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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 9 of 16

in HBV-related hepatocellular carcinoma by downregulation of AQP5 [126] . These findings suggest that
AQP5 may be a potential therapeutic target for HCC. AQP9 is the main aquaglyceroporin in the liver
and its mRNA and protein levels are downregulated in HCC tissues compared to normal hepatocytes.
Moreover, AQP9 over-expression inhibits hepatocellular carcinoma by upregulating FOXO1 expression,
and suppresses invasion by inhibiting epithelial-to-mesenchymal transition. These findings suggest that the
restoration of AQP9 expression can inhibit development of liver cancer [127,128] .

The TRP channel family has gained great relevance due to its role in several diseases. A recent study
+
2+
investigated the roles of the Na /Ca exchanger 1 (NCX1) and the canonical transient receptor potential
channel 6 (TRPC6) in regulating TGFβ in human HCC. They found that TGFβ induces the formation and
activation of a TRPC6/NCX1 molecular complex, which mediates the effects of TGFβ on the migration,
invasion, and intrahepatic metastasis of HCC. These findings suggest TRPC6 and NCX1 as potential
targets for HCC therapy [129,130] . HCC develops multi-drug resistance in most cases; interestingly, multi-
drug resistance regulation by TRPC6 and calcium-dependence has been shown in HCC cells [131] . Silencing
2+
of TRPC1 channels suppressed cell proliferation while store-operated Ca entry was significantly
increased [132,133] . On the other hand, it has been found that high expression of the vanilloid receptor-1
(TRPV1) is associated with better prognosis of HCC patients [134] .

The combined effect of static magnetic field and anti-cancer drugs has gained great interest in cancer. Static
magnetic field enhances the anti-cancer effect of capsaicin on HepG2 cells through the mitochondria-
dependent apoptosis pathway. This synergy may be explained if static magnetic field increased the binding
efficiency of capsaicin to TRPV1 channels [135] . TRPV2 contributes to the stemness of liver cancer and is
a potential target in the treatment of human liver cancer patients [136] . TRPV4 is over-expressed in HCC
tissues when compared with non-tumoral liver. Furthermore, pharmacological inhibition of TRPV4
suppressed cell proliferation, induced apoptosis, and decreased the cell migration capability by attenuating
the epithelial-to-mesenchymal transition process in HCC via modulation of the ERK signaling pathway [137] .
TRPM7 channels play a role in the migration and invasion of different types of cancer; actually, bradykinin
promotes cell migration and invasion of HCC cells via TRPM7 channels [138] .

ASICs are H -, Ca -, and Na -gated cation channels activated by changes in the extracellular pH, and
+
+
2+
ASIC1α (ASIC1a) has been associated with tumor proliferation and migration. ASIC1α is overexpressed
in HCC tissues and associated with advanced clinical stage. Silencing of ASIC1α expression inhibited the
migration and invasion of HCC cells, suggesting a novel approach for HCC therapy [139] .
The R-Tf-D-LP4 cell-penetrating peptide derived from the mitochondrial multifunctional protein VDAC1
(voltage-dependent anion channel) induced apoptosis in liver cancer cell lines and inhibited liver tumor
growth in vivo, representing a promising therapeutic approach for HCC [140] . Inositol 1,4,5-trisphosphate
2+
receptors (ITPRs) are intracellular Ca channels. ITPR3 is either absent or expressed at low levels in
normal hepatocytes, but it is over-expressed in HCC patients; its increased expression level was associated
with poor survival. Besides, cell proliferation and liver regeneration were enhanced in vivo, and ITPR3
deletion in human HCC cells increased apoptosis [141] .

Discussion: ion channels as potential tools for chronic liver diseases and HCC prevention,
diagnosis, and therapy
HCC is a leading cause of cancer-death worldwide and is one of the most chemo-resistant tumors [3,142] .
The combination of new therapeutic targets with existing therapies may be very helpful. Several ion
channels play very important roles in cancer-associated processes including inflammation, oxidative stress,
cell proliferation, apoptosis, migration, invasion, angiogenesis, metastases, and drug response. These
proteins are differentially expressed in HCC and liver diseases compared to their expression in the healthy