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Martini et al. Hepatoma Res 2018;4:28 I http://dx.doi.org/10.20517/2394-5079.2018.50 Page 5 of 9

levels of SerpinB3 have been found overexpressed, together with TGF-β1, in the subset of aggressive forms of
hepatocellular carcinoma, characterized by early tumor recurrence after surgical resection .
[8]

The tight correlation between SerpinB3 and TGF-β, that requires the integrity of the RSL of SerpinB3, as
documented by in vitro studies , has been also confirmed in non-tumor cirrhotic livers. The alterations of
[40]
the microenvironment, characterized by the presence of chronic inflammation associated with liver fibrosis,
typical features of the cirrhosis status, have been identified as a hallmark of liver carcinogenesis. In fact,
more than 80% of the cases of hepatocellular carcinoma arise in livers with cirrhosis, a condition which
constitute a real precancerous stage . Activated hepatic stellate cells (HSC) represent key drivers of liver
[41]
fibrosis and extracellular matrix (ECM) remodeling , and a recent study has demonstrated that SerpinB3 is
[42]
able to directly activate human HSC, resulting in a strong up-regulation of the expression of genes involved
in fibrogenesis and angiogenesis .
[43]
In recent years there is growing evidence that the impairment of immune surveillance plays a pivotal role in
liver cancer development and progression . In this context, TGF-β is a key player, suppressing proper anti-
[44]
tumor immune responses , through the induction of regulatory T cells (Tregs) that have a profound ability
[44]
to control immune responses [45,46] and SerpinB3 might be also involved in the immune escape mechanism
by enhancing TGF-β production. Other findings through which SerpinB3 seems to promote the immune
impairment are its ability to inhibit the intratumor infiltration by natural killer cells and to reduce the
[47]
inflammatory response in other experimental settings .
[48]
Diagnostic and prognostic significance
One of the most important and yet unmet needs in clinical settings is the availability of serological markers
to identify patients with cirrhosis at higher risk of HCC development. Since the incidence of hepatocellular
carcinoma in individuals with cirrhosis is 3%-5% per year , the identification of the subgroup of patients
[49]
with possible HCC development within the next few years would allow the development of a personalized
clinical management and more effective early therapeutic interventions. On the basis of the oncogenic
potential of SerpinB3, and of the reported findings of the presence of SERPINB3/4 isoforms (or SCCA) in
the vast majority of HCCs specimens , in the last years ELISA assays have been developed to assess the
[36]
presence of SCCA as free protein and/or bound to IgM as circulating immune complexes in serum . The
[50]
occurrence of biomarker-IgM immune complexes has been described as the result of cancer immunoediting,
in which natural IgMs are important players of the innate immune system preventing tumor formation .
[51]
Free SCCA is barely detectable in serum of patients with advanced liver disease and primary liver cancer,
while this molecule was found coupled to IgMs (SCCA-IgM) in the majority of patients with HCC, whereas
in the healthy control population their levels were below the limit of detection .
[50]
Patients with cirrhosis
The concentration of circulating SCCA-IgM has been found progressively increased at different stages of liver
disease, from chronic hepatitis to cirrhosis and HCC, reflecting the extent of SCCA protein overexpression
in the liver . In individual patients, the progressive increase of SCCA-IgM over time was remarkable in
[52]
cirrhotic patients who developed HCC, and resulted unchanged in the majority of the cirrhotic patients
without evidence of liver cancer during the same time interval . These data have been confirmed in another
[52]
retrospective study , where baseline values of serological SCCA-IgM were nearly 4-fold higher in patients
[53]
who developed HCC than in those without HCC progression. In addition, SCCA-IgM values ≤ 200 AU/mL
accurately identified patients at low risk of liver cancer in the subsequent year, with a negative predictive
value of 97% .
[53]

In agreement with these findings, the prognostic role of this biomarker was confirmed in a prospective
study showing that, among patients matched for clinical stage of cirrhosis, those with baseline levels of