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Page 8 of 16 Chávez-López et al. Hepatoma Res 2020;6:14 I http://dx.doi.org/10.20517/2394-5079.2019.023

function studies showed that KCNQ1 exhibited remarkable inhibitory roles on tumor metastasis in vitro
and in vivo; thus, this channel could represent a prognostic marker, as well as a promising therapeutic
target for HCC [105] . Another study found that the KCNJ11 channel was differentially expressed in HCC,
and it predicted the poor prognosis in HCC patients. KCNJ11 promotes tumor progression through
interaction with lactate dehydrogenase A (LDHA). Pharmacological inhibition of LDHA or knockdown of
KCNJ11 expression inhibited cell proliferation, promoted apoptosis, and reduced cell invasive capacity [106] .
K channels regulate mitogen-induced proliferation in the human liver cell lines HepG2, which could
ATP
[37]
have implications for liver growth control and serve as a potential therapeutic target . The voltage-gated
potassium channel ether à-go-go-1 (Eag1) has gained enormous interest in cancer research because of
its oncogenic properties [107-109] . Eag1 channels have also been proposed as early tumor biomarkers and
therapeutic targets for different types of cancers [110,111] . Moreover, the inhibition of Eag1 reduces tumor
cell proliferation in vitro and in vivo [112-114] . We reported that HepG2 and HuH-7 HCC cells displayed Eag1
channel expression, and that the anti-histamine astemizole (a non-specific Eag1 inhibitor) decreased cell
proliferation and induced apoptosis in both cell lines. In addition, an increase in Eag1 expression was
found during HCC development in rats. Astemizole treatment prevented HCC development and seems to
induce tumor regression in rats with HCC [115] .

T-type calcium channels play an important role in cell cycle progression in different types of cancer [116] .
The expression of the three T-type calcium channel subunits was observed in HCC cell lines and T-type
channel blockage with mibefradil decreased cell proliferation in the SNU449 cell line [117] . P2 purinergic
receptors are overexpressed in certain cancer tissues; the levels of P2Y2 receptor are enhanced in HCC
2+
compared with human normal hepatocytes. These receptors are involved in ATP-induced (Ca ) increase.
i
Silencing P2Y2R expression inhibited ATP-induced human HCC cell proliferation and migration, and
P2Y2R blockage inhibited cell growth in mice [21,118] . In addition, high P2X3 receptor expression is associated
with poor recurrence-free survival in HCC, while high P2Y13 expression is associated with improved
recurrence-free survival. Moreover, extracellular nucleotide treatment induce cell cycle progression and
extracellular ATP-mediated activation of P2X3 receptors promotes proliferation of HCC cells [119] . SOCE
2+
2+
is a major Ca influx pathway controlling the intracellular Ca concentration in normal hepatocytes and
2+
HCC cells, and Ca influx has been demonstrated to be involved in liver oncogenesis. Accordingly, the
blockade of SOCE inhibits hepatocarcinoma cell migration and invasion, by regulating focal adhesion
turnover [120] . The activation of SOCE channels is implicated in cancer cell chemoresistance, although the
2+
underlying molecular mechanisms are not well understood. However, inhibition of Orai1-mediated Ca
entry enhances chemosensitivity to 5-fluorouracil of HepG2 hepatocarcinoma cells [121] . The specific roles
and molecular mechanisms of calcium entry in drug response deserve further investigation.

CIC-3 chloride channels have multiple functions in tumorigenesis and tumor growth in HCC; the CIC-3
channel blocker DIDS (4,4’-diisothiocyanostilbene-2,2’-disulfonic acid) arrests the cell at the G1 phase,
inhibiting the proliferation of Hep3B HCC cells [122] . Proteomic approaches found that the chloride
intracellular channel 1 (CLIC1) is upregulated in HCC tissues, and that it participates in HCC migration
and invasion by targeting maspin [123] .

The voltage-gated sodium channel β1 subunit was proposed as a cell adhesion molecule in some HCC
cell lines. The analgesic-antitumor peptide (a scorpion toxin polypeptide with antitumor activity) inhibits
the migration and invasion of HepG2 cells by an upregulated VGSC β1 subunit [124] . Additionally the over-
[96]
expression of Nav channels has been observed in an HCC in vivo model .
1.2
AQP5 is highly expressed in HCC cell lines and its downregulation inhibits HCC cell invasion and tumor
metastasis. Downregulation of AQP5 suppressed the epithelial-to-mesenchymal transition process in HCC
cells [125] . Another report found that microRNA-325-3p inhibits cell proliferation and induces apoptosis