channels are involved in many biological functions such as epithelial fluid secretion, cell-volume
regulation, modulation of excitability, smooth-muscle relaxation, and pH regulation. Cystic fibrosis is a
−
[27]
disease where the relevance of alterations in chloride flux has been shown . Cl channels are involved in
apoptosis, and in cancer cells these proteins promote proliferation, migration, and invasion [14,21,28-30] . These
channels are over-expressed in many cancer tissues including liver compared to noncancerous tissues, and
[31]
are significantly associated with tumor size, metastasis, and poor prognosis .

Before going into the details of ion channels in liver diseases leading to HCC, we first review some of the
channels for which expression has been reported in the normal liver.

ION CHANNELS IN HEALTHY LIVER
The importance of ion channels in different functions of the normal healthy liver has been reported by
several studies. Water crosses the plasma membrane either directly through the lipid bilayer or via protein
[32]
water channels [aquaporins (AQPs)] . The liver expresses at least six AQPs (AQP1, -3, -7, -8, -9, and -11).
Immunohistochemical studies showed the expression of AQPs in different hepatic cell types including
cholangiocytes (AQP1 and -7), endothelial cells (AQP1), Kupffer cells (AQP3), and hepatocytes, (AQP7,
[33]
-8, and -9) [33,34] . AQP8 and -9 are relevant for bile synthesis regulation, secretion, and modification .
Additionally, AQP9 functions as a glycerol channel in the liver .
[35]
The ATP-sensitive potassium channel (K ) is composed of two types of subunits, namely an inwardly
ATP
+
rectifying K channel (Kir6.x) and a sulfonylurea receptor. Kir6.x subunits form the pore, while sulfonylurea
receptor subunits have regulatory activity. Depending on its localization at the plasma membrane or in
organelles, these channels are classified as sarcolemmal (“sarcK ”), mitochondrial (“mitoK ”), or nuclear
ATP
ATP
(“nucK ”) channels [36,37] . Interestingly, K channel opening has been shown to alleviate liver injury by
ATP
ATP
preventing inflammation and increasing the liver tolerance to ischemia/reperfusion injury [38,39] . Besides,
[37]
DNA synthesis demonstrated that these channels play significant roles in liver growth control .
Nucleotides act as extracellular signaling molecules via purinergic receptors. These receptors are separated
into seven P2X ionotropic receptors and eight P2Y G protein-coupled receptors [40,41] . For instance, the
P2X4 receptor is the dominant P2X isoform expressed in cholangiocytes in the liver [42,43] . ATP is released
by hepatocytes, and it regulates hepatocyte glycogen metabolism, cell volume, bile formation, and other
cell functions. When activated by ATP, P2X receptors function as cation-permeable channels that allow the
influx of sodium and calcium ions [42,43] . Interestingly the expression of P2X7 receptors is decreased in HCC
[43]
Huh-7 cells .
+
[44]
Acid sensing ion channels (ASICs) are H channels that mediate tumor cell migration and invasion ,
2+
[45]
and store-operated calcium entry (SOCE) controls HCC cell proliferation and migration . T-type Ca