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Page 2 of 16 Chávez-López et al. Hepatoma Res 2020;6:14 I http://dx.doi.org/10.20517/2394-5079.2019.023

INTRODUCTION
Cancer is a leading cause of death worldwide, despite the existence of hundreds of clinical trials testing
[1,2]
novel therapies . There are several types of liver cancer including hepatoblastoma, cholangiocarcinoma,
[3-7]
and angiosarcoma, but hepatocellular carcinoma (HCC) accounts for up to 90% of primary liver cancers .
Liver cancer is one of the malignancies with the worst prognosis, representing the second leading cause of
[3-5]
cancer-related deaths in the world .
The liver plays a central role in regulating whole-body carbohydrate, lipid, and protein homeostasis, as well
as playing additional very important physiological roles including the synthesis and transport of bile acids
[6,8]
and the detoxification of endogenous and exogenous metabolites . This very important organ is exposed
to several factors including infections by hepatitis viruses B and C, alcohol use, aflatoxin B1, and fatty
diet. Several of these factors lead to liver cirrhosis, which is the major HCC-associated risk factor [6,9-11] . In
fact, a significant percentage (> 80%) of HCC patients previously had liver cirrhosis. Unfortunately, HCC
is rarely detected at early stages, and is usually fatal within a few months of diagnosis. The percentage of
mortality-to incidence ratio of liver cancer is very high; it is more than 90% globally, reaching up to 100%
[1]
in some countries . Therefore, novel early HCC markers and therapeutic strategies are urgently needed.
In this regard, ion channels have gained great interest in oncology, as novel tools for both diagnosis and
[5]
treatment . Here, we summarize most of the research associating ion channels with HCC. We also discuss
the potential tumorigenic mechanisms of action of ion channels in HCC, as well as ion channel-based
therapies for HCC prevention and treatment. The growing research field of ion channels in cancer may lead
to reduce the incidence and mortality of liver cancer.

ION CHANNELS AND CANCER
Ionic channels are pore-forming membrane proteins allowing ion flux across membranes, including the
plasma membrane and those from of intracellular organelles. In most cases, these proteins selectively
[12]
transport specific ions and the vast majority need special stimulus to be activated . These gating stimuli
include changes in membrane potential (voltage-gated ion channels), different ligands such as hormones or
neurotransmitters, temperature, mechanical forces, etc. Thus, the role of ion channels in human physiology
comprises very important phenomena such as neural transmission, cardiac function, hormone release,
sensory physiology, etc. Accordingly, many channelopathies exist including epilepsy, cardiac arrhythmias,
[12]
renal diseases, blindness, skeletal muscle disorders, etc. . Cancer is a multi-factorial disease characterized
by an increased cell proliferation rate; ion channels are essential for regulation of proliferation and are also
involved in many relevant processes occurring during carcinogenesis, which convert these proteins into
potential cancer diagnostic tools and therapeutic targets.

Ion channels associated with cancer
The roles that ion channels have during carcinogenesis depend on the step of tumor development and the
tissue type [13,14] .

Calcium channels participate in pivotal functions in the body such as regulation of blood pressure, muscle
contraction, secretion, metabolism, excitability, and cell proliferation . These channels are important
[15]
in the cell cycle, especially to enter and accomplish the S and M phase [14-18] ; thus, their participation in
cancer cell proliferation is very relevant [14,16,17] . In addition, because these ions are very important for cell
migration, they also play a very important role in cancer cell migration and metastasis [16-19] .

Potassium channels play crucial roles in every cell type and in all species. Based on their structure and
function, they are categorized into three major classes: the voltage-gated (Kv), inwardly rectifying (Kir),
and tandem pore domain (K2P) channels. Furthermore, various messengers can stimulate the ligand-