SERPINB3 modulates TGF-β expression in chronic liver disease

Turato, Cristian; Calabrese, Fiorella; Biasiolo, Alessandra; Quarta, Santina; Ruvoletto, Mariagrazia; Tono, Natascia; Paccagnella, Daniela; Fassina, Giorgio; Merkel, Carlo; Harrison, Tim J.; Gatta, Angelo; Pontisso, Patrizia

doi:10.1038/labinvest.2010.55

Cited by 47 publications

(70 citation statements)

References 41 publications

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“…Recent results indicate that SERPINB3 can induce RSL-dependent TGF-b1 synthesis and the effect is modulated by single amino acid mutation in the reactive loop. 20 In chronically damaged livers, a parallel over-expression of SERPINB3 and TGF-b1 was correlated directly to the fibrosis stage, as Figure 4 Inhibition of papain by SERPINB3 isoforms. The interaction of papain with SERPINB3 wild-type and SCCA-PD was studied under pseudo-first-order conditions.…”

Section: Discussionmentioning

confidence: 96%

Increased antiprotease activity of the SERPINB3 polymorphic variant SCCA-PD

Turato

Biasiolo

Pengo³

et al. 2011

Exp Biol Med (Maywood)

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SERPINB3 has been found in chronic liver damage and hepatocellular carcinoma, but not in normal liver. By direct mRNA sequencing, a new SERPINB3 polymorphism (SCCA-PD) has been identified, presenting the substitution Gly351Ala in the reactive center loop of the protein. The prevalence of the SCCA-PD isoform has been found to be significantly higher in patients with cirrhosis than in patients with chronic liver disease and in normal subjects. The aim of this study was to investigate the biological and functional activity of SERPINB3 isoforms using in vitro models. HepG2 and Huh7 cells lines were transfected with plasmid vectors containing wild-type SERPINB3 or its polymorphic variant SCCA-PD and their expression at transcriptional and protein level was determined. To assess the functional activity, both recombinant proteins were produced and kinetic analysis was carried out using papain and cathepsin-L as target proteases. In addition, the inhibition of JNK kinase activity by SERPINB3 isoforms was assessed. The crystal structure of wild-type SERPINB3 at 2.7 Å resolution was used for preparation of refined 3D models of the two isoforms. The results showed that transcriptional activity and protein expression of the two isoforms were similar in both transfected cell lines. Both SERPINB3 preparations exerted a dose-dependent protease inhibitory activity, but the effect of SCCA-PD was higher than that of the wild-type isoform. This result was supported by 3D modelling, where increased hydrophobic profile of the SCCA-PD isoform, introduced by the G351A mutation, was detected. In addition, at high protein concentration, SCCA-PD revealed a 16% higher inhibitory effect on c-Jun phosphorylation by JNK1, compared with wild-type SERPINB3. In conclusion, the single amino acid substitution in the SERPINB3 reactive site loop improves the functional activity of SCCA-PD isoform. This different antiprotease activity might favor disease progression in patients carrying this polymorphism.

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Section: Discussionmentioning

confidence: 96%

Increased antiprotease activity of the SERPINB3 polymorphic variant SCCA-PD

Turato

Biasiolo

Pengo³

et al. 2011

Exp Biol Med (Maywood)

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“…It has been demonstrated that in patients with chronic hepatitis undergoing standard antiviral treatment and achieving a sustained virological response there was a significant decrease in serum levels of SCCA-IgM at the end of treatment and up to 1 year of follow-up [21]. We might speculate that the damage inferred by a metabolic imbalance could be different from that caused by viral chronic infection, in which the use of SCCA-IgM has been validated [14, 16, 19-22]. Indeed, it is well known that adipose tissue is characterized by a state of low-grade inflammation that is the basis of the pathogenesis of NAFLD [38].…”

Section: Discussionmentioning

confidence: 99%

“…The two isoforms SCCA1 (SERPINB3) and SCCA2 (SERPINB4) are physiologically expressed in squamous epithelia, in endothelial cells of the veins, in the walls of arteries [14], and in peripheral blood mononuclear cells [15]. It has been reported that SERPINB3 induces TGFβ expression in chronic liver disease [16] and promotes fibrogenesis in experimental models [17]. Data indicate that SERPINB3 protects cellular from apoptotic death caused by different kinds of stimuli [18], inducing cell proliferation and increasing invasiveness potential.…”

Section: Introductionmentioning

confidence: 99%

SCCA-IgM as a Potential Biomarker of Non-Alcoholic Fatty Liver Disease in Patients with Obesity, Prediabetes and Diabetes Undergoing Sleeve Gastrectomy

et al. 2019

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Background: Non-alcoholic fatty liver disease (NAFLD) has a high prevalence in obesity and its presence should be screened. Laparoscopic sleeve gastrectomy (LSG) is an effective treatment for obesity, but its effects on NAFLD are still to be firmly established. The diagnosis of non-alcoholic steatohepatitis (NASH) is currently performed by liver biopsy, a costly and invasive procedure. Squamous cell carcinoma antigen-IgM (SCCA-IgM) is a biomarker of viral hepatitis to hepatocellular carcinoma development and its role in NAFLD to NASH progression has not yet been investigated. Objective: The aim of this study was to evaluate SCCA-IgM as a non-invasive biomarker of NAFLD/NASH in patients with different degrees of metabolic-complicated obesity before and after LSG. Method: Fifty-six patients with obesity were studied before and 12 months after LSG; anthropometric, biochemical, clinical, and imaging data were collected. Results: At baseline steatosis was strongly associated with the glycaemic profile (p = 0.016) and was already present in prediabetic patients with obesity (82%). Only 3 patients had an SCCA-IgM level above the normal cut-off. SCCA-IgM titre did not change according to glycaemic profile or steatosis. Metabolic and inflammatory factors and transaminases significantly reduced after LSG-induced weight loss, except for SCCA-IgM. The ALT/AST ratio decreased post-LSG correlated with BMI (r = 0.297, p = 0.031), insulin (r = 0.354, p = 0.014), and triglycerides (r = 0.355, p = 0.009) reduction. Conclusions: Our results confirm the tight link between NAFLD and metabolic complications, suggesting prediabetes as a new risk factor of steatosis. SCCA-IgM does not seem to have a role in the identification and prognosis of NAFLD.

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“…These important clinical findings were confirmed at the mole cular level: SCCA expression in liver tumor has been correlated with liver regeneration activity (expressed by MIB-I-labeling index) [39] , and increased proliferation was also documented in hepatoma cell lines overexpressing SERPINB3 and in a mouse model transgenic for this serpin [39,40] . Recent data indicate that SERPINB3 is highly expressed in the hepatic stem/progenitor cell compartment of both fetal and adult livers [41] ; moreover, after induction by HIF2-alpha in an hypoxic environment [42] , SERPINB3 was shown to be crucial for tumour invasiveness and metastasis, since it promotes epithelial-mesenchymal transition [39] and transforming growth factor-beta production [43] (Figure 1). …”

Section: Sccamentioning

confidence: 99%

Clinical applications of squamous cell carcinoma antigen-immunoglobulins M to monitor chronic hepatitis C

Martini

Gallotta

Pontisso

et al. 2015

WJH

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Hepatitis C virus (HCV) is the main cause of chronic liver disease and cirrhosis in Western countries. Over time, the majority of cirrhotic patients develop hepatocellular carcinoma (HCC), one of the most common fatal cancers worldwide -fourth for incidence rate. A high public health priority need is the development of biomarkers to screen for liver disease progression and for early diagnosis of HCC development, particularly in the high risk population represented by HCV-positive patients with cirrhosis. Several studies have shown that serological determination of a novel biomarker, squamous cell carcinoma antigen-immunoglobulins M (SCCA-IgM), might be useful to identify patients with progressive liver disease. In the initial part of this review we summarize the main clinical studies that have investigated this new circulating biomarker on HCV-infected patients, providing evidence that in chronic hepatitis C SCCA-IgM may be used to monitor progression of liver disease, and also to assess the virological response to antiviral treatment. In the last part of this review we address other, not less important, clinical applications of this biomarker in hepatology. Core tip: A high public health priority need is the development of biomarkers to screen for liver disease progression in hepatitis C virus (HCV)-positive patients. Serological squamous cell carcinoma antigen-immunoglobulins M has shown the ability to identify patients with progressive liver disease and patients at higher risk of hepatocellular carcinoma development. In this review we summarize the main clinical studies performed using this new circulating biomarker for monitoring cirrhosis progression in HCV-positive patients and to evaluate virological response to antiviral treatment. Clinical applications of squamous cell carcinoma antigenimmunoglobulins M to monitor chronic hepatitis C Martini A, Gallotta A, Pontisso P, Fassina G. Clinical applications of squamous cell carcinoma antigen-immunoglobulins M to monitor chronic hepatitis C. MINIREVIEWS

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SERPINB3 modulates TGF-β expression in chronic liver disease

Cited by 47 publications

References 41 publications

Increased antiprotease activity of the SERPINB3 polymorphic variant SCCA-PD

Increased antiprotease activity of the SERPINB3 polymorphic variant SCCA-PD

SCCA-IgM as a Potential Biomarker of Non-Alcoholic Fatty Liver Disease in Patients with Obesity, Prediabetes and Diabetes Undergoing Sleeve Gastrectomy

Clinical applications of squamous cell carcinoma antigen-immunoglobulins M to monitor chronic hepatitis C

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