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Page 2 of 9 Martini et al. Hepatoma Res 2018;4:28 I http://dx.doi.org/10.20517/2394-5079.2018.50

future . This increase in incidence, despite the control of hepatitis B virus and hepatitis C virus infections by
[1]
vaccination and treatments, is expected by the rising levels of obesity and its metabolic complications .
[2]
Despite intensive surveillance programs, considerable recent therapeutic advances and the use of potentially
radical treatments, clinical outcome of HCC remains still poor, with the majority of patients presenting with
advanced disease not eligible for curative therapy . These treatments are indeed applicable only for early
[3]
stage tumors and include resection, liver transplantation and percutaneous ablation, while transarterial
chemoembolization (TACE) and sorafenib are regarded as non-curative treatments, able to improve
survival in intermediate and advanced stages, respectively . The identification of novel therapeutic targets
[1]
is limited by the well-known intra-nodule and inter-nodule tumour heterogeneity and heterogeneity in
tumour evolution . It is known indeed the each HCC is composed of a unique combination of somatic
[4]
alterations, including genetic, epigenetic, transcriptomic and metabolic events that form its unique molecular
fingerprint . The biological characteristics of the tumor are also enriched by the presence of a frequent
[4]
underlying chronic liver disease that leads to a persistent exposure to chronic inflammation and oxidative
stress by cirrhotic hepatocytes . In parallel to this pathological heterogeneity, gene expression profiling has
[4]
allowed the establishment of several HCC transcriptomic classifications . One of these recently identified
[5-7]
molecular subclasses (S1) of HCC, associated with poor prognosis, is characterized by aberrant activation of
Wnt signaling and transforming growth factor-beta activation . This peculiar S1 signature is characterized
[6]
by overexpression of genes associated to epithelial-to-mesenchymal transition (EMT), a process originally
described for embryo development and now believed to be involved in tumor invasion and metastasis and
known to be regulated by TGF-beta in HCC . It is interesting to note that high levels of SerpinB3 expression
[6]
were identified recently only in this subclass .
[8]

PHYSIOLOGICAL CHARACTERISTICS AND BIOLOGICAL FUNCTIONS OF SERPINB3
SerpinB3 (formerly known as squamous cell carcinoma antigen-1 or SCCA1) is a member of the family
of serine-protease inhibitors (SERPINS). SerpinB3 and its highly homologous isoform SerpinB4 (formerly
known as squamous cell carcinoma antigen-2 or SCCA2) were originally purified from a squamous cell
carcinoma of the uterine cervix . They are encoded by two separate genes located on chromosome 18q21.3,
[9]
which share a high degree of homology (up to 98%). The two encoded glycoproteins have a molecular
weight of 45 kDa and are composed by 390 amino acids with up to 92% similar composition . SerpinB3
[10]
and SerpinB4 show distinct properties and substrate specificities: the former inhibits papain-like cysteine
proteases , whereas the latter inhibits both serine and cysteine proteases . The specific function or target
[12]
[11]
depends mainly on the variety of the reactive-site loop (RSL), in which only 7 out of 13 amino acid residues
(54%) are identical, and this reactive site is involved in the interaction with the protease, its recognition, and
cleavage, resulting in its inhibition . SERPINB3/B4 are localized predominantly in the cytosol, however,
[13]
they have also been detected in other subcellular compartments including lysosomes, mitochondria, the
[10]
nucleus, and may function extracellularly . The localization of SerpinB3/B4 in the nucleus probably
depends on physiological state of the cell. While these isoforms are detectable only in the cytoplasm at basal
state in cell lines, they have been found in the nucleus in response to UV irradiation. In addition, in clinical
samples, nuclear localization of SerpinB3/B4 has been commonly reported in various types of cancers, in
psoriasis and in idiopathic pulmonary fibrosis .
[10]

Regarding their tissue expression, SerpinB3/B4 are physiologically expressed in the basal and parabasal
layers of normal squamous epithelium , and they are overexpressed in neoplastic cells of epithelial
[14]
origin [15,16] . These proteins are frequently co-expressed in other organs, such as bladder, uterus, esophagus,
lung, prostate, testis, thymus, and trachea, but the biological significance of SerpinB3/B4 in normal tissue
development and function remains largely unknown .
[10]