|Written||2014-06||Cristian Turato, Patrizia Pontisso|
|Department of Medicine, University of Padua, Padua, Italy|
|Abstract||Review on SERPINB3, with data on DNA/RNA, on the protein encoded and where the gene is implicated.|
|serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 3|
|serpin peptidase inhibitor, clade B (ovalbumin), member 3|
|Location||18q21.33 [Link to chromosome band 18q21]|
|Location_base_pair||Starts at 63655197 and ends at 63661963 bp from pter ( according to hg19-Feb_2009) [Mapping SERPINB3.png]|
|Local_order||According to Entrez-Gene, SERPINB3 maps to NC_000018.10 in the region between 63655197 and 63661963, complement and span 6767 bases. Flanked by SERPINB4 and SERPINB11.|
|Note||SERPINB3, also known as SCCA1, encodes members of the serpins family. The serpins are a family of protease inhibitors originally grouped together as serine protease inhibitors, most of which are secreted (Silverman et al., 2004). The clade B serpins comprise a number of proteins including SERPINB3. In the early 1990's (Takeshima et al., 1992) it was recognized as circulating "squamous cell carcinoma antigen" (SCCA1) that was present in a substantial fraction of sera from patients bearing squamous cell cancers of the cervix. Later on it was found to be associated with other types of cancer of epithelial or endodermal origins, including lung cancer, head and neck cancer, and hepatocellular carcinoma (Schneider et al., 1995; Pontisso et al., 2004).|
|Figure 1. A) SERPINB3 maps in chromosome 18q21.3 (NC_000018.10) in the region between 63655197 and 63661963. Local order and flanked genes are reported. B) Map of a SERPINB3 transcript mRNA (NM_006919.2) showing its organization in 8 exon.|
|Description||According to the NCBI map viewer, the gene is located on chromosome 18q21.3 (NCBI Reference Sequence: NC_000018.10) and encompasses 6767 bp.|
|Transcription|| 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).
|Pseudogene||No known pseudogene.|
|Figure 2. SERPINB3 protein mature chain. Site of Reactive Center Loop (RSL) (blue), and described variants (green) are indicated. Potential site of splicing variant missing amino acids 205-256 are also reported (yellow).|
|Description|| 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-O'Donnell, 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).
|Expression|| 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, Hassal's 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).
|Localisation|| 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).
|Function|| 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).
|Homology|| 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).
|Note|| 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).
|Note|| Several papers have documented the key role of SERPINB3 in Hepatocellular Carcinoma (HCC).|
SERPINB3 is almost undetectable in normal liver but it is expressed in HCC cells and in cells of highly dysplastic nodules and hepatocytes of peri-tumoral cirrhotic tissue, suggesting that SERPINB3 expression may represent a relatively early event in hepatocarcinogenesis (Guido et al., 2008).
SERPINB3 has been proposed as a serological biomarker that, alone or in combination with α-fetoprotein, may improve the sensitivity of HCC diagnosis (Beneduce et al., 2005; Giannelli et al., 2007a). Circulating SERPINB3-IgM immuno-complexes have been described in cirrhotic patients at higher risk of HCC development (Pontisso et al., 2006) and in patients with HCC diagnosis (Beneduce et al., 2005).
Moreover, it has been reported that human hepatoma cells, stably transfected in order to over-express SERPINB3, exhibited a significant increase in proliferation rate and unequivocal evidence of invasiveness and Epithelial to Mesenchimal Transition, then potentially acting as a putative paracrine mediator able to favor cancer cell growth and metastatic invasiveness (Quarta et al., 2010).
In addition a very recent study revealed that high levels of SERPINB3 were detectable in 22% of HCCs specimens from cirrhotic patients and were found to be significantly associated with early tumor recurrence, then representing a candidate prognostic marker able to identify the subset of most aggressive HCCs (Turato et al., 2014b).
|Note|| Elevated levels of Squamous cell carcinoma antigen (SCC-Ag) is secreted by non-small cell lung tumours (NSCLC) and can be detected in serum (Mino et al., 1988).|
It has been reported that preoperative SCC-Ag level in serum and its postoperative decrease have prognostic significance in NSCLC (Vassilakopoulos et al., 2001).
Moreover, in another study, tumor transcriptome analysis has revealed the predictive and prognostic impact of lysosomal protease inhibitors (SERPINB3 and cystatin C) with clinical response in platinum-based chemotherapy - treated in NSCLC patients (Petty et al., 2006). These molecules potentially represent novel targets for NSCLC therapeutics.
|Note|| In a model of human epithelial ovarian cancer (EOC) using chickens, the most relevant animal model, SERPINB3 mRNA was induced in cancerous, but not normal ovaries, and it was abundant only in the glandular epithelium of cancerous ovaries of chickens.|
In addition, strong expression of SERPINB3 protein was reported as prognostic factor for platinum drug resistance and for poor progression-free survival in patients with EOC (Lim et al., 2012).
|Note|| Elevated expression of SERPINB3 is associated with both high grade and advanced stage human breast carcinomas. In addition, it has been reported that SCCA-positive breast tumors have a worse clinical outcome, including decreased overall survival and recurrence free survival (Catanzaro et al., 2011).|
Furthermore, SERPINB3 positivity predicted poor survival in patients treated with anthracycline-based chemotherapy (Collie-Duguid et al., 2012).
The implication of SERPINB3 in breast cancer may provide a novel diagnostic approach that will help to understand the initiation and advancement of breast cancer and provide new therapeutic options.
|Note|| Hepatoblastoma (HB) is the most common liver malignancy in early childhood and it is considered an embryonal tumour of the liver.|
According to a recent paper, SERPINB3 was overexpressed in 79% of the cases of HBs. Moreover, by immunohistochemistry SERPINB3 expression was found mainly in the embryonic, blastemal, small cell undifferentiated (SCUD) components of HB. High SERPINB3 reactivity was also detected in neoplastic cell clusters of portal vein tumour thrombosis. Furthermore a direct correlation was observed between SERPINB3 gene expression and tumour extension, suggesting that this serpin might help in defining the risk profile of children affected by this neoplasm (Turato et al., 2012).
|Note|| Alteration in serpin function was shown to associate with deregulation of cell survival as well as with some autoimmune traits, meaning that people carrying serpin dysfunction often display an altered immune response. A recent study explored SERPINB3 expression in patients with impaired immune response to assess the potential involvement of SERPINB3 in the deregulation of B-cell reactivity.|
Although serpins mainly act at the intracellular level, membrane-bound expression of SERPINB3 was recently demonstrated also on peripheral blood mononuclear cells, especially on CD27+ B cells. Interestingly, SERPINB3 was found to be absent on autoimmune diseases as SLE (systemic lupus erythematosus) CD27+ B lymphocytes, consistent with its expression being suppressed by high levels of type I interferon, which is a typical finding in SLE (Vidalino et al., 2012).
Since SERPINB3 displays an antiapoptotic behavior, alterations in its expression might contribute to the apoptotic deregulation seen in SLE, thereby increasing the autoantigen burden (Vidalino et al., 2009). Then, SERPINB3 expression and CD27 positivity were found to be directly related, suggesting that this serpin might also be implicated in normal B cell activation. It has to be noted that the peripheral B cell repertoire and particularly CD27+ B cell number is heterogeneously altered in SLE (Korganow et al., 2010).
In summary, these results may suggest a role for SERPINB3 in maintaining immune homeostasis, and that the impairment in serpin function may contribute to the development of autoimmune disorders.
|Note|| Idiopathic pulmonary fibrosis (IPF), with its histopathological signature of usual interstitial pneumonia is a chronic progressive disorder of interstitial lung disease of unknown etiology with a poor prognosis.|
It has been reported overexpression of SERPINB3 in lung tissue of IPF patients compared with other forms of interstitial lung diseases and normal lungs. In IPF, SERPINB3 was abnormally secreted by metaplastic epithelial cells other than bronchial cells where it is normally expressed (Calabrese et al., 2008).
Moreover, mice transgenic for human SERPINB3, showed higher TGF-β expression and more extended pulmonary fibrosis than controls (Lunardi et al., 2011).
In addition, it has been reported that SERPINB3 immunocomplexed is increased in scleroderma patients with lung fibrosis (Giannelli et al., 2007b).
|Note|| Cholesteatoma is a destructive and expanding growth consisting of keratinizing squamous epithelium in the middle ear and/or mastoid process.|
Recent data suggest that SERPINB3, STAT3, cathepsin K, and cathepsin L are associated with the proliferation and growth of cholesteatoma and that these proteins may be influential factors in cholesteatoma growth (Ho et al., 2012).
|Note|| Many intrinsic and extrinsic factors are associated with the stratum corneum (SC) barrier disruption. In the study of Katagiri C, it has been reported a high correlation between SERPINB3 and transepidermal water loss (TEWL). This finding was confirmed by means of a barrier disruption study with a topical oleic acid treatment: subjects with high levels of SERPINB3 readily developed impaired SC barrier function. Furthermore, SERPINB3 content showed a very high correlation with the number of parakeratotic cells in the cornified layer of the skin. These findings indicate that SERPINB3 can be considered a marker of parakeratosis and may play an inhibitory role in the process of nuclear digestion (Katagiri et al., 2010).|
It has been also reported that Cathepsin L (a target of SERPINB3) is one of the lysosomal acid proteinases recently identified in psoriatic epidermis (Kawada et al., 1997) together with various proteinases including tryptase, chymase, and cathepsin G (targets of SERPINB4: see homology in previous paragraph) released by degranulation in psoriatic lesion (Harvima et al., 1993).
Takeda A, et al., have shown that SERPINB3/4 isoforms (SERPINB3 and SERPINB4) are indeed predominantly present along the periphery of the intercellular space in the upper spinous cell layer of psoriatic epidermis from patients with a high serum SERPINB3/4 level. In addition, SERPINB3/4 immunoreactivity was detected around the degranulated cells near the dermo-epidermal junction as well as in the granules of filtrated cells. Furthermore, strong positive staining for SERPINB3/4 was also found in nuclei of granular layer cells and a considerable number of cells in the elongated rete rete ridges of psoriatic epidermis. In particular, SERPINB3 mRNA was ubiquitously expressed in all normal skin, and significantly overexpressed in psoriatic skin tissues. On the other hand, SERPINB4 mRNA expression was specific for psoriatic skin tissues, while it was absent in normal epidermis (Takeda et al., 2002)
|Entity||Asthma related pathology|
|Note|| A protective role of SERPINB3 in asthma was initially suggested by a microarray analysis of human bronchial epithelial cell cultures after stimulation with IL-4 and IL-13 (Hansel and Diette, 2007). This serpin may exert its protective role by inhibiting endogenous proteases associated with the inflammatory response.|
Further studies indicated that SERPINB3 serum levels were increased in patients with bronchial asthma, asthma exacerbation and in patients with allergic rhinitis (Izuhara, 2003; Nishi et al., 2005; Suzuki et al., 2010).
|Serpin B3/B4, activated by STAT3, promote survival of squamous carcinoma cells.|
|Ahmed ST, Darnell JE Jr.|
|Biochem Biophys Res Commun. 2009 Jan 23;378(4):821-5. doi: 10.1016/j.bbrc.2008.11.147. Epub 2008 Dec 12.|
|Comparative genomic analysis of the clade B serpin cluster at human chromosome 18q21: amplification within the mouse squamous cell carcinoma antigen gene locus.|
|Askew DJ, Askew YS, Kato Y, Turner RF, Dewar K, Lehoczky J, Silverman GA.|
|Genomics. 2004 Jul;84(1):176-84.|
|Squamous cell carcinoma antigen-immunoglobulin M complexes as novel biomarkers for hepatocellular carcinoma.|
|Beneduce L, Castaldi F, Marino M, Quarta S, Ruvoletto M, Benvegnu L, Calabrese F, Gatta A, Pontisso P, Fassina G.|
|Cancer. 2005 Jun 15;103(12):2558-65.|
|Overexpression of squamous cell carcinoma antigen in idiopathic pulmonary fibrosis: clinicopathological correlations.|
|Calabrese F, Lunardi F, Giacometti C, Marulli G, Gnoato M, Pontisso P, Saetta M, Valente M, Rea F, Perissinotto E, Agostini C.|
|Thorax. 2008 Sep;63(9):795-802. doi: 10.1136/thx.2007.088583. Epub 2008 Mar 14.|
|Hypoxia up-regulates SERPINB3 through HIF-2a in human liver cancer cells.|
|Cannito S, Turato C, Paternostro C, Biasiolo A, Colombatto S, Cambieri I, Quarta S, Novo E, Morello E, Villano G, Fasolato S, Musso T, David E, Tusa I, Rovida E, Autelli R, Smedile A, Cillo U, Pontisso P, Parola M.|
|Oncotarget. 2014 Dec 10. [Epub ahead of print]|
|Co-expression of the squamous cell carcinoma antigens 1 and 2 in normal adult human tissues and squamous cell carcinomas.|
|Cataltepe S, Gornstein ER, Schick C, Kamachi Y, Chatson K, Fries J, Silverman GA, Upton MP.|
|J Histochem Cytochem. 2000 Jan;48(1):113-22.|
|Oncogenic Ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3/B4.|
|Catanzaro JM, Sheshadri N, Pan JA, Sun Y, Shi C, Li J, Powers RS, Crawford HC, Zong WX.|
|Nat Commun. 2014 Apr 23;5:3729. doi: 10.1038/ncomms4729.|
|SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I.|
|Ciscato F, Sciacovelli M, Villano G, Turato C, Bernardi P, Rasola A, Pontisso P.|
|Oncotarget. 2014 May 15;5(9):2418-27.|
|SerpinB3, a new prognostic tool in breast cancer patients treated with neoadjuvant chemotherapy.|
|Collie-Duguid ES, Sweeney K, Stewart KN, Miller ID, Smyth E, Heys SD.|
|Breast Cancer Res Treat. 2012 Apr;132(3):807-18. doi: 10.1007/s10549-011-1625-9. Epub 2011 Jun 22.|
|Cloning and expression of a novel hepatitis B virus-binding protein from HepG2 cells.|
|De Falco S, Ruvoletto MG, Verdoliva A, Ruvo M, Raucci A, Marino M, Senatore S, Cassani G, Alberti A, Pontisso P, Fassina G.|
|J Biol Chem. 2001 Sep 28;276(39):36613-23. Epub 2001 Jun 1.|
|Squamous cellular carcinoma immunocomplexed is increased in scleroderma patients with lung fibrosis.|
|Giannelli G, Iannone F, Fransvea E, Chiala A, Lapadula G, Antonaci S.|
|Clin Exp Rheumatol. 2007b Sep-Oct;25(5):794-5.|
|Squamous cell carcinoma antigen in human liver carcinogenesis.|
|Guido M, Roskams T, Pontisso P, Fassan M, Thung SN, Giacomelli L, Sergio A, Farinati F, Cillo U, Rugge M.|
|J Clin Pathol. 2008 Apr;61(4):445-7. Epub 2007 Sep 24.|
|Gene expression profiling in human asthma.|
|Hansel NN, Diette GB.|
|Proc Am Thorac Soc. 2007 Jan;4(1):32-6. (REVIEW)|
|Mast cell tryptase and chymase in developing and mature psoriatic lesions.|
|Harvima IT, Naukkarinen A, Paukkonen K, Harvima RJ, Aalto ML, Schwartz LB, Horsmanheimo M.|
|Arch Dermatol Res. 1993;285(4):184-92.|
|Effect of SCCA1 and SCCA2 on the suppression of TNF-alpha-induced cell death by impeding the release of mitochondrial cytochrome c in an oral squamous cell carcinoma cell line.|
|Hashimoto K, Kiyoshima T, Matsuo K, Ozeki S, Sakai H.|
|Tumour Biol. 2005 Jul-Aug;26(4):165-72. Epub 2005 Jul 6.|
|Cholesteatoma growth and proliferation: relevance with serpin B3.|
|Ho KY, Huang HH, Hung KF, Chen JC, Chai CY, Chen WT, Tsai SM, Chien CY, Wang HM, Wu YJ.|
|Laryngoscope. 2012 Dec;122(12):2818-23. doi: 10.1002/lary.23547.|
|A surprising new protein superfamily containing ovalbumin, antithrombin-III, and alpha 1-proteinase inhibitor.|
|Hunt LT, Dayhoff MO.|
|Biochem Biophys Res Commun. 1980 Jul 31;95(2):864-71.|
|Structure of a serpin-protease complex shows inhibition by deformation.|
|Huntington JA, Read RJ, Carrell RW.|
|Nature. 2000 Oct 19;407(6806):923-6.|
|The role of interleukin-4 and interleukin-13 in the non-immunologic aspects of asthma pathogenesis.|
|Clin Chem Lab Med. 2003 Jul;41(7):860-4. (REVIEW)|
|Up-regulation of serpin SCCA1 is associated with epidermal barrier disruption.|
|Katagiri C, Iida T, Nakanishi J, Ozawa M, Aiba S, Hibino T.|
|J Dermatol Sci. 2010 Feb;57(2):95-101. doi: 10.1016/j.jdermsci.2009.09.004. Epub 2010 Jan 7.|
|Expression and function of squamous cell carcinoma antigen.|
|Anticancer Res. 1996 Jul-Aug;16(4B):2149-53. (REVIEW)|
|Processing of cathepsins L, B and D in psoriatic epidermis.|
|Kawada A, Hara K, Kominami E, Hiruma M, Noguchi H, Ishibashi A.|
|Arch Dermatol Res. 1997 Jan;289(2):87-93.|
|Peripheral B cell abnormalities in patients with systemic lupus erythematosus in quiescent phase: decreased memory B cells and membrane CD19 expression.|
|Korganow AS, Knapp AM, Nehme-Schuster H, Soulas-Sprauel P, Poindron V, Pasquali JL, Martin T.|
|J Autoimmun. 2010 Jun;34(4):426-34. doi: 10.1016/j.jaut.2009.11.002. Epub 2009 Dec 5.|
|SERPINB3 in the chicken model of ovarian cancer: a prognostic factor for platinum resistance and survival in patients with epithelial ovarian cancer.|
|Lim W, Kim HS, Jeong W, Ahn SE, Kim J, Kim YB, Kim MA, Kim MK, Chung HH, Song YS, Bazer FW, Han JY, Song G.|
|PLoS One. 2012;7(11):e49869. doi: 10.1371/journal.pone.0049869. Epub 2012 Nov 21.|
|Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice.|
|Lunardi F, Villano G, Perissinotto E, Agostini C, Rea F, Gnoato M, Bradaschia A, Valente M, Pontisso P, Calabrese F.|
|Lab Invest. 2011 Jun;91(6):945-54. doi: 10.1038/labinvest.2011.1. Epub 2011 Mar 14.|
|Availability of tumor-antigen 4 as a marker of squamous cell carcinoma of the lung and other organs.|
|Mino N, Iio A, Hamamoto K.|
|Cancer. 1988 Aug 15;62(4):730-4.|
|Squamous cell carcinoma antigen suppresses radiation-induced cell death.|
|Murakami A, Suminami Y, Hirakawa H, Nawata S, Numa F, Kato H.|
|Br J Cancer. 2001 Mar 23;84(6):851-8.|
|Squamous cell carcinoma-related antigen in children with acute asthma.|
|Nishi N, Miyazaki M, Tsuji K, Hitomi T, Muro E, Zaitsu M, Yamamoto S, Inada S, Kobayashi I, Ichimaru T, Izuhara K, Nagumo F, Yuyama N, Hamasaki Y.|
|Ann Allergy Asthma Immunol. 2005 Mar;94(3):391-7.|
|Tumor transcriptome reveals the predictive and prognostic impact of lysosomal protease inhibitors in non-small-cell lung cancer.|
|Petty RD, Kerr KM, Murray GI, Nicolson MC, Rooney PH, Bissett D, Collie-Duguid ES.|
|J Clin Oncol. 2006 Apr 10;24(11):1729-44. Epub 2006 Mar 20.|
|Progressive increase of SCCA-IgM immune complexes in cirrhotic patients is associated with development of hepatocellular carcinoma.|
|Pontisso P, Quarta S, Caberlotto C, Beneduce L, Marino M, Bernardinello E, Tono N, Fassina G, Cavalletto L, Gatta A, Chemello L.|
|Int J Cancer. 2006 Aug 15;119(4):735-40.|
|SERPINB3 induces epithelial-mesenchymal transition.|
|Quarta S, Vidalino L, Turato C, Ruvoletto M, Calabrese F, Valente M, Cannito S, Fassina G, Parola M, Gatta A, Pontisso P.|
|J Pathol. 2010 Jul;221(3):343-56. doi: 10.1002/path.2708.|
|The ovalbumin family of serpin proteins.|
|FEBS Lett. 1993 Jan 4;315(2):105-8.|
|Surface expression of squamous cell carcinoma antigen (SCCA) can be increased by the preS1(21-47) sequence of hepatitis B virus.|
|Ruvoletto MG, Tono N, Carollo D, Vilei T, Trentin L, Muraca M, Marino M, Gatta A, Fassina G, Pontisso P.|
|J Gen Virol. 2004 Mar;85(Pt 3):621-4.|
|Squamous cell carcinoma antigen 2 is a novel serpin that inhibits the chymotrypsin-like proteinases cathepsin G and mast cell chymase.|
|Schick C, Kamachi Y, Bartuski AJ, Cataltepe S, Schechter NM, Pemberton PA, Silverman GA.|
|J Biol Chem. 1997 Jan 17;272(3):1849-55.|
|Cross-class inhibition of the cysteine proteinases cathepsins K, L, and S by the serpin squamous cell carcinoma antigen 1: a kinetic analysis.|
|Schick C, Pemberton PA, Shi GP, Kamachi Y, Cataltepe S, Bartuski AJ, Gornstein ER, Bromme D, Chapman HA, Silverman GA.|
|Biochemistry. 1998 Apr 14;37(15):5258-66.|
|A serine proteinase inhibitor locus at 18q21.3 contains a tandem duplication of the human squamous cell carcinoma antigen gene.|
|Schneider SS, Schick C, Fish KE, Miller E, Pena JC, Treter SD, Hui SM, Silverman GA.|
|Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3147-51.|
|Human clade B serpins (ov-serpins) belong to a cohort of evolutionarily dispersed intracellular proteinase inhibitor clades that protect cells from promiscuous proteolysis.|
|Silverman GA, Whisstock JC, Askew DJ, Pak SC, Luke CJ, Cataltepe S, Irving JA, Bird PI.|
|Cell Mol Life Sci. 2004 Feb;61(3):301-25. (REVIEW)|
|Crystal structure of ovalbumin as a model for the reactive centre of serpins|
|Stein PE, Leslie AG, Finch JT, Turnell WG, McLaughlin PJ, Carrell RW.|
|Nature. 1990 Sep 6;347(6288):99-102.|
|Inhibition of apoptosis in human tumour cells by the tumour-associated serpin, SCC antigen-1.|
|Suminami Y, Nagashima S, Vujanovic NL, Hirabayashi K, Kato H, Whiteside TL.|
|Br J Cancer. 2000 Feb;82(4):981-9.|
|Relationship between squamous cell carcinoma antigen and the clinical severity of allergic rhinitis caused by Dermatophagoides farinae and Japanese cedar pollen.|
|Suzuki K, Inokuchi A, Miyazaki J, Kuratomi Y, Izuhara K.|
|Ann Otol Rhinol Laryngol. 2010 Jan;119(1):22-6.|
|Overexpression of serpin squamous cell carcinoma antigens in psoriatic skin.|
|Takeda A, Higuchi D, Takahashi T, Ogo M, Baciu P, Goetinck PF, Hibino T.|
|J Invest Dermatol. 2002 Jan;118(1):147-54.|
|Squamous cell carcinoma antigen is a potent inhibitor of cysteine proteinase cathepsin L.|
|Takeda A, Yamamoto T, Nakamura Y, Takahashi T, Hibino T.|
|FEBS Lett. 1995 Feb 6;359(1):78-80.|
|Expression of mRNA of SCC antigen in squamous cells.|
|Takeshima N, Suminami Y, Takeda O, Abe H, Okuno N, Kato H.|
|Tumour Biol. 1992;13(5-6):338-42.|
|Increased antiprotease activity of the SERPINB3 polymorphic variant SCCA-PD.|
|Turato C, Biasiolo A, Pengo P, Frecer V, Quarta S, Fasolato S, Ruvoletto M, Beneduce L, Zuin J, Fassina G, Gatta A, Pontisso P.|
|Exp Biol Med (Maywood). 2011 Mar;236(3):281-90. doi: 10.1258/ebm.2011.010229. Epub 2011 Mar 7.|
|Over-expression of SERPINB3 in hepatoblastoma: a possible insight into the genesis of this tumour?|
|Turato C, Buendia MA, Fabre M, Redon MJ, Branchereau S, Quarta S, Ruvoletto M, Perilongo G, Grotzer MA, Gatta A, Pontisso P.|
|Eur J Cancer. 2012 May;48(8):1219-26. doi: 10.1016/j.ejca.2011.06.004. Epub 2011 Jul 5.|
|SERPINB3 modulates TGF-beta expression in chronic liver disease.|
|Turato C, Calabrese F, Biasiolo A, Quarta S, Ruvoletto M, Tono N, Paccagnella D, Fassina G, Merkel C, Harrison TJ, Gatta A, Pontisso P.|
|Lab Invest. 2010 Jul;90(7):1016-23. doi: 10.1038/labinvest.2010.55. Epub 2010 Mar 8.|
|Squamous cell carcinoma antigen-1 (SERPINB3) polymorphism in chronic liver disease.|
|Turato C, Ruvoletto MG, Biasiolo A, Quarta S, Tono N, Bernardinello E, Beneduce L, Fassina G, Cavalletto L, Chemello L, Merkel C, Gatta A, Pontisso P.|
|Dig Liver Dis. 2009 Mar;41(3):212-6. doi: 10.1016/j.dld.2008.06.001. Epub 2008 Jul 25.|
|MicroRNAs and SerpinB3 in hepatocellular carcinoma.|
|Turato C, Simonato D, Quarta S, Gatta A, Pontisso P.|
|Life Sci. 2014a Mar 28;100(1):9-17. doi: 10.1016/j.lfs.2014.01.073. Epub 2014 Feb 2. (REVIEW)|
|SERPINB3 is associated with TGF-β1 and cytoplasmic β-catenin expression in hepatocellular carcinomas with poor prognosis.|
|Turato C, Vitale A, Fasolato S, Ruvoletto M, Terrin L, Quarta S, Ramirez Morales R, Biasiolo A, Zanus G, Zali N, Tan PS, Hoshida Y, Gatta A, Cillo U, Pontisso P.|
|Br J Cancer. 2014b May 27;110(11):2708-15. doi: 10.1038/bjc.2014.246. Epub 2014 May 8.|
|Circulating serpin tumor markers SCCA1 and SCCA2 are not actively secreted but reside in the cytosol of squamous carcinoma cells.|
|Uemura Y, Pak SC, Luke C, Cataltepe S, Tsu C, Schick C, Kamachi Y, Pomeroy SL, Perlmutter DH, Silverman GA.|
|Int J Cancer. 2000 Jul 20;89(4):368-77.|
|Squamous cell carcinoma antigen 1 promotes caspase-8-mediated apoptosis in response to endoplasmic reticulum stress while inhibiting necrosis induced by lysosomal injury.|
|Ullman E, Pan JA, Zong WX.|
|Mol Cell Biol. 2011 Jul;31(14):2902-19. doi: 10.1128/MCB.05452-11. Epub 2011 May 16.|
|Diagnostic and prognostic significance of squamous cell carcinoma antigen in non-small cell lung cancer.|
|Vassilakopoulos T, Troupis T, Sotiropoulou C, Zacharatos P, Katsaounou P, Parthenis D, Noussia O, Troupis G, Papiris S, Kittas C, Roussos C, Zakynthinos S, Gorgoulis V.|
|Lung Cancer. 2001 May;32(2):137-44.|
|SERPINB3 expression on B-cell surface in autoimmune diseases and hepatitis C virus-related chronic liver infection.|
|Vidalino L, Doria A, Quarta SM, Crescenzi M, Ruvoletto M, Frezzato F, Trentin L, Turato C, Parolin MC, Ghirardello A, Iaccarino L, Cavalletto L, Chemello L, Gatta A, Pontisso P.|
|Exp Biol Med (Maywood). 2012 Jul;237(7):793-802. doi: 10.1258/ebm.2012.012024. Epub 2012 Jul 24.|
|Hepatic progenitor cells express SerpinB3.|
|Villano G, Turato C, Quarta S, Ruvoletto M, Ciscato F, Terrin L, Semeraro R, Paternostro C, Parola M, Alvaro D, Bernardi P, Gatta A, Pontisso P.|
|BMC Cell Biol. 2014 Feb 11;15:5. doi: 10.1186/1471-2121-15-5.|
|Crystal structure of SCCA1 and insight about the interaction with JNK1.|
|Zheng B, Matoba Y, Kumagai T, Katagiri C, Hibino T, Sugiyama M.|
|Biochem Biophys Res Commun. 2009 Feb 27;380(1):143-7. doi: 10.1016/j.bbrc.2009.01.057. Epub 2009 Jan 21.|
|This paper should be referenced as such :|
|C Turato, P Pontisso|
|SERPINB3 (Serpin Peptidase Inhibitor, Clade B (Ovalbumin), Member 3)|
|Atlas Genet Cytogenet Oncol Haematol. 2015;19(3):202-209.|
|Free journal version : [ pdf ] [ DOI ]|
|On line version : http://AtlasGeneticsOncology.org/Genes/SERPINB3ID42265ch18q21.html|
|HGNC (Hugo)||SERPINB3 10569|
|Entrez_Gene (NCBI)||SERPINB3 6317 serpin family B member 3|
|Aliases||HsT1196; SCC; SCCA-1; SCCA-PD;|
|SCCA1; SSCA1; T4-A|
|Ensembl hg19 (Hinxton)||ENSG00000057149 [Gene_View]|
|Ensembl hg38 (Hinxton)||ENSG00000057149 [Gene_View] chr18:63655197-63661963 [Contig_View] SERPINB3 [Vega]|
|Genetics Home Reference (NIH)||SERPINB3|
|Genomic and cartography|
|GoldenPath hg38 (UCSC)||SERPINB3 - chr18:63655197-63661963 - 18q21.33 [Description] (hg38-Dec_2013)|
|GoldenPath hg19 (UCSC)||SERPINB3 - 18q21.33 [Description] (hg19-Feb_2009)|
|Ensembl||SERPINB3 - 18q21.33 [CytoView hg19] SERPINB3 - 18q21.33 [CytoView hg38]|
|Mapping of homologs : NCBI||SERPINB3 [Mapview hg19] SERPINB3 [Mapview hg38]|
|Gene and transcription|
|Genbank (Entrez)||AB046399 AF428135 AF428136 AF428137 AF428138|
|RefSeq transcript (Entrez)||NM_006919|
|RefSeq genomic (Entrez)|
|Consensus coding sequences : CCDS (NCBI)||SERPINB3|
|Cluster EST : Unigene||Hs.227948 [ NCBI ]|
|Alternative Splicing Gallery||ENSG00000057149|
|Gene Expression||SERPINB3 [ NCBI-GEO ] SERPINB3 [ EBI - ARRAY_EXPRESS ] SERPINB3 [ SEEK ] SERPINB3 [ MEM ]|
|Gene Expression Viewer (FireBrowse)||SERPINB3 [ Firebrowse - Broad ]|
|SOURCE (Princeton)||Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]|
|Genevisible||Expression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  |
|BioGPS (Tissue expression)||6317|
|GTEX Portal (Tissue expression)||SERPINB3|
|Protein : pattern, domain, 3D structure|
|UniProt/SwissProt||P29508 [function] [subcellular_location] [family_and_domains] [pathology_and_biotech] [ptm_processing] [expression] [interaction]|
|NextProt||P29508 [Sequence] [Exons] [Medical] [Publications]|
|With graphics : InterPro||P29508|
|Splice isoforms : SwissVar||P29508|
|Domaine pattern : Prosite (Expaxy)||SERPIN (PS00284)|
|Domains : Interpro (EBI)||Serpin_CS Serpin_dom Serpin_fam|
|Domain families : Pfam (Sanger)||Serpin (PF00079)|
|Domain families : Pfam (NCBI)||pfam00079|
|Domain families : Smart (EMBL)||SERPIN (SM00093)|
|Conserved Domain (NCBI)||SERPINB3|
|DMDM Disease mutations||6317|
|PDB (SRS)||2ZV6 4ZK0 4ZK3|
|PDB (PDBSum)||2ZV6 4ZK0 4ZK3|
|PDB (IMB)||2ZV6 4ZK0 4ZK3|
|PDB (RSDB)||2ZV6 4ZK0 4ZK3|
|Structural Biology KnowledgeBase||2ZV6 4ZK0 4ZK3|
|SCOP (Structural Classification of Proteins)||2ZV6 4ZK0 4ZK3|
|CATH (Classification of proteins structures)||2ZV6 4ZK0 4ZK3|
|Human Protein Atlas||ENSG00000057149|
|Protein Interaction databases|
|Ontologies - Pathways|
|Ontology : AmiGO||virus receptor activity protease binding serine-type endopeptidase inhibitor activity serine-type endopeptidase inhibitor activity cysteine-type endopeptidase inhibitor activity extracellular region extracellular space nucleus cytoplasm positive regulation of cell proliferation negative regulation of peptidase activity positive regulation of epithelial to mesenchymal transition positive regulation of endopeptidase activity negative regulation of endopeptidase activity positive regulation of cell migration cytoplasmic vesicle vesicle autocrine signaling azurophil granule lumen paracrine signaling negative regulation of catalytic activity neutrophil degranulation negative regulation of JUN kinase activity negative regulation of proteolysis viral entry into host cell extracellular exosome|
|Ontology : EGO-EBI||virus receptor activity protease binding serine-type endopeptidase inhibitor activity serine-type endopeptidase inhibitor activity cysteine-type endopeptidase inhibitor activity extracellular region extracellular space nucleus cytoplasm positive regulation of cell proliferation negative regulation of peptidase activity positive regulation of epithelial to mesenchymal transition positive regulation of endopeptidase activity negative regulation of endopeptidase activity positive regulation of cell migration cytoplasmic vesicle vesicle autocrine signaling azurophil granule lumen paracrine signaling negative regulation of catalytic activity neutrophil degranulation negative regulation of JUN kinase activity negative regulation of proteolysis viral entry into host cell extracellular exosome|
|Pathways : KEGG||Amoebiasis|
|REACTOME Pathways||R-HSA-6798695 [pathway]|
|Atlas of Cancer Signalling Network||SERPINB3|
|Orthology - Evolution|
|Phylogenetic Trees/Animal Genes : TreeFam||SERPINB3|
|Homologs : HomoloGene||SERPINB3|
|Homology/Alignments : Family Browser (UCSC)||SERPINB3|
|Gene fusions - Rearrangements|
|Polymorphisms : SNP and Copy number variants|
|NCBI Variation Viewer||SERPINB3 [hg38]|
|dbSNP Single Nucleotide Polymorphism (NCBI)||SERPINB3|
|Exome Variant Server||SERPINB3|
|ExAC (Exome Aggregation Consortium)||SERPINB3 (select the gene name)|
|Genetic variants : HAPMAP||6317|
|Genomic Variants (DGV)||SERPINB3 [DGVbeta]|
|DECIPHER||SERPINB3 [patients] [syndromes] [variants] [genes]|
|CONAN: Copy Number Analysis||SERPINB3|
|ICGC Data Portal||SERPINB3|
|TCGA Data Portal||SERPINB3|
|Broad Tumor Portal||SERPINB3|
|OASIS Portal||SERPINB3 [ Somatic mutations - Copy number]|
|Somatic Mutations in Cancer : COSMIC||SERPINB3 [overview] [genome browser] [tissue] [distribution]|
|Mutations and Diseases : HGMD||SERPINB3|
|LOVD (Leiden Open Variation Database)||Whole genome datasets|
|LOVD (Leiden Open Variation Database)||LOVD - Leiden Open Variation Database|
|LOVD (Leiden Open Variation Database)||LOVD 3.0 shared installation|
|DgiDB (Drug Gene Interaction Database)||SERPINB3|
|DoCM (Curated mutations)||SERPINB3 (select the gene name)|
|CIViC (Clinical Interpretations of Variants in Cancer)||SERPINB3 (select a term)|
|Cancer3D||SERPINB3(select the gene name)|
|Impact of mutations||[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]|
|Genetic Testing Registry||SERPINB3|
|Huge Navigator||SERPINB3 [HugePedia]|
|snp3D : Map Gene to Disease||6317|
|Clinical trials, drugs, therapy|
|Chemical/Protein Interactions : CTD||6317|
|Chemical/Pharm GKB Gene||PA35538|
|canSAR (ICR)||SERPINB3 (select the gene name)|
|PubMed||103 Pubmed reference(s) in Entrez|
|GeneRIFs||Gene References Into Functions (Entrez)|
|REVIEW articles||automatic search in PubMed|
|Last year publications||automatic search in PubMed|
Search in all EBI
|© Atlas of Genetics and Cytogenetics in Oncology and Haematology||indexed on : Mon May 22 09:23:02 CEST 2017|
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