Pro-oncogenic role of SerpinB3 in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most relevant sanitary problems for its prevalence and poor prognosis. This tumor is characterized by highly heterogeneous features, both at clinical and molecular level. SerpinB3 (squamous cell carcinoma antigen-1 or SCCA1) is a serine-protease inhibitor that protects cells from oxidative stress conditions, but in chronic liver damage it may lead to HCC through different strategies, including inhibition of apoptosis, induction of epithelial to mesenchymal transition, cell proliferation and invasiveness. Mechanisms of tumor growth promotion induced by SerpinB3 encompass the inhibition of intratumor infiltration of natural killer cells and the up-regulation of Myc oncogene. Recently this serpin has also been identified as a Ras-responsive factor and modulator of metabolic pathways. In the liver SerpinB3 is undetectable in normal hepatocytes, but its expression progressively increases in chronic liver diseases, dysplastic nodules and hepatocellular carcinoma, especially in those with poor prognosis, in which it could also exert immunomodulatory effects. In serum SerpinB3/4 isoforms (or SCCA) circulate bound to IgMs (SCCA-IgM) in patients with HCC, and in patients with cirrhosis their levels have been found correlated to the risk of HCC development. Preliminary findings in patients with HCC revealed that SCCA-IgM levels are predictive of HCC prognosis.

Keywords

SerpinB3 / chronic liver disease / hepatocellular carcinoma / chronic inflammation / SCCA-IgM

References

[1] Forner A,Bruix J.Hepatocellular carcinoma.Lancet2018;391:13011314

[2] Valery PC,Clark PJ,McGlynn KA.Projections of primary liver cancer to 2030 in 30 countries worldwide.Hepatology2017;

[3] Calderaro J,Imbeaud S,Letouzé E,Laurent C,Azoulay D,Nault JC.Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification.J Hepatol2017;67:727-38

[4] Schulze K,Villanueva A.Genetic profiling of hepatocellular carcinoma using next-generation sequencing.J Hepatol2016;65:1031-42

[5] Zucman-Rossi J,Nault JC.Genetic landscape and biomarkers of hepatocellular carcinoma.Gastroenterology2015;149:1226-39.e4

[6] Hoshida Y,Kobayashi M,Brunet JP,Villanueva A,Ikeda K,Watanabe G,Friedman SL,Llovet JM.Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma.Cancer Res2009;69:7385-92 PMCID:PMC3549578

[7] Lee JS,Heo J,Sun Z,Durnez A,Thorgeirsson SS.Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling.Hepatology2004;40:667-76

[8] Turato C,Fasolato S,Terrin L,Ramirez Morales R,Zanus G,Tan PS,Gatta A,Pontisso P.SERPINB3 is associated with TGF-beta1 and cytoplasmic beta-catenin expression in hepatocellular carcinomas with poor prognosis.Br J Cancer2014;110:2708-15 PMCID:PMC4037839

[9] Kato H.Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma.Cancer1977;40:1621-8

[10] Sun Y,Zong WX.SERPINB3 and B4: from biochemistry to biology.Semin Cell Dev Biol2017;62:170-7 PMCID:PMC5318283

[11] Schick C,Bartuski AJ,Schechter NM.The reactive site loop of the serpin SCCA1 is essential for cysteine proteinase inhibition.Proc Natl Acad Sci U S A1998;95:13465-70 PMCID:PMC24842

[12] Schick C,Bartuski AJ,Schechter NM,Silverman GA.Squamous cell carcinoma antigen 2 is a novel serpin that inhibits the chymotrypsin-like proteinases cathepsin G and mast cell chymase.J Biol Chem1997;272:1849-55

[13] Masumoto K,Arima K,Izuhara K.Inhibitory mechanism of a cross-class serpin, the squamous cell carcinoma antigen 1.J Biol Chem2003;278:45296-304

[14] Silverman GA,Carrell RW,Coughlin PB,Irving JA,Luke CJ,Pemberton PA,Salvesen GS,Whisstock JC.The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature..J Biol Chem2001;276:33293-6

[15] Kato H.Expression and function of squamous cell carcinoma antigen.Anticancer Res1996;16:2149-53

[16] Cataltepe S,Schick C,Chatson K,Silverman GA.Co-expression of the squamous cell carcinoma antigens 1 and 2 in normal adult human tissues and squamous cell carcinomas.J Histochem Cytochem2000;48:113-22

[17] Takeda A,Iwasawa A,Hibino T.Aberrant expression of serpin squamous cell carcinoma antigen 2 in human tumor tissues and cell lines: evidence of protection from tumor necrosis factor-mediated apoptosis.Biol Chem2002;383:1231-6

[18] Cannito S,Paternostro C,Colombatto S,Quarta S,Morello E,Fasolato S,David E,Rovida E,Smedile A,Pontisso P.Hypoxia up-regulates SERPINB3 through HIF-2alpha in human liver cancer cells.Oncotarget2015;6:2206-21 PMCID:PMC4385846

[19] Turato C,Sebastiani G,Morello E,Biasiolo A,Parola M,Pontisso P.Serpinb3 is overexpressed in the liver in presence of iron overload.J Investig Med2018;66:32-8

[20] Suminami Y,Vujanovic NL,Kato H.Inhibition of apoptosis in human tumour cells by the tumour-associated serpin, SCC antigen-1.Br J Cancer2000;82:981-9 PMCID:PMC2374407

[21] Vidalino L,Quarta S,Gatta A.SERPINB3, apoptosis and autoimmunity.Autoimmun Rev2009;9:108-12

[22] Katagiri C,Kadoya K.Serpin squamous cell carcinoma antigen inhibits UV-induced apoptosis via suppression of c-JUN NH2-terminal kinase.J Cell Biol2006;172:983-90 PMCID:PMC2063756

[23] Murakami A,Hirakawa H,Numa F.Squamous cell carcinoma antigen suppresses radiation-induced cell death.Br J Cancer2001;84:851-8 PMCID:PMC2363809

[24] Ciscato F,Villano G,Bernardi P,Pontisso P.SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I.Oncotarget2014;5:2418-27 PMCID:PMC4058015

[25] Quarta S,Turato C,Calabrese F,Cannito S,Parola M,Pontisso P.SERPINB3 induces epithelial-mesenchymal transition.J Pathol2010;221:343-56

[26] Villano G,Ruvoletto MG,Vidalino L,Tono N,Calabrese F,Dedja A,Gatta A.Role of squamous cell carcinoma antigen-1 on liver cells after partial hepatectomy in transgenic mice.Int J Mol Med2010;25:137-43

[27] Turato C,Simonato D,Morello E,Quarta S,Ruvoletto M,Fasolato S,Cillo U,Parola M.SerpinB3 and Yap interplay increases Myc oncogenic activity.Sci Rep2015;5:17701 PMCID:PMC4669520

[28] Catanzaro JM,Pan JA,Shi C,Powers RS,Zong WX.Oncogenic Ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3/B4.Nat Commun2014;5:3729 PMCID:PMC4025922

[29] Fasolato S,Ruvoletto M,Zanus G,Babetto E,Battocchio MA,Turato C,Cillo U,Vettor R.SerpinB3 induces dipeptidyl-peptidase IV/CD26 expression and its metabolic effects in hepatocellular carcinoma.Life Sci2018;200:134-41

[30] Shirakawa J,Ohnuma K,Ito Y,Sasaki H,Amo K,Morimoto C,Terauchi Y.Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice.Diabetes2011;60:1246-57 PMCID:PMC3064098

[31] Akarte AS,Gandhi S.Chronic DPP-IV inhibition with PKF-275-055 attenuates inflammation and improves gene expressions responsible for insulin secretion in streptozotocin induced diabetic rats.Eur J Pharm Sci2012;47:456-63

[32] Blaslov K,Zibar K.Incretin based therapies: a novel treatment approach for non-alcoholic fatty liver disease.World J Gastroenterol2014;20:7356-65 PMCID:PMC4064081

[33] Villano G,Ceolotto G,Calabrese F,Tono N,Biasiolo A,Merkel C,Gatta A.SERPINB3 is associated with longer survival in transgenic mice.Sci Rep2013;3:3056 PMCID:PMC3808827

[34] Martini A,Guido M,Biasiolo A,Gallotta A,Merkel C,Negro F.HCV genotype 3 and squamous cell carcinoma antigen (SCCA)-IgM are independently associated with histological features of NASH in HCV-infected patients.J Viral Hepat.2015;22:800-8

[35] Guido M,Pontisso P,Thung SN,Sergio A,Cillo U.Squamous cell carcinoma antigen in human liver carcinogenesis.J Clin Pathol2008;61:445-7

[36] Pontisso P,Benvegnu L,Belluco C,Marino M,Nitti D,Fassina G.Overexpression of squamous cell carcinoma antigen variants in hepatocellular carcinoma.Br J Cancer2004;90:833-7 PMCID:PMC2410161

[37] Trerotoli P,Angelotti U,Lupo L,Mangia A,Giannelli G.Tissue expression of Squamous Cellular Carcinoma Antigen (SCCA) is inversely correlated to tumor size in HCC.Mol Cancer2009;8:29 PMCID:PMC2693114

[38] Turato C,Fabre M,Branchereau S,Ruvoletto M,Grotzer MA,Pontisso P.Over-expression of SERPINB3 in hepatoblastoma: a possible insight into the genesis of this tumour?.Eur J Cancer2012;48:1219-26

[39] Villano G,Quarta S,Ciscato F,Semeraro R,Parola M,Bernardi P,Pontisso P.Hepatic progenitor cells express SerpinB3.BMC Cell Biol2014;15:5 PMCID:PMC3927218

[40] Turato C,Biasiolo A,Ruvoletto M,Paccagnella D,Merkel C,Gatta A.SERPINB3 modulates TGF-beta expression in chronic liver disease.Lab Invest2010;90:1016-23

[41] Hernandez-Gea V,Friedman SL.Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma.Gastroenterology2013;144:512-27 PMCID:PMC3578068

[42] Friedman SL.Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.Physiol Rev2008;88:125-72 PMCID:PMC2888531

[43] Novo E,Turato C,Paternostro C,Biasiolo A,Morello E,Miglietta A,Sutti S,Albano E,Pontisso P.SerpinB3 promotes pro-fibrogenic responses in activated hepatic stellate cells.Sci Rep2017;7:3420-3 PMCID:PMC5469760

[44] Ringelhan M,O'Connor T,Heikenwalder M.The immunology of hepatocellular carcinoma.Nat Immunol2018;19:222-32

[45] Roth GS.Liver immunotolerance and hepatocellular carcinoma: patho-physiological mechanisms and therapeutic perspectives.Eur J Cancer2017;87:101-12

[46] Carambia A,Schwinge D,Laschtowitz A,Wraith DC,Schramm C,Heeren J.TGF-β-dependent induction of CD4+CD25+Foxp3+ Tregs by liver sinusoidal endothelial cells.J Hepatol2014;61:594-9

[47] Suminami Y,Murakami A,Gondo T,Numa F,Kato H.Suppression of a squamous cell carcinoma (SCC)-related serpin, SCC antigen, inhibits tumor growth with increased intratumor infiltration of natural killer cells.Cancer Res2001;61:1776-80

[48] Lunardi F,Perissinotto E,Rea F,Bradaschia A,Pontisso P.Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice.Lab Invest2011;91:945-54

[49] Fattovich G,Degos F,Diodati G,Nevens F,Mura D,Thomas H,Casarin C,Fuschi P,Tocco A,Galassini R,Schalm SW.Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients.Gastroenterology1997;112:463-72

[50] Beneduce L,Marino M,Ruvoletto M,Calabrese F,Pontisso P.Squamous cell carcinoma antigen-immunoglobulin M complexes as novel biomarkers for hepatocellular carcinoma.Cancer2005;103:2558-65

[51] Rubin B.Natural immunity has significant impact on immune responses against cancer.Scand J Immunol2009;69:275-90

[52] Pontisso P,Caberlotto C,Marino M,Tono N,Cavalletto L,Chemello L.Progressive increase of SCCA-IgM immune complexes in cirrhotic patients is associated with development of hepatocellular carcinoma.Int J Cancer2006;119:735-40

[53] Buccione D,Gallotta A,Di Donato R,Saitta C,Di Micoli A,Picciotto A.F-9 Serum SCCA-IgM as a predictor of hepatocellular carcinoma (HCC) in patients with liver cirrhosis.Open J Gastroenterol2011;2:56-61

[54] Biasiolo A,Fasolato S,Martini A,Fassina G,Gatta A.Squamous cell carcinoma antigen-IgM is associated with hepatocellular carcinoma in patients with cirrhosis: a prospective study.Dig Liver Dis2016;48:197-202

[55] Pozzan C,Piciocchi M,Maddalo G,Giacomin A,Cillo U.Diagnostic and prognostic role of SCCA-IgM serum levels in hepatocellular carcinoma (HCC).J Gastroenterol Hepatol2014;29:1637-44

[56] Guarino M,Gallotta A,Paneghetti L,Tuccillo C,Caporaso N.Circulating SCCA-IgM complex is a useful biomarker to predict the outcome of therapy in hepatocellular carcinoma patients.Scand J Clin Lab Invest2017;77:448-53

[57] Sica A,Mantovani A.Macrophage plasticity and polarization in liver homeostasis and pathology.Hepatology2014;59:2034-42

[58] Sheshadri N,Bott AJ,Ullman E,Pan JA,Crawford HC,Zong WX.SCCA1/SERPINB3 promotes oncogenesis and epithelial-mesenchymal transition via the unfolded protein response and IL6 signaling.Cancer Res2014;74:6318-29 PMCID:PMC4216755

[59] Vidalino L,Quarta SM,Ruvoletto M,Trentin L,Parolin MC,Iaccarino L,Chemello L,Pontisso P.SERPINB3 expression on B-cell surface in autoimmune diseases and hepatitis C virus-related chronic liver infection.Exp Biol Med2012;237:793-802

[60] Chechlinska M,Brzoska-Wojtowicz E,Ptaszynski K,Kaminska J.Squamous cell carcinoma antigen 1 and 2 expression in cultured normal peripheral blood mononuclear cells and in vulvar squamous cell carcinoma.Tumour Biol2010;31:559-67 PMCID:PMC2953620