Role of SERPINB3 in hepatocellular carcinoma
Patrizia Pontisso
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* Department of Medicine, University of Padua, Italy
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The left cartoons depict the site of the oblique ultrasonographic scan at the right hypochondrium (top) and the resulting longitudinal section of gallbladder. A. A finely echogenic, dense, gravity-dependent, slowly mobile biliary sludge is seen occupying about 40% of the gallbladder lumen (thick arrows). The thickness of the gallbladder wall is not increased. <span class="elsevierStyleBold">B.</span> Two mobile echogenic gallstones are indicated within the gallbladder lumen, layering on the distal wall. Each stone size is about 0.5 cm in diameter. C. A 1.5 cm gallstone in diameter (arrow) is detected in the gallbladder infundibulum and is surrounded by biliary sludge (triangle). The asterisk indicates the posterior acoustic shadowing typical of gallstones.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Ornella de Bari, Tony Y. Wang, Min Liu, Chang-Nyol Paik, Piero. Portincasa, David Q.-H. Wang" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Ornella de" "apellidos" => "Bari" ] 1 => array:2 [ "nombre" => "Tony Y." "apellidos" => "Wang" ] 2 => array:2 [ "nombre" => "Min" "apellidos" => "Liu" ] 3 => array:2 [ "nombre" => "Chang-Nyol" "apellidos" => "Paik" ] 4 => array:2 [ "nombre" => "Piero." "apellidos" => "Portincasa" ] 5 => array:3 [ "preGrado" => "M.D., Ph.D." "nombre" => "David Q.-H." "apellidos" => "Wang" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119309755?idApp=UINPBA00004N" "url" => "/16652681/0000001300000006/v1_201906150917/S1665268119309755/v1_201906150917/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1665268119309731" "issn" => "16652681" "doi" => "10.1016/S1665-2681(19)30973-1" "estado" => "S300" "fechaPublicacion" => "2014-11-01" "aid" => "70729" "copyright" => "Fundación Clínica Médica Sur, A.C." "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "edi" "cita" => "Ann Hepatol. 2014;13:719-21" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 99 "formatos" => array:3 [ "EPUB" => 9 "HTML" => 46 "PDF" => 44 ] ] "en" => array:8 [ "idiomaDefecto" => true "titulo" => "MELD exception for liver transplantation in portopulmonary hypertension: current implementation and future considerations" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "719" "paginaFinal" => "721" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Mateo Porres-Aguilar, Sonja D. Bartolome, Andres Duarte-Rojo" "autores" => array:3 [ 0 => array:3 [ "preGrado" => "M.D., FACP" "nombre" => "Mateo" "apellidos" => "Porres-Aguilar" ] 1 => array:2 [ "nombre" => "Sonja D." "apellidos" => "Bartolome" ] 2 => array:2 [ "nombre" => "Andres" "apellidos" => "Duarte-Rojo" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119309731?idApp=UINPBA00004N" "url" => "/16652681/0000001300000006/v1_201906150917/S1665268119309731/v1_201906150917/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "titulo" => "Role of SERPINB3 in hepatocellular carcinoma" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "722" "paginaFinal" => "727" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Patrizia Pontisso" "autores" => array:1 [ 0 => array:4 [ "nombre" => "Patrizia" "apellidos" => "Pontisso" "email" => array:1 [ 0 => "patrizia@unipd.it" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:3 [ "entidad" => "Department of Medicine, University of Padua, Italy" "etiqueta" => "*" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "*" "correspondencia" => "Correspondence and reprint request:" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 530 "Ancho" => 503 "Tamanyo" => 28168 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Schematic diagram of the extent of SERPINB3 and SERPINB4 (SERPINB3/4) isoforms expression in the liver. Normal hepatocytes do not express this serpin and its expression progressively increases in relation to the extent of liver damage. The highest levels are detectable in dysplastic nodules and early HCC. No data are available to date on HCC metastases.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0015">Introduction</span><p id="p0005" class="elsevierStylePara elsevierViewall">Hepatocellular carcinoma (HCC) is one of the most common forms of cancer and of cancer-related death in the world.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> HCC nearly always develops in the setting of liver cirrhosis and hepatitis B and C viral infections, alcohol abuse and metabolic syndrome are the main risk factors.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The annual incidence of tumor development in cirrhotic patients varies from 1 to 6% and this wide range reflects differences in age, gender, etiology and duration of cirrhosis in the different studied groups.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Advanced age and male sex have been found indeed independent risk factors for hepatocellular carcinoma development in patients with cirrhosis.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> HCC mortality index is very high, since most of the patients die within few years after diagnosis and less than 5% survive after five years.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In addition, this tumor is extremely heterogeneous, due to the complex interplay between the biological characteristics of the tumor and the frequent presence of an underlying chronic liver disease. Despite intensive surveillance programs, considerable recent therapeutic advances and use of potentially radical treatments, prognosis and life expectancy remain still poor in this setting. Curative treatments are applicable for early stage tumors only 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.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0020">Molecular mechanisms of liver carcinogenesis</span><p id="p0010" class="elsevierStylePara elsevierViewall">Hepatocarcinogenesis is a multistep phenomenon and during the progression phase activation of cellular oncogenes, over-expression of growth factors, inactivation of tumor suppressor genes, miRNA deregulation and possibly telomerase activation, may contribute to the development of the neoplastic phenotype. In the last years data about molecular mechanisms of liver carcinogenesis, signal transduction pathways and potential therapeutic targets have been accumulated, providing new encouraging treatment options.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> At molecular level major classes of HCC, according to gene sets profiles responsible for cell proliferation and survival, have been recognized. Aberrant activation of several signaling cascades such as epidermal growth factor receptor (EGFR), Ras/ERK, PI3-K/mTOR, HGF, Wnt, Hedgehog and apoptotic signaling have been defined.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Recent human studies have identified a molecular subclass (S1) of HCC associated with poor prognosis that is characterized by aberrant activation of Wnt signaling and TGF-beta activation. This peculiar S1 signature is characterized 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.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Serpinb3 and Liver Cancer</span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">Carcinogenic potential of SERPINB3</span><p id="p0015" class="elsevierStylePara elsevierViewall">SERPINB3 (formerly known as squamous cell carcinoma antigen-1 or SCCA1) is a member of the family of serine-protease inhibitors (SERPINS).<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Available data suggest that this serpin may lead to hepatocellular carcinoma through different strategies (<a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a>). Initial studies indicate that SERPINB3 has an anti-apoptotic effect, since in cancer cells it was found to confer resistance to drug-induced apoptosis by inhibiting lysosomal cathepsin proteases<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> and consequent inhibition of the release of mitochondrial cytochrome c. Under a variety of stress conditions this serpin also displays a protective role, with an anti-apoptotic function unrelated to its proteinase inhibition activity.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Indeed, SERPINB3 protects cells from exposure to radiation through an inhibitory effect either on the MAP family kinase JNK<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> or p38.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> More recent findings have demonstrated a novel mechanism of action of SER-PINB3, which could contribute to tumor cell resistance to anti-neoplastic drugs. This molecule was found indeed located in the inner mitochondrial compartments, where its binding to the respiratory Complex I protected cells from the toxicity of chemotherapeutic agents with a pro-oxidant action such as doxorubicin and cisplatin.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The serpin reduced ROS generation induced by these compounds, a crucial step responsible for the opening of the mitochondrial permeability transition pore (PTP), irreversibly committing cells to apoptotic death.</p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0020" class="elsevierStylePara elsevierViewall">In addition, SERPINB3 induces EMT and decrease of desmosomal junctions, leading to cell proliferation, increased number of colony formation in soft agar and cell invasiveness.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> In mice transgenic for SEPRINB3 lower expression of the p66shc gene, known as a signaling protein implicated in receptor tyrosine kinase signal transduction,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> has been described.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Experimental studies have also reported that these transgenic mice showed higher liver regenerative potential compared to wild-type mice, supporting a role of this protein in promoting cell growth and proliferation.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Further mechanisms of tumor growth promotion induced by SERPINB3 include the inhibition of intratumor infiltration of natural killer cells<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and the up-regulation of Myc oncogene transcription.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Recent findings indicate that SERPINB3/SERPINB4 isoforms are a Ras-responsive factor that plays an important role in Rasassociated cytokine production and tumorigenesis.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Expression of SERPINB3 in liver cancer tissue</span><p id="p0025" class="elsevierStylePara elsevierViewall">In the liver SERPINB3 and SERPINBB4 isoforms (known as squamous cell carcinoma antigen or SCCA), are undetectable in normal hepatocytes, but their expression progressively increases in chronic liver diseases<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> as a cellular response to chronic liver damage. Higher levels are detectable in dysplastic nodules<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> and in hepatocellular carcinoma,<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>,<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> suggesting that they may be also involved in relatively early events of hepatocarcinogenesis (<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>). Recent studies indicate that SERPINB3 is highly expressed in hepatic stem/progenitor cells of both foetal and adult livers.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> This compartment is composed by quiescent cells that proliferate under oxidative stress conditions. The occurrence of progenitor cell proliferation in humans has been described in the late stages of cirrhosis and tumors showing hepatic progenitor cell features have a worse prognosis and a higher recurrence rate compared to tumors lacking these characteristics.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a>,<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> In agreement with these findings, high SERPINB3 levels have been detected in HCC of patients with early tumor recurrence after surgical resection.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> In this subset, a significant correlation of the serpin with over-expression of TGF-β and of β-catenin was typically found. Transcriptome data-metanalysis further supported these findings, showing accumulation of SERPINB3 in the S1 poor prognosis subclass.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> SERPINB3 has been detected recently also in hepatoblastoma, the embryonal tumor of the liver, where a direct correlation was observed between its gene expression, the up-regulation of Myc oncogene and tumor extension.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><elsevierMultimedia ident="f0010"></elsevierMultimedia></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Diagnostic and prognostic significance of SERPINB3/4 in serum</span><p id="p0030" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="l0005"><li class="elsevierStyleListItem" id="u0005"><span class="elsevierStyleLabel">•</span><p id="p0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HCC-diagnosis.</span> 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 presence of SCCA as free protein and/or as circulating immune complexes in serum.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>,<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Free SCCA was not detected at significant levels in HCV infected patients with HCC, but this molecule was found coupled to IgMs (SCCA-IgM) to form circulating immunecomplexes in the majority of patients with HCC, whereas in the healthy control population their levels were below the limit of detection.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> The concentration of circulating SCCA-IgM, detected by a commercially available ELISA assay (SCCA-IC, Xeptagen), increased progressively at different stages of liver disease, from chronic hepatitis to cirrhosis and HCC, reflecting the extent of SCCA overexpression detected by immunohistochemistry in liver specimens. SCCA-IgM did not overlap with AFP, offering the possibility to increase the sensitivity for HCC detection without loosing specificity. The occurrence of this biomarker-IgM immune complex seems to be supported by the recent immunoediting model that considers natural IgMs as one of the most important players of the innate immune system.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> This pathway likely reflects host immune protective mechanisms trying to apply selective pressure on newly developed transformed cells in order to control tumor growth. The neo-epitopes, present on the tumor cells surface, recognized by commonly circulating natural IgM, are able to enhance phagocytic clearance of transformed cell by macrophages and dendritic cells.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> The possible interfering effect of rheumatoid factor in SCCA-IgM reactivity, found more frequently in HCV infected patients, has been excluded in artificially created samples, where the same results in terms of reactivity for SCCA-IgM were obtained, regardless of the presence of rheumatoid factor.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p></li><li class="elsevierStyleListItem" id="u0010"><span class="elsevierStyleLabel">•</span><p id="p0040" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Fibrosis progression in chronic hepatitis.</span> The behaviour of SCCA-IgM in serum over time has been also analysed in untreated patients with chronic hepatitis in relation to histological progression of the fibrosis stage.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> After a median period of 6 years a significant increase of SCCAIgM levels was observed in patients with histological fibrosis score increase > 2, but not in those without histologic deterioration. These findings suggest that monitoring SCCA-IgM levels over time might become a useful approach to identify patients with chronic hepatitis at higher risk for cirrhosis development.</p></li><li class="elsevierStyleListItem" id="u0015"><span class="elsevierStyleLabel">•</span><p id="p0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Antiviral therapy.</span> In HCV infected patients treated with pegylated interferon and ribavirin a significant decrease in median SCCA-IgM levels at the end of treatment, persisting up to a year of follow-up, has been described in patients with sustained virologic response, both in patients with chronic hepatitis<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> and with cirrhosis.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> No significant modifications were observed in non responder patients, indicating that SCCA-IgM monitoring in serum may be a reliable independent prognostic marker of therapeutic effectiveness in anti-HCV positive patients undergoing antiviral therapy.</p></li><li class="elsevierStyleListItem" id="u0020"><span class="elsevierStyleLabel">•</span><p id="p0050" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Risk of HCC development in patients with cirrhosis.</span> The behaviour of SCCA-IgM in relation to HCC development has been evaluated in a cohort of HCV infected patients with cirrhosis prospectively followed up for a median period 4 years.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> The increase over time of SCCA-IgM, assessed within at least one year before clinical diagnosis of HCC, was remarkably higher in the group of patients who developed HCC than in patients who did not develop HCC during the same period of follow-up, while AFP increase was not significantly different. This initial study indicates that the assessment of SCCA-IgM behaviour over time might be useful to identify cirrhotic patients at higher risk of HCC development. These data have been confirmed in another retrospective study, addressed to evaluate whether the levels of SCCA-IgM in serum could identify HCV positive cirrhotic patients at risk of HCC development.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> The SCCA-IgM value ≤ 200 AU/ mL accurately identified patients at low risk of liver cancer in the subsequent year, with a negative predictive value of 97%. Considering an annual HCC incidence ≤ 3%, patients with SCCA-IgM ≤ 200 AU/mL had an HCC risk below the accepted threshold of a cost-effective surveillance (1.5%).<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> If the results of this pilot study will be confirmed in larger studies, the authors propose that SCCA-IgM serum measurement might implement the current protocol of surveillance of cirrhotic patients,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> introducing a two step (with different costs) surveillance, consisting in an initial serological surveillance, based on the annual monitoring of this biomarker, and the conventional surveillance by semiannual ultrasound when SCCA-IgM becomes > 200 AU/mL. This proposal could improve the cost/effectiveness of surveillance of HCV infected patients at risk of HCC with an acceptable number of missed early diagnoses.</p></li><li class="elsevierStyleListItem" id="u0025"><span class="elsevierStyleLabel">•</span><p id="p0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HCC prognosis.</span> In a recent study SCCA-IgM proved efficient in the prediction of HCC prognosis, identifying HCC patients with long overall and progression-free survival.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> Median survival was indeed 48 months (C.I. 29-66) for patients with low (≤ 130 AU/mL) SCCA-IgM and 26 months (C.I. 22-30) for those with high SCCAIgM (> 130 AU/mL). At multivariate analysis tumour size and SCCA-IgM levels were identified as the only independent predictors of survival. In addition, SCCA-IgM levels correlated with overall response to treatment (including surgery, TACE, percutaneous ablation), with a median time to progression of 14 months in patients with low SCCA-IgM, <span class="elsevierStyleItalic">vs.</span> 6 months in those with high SCCA-IgM levels. Additional studies however are required to confirm these preliminary data and to better assess the behaviour of this oncomarker in relation to different methodologies of HCC treatment.</p></li></ul></p></span></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Acknowledgments</span><p id="p0060" class="elsevierStylePara elsevierViewall">I wish to thank my collaborators of the Molecular Hepatology Group (Alessandra Biasiolo, Santina Quarta, Mariagrazia Ruvoletto, Cristian Turato, Gianmarco Villano, Liliana Terrin, Natascia Tono, Andrea Martini, Davide Simionato), the colleagues of the Medical Clinic 5 and our Director Prof. Angelo Gatta, Giorgio Fassina and Andrea Gallotta (Xeptagen, Venice) for their important contributions to the knowledge of SERPINB3 in the biological and clinical fields of hepatology.</p></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Abbreviations</span><p id="p0065" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="u0030"><span class="elsevierStyleLabel">•</span><p id="p0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">EMT:</span> epithelial-to-mesenchymal transition.</p></li><li class="elsevierStyleListItem" id="u0035"><span class="elsevierStyleLabel">•</span><p id="p0075" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HCC:</span> hepatocellular carcinoma.</p></li><li class="elsevierStyleListItem" id="u0040"><span class="elsevierStyleLabel">•</span><p id="p0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SCCA:</span> squamous cell carcinoma antigen.</p></li><li class="elsevierStyleListItem" id="u0045"><span class="elsevierStyleLabel">•</span><p id="p0085" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">TACE:</span> transarterial chemoembolization.</p></li></ul></p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:7 [ 0 => array:3 [ "identificador" => "xres1207220" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abs0010" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1124266" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "s0005" "titulo" => "Introduction" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "s0010" "titulo" => "Molecular mechanisms of liver carcinogenesis" ] ] ] 3 => array:3 [ "identificador" => "s0015" "titulo" => "Serpinb3 and Liver Cancer" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "s0020" "titulo" => "Carcinogenic potential of SERPINB3" ] 1 => array:2 [ "identificador" => "s0025" "titulo" => "Expression of SERPINB3 in liver cancer tissue" ] 2 => array:2 [ "identificador" => "s0030" "titulo" => "Diagnostic and prognostic significance of SERPINB3/4 in serum" ] ] ] 4 => array:2 [ "identificador" => "s0035" "titulo" => "Acknowledgments" ] 5 => array:2 [ "identificador" => "s0040" "titulo" => "Abbreviations" ] 6 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-11-06" "fechaAceptado" => "2014-05-22" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1124266" "palabras" => array:3 [ 0 => "Serine-protease inhibitors" 1 => "Liver disease progression" 2 => "Carcinogenesis" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">SERPINB3 (formerly known as squamous cell carcinoma antigen-1 or SCCA1) is a member of the family of serine-protease inhibitors. SERPINB3 protects cells from oxidative stress conditions, but in chronic liver damage this serpin may lead to hepatocellular carcinoma through different strategies, including inhibition of apoptosis, induction of epithelial to mesenchymal transition and decrease of desmosomal junctions, cell proliferation and invasiveness. SERPINB3 may also contribute to tumor cell resistance to anti-neoplastic drugs through its binding to the respiratory Complex I, protecting cells from the pro-oxidant action of chemotherapeutic agents. Mechanisms of tumor growth promotion induced by SERPINB3 include the inhibition of intratumor infiltration of natural killer cells, up-regulation of Myc oncogene and the recent identification of this serpin as a Ras-responsive factor. In the liver SERPINB3 and SERPINBB4 isoforms (known as squamous cell carcinoma antigen or SCCA) are undetectable in normal hepatocytes, but their expression progressively increases in chronic liver diseases, dysplastic nodules and hepatocellular carcinoma. High SERPINB3 levels have been recently detected in HCC tissue of patients with early tumor recurrence after surgical resection. In serum SERPINB3/4 isoforms (or SCCA) are detectable bound to IgMs (SCCA-IgM) in the majority of HCV infected patients with HCC and in patients with cirrhosis their levels and/or the progressive increase have been found correlated to the risk of HCC development. Preliminary findings in patients with HCC revealed that SCCA-IgM was predictive of HCC prognosis, since low levels of this biomarker were able to identify HCC patients with long overall and progression-free survival.</p></span>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 360 "Ancho" => 503 "Tamanyo" => 21333 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Schematic representation of the main biological activities ascribed to SERPINB3.</span> → <span class="elsevierStyleItalic">indicates induction,</span> ⊣ <span class="elsevierStyleItalic">indicates inhibition. EMT: epithelial to mesenchymal transition.</span></p>" ] ] 1 => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 530 "Ancho" => 503 "Tamanyo" => 28168 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Schematic diagram of the extent of SERPINB3 and SERPINB4 (SERPINB3/4) isoforms expression in the liver. Normal hepatocytes do not express this serpin and its expression progressively increases in relation to the extent of liver damage. The highest levels are detectable in dysplastic nodules and early HCC. No data are available to date on HCC metastases.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0010" "bibliografiaReferencia" => array:42 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epidemiology of hepatocellular carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Sherman M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000315223" "Revista" => array:7 [ "tituloSerie" => "Oncology" "fecha" => "2010" "volumen" => "78" "numero" => "Suppl. 1" "paginaInicial" => "7" "paginaFinal" => "10" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20616577" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2." 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 0 | 4 |
| 2024 October | 30 | 6 | 36 |
| 2024 September | 30 | 7 | 37 |
| 2024 August | 35 | 6 | 41 |
| 2024 July | 27 | 3 | 30 |
| 2024 June | 43 | 6 | 49 |
| 2024 May | 57 | 2 | 59 |
| 2024 April | 62 | 6 | 68 |
| 2024 March | 51 | 2 | 53 |
| 2024 February | 24 | 9 | 33 |
| 2024 January | 35 | 2 | 37 |
| 2023 December | 31 | 3 | 34 |
| 2023 November | 25 | 6 | 31 |
| 2023 October | 45 | 2 | 47 |
| 2023 September | 33 | 5 | 38 |
| 2023 August | 33 | 2 | 35 |
| 2023 July | 35 | 2 | 37 |
| 2023 June | 49 | 6 | 55 |
| 2023 May | 70 | 6 | 76 |
| 2023 April | 55 | 1 | 56 |
| 2023 March | 52 | 5 | 57 |
| 2023 February | 31 | 2 | 33 |
| 2023 January | 25 | 2 | 27 |
| 2022 December | 28 | 11 | 39 |
| 2022 November | 28 | 7 | 35 |
| 2022 October | 19 | 6 | 25 |
| 2022 September | 17 | 6 | 23 |
| 2022 August | 24 | 8 | 32 |
| 2022 July | 20 | 13 | 33 |
| 2022 June | 14 | 5 | 19 |
| 2022 May | 22 | 4 | 26 |
| 2022 April | 14 | 7 | 21 |
| 2022 March | 22 | 6 | 28 |
| 2022 February | 18 | 6 | 24 |
| 2022 January | 52 | 7 | 59 |
| 2021 December | 18 | 7 | 25 |
| 2021 November | 30 | 9 | 39 |
| 2021 October | 26 | 13 | 39 |
| 2021 September | 25 | 6 | 31 |
| 2021 August | 29 | 5 | 34 |
| 2021 July | 16 | 10 | 26 |
| 2021 June | 8 | 11 | 19 |
| 2021 May | 22 | 5 | 27 |
| 2021 April | 42 | 11 | 53 |
| 2021 March | 22 | 4 | 26 |
| 2021 February | 7 | 10 | 17 |
| 2021 January | 20 | 8 | 28 |
| 2020 December | 25 | 5 | 30 |
| 2020 November | 23 | 5 | 28 |
| 2020 October | 25 | 8 | 33 |
| 2020 September | 10 | 6 | 16 |
| 2020 August | 7 | 5 | 12 |
| 2020 July | 9 | 1 | 10 |
| 2020 June | 6 | 0 | 6 |
| 2020 May | 14 | 5 | 19 |
| 2020 April | 13 | 3 | 16 |
| 2020 March | 5 | 5 | 10 |
| 2020 February | 12 | 2 | 14 |
| 2020 January | 2 | 1 | 3 |
| 2019 December | 4 | 5 | 9 |
| 2019 November | 6 | 3 | 9 |
| 2019 October | 0 | 3 | 3 |
| 2019 September | 1 | 1 | 2 |
| 2019 August | 1 | 0 | 1 |
| 2019 July | 2 | 10 | 12 |
| 2019 June | 3 | 7 | 10 |
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