Page 72 - Read Online

Chávez-López et al. Hepatoma Res 2020;6:14 I http://dx.doi.org/10.20517/2394-5079.2019.023 Page 7 of 16

lumen. Accordingly, SOCE is substantially inhibited in steatotic hepatocytes. This inhibition enhances
lipid accumulation by positive feedback and may contribute to the development of NASH and insulin
resistance [8,84] . The antidiabetic drug exendin-4 reverses the lipid-induced inhibition of SOCE and decreases
[8]
liver lipid with rapid onset .
Two-pore channels (TPCs) are cation-selective intracellular ion channels, and their activation mediates
calcium release from lysosomal stores. TPC2-deficient mice show hepatic cholesterol accumulation,
hyperlipoproteinanemia, and finally NASH [21,85] . Interestingly, the activation of transient receptor potential
type vanilloid 1 (TRPV1) by capsaicin prevents nonalcoholic fatty liver disease [86,87] . Additionally, the
TRPV4, TRPC6, TRPM7, and acid-sensing ion channels (ASIC1a) have been suggested as liver fibrosis
mediators. The blockage of these channels inhibits hepatic fibrosis, positioning them as promising
therapeutic targets [88-91] .

Liver cirrhosis and ion channels
Liver cirrhosis from any cause is the most important clinical risk factor for HCC with an annual incidence
between 2% and 4%. The transition from chronic liver disease to cirrhosis involves inflammation
and activation of hepatic stellate cells with ensuing fibrogenesis and angiogenesis. Liver cirrhosis is
characterized by diffuse regenerative nodule of hepatocytes surrounded by dense fibrotic septa with
subsequent parenchymal extinction and liver structure collapse. Over time, compensated cirrhosis may
progress to decompensated cirrhosis that results in liver failure and death [3,92-94] .

As stated above, TRPV4, TRPC6, TRPM7, and ASIC1a channels could act as liver fibrosis mediators.
Fibrosis is the prelude to cirrhosis, thus these channels might somehow also modulate cirrhosis. Other
[95]
studies have also observed over-expression of TRPV2 , TRPC6, Nav1.2, and K Ca3.1 channels as well as the
2+
[96]
Abcc3 transporter in liver cirrhosis, suggesting them as potential markers of the disease. Ca signals
2+
mediate the hepatic effects of numerous hormones and growth factors. Liver Ca signals are elicited by
2+
the intracellular Ca channel inositol trisphosphate receptor (ITPRs). Three isoforms of this receptor have
been identified, and cirrhosis affects the isoform expression .
[97]
Some reports have shown an overexpression of AQP1 in liver cirrhosis ; this protein contributes to
[98]
[99]
microvascular resistance in cirrhosis . It has been also proposed that AQP1 polymorphism may be
involved in the genetic susceptibility to develop water retention in patients with liver cirrhosis [100] . The
+
large conductance K Ca1.1 K channels (BK) are activated by membrane depolarization and/or elevations in
2+
intracellular Ca concentration. Cirrhotic livers display increased activity of BK channels; accordingly,
blockage of these channels increased the baseline portal perfusion pressure in cirrhotic livers [21,101] .
Liver cirrhosis is associated with enhanced renal tubular sodium retention, but the mechanism involved
is unknown. Interestingly, liver cirrhosis is associated with increased renal abundance of the NaCl
cotransporter [102] . Then, diverse ion channels may serve as potential markers and drug targets for several
liver diseases leading to HCC; if so, these proteins could be used as targets for HCC prevention.

Ion channels in hepatocellular carcinoma
Because the above-mentioned liver diseases may lead to HCC, and because cancer is a multi-factorial
disease, a significant amount of ion channels have been studied as potential markers and therapeutic targets
of this very poor prognosis malignancy.

Potassium channels play an important role in a variety of carcinoma cells. K Ca3.1 channels are over-expressed
in HCC and the channel blockade with TRAM-34 inhibits HCC cell proliferation in a time- and dose-
dependent manner [103,104] . A recent work showed that KCNQ1 was frequently downregulated in HCC cell
lines and HCC tissues, and that HCC patients with low KCNQ1 expression had poor prognosis. Gain-of-