Page 304 - Read Online

Page 4 of 9 Martini et al. Hepatoma Res 2018;4:28 I http://dx.doi.org/10.20517/2394-5079.2018.50

Figure 2. Biological activities determined by SerpinB3, with particular regard to metabolism and immune response modulation

mice transgenic for liver SerpinB3 showed higher liver regenerative ability compared to wild-type mice,
supporting a role of this protein in promoting cell growth and proliferation . Other mechanisms of tumor
[26]
growth promotion induced by SerpinB3 include the up-regulation of Myc oncogene transcription with two
different strategies : the first mechanism is through the intracellular SerpinB3 antiprotease activity that
[27]
blocks its cleavage exerted by Calpain, preventing the generation of the non-oncogenic cytoplasmic Myc-
nick form and allowing nuclear translocation of Myc with pro-oncogenic activity. The second one consists in
the transcriptional induction of Myc, through the increase of Yap pathway . Furthermore, recent findings
[27]
indicate that SerpinB3/SerpinB4 isoforms are a Ras-responsive factor that plays an important role in Ras-
associated cytokine production and tumorigenesis .
[28]

Metabolic functions
Recent findings indicate that SerpinB3 can determine metabolic alterations in the liver through the
induction of dipeptidyl peptidase-4 (DPPIV/CD26), a transmembrane glycoprotein, that is increased in
various malignant tumors, including HCC, and the expression of these two molecules was found positively
correlated in HCCs and in the surrounding cirrhotic tissue . Hepatoma cells overexpressing SerpinB3
[29]
showed increased DPPIV/CD26 levels and these features were associated with an increase in lipid droplet
formation and with decreased glycogen deposition, typical features induced by DPPIV/CD26 [30-32] [Figure 2].
These results are in agreement with previous findings, reporting remarkable lipid accumulation and glycogen
depletion in the liver of SerpinB3-transgenic mice . In addition, SerpinB3 was found overexpressed in
[33]
human livers with NASH , a condition at risk of HCC development. It is worth to note that SerpinB3
[34]
determined also a decreased oxygen consumption rate , as a possible consequence of its physical interaction
[29]
with mitochondrial respiratory complex I .
[24]
SerpinB3 in liver cancer
In the liver SerpinB3 and its isoform SerpinB4, are undetectable in normal hepatocytes, but their expression
progressively increases in chronic liver disease, in dysplastic nodules and in HCC [36,37] , suggesting their
[35]
involvement in relatively early events of hepatocarcinogenesis . SerpinB3 has also been detected in
[35]
hepatoblastoma, the embryonal tumor of the liver, especially in the most aggressive forms, where a direct
correlation was observed between its gene expression, the up-regulation of Myc oncogene and tumor extension .
[38]
The presence of SerpinB3 has been further described in liver stem/progenitor cells positive for the hepatic
epithelial cell adhesion molecule (EpCAM), both in human fetal livers and in adult livers with cirrhosis, and
these findings were corroborated by the induction of this serpin in a mouse model of liver stem/progenitor
cell activation . Liver tumors with stemness signature are highly aggressive, and along this line the highest
[39]