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Kouroumalis et al. Hepatoma Res 2018;4:34 I http://dx.doi.org/10.20517/2394-5079.2018.33 Page 5 of 18

subtypes involved and are not similar to all cell types. SSTR1 acts through the stimulation of the tyrosine
phosphatase SHP-2, activation of the MAP kinase ERK pathway and induction of the p21Waf1:Cip1 , while
[44]
the SSTR5 acts through inhibition of guanylate cyclase, and MAP kinase ERK . The cytostatic role of
[45]
the SSTR2 has been connected to the modulation of ERK1/2 signaling pathway and the activation of
[46]
the phosphotyrosine phosphatases (PTPs) SHP-1, SHP-2 and PTPη. SHP-1 induces proapoptoptic caspase-
mediated signals and also causes apoptosis by activation of the NF-κB leading to the inhibition of the JNK
anti-apoptotic effects. Activation of PTPη, dephosphorylates intracellular effectors such as the ERK and the
PI3K/Akt pathways leading to upregulation of the cyclin kinase inhibitors p21cip1/waf1 and p27kip1. Cells
are therefore accumulated in the G1 phase and cell proliferation is blocked [8,47] . pERK1/2 was inhibited in
response to natural SST while receptor-specific agonist treatment caused a dual effect: inhibition at lower
concentrations and activation at higher concentrations .
[48]
Earlier studies also pointed out that SSTR2, but not SSTR3, mediated induction of cyclin-dependent kinase
inhibitors p21 and p27Kip1 leading to cell cycle arrest . However, a recent report has shown that SSTR2 and
[49]
SSTR3 co-expression strongly induced p21 and p27Kip1 expression and therefore had a cytostatic effect .
[48]
Inherent to the anti-proliferative effect of SST is the induction of apoptosis whether dependent or independent
of p53 [34,50,51] . Apoptosis induction is mediated by either the SSTR2 activation or the co-expression and
heterodimerization of SSTR2 and SSTR3 [48,52] .

Caspase-mediated signaling pathways of octreotide antitumor activity in HepG2 cells were also reported from
our lab. We have observed an interesting phenomenon that may have therapeutic implications. Measuring
activities of various caspases and apoptosis in HepG2 cells we found that octreotide decreased proliferation
only at concentrations of 10 mol/L, while lower concentrations increased proliferation, indicating that
-8
measurements of serum octreotide levels may be important, at least in clinical trials, to verify optimal
therapeutic drug concentrations .
[53]

There are additional molecular pathways through which SST and SSAs increase apoptosis in a time and dose
dependent manner in human hepatoma cells. Thus, they were found to increase expression rates of the Fas-
Fas ligand system leading to apoptosis .
[54]

Another intriguing mechanism is the facilitation of apoptosis by endogenous opioids. We have demonstrated
in HepG2 cells that opioids inhibit proliferation and induce apoptosis. Since functional opioid receptors
were not found on HepG2 cells we demonstrated that opioids bind to somatostatin receptors activating
[55]
a PTP signaling cascade . Interestingly, a native functional endogenous opioid system was recently
described. Opioid growth factor (OGF) and its receptor were identified in hepatoma cell lines and in
specimens from HCC. OGF inhibited tumor cell replication by inhibition of DNA synthesis without
interfering with apoptosis .
[56]
Direct or indirect inhibition of various trophic factors associated with the progress of HCC
One of the most important systems involved in tumor progression is the growth hormone-insulin-like
growth factor-somatostatin (GH-IGF-SST) system. Several components of this system have been shown to
be regulators of hepatocarcinogenesis [57-59] . In particular over-expression of IGF1 receptor and decrease of
IGF-binding proteins have been described in patients with HCC and hepatoma cell lines. Interestingly an
increase of cathepsin D, an acid serum protease that cleaves IGF binding proteins, has also been described
in HCC [60,61] . Many studies have evaluated the relation between increased levels of IGF1 receptors and liver
diseases and the oncogenic role of IGF2 and its implication in angiogenesis, migration and, consequently, in
tumor progression .
[62]