According to the NCBI map viewer, the gene is located on chromosome 18q21.3 (NCBI Reference Sequence: NC_000018.10) and encompasses 6767 bp.

The SERPINB3 gene comprises eight exons and seven introns which commonly encoded a 1,793 kb mRNA. The ATG start is located in exon 2 with the stop codon in exon 8.
Transcription control is regulated by STAT3. STAT3 occupies the promoter of SERPINB3/B4 and siRNA removal of SERPINB3/B4 mRNA caused cell death in HN13 head and neck cancer cells. Thus persistently activated STAT3 is a required part of the continuous activation of SERPINB3/B4 genes, which protects tumor cells from dying (Ahmed and Darnell, 2009).
Moreover recent mechanistic experiments and ChIP assays reveal that SERPINB3 increased expression in response to hypoxic conditions is specifically mediated by the binding of HIF-2α to the SERPINB3 promoter (Cannito et al., 2014).

No known pseudogene.

SERPINB3 encodes a 390 amino acid 44,56 Kda protein, which shows sequence homology to the ovalbumin family of serine protease inhibitors (Ov-serpin) (Remold-ODonnell, 1993), a subfamily of the large serpin superfamily. Serpins have a highly ordered tertiary structure defined by the crystal structure of the prototype molecule α1-antitrypsin, consisting of nine α-helices and three β-sheets arranged in a stressed configuration with the reactive center, which has the unusual feature of being the most variable region, located in an exposed loop (Hunt and Dayhoff, 1980).
The mechanism of protease inhibition by serpins involves a profound change in conformation, initiated by interaction of the protease with the reactive site loop of the serpin (RSL) (amino acids 340-368). RSL consists of a loop projecting from the body of the protein, comprising a hinge region and a variable RSL (Huntington et al., 2000).
Biochemical analysis of recombinant SERPINB3 shows that it is a potent cross-class inhibitor of papain-like cysteine proteinases such as cathepsin L, cathepsin S and cathepsin K (Schick et al., 1998).
An isoform produced by alternative splicing has been reported. The sequence of this isoform differs from the canonical sequence for 205-256 amino acid missing (Fig.2).

SERPINB3 is expressed in the spinous and granular layers of normal squamous epithelium, in several organs including: epithelium of the tongue, esophagus, tonsil, cervix uterine, vagina, Hassals corpuscles of the thymus and some areas of the skin. SERPINB3 was also detected in saliva, respiratory secretions and amniotic fluid samples from healthy individuals (Kato, 1996; Cataltepe et al., 2000). Moreover, SERPINB3 was recently reported to be expressed on CD27+ B lymphocytes (Vidalino et al., 2012).
In particular, immunohistochemistry analysis revealed positive staining in sweat glands in the dermis of the skin, endothelial cells of the veins and arteries walls in the intestine.
Within the normal liver, SERPINB3 protein expression was seen in portal interlobular ducts, in the walls (myocytes of the media) of the large and medium sized hepatic arteries and sometimes in the endothelial cells of the portal veins.
Normal hepatocytes, sinusoidal cells and Kupffer cells do not exhibit any reactivity, except some hepatocytes in the limiting plate that can show focal faint positivity (Turato et al., 2012).
HepCAM positive liver stem cells from both foetal and adult livers also express SERPINB3 (Villano et al., 2014).
Initially, SERPINB3 was discovered as a serological marker for advanced squamous cell tumors in the cervix (Uemura et al., 2000), and was later found to be associated with other types of cancer with epithelial or endodermal origins. Moreover, elevated expression of SERPINB3 is associated with high-grade breast carcinoma and correlates with estrogen receptor/progesterone receptor double negative tumors as well as with a poor prognosis for breast cancer patients (Catanzaro et al., 2011).

SERPINB3 may be found in cytoplasmic and pericellular locations (Uemura et al., 2000). Moreover an additional surface localization for this serpin has been reported (De Falco et al., 2001; Vidalino et al., 2012).
Although it was initially reported that SERPINB3 is a cytosolic protein, its nuclear localization has been also described recently, expanding the potential range of physiological functions of this molecule. Under certain conditions, such as following exposure to UV irradiation, SERPINB3 is translocated into the nucleus. Although SERPINB3 does not possess a nuclear localization signal, it binds with c-Jun NH2-terminal kinase-1 (JNK1), and upon JNK1 activation SERPINB3 enters the nucleus (Katagiri et al., 2006).
In addition, other studies have shown that SERPINB3 may be secreted in serum and can predict HCC development in patients with cirrhosis (Pontisso et al., 2006).

SERPINB3 is physiologically involved in the regulation of differentiation in normal squamous epithelium and is overexpressed in neoplastic tissue of epithelial origin, where it might be involved in the apoptotic pathway as a protease inhibitor (Suminami et al., 1998).
Regarding their role in normal epithelia, it has been suggested that SCCA isoforms may protect from bacterial, viral cystein proteases (Suminami et al., 1998), and mast cell chymase (Schick et al., 1997).
As a protease inhibitor, SERPINB3 is able to inhibit cysteine proteases (cathepsins L, S, K and papain) (Schick et al., 1998), and in cancer cells it confers resistance to drug-induced apoptosis by inhibiting lysosomal cathepsin proteases (Suminami et al., 2000). However, under a variety of stress conditions SERPINB3 displays an anti-apoptotic function unrelated to its proteinase inhibition activity (Vidalino et al., 2009; Ciscato et al., 2014). Indeed, SERPINB3 protects cells from exposure to radiation through an inhibitory effect either on the MAP family of c-Jun terminal kinase (JNK) (Katagiri et al., 2006) and the interaction between SERPINB3 and JNK1 was also supported by the crystallographic study (Zheng et al., 2009); or with a decreased phosphorylation of the proapoptotic p38 mitogen-activated protein kinase on p38 (Murakami et al., 2001). In epithelial ovarian cancer cells exposed to cisplatin, SERPINB3 expression is associated with drug resistance and poor progression-free survival (Ullman et al., 2011; Lim et al., 2012), whereas it inhibits the release of mitochondrial cytochrome c in squamous cell carcinoma after treatment with TNF-α (Hashimoto et al., 2005), or with DNA alkylating agents (Ullman et al., 2011).
Moreover, SERPINB3 expression is associated with poor survival in patients with breast cancer treated with anthracycline-based neoadjuvant chemotherapy (Collie-Duguid et al., 2012) and in patients with epithelial ovarian cancer a high SERPINB3 expression is a prognostic factor for platinum resistance and shorter progression-free survival (Lim et al., 2012).
In addition, recent results, reported that SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I (Ciscato et al., 2014).
Experiments carried out with serum-derived HBV particles have demonstrated that isolated SERPINB3 protein is able to bind preS1 encoded sequence HBV surface protein, allowing virus entry into human hepatocytes and also peripheral blood mononuclear cells, underlying its potential biological role in HBV infection (De Falco et al., 2001; Pontisso et al., 1991; Ruvoletto et al., 2004).
This serpin induces also cell proliferation and deregulation of adhesion processes, leading to epithelial-mesenchymal transition (EMT) with increased invasiveness potential (Quarta et al., 2010). In addition, it has been reported that it induces TGF-β expression (Calabrese et al., 2008; Turato et al., 2010) and promotes fibrogenesis in experimental models (Lunardi et al., 2011).
In addition, SERPINB3 may enhance its oncogenic potential through inhibition of several tumor suppressive miRNAs (Turato et al., 2014a) and could play a role in the development of cancer phenotype.
More recently, it has been reported that increased SERPINB3 expression leads to inhibition of protein turnover, unfolded protein response, activation of NF-kB and is essential for Ras-mediated cytokine production and tumour growth (Catanzaro et al., 2014).

SERPINB3 and SERPINB4 isoforms, also known as squamous cell carcinoma antigen 1 and 2 (SCCA1 and SCCA2) are highly homologous, 91% identical at the amino acid level (Suminami et al., 1991), share conserved tertiary structure, and use a unique conformational rearrangement for their inhibitory activity (Stein et al., 1990). However, SERPINB3 and SERPINB4 show distinct properties and substrates: SERPINB3 inhibits papain-like cysteine proteinases, cathepsins K, L, and S while SCCA2 inhibits chymotrypsin-like serine proteinases, cathepsin G and mast cell chymase (Takeda et al., 1995; Schick et al., 1997).
In mouse, SCCA locus (SERPINB3 and SERPINB4) was expanded and contained four genes, Serpinb3a, -b3b, -b3c, and -b3d, and three pseudogenes, Serpinb3-ps1, -ps-2, and -ps-3. Percentage protein sequences identity: 55-59%) (Askew et al., 2004).
Moreover similarity-to-human data found for SERPINB3 was found in: worm (Caenorhabditis elegans), fruit fly (Drosophila melanogaster), mosquito (Anopheles gambiae), chicken (Gallus gallus), mouse (Mus musculus), rattus (Rattus norvegicus) and chimpanzee (Pan troglodytes).

Maps of different Single-nucleotide polymorphisms (SNP) in human SERPINB3 are reported in Fig.2. Only SNP rs3180227 has beeen well characterised (Turato et al., 2009).
This polymorphic variant (also know as SCCA-PD) presents the 351G/A mutation in the variable reactive site loop (RSL) of the protein (GenBank accession number: AY190327).
The prevalence of SCCA-PD was 24% in the normal population, while in patients with cirrhosis it was 45%, supporting the hypothesis of a higher contribution of this isoform to liver disease progression. In addition, the specific amino acid change detected in the reactive center of this SNP might confer a different biological behavior to the serpin improving the antiprotease activity of SERPINB3 (Turato et al., 2011).