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Page 2 of 18 Kouroumalis et al. Hepatoma Res 2018;4:34 I http://dx.doi.org/10.20517/2394-5079.2018.33

death, after cancers of stomach and lung. HCC global incidence varies usually following the distribution of
hepatitis B or C viruses. It is highest in China, eastern Asia and Africa (20-35 per 100,000 population) and
low (< 5 per 100,000) in Northern Europe and the USA. Mediterranean and eastern European countries have
an intermediate rate of 10-20 per 100,000 population .
[1-3]
In 1968, a hormone secretion inhibitory molecule was described, later cloned and named somatostatin . The
[4]
somatostatin (SST) protein has two active forms created by alternative cleavage of a single pre-protein: the
14 amino acids SST14 and the 28 amino acids SST28, different only in potency but not in function . It soon
[5]
became obvious that SST had many potential therapeutic implications but the natural molecules had the
inherent drawback of a very short half-life (less than 3 min) that made in vitro and in vivo applications very
difficult. Therefore somatostatin analogues (SSA), namely octreotide, vapreotide, lanreotide and pasireotide
were later synthesized to overcome the difficulty .
[6-8]
Extensive research resulted in identification and cloning of five somatostatin receptor (SSTR) subtypes
(SSTR1- SSTR5) with two splice variants (SSTR2A and SSTR2B) for SST2. They are a family of transmembrane
G-protein-coupled receptors and are encoded by separate genes on different chromosomes. All five receptors
bind natural SST14 and SST28 with a high affinity. The synthetic analogues bind to some but not all receptors
with varying affinity. Octreotide and Lanreotide have a binding affinity only for SST2 and SST5 while
pasireotide binds to all receptors with the exception of SST4 [9,10] .

Several intracellular pathways are activated after binding SST or its analogues to the receptors leading to
down-stream signaling and modulation of adenylyl cyclase (AC) (SSTRs 1-5), phosphotyrosine phosphatases
(PTPs) (SSTRs 1-3) and mitogen activated protein kinase (MAPK) (SSTR4), as well as calcium and potassium
channels and the sodium-proton antiporter [6,9,11-13] .

Research data have made clear that somatostatin has several antineoplastic actions and could be used in
clinical applications in various human cancers , including HCC. An extensive review has been recently
[14]
published . The present report will therefore summarize both experimental and clinical data on the use of
[10]
SST and SSA in HCC.

EXPERIMENTAL DATA
There are many reports providing strong evidence that somatostatin may have an effect on HCC. Research
is focused on the variability of SSTRs present in isolated cells and liver tissue, but also on functional aspects
of the activation of these receptors.

SST receptors in liver cells
Hepatoma cells
Hep G2 cells are the most widely used human hepatoma cell line in liver research. The presence of mRNA
of only 2, 3 and 4 SSTR subtypes was demonstrated in these cells by Northern blotting but inconsistent
[15]
results have been reported.

Another report found that cultured HepG2 cells expressed all five SSTRs, at both the protein and mRNA
levels, while HuH7 hepatoma cells lack SSTR3 . Using immunohistochemical staining, HepG2 cells were
[16]
reported to display weak expression of SSTR2 and moderate levels of SSTR5. Hep3B cells showed weak
expression of SSTR3 and strong SSTR2 and SSTR5 staining while HuH7 cells additionally stained positive
also for SSTR1, but not SSTR3 .
[17]
Our laboratory reported that HepG2 cells were found to express SSTR2, SSTR3 and SSTR5 receptors by
RT-PCR. All these SSTRs were shown to have a mainly intracellular distribution with different individual