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Rahmani D, Taheri RA, Moosazadeh Moghaddam M. Targeted delivery of curcumin and CM11 peptide against hepatocellular carcinoma cells based on binding affinity of PreS1-coated chitosan nanoparticles to SB3 protein. Amino Acids 2025; 57:12. [PMID: 39862295 PMCID: PMC11762422 DOI: 10.1007/s00726-024-03438-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 12/18/2024] [Indexed: 01/27/2025]
Abstract
In recent years, the use of cationic peptides as alternative drugs with anticancer activity has received attention. In this study, the targeted release of curcumin (Cur) and CM11 peptide alone and together against hepatocellular carcinoma (HCC) was evaluated using chitosan nanoparticles (CS NPs) coated with Pres1 that target the SB3 antigen of HCC cells (PreS1-Cur-CM11-CS NPs). SB3 protein is the specific antigen of HCC and the PreS1 peptide is a part of the hepatitis B antigen, which can specifically bind to the SB3 protein. Chitosan was used to prepare NPs. To Cur and CM11 loading, drugs were added to the CS solution in appropriate concentrations. Pres1 was coupled to the surface of the NPs using EDC catalyst to target NPs against HepG2 cells. SEM and DLS analysis confirmed that the PreS1-Cur-CM11-CS NPs had a size of about 132 nm, the ideal size for penetrating the cell membrane. The loading of Cur and CM11 was equal to 87% and 65%, respectively, which had a sustained and better release in the acidic environment than in the physiological environment. The MTT assay showed that PreS1-Cur-CM11-CS NPs act in a targeted and specific manner with the highest toxicity on the HepG2 cells compared to the control by a decrease in viability of about 26% after 48 h based on cell apoptosis. The results showed that PreS1-Cur-CM11-CS NPs are capable of targeted and specific drug release against HepG2 cancer cells and have significant potential to fight this cancer.
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Affiliation(s)
- Danial Rahmani
- Tissue Engineering and Regenerative Medicine Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ramezan Ali Taheri
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mehrdad Moosazadeh Moghaddam
- Tissue Engineering and Regenerative Medicine Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Cagnin S, Pontisso P, Martini A. SerpinB3: A Multifaceted Player in Health and Disease-Review and Future Perspectives. Cancers (Basel) 2024; 16:2579. [PMID: 39061218 PMCID: PMC11274807 DOI: 10.3390/cancers16142579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/10/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
SerpinB3, a member of the serine-protease inhibitor family, has emerged as a crucial player in various physiological and pathological processes. Initially identified as an oncogenic factor in squamous cell carcinomas, SerpinB3's intricate involvement extends from fibrosis progression and cancer to cell protection in acute oxidative stress conditions. This review explores the multifaceted roles of SerpinB3, focusing on its implications in fibrosis, metabolic syndrome, carcinogenesis and immune system impairment. Furthermore, its involvement in tissue protection from oxidative stress and wound healing underscores its potential as diagnostic and therapeutic tool. Recent studies have described the therapeutic potential of targeting SerpinB3 through its upstream regulators, offering novel strategies for cancer treatment development. Overall, this review underscores the importance of further research to fully elucidate the mechanisms of action of SerpinB3 and to exploit its therapeutic potential across various medical conditions.
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Affiliation(s)
| | - Patrizia Pontisso
- Department of Medicine, University of Padova, 35123 Padova, Italy; (S.C.); (A.M.)
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Xu D, Zhuang X, Ma H, Li Z, Wei L, Luo J, Han H. Altered tumor microenvironment heterogeneity of penile cancer during progression from non-lymphatic to lymphatic metastasis. Cancer Med 2024; 13:e70025. [PMID: 39003681 PMCID: PMC11246611 DOI: 10.1002/cam4.70025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 07/03/2024] [Accepted: 07/08/2024] [Indexed: 07/15/2024] Open
Abstract
BACKGROUND Lymphatic metastasis is the major challenge in the treatment of penile cancer. The prognosis of individuals with lymphatic metastasis is extremely poor. Therefore, early identification of disease progression and lymphatic metastasis is an urgent task for researchers in penile cancer worldwide. METHODS In this study, using single-cell RNA sequencing, an immune landscape was established for the cancer ecosystem based on 46,861 cells from six patients with penile cancer (four with lymphatic metastasis [stage IV] and two without lymphatic metastasis [stage I]). Using bulk RNA sequencing, the discrepancy between the cancers and their respective metastatic lymph nodes was depicted based on seven patients with penile cancer. RESULTS The interaction between epithelial cells, fibroblasts, and endothelial cells, and the functional cooperation among invasion, epithelial-mesenchymal transition, and angiogenesis were found to be important landscapes in the penile cancer ecosystem, playing important roles in progression of cancer and lymph node metastasis. CONCLUSIONS This study is the first to investigate the altered tumor microenvironment heterogeneity of penile cancer as it evolves from non-lymphatic to lymphatic metastasis and provides insights into the mechanisms underlying malignant progression, the premetastatic niche, and lymphatic metastasis in penile cancer.
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Affiliation(s)
- Da‐Ming Xu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouP. R. China
- Department of UrologySun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Xiao‐Yu Zhuang
- Department of AnesthesiologySecond Affiliated Hospital of Shantou University Medical CollegeShantouP. R. China
| | - Hua‐Li Ma
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouP. R. China
- Department of RadiologySun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Zai‐Shang Li
- Department of Urology, Shenzhen People's HospitalThe Second Clinic Medical College of Jinan UniversityShenzhenP. R. China
| | - Li‐Chao Wei
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouP. R. China
- Department of UrologySun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Jun‐Hang Luo
- Department of Urology, First Affiliated HospitalSun Yat‐sen UniversityGuangzhouP. R. China
- Institute of Precision Medicine, First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouP. R. China
| | - Hui Han
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouP. R. China
- Department of UrologySun Yat‐sen University Cancer CenterGuangzhouP. R. China
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Villano G, Novo E, Turato C, Quarta S, Ruvoletto M, Biasiolo A, Protopapa F, Chinellato M, Martini A, Trevellin E, Granzotto M, Cannito S, Cendron L, De Siervi S, Guido M, Parola M, Vettor R, Pontisso P. The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitis. Mol Metab 2024; 81:101889. [PMID: 38307387 PMCID: PMC10864841 DOI: 10.1016/j.molmet.2024.101889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 01/11/2024] [Accepted: 01/26/2024] [Indexed: 02/04/2024] Open
Abstract
OBJECTIVE The serine protease inhibitor SerpinB3 has been described as critical mediator of liver fibrosis and it has been recently proposed as an additional hepatokine involved in NASH development and insulin resistance. Protease Activated Receptor 2 has been identified as a novel regulator of hepatic metabolism. A targeted therapeutic strategy for NASH has been investigated, using 1-Piperidine Propionic Acid (1-PPA), since this compound has been recently proposed as both Protease Activated Receptor 2 and SerpinB3 inhibitor. METHODS The effect of SerpinB3 on inflammation and fibrosis genes was assessed in human macrophage and stellate cell lines. Transgenic mice, either overexpressing SerpinB3 or carrying Serpinb3 deletion and their relative wild type strains, were used in experimental NASH models. Subgroups of SerpinB3 transgenic mice and their controls were also injected with 1-PPA to assess the efficacy of this compound in NASH inhibition. RESULTS 1-PPA did not present significant cell and organ toxicity and was able to inhibit SerpinB3 and PAR2 in a dose-dependent manner. This effect was associated to a parallel reduction of the synthesis of the molecules induced by endogenous SerpinB3 or by its paracrine effects both in vitro and in vivo, leading to inhibition of lipid accumulation, inflammation and fibrosis in experimental NASH. At mechanistic level, the antiprotease activity of SerpinB3 was found essential for PAR2 activation, determining upregulation of the CCAAT Enhancer Binding Protein beta (C/EBP-β), another pivotal regulator of metabolism, inflammation and fibrosis, which in turn determined SerpinB3 synthesis. CONCLUSIONS 1-PPA treatment was able to inhibit the PAR2 - C/EBP-β - SerpinB3 axis and to protect from NASH development and progression, supporting the potential use of a similar approach for a targeted therapy of NASH.
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Affiliation(s)
- Gianmarco Villano
- Dept. of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Italy
| | - Erica Novo
- Dept. of Clinical and Biological Sciences, University of Torino, Italy
| | | | | | | | | | | | | | | | | | | | - Stefania Cannito
- Dept. of Clinical and Biological Sciences, University of Torino, Italy
| | | | | | - Maria Guido
- Dept. of Medicine, University of Padova, Italy
| | - Maurizio Parola
- Dept. of Clinical and Biological Sciences, University of Torino, Italy
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Martini A, Turato C, Cannito S, Quarta S, Biasiolo A, Ruvoletto M, Novo E, Marafatto F, Guerra P, Tonon M, Clemente N, Bocca C, Piano SS, Guido M, Gregori D, Parola M, Angeli P, Pontisso P. The polymorphic variant of SerpinB3 (SerpinB3-PD) is associated with faster cirrhosis decompensation. Aliment Pharmacol Ther 2024; 59:380-392. [PMID: 37990490 DOI: 10.1111/apt.17804] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/24/2023] [Accepted: 10/28/2023] [Indexed: 11/23/2023]
Abstract
BACKGROUND SerpinB3 is a cysteine protease inhibitor involved in liver disease progression due to its proinflammatory and profibrogenic properties. The polymorphic variant SerpinB3-PD (SB3-PD), presents a substitution in its reactive centre loop, determining the gain of function. AIMS To disclose the clinical characteristics of a cohort of patients with cirrhosis in relation to the presence of SB3-PD and to assess the effect of this genetic variant on fibrogenic and inflammatory cytokines in vitro. METHODS We assessed SB3 polymorphism in 90 patients with cirrhosis, prospectively followed up in our referral centre. We used HepG2 and HuH-7 cells transfected to overexpress either wild-type SB3 (SB3-WT) or SB3-PD to assess their endogenous effect, while LX2 and THP-1 cells were treated with exogenous SB3-WT or SB3-PD proteins. RESULTS Patients carrying SB3-PD had more severe portal hypertension and higher MELD scores, than patients carrying SB3-WT. In multivariate analysis, SB3-PD was an independent predictor of cirrhosis complications. Patients with SB3-PD polymorphism presented with more severe liver fibrosis and inflammatory features. Hepatoma cells overexpressing SB3-PD showed higher TGF-β1 expression than controls. The addition of recombinant SB3-PD induced an up-regulation of TGF-β1 in LX2 cells and a more prominent inflammatory profile in THP-1 cells, compared to the effect of SB3-WT protein. CONCLUSIONS The polymorphic variant SB3-PD is highly effective in determining activation of TGF-β1 and inflammation in vitro. Patients with cirrhosis who carry SB3-PD polymorphism may be more prone to develop severe liver disease progression. However, further validation studies are warranted to support the in vivo relevance of this polymorphism.
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Affiliation(s)
- Andrea Martini
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Cristian Turato
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Stefania Cannito
- Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Santina Quarta
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Alessandra Biasiolo
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Mariagrazia Ruvoletto
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Erica Novo
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Filippo Marafatto
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Pietro Guerra
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Marta Tonon
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Nausicaa Clemente
- Department of Health Science, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale, Novara, Italy
| | - Claudia Bocca
- Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Salvatore Silvio Piano
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Maria Guido
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Dario Gregori
- Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Maurizio Parola
- Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Patrizia Pontisso
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
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Guerra P, Martini A, Pontisso P, Angeli P. Novel Molecular Targets for Immune Surveillance of Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:3629. [PMID: 37509293 PMCID: PMC10377787 DOI: 10.3390/cancers15143629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/06/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common and aggressive cancer with a high mortality rate. The incidence of HCC is increasing worldwide, and the lack of effective screening programs often results in delayed diagnosis, making it a challenging disease to manage. Immunotherapy has emerged as a promising treatment option for different kinds of cancers, with the potential to stimulate the immune system to target cancer cells. However, the current immunotherapeutic approaches for HCC have shown limited efficacy. Since HCC arises within a complex tumour microenvironment (TME) characterized by the presence of various immune and stromal cell types, the understanding of this interaction is crucial for the identification of effective therapy. In this review, we highlight recent advances in our understanding of the TME of HCC and the immune cells involved in anti-tumour responses, including the identification of new possible targets for immunotherapy. We illustrate a possible classification of HCC based on the tumour immune infiltration and give evidence about the role of SerpinB3, a serine protease inhibitor involved in the regulation of the immune response in different cancers.
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Affiliation(s)
- Pietro Guerra
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
| | - Andrea Martini
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
| | - Patrizia Pontisso
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
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Quarta S, Cappon A, Turato C, Ruvoletto M, Cannito S, Villano G, Biasiolo A, Maggi M, Protopapa F, Bertazza L, Fasolato S, Parola M, Pontisso P. SerpinB3 Upregulates Low-Density Lipoprotein Receptor-Related Protein (LRP) Family Members, Leading to Wnt Signaling Activation and Increased Cell Survival and Invasiveness. BIOLOGY 2023; 12:771. [PMID: 37372056 DOI: 10.3390/biology12060771] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/12/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023]
Abstract
Abnormal activation of the Wnt-β-catenin signaling cascade is involved in tumor growth and dissemination. SerpinB3 has been shown to induce β-catenin, and both molecules are overexpressed in tumors, particularly in those with poor prognoses. The aim of this study was to evaluate the ability of SerpinB3 to modulate the Wnt pathway in liver cancer and in monocytic cells, the main type of inflammatory cells in the tumor microenvironment. The Wnt cascade, Wnt co-receptors, and low-density lipoprotein receptor-related protein (LRP) members were analyzed in different cell lines and human monocytes in the presence or absence of SerpinB3. The Wnt-β-catenin axis was also evaluated in liver tumors induced in mice with different extents of SeprinB3 expression. In monocytic cells, SerpinB3 induced a significant upregulation of Wnt-1/7, nuclear β-catenin, and c-Myc, which are associated with increased cell lifespan and proliferation. In liver tumors in mice, the expression of β-catenin was significantly correlated with the presence of SerpinB3. In hepatoma cells, Wnt co-receptors LRP-5/6 and LRP-1, implicated in cell survival and invasiveness, were upregulated by SerpinB3. The LRP pan-inhibitor RAP not only induced a decrease in LRP expression, but also a dose-dependent reduction in SerpinB3-induced invasiveness. In conclusion, SerpinB3 determines the activation of the Wnt canonical pathway and cell invasiveness through the upregulation of LRP family members.
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Affiliation(s)
- Santina Quarta
- Department of Medicine, University of Padova, 35128 Padua, Italy
| | - Andrea Cappon
- Department of Medicine, University of Padova, 35128 Padua, Italy
| | - Cristian Turato
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | | | - Stefania Cannito
- Department of Clinical and Biological Sciences, University of Torino, 10124 Turin, Italy
| | - Gianmarco Villano
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, 35128 Padua, Italy
| | | | - Maristella Maggi
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Francesca Protopapa
- Department of Clinical and Biological Sciences, University of Torino, 10124 Turin, Italy
| | - Loris Bertazza
- Department of Medicine, University of Padova, 35128 Padua, Italy
| | - Silvano Fasolato
- Department of Medicine, University of Padova, 35128 Padua, Italy
| | - Maurizio Parola
- Department of Clinical and Biological Sciences, University of Torino, 10124 Turin, Italy
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Biasiolo A, Sandre M, Ferro S, Quarta S, Ruvoletto M, Villano G, Turato C, Guido M, Marin O, Pontisso P. Epitope-Specific Anti-SerpinB3 Antibodies for SerpinB3 Recognition and Biological Activity Inhibition. Biomolecules 2023; 13:biom13050739. [PMID: 37238609 DOI: 10.3390/biom13050739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/13/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
SerpinB3 is a serine protease inhibitor that plays a relevant role in disease progression and cancer by increasing fibrosis, cell proliferation, and invasion, besides conferring resistance to apoptosis. The mechanisms underlying these biological activities are not yet fully understood. The aim of this study was to generate antibodies directed against different SerpinB3 epitopes to better investigate their biological role. Five exposed epitopes were identified using the software DNASTAR Lasergene and the corresponding synthetic peptides were used for NZW rabbit immunization. Anti-P#2 and anti-P#4 antibodies were able to recognize both SerpinB3 and SerpinB4 by ELISA. Anti-P#5 antibody, produced against the reactive site loop of SerpinB3, showed the greatest specific reactivity for human SerpinB3. This antibody was able to recognize SerpinB3 at nuclear level, while anti-P#3 antibody recognized SerpinB3 only at cytoplasmic level, both by immunofluorescence and by immunohistochemistry. The biological activity of each antibody preparation was assessed in HepG2 cells overexpressing SerpinB3 and anti-P#5 antibody reduced proliferation by 12% cell and cell invasion by 75%, while trivial results were obtained with the other antibody preparations. These findings indicate that the reactive site loop of SerpinB3 is essential for the invasiveness features induced by this serpin and it could become a novel druggable target.
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Affiliation(s)
- Alessandra Biasiolo
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
| | - Michele Sandre
- Department of Biomedical Sciences, University of Padova, Via Colombo 3, 35131 Padova, Italy
| | - Stefania Ferro
- Department of Biomedical Sciences, University of Padova, Via Colombo 3, 35131 Padova, Italy
| | - Santina Quarta
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
| | - Mariagrazia Ruvoletto
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
| | - Gianmarco Villano
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
| | - Cristian Turato
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Maria Guido
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
| | - Oriano Marin
- Department of Biomedical Sciences, University of Padova, Via Colombo 3, 35131 Padova, Italy
| | - Patrizia Pontisso
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
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Bile detection of squamous cell carcinoma antigen (SCCA) in extrahepatic cholangiocarcinoma. Dig Liver Dis 2022; 55:534-540. [PMID: 36369195 DOI: 10.1016/j.dld.2022.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 10/08/2022] [Accepted: 10/13/2022] [Indexed: 11/10/2022]
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is a rare biliary tract tumor with poor prognosis that often is challenging to diagnose and the majority of patients present with advanced stage. Squamous cell carcinoma antigen 1 (SCCA1) overexpression has been found in different tumors associated with poor prognosis and chemoresistance. AIMS To assess the presence and possible prognostic role of SCCA1/2 isoforms in bile and serum of patients with CCA. METHODS Forty seven surgical patients (36 with CCA and 11 with benign diseases) were prospectively included in the study. Serum and bile specimens were collected at the time of surgery and free and IgM-complexed SCCA was quantified by ELISA (Xeptagen, srl). RESULTS Free or IgM linked SCCA was rarely found in serum, while SCCA was detectable in bile samples of patients with CCA, especially in those with extrahepatic form (43% vs 17%, p = 0.008), but not in controls. Despite similar tumor stage, these positive patients presented a trend toward a higher percentage of portal invasion (27% vs 15%) and of tumor recurrence than negative cases (62% vs 40%), although the difference was not statistically significant. CONCLUSION These preliminary results indicate that bile testing for SCCA is a specific marker of extrahepatic CCA, with potential prognostic value.
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Turato C, Vairetti M, Cagna M, Biasiolo A, Ferrigno A, Quarta S, Ruvoletto M, De Siervi S, Pontisso P, Di Pasqua LG. SerpinB3 administration protects liver against ischemia-reperfusion injury. Eur J Histochem 2022; 66. [DOI: 10.4081/ejh.2022.3561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 10/12/2022] [Indexed: 11/07/2022] Open
Abstract
We have investigated the change in SerpinB3 during hepatic ischemia and the potential role of its antiprotease activity in cell protection by the administration of wild-type SerpinB3 (SerpinB3-WT) or active loop-deleted recombinant SerpinB3 protein (SerpinB3-D) in a rat model of ischemia (60 min)/reperfusion (60 min) (I/R). A time-dependent increase of SerpinB3, both at transcription and protein level, was found in ischemic livers after 60, 120 and 180 min. SerpinB3-WT decreased polymorphonuclear cell infiltration and serum enzymes and increased ATP when compared with I/R group. These events were not obtained using SerpinB3-D. No significant changes in both liver SerpinB3 mRNA and protein were found in all I/R groups considered. The present data show that the administration of SerpinB3-WT reduced the I/R injury and this effect appears to be dependent on its anti-protease activity.
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Effects of Sensitized Sorafenib with a Paeoniflorin and Geniposide Mixture on Liver Cancer via the NF- κB-HIF-2 α-SerpinB3 Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1911311. [PMID: 36285158 PMCID: PMC9588328 DOI: 10.1155/2022/1911311] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 08/18/2022] [Accepted: 09/28/2022] [Indexed: 11/17/2022]
Abstract
Purpose This study focused on determining the anticancer effect of paeoniflorin and geniposide mixture (PFGS) combined with sorafenib (Sor) in hepatocellular carcinoma (HCC) and, in particular, whether PFGS increases the antitumor effect of Sor by modulating the NF-κB/HIF-2α/SerpinB3 pathway. Methods The H22 hepatoma tumor-bearing mouse model was treated with PFGS, Sor, and a combination of the two drugs for 12 days. The effects of PFGS combined with Sor on tumor growth and apoptosis and the expression of NF-κB, HIF-2α, and SerpinB3 in tumor tissue were assessed. In addition, Sor-resistant hepatoma cells were treated with PFGS, Sor, and the combination of the two drugs in vitro. The effects of PFGS combined with Sor on cell proliferation and invasion and the protein expression of NF-κB p65, HIF-2α, and SerpinB3 were investigated. Results PFGS combined with Sor treatment synergistically inhibited tumor growth in HCC tumor-bearing mice. Immunostaining showed that PFGS combined with Sor treatment significantly decreased the expression of Ki-67 and obviously induced apoptosis in the tumor compared with a single treatment. Similarly, PFGS combined with Sor treatment significantly downregulated the expression of NF-κB, HIF-2α, and SerpinB3 in the tumor compared with a single treatment. Additionally, PFGS combined with Sor markedly inhibited cell proliferation and invasion and activation of the NF-κB/HIF-2α/SerpinB3 pathway in Sor-resistant hepatoma cells compared with a single treatment. Conclusion Our study demonstrated that PFGS synergistically increased the antiliver cancer effects of Sor by lowering activation of the NF-κB/HIF-2α/SerpinB3 pathway. These findings provided a scientific foundation for clinical studies using PFGS and Sor to treat liver cancer.
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Semisolid Wet Sol–Gel Silica/Hydroxypropyl Methyl Cellulose Formulation for Slow Release of Serpin B3 Promotes Wound Healing In Vivo. Pharmaceutics 2022; 14:pharmaceutics14091944. [PMID: 36145692 PMCID: PMC9503603 DOI: 10.3390/pharmaceutics14091944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/06/2022] [Accepted: 09/08/2022] [Indexed: 11/30/2022] Open
Abstract
Foot ulcerations are a disabling complication of diabetes and no treatment is currently available based on disease mechanisms. The protein serpin B3 (SB3) was identified as a positive biomarker of successful diabetic wound healing; therefore, its exogenous administration may promote healing. The topical administration of SB3 is challenging due to its protein nature. Physical entrapment in wet sol–gel silica can stabilize the protein’s conformation and permit its sustained delivery. However, irreversible syneresis and poor viscoelastic properties hamper wet sol–gel silica application as a semisolid vehicle. To overcome these limits, a sol–gel silica/hydroxypropylmethylcellulose (HPMC) hydrogel blend was developed. SB3 entrapped in 8% SiO2 wet sol–gel silica preserved its structure, was stabilized against denaturation, and was slowly released for at least three days. Blending a silica gel with an HPMC–glycerol (metolose-G) hydrogel permitted spreadability without affecting the protein’s release kinetics. When administered in vivo, SB3 in silica/metolose-G—but not in solution or in metolose-G alone—accelerated wound healing in SB3 knockout and diabetic mouse models. The results confirmed that SB3 is a new pharmacological option for the treatment of chronic ulcers, especially when formulated in a slow-releasing vehicle. Silica–metolose-G represents a novel type of semisolid dosage form which could also be applied for the formulation of other bioactive proteins.
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Di Maira G, Foglia B, Napione L, Turato C, Maggiora M, Sutti S, Novo E, Alvaro M, Autelli R, Colombatto S, Bussolino F, Carucci P, Gaia S, Rosso C, Biasiolo A, Pontisso P, Bugianesi E, Albano E, Marra F, Parola M, Cannito S. Oncostatin M is overexpressed in NASH-related hepatocellular carcinoma and promotes cancer cell invasiveness and angiogenesis. J Pathol 2022; 257:82-95. [PMID: 35064579 PMCID: PMC9315146 DOI: 10.1002/path.5871] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 12/03/2021] [Accepted: 01/13/2022] [Indexed: 12/03/2022]
Abstract
Oncostatin M (OSM) is a pleiotropic cytokine of the interleukin (IL)-6 family that contributes to the progression of chronic liver disease. Here we investigated the role of OSM in the development and progression of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The role of OSM was investigated in (1) selected cohorts of NAFLD/NASH HCC patients, (2) liver cancer cells exposed to human recombinant OSM or stably transfected to overexpress human OSM, (3) murine HCC xenografts, and (4) a murine NASH-related model of hepatic carcinogenesis. OSM was found to be selectively overexpressed in HCC cells of NAFLD/NASH patients, depending on tumor grade. OSM serum levels, barely detectable in patients with simple steatosis or NASH, were increased in patients with cirrhosis and more evident in those carrying HCC. In this latter group, OSM serum levels were significantly higher in the subjects with intermediate/advanced HCCs and correlated with poor survival. Cell culture experiments indicated that OSM upregulation in hepatic cancer cells contributes to HCC progression by inducing epithelial-to-mesenchymal transition and increased invasiveness of cancer cells as well as by inducing angiogenesis, which is of critical relevance. In murine xenografts, OSM overexpression was associated with slower tumor growth but an increased rate of lung metastases. Overexpression of OSM and its positive correlation with the angiogenic switch were also confirmed in a murine model of NAFLD/NASH-related hepatocarcinogenesis. Consistent with this, analysis of liver specimens from human NASH-related HCCs with vascular invasion showed that OSM was expressed by liver cancer cells invading hepatic vessels. In conclusion, OSM upregulation appears to be a specific feature of HCC arising on a NAFLD/NASH background, and it correlates with clinical parameters and disease outcome. Our data highlight a novel pro-carcinogenic contribution for OSM in NAFLD/NASH, suggesting a role of this factor as a prognostic marker and a putative potential target for therapy. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Giovanni Di Maira
- Department of Clinical and Experimental Medicine and Center DenotheUniversity of FirenzeFirenzeItaly
| | - Beatrice Foglia
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical PathologyUniversity of TorinoTorinoItaly
| | - Lucia Napione
- Laboratory of Vascular Oncology Candiolo Cancer Institute – FPO IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico)TorinoItaly
- Department of Applied Science and TechnologyPolitecnico di TorinoTorinoItaly
| | - Cristian Turato
- Department of Molecular MedicineUniversity of PaviaPaviaItaly
| | - Marina Maggiora
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical PathologyUniversity of TorinoTorinoItaly
| | - Salvatore Sutti
- Department of Health Sciences and Interdisciplinary Research Center for Autoimmune DiseasesUniversity Amedeo Avogadro of East PiedmontNovaraItaly
| | - Erica Novo
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical PathologyUniversity of TorinoTorinoItaly
| | - Maria Alvaro
- Laboratory of Vascular Oncology Candiolo Cancer Institute – FPO IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico)TorinoItaly
- Department of OncologyUniversity of TorinoTorinoItaly
| | - Riccardo Autelli
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical PathologyUniversity of TorinoTorinoItaly
| | | | - Federico Bussolino
- Laboratory of Vascular Oncology Candiolo Cancer Institute – FPO IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico)TorinoItaly
- Department of OncologyUniversity of TorinoTorinoItaly
| | - Patrizia Carucci
- Division of GastroenterologyCittà della Salute e della Scienza University‐HospitalTurinItaly
| | - Silvia Gaia
- Division of GastroenterologyCittà della Salute e della Scienza University‐HospitalTurinItaly
| | - Chiara Rosso
- Department of Medical SciencesUniversity of TorinoTorinoItaly
| | | | | | | | - Emanuele Albano
- Department of Health Sciences and Interdisciplinary Research Center for Autoimmune DiseasesUniversity Amedeo Avogadro of East PiedmontNovaraItaly
| | - Fabio Marra
- Department of Clinical and Experimental Medicine and Center DenotheUniversity of FirenzeFirenzeItaly
| | - Maurizio Parola
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical PathologyUniversity of TorinoTorinoItaly
| | - Stefania Cannito
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical PathologyUniversity of TorinoTorinoItaly
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Squamous Cell Carcinoma Antigen: Clinical Application and Research Status. Diagnostics (Basel) 2022; 12:diagnostics12051065. [PMID: 35626221 PMCID: PMC9139199 DOI: 10.3390/diagnostics12051065] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 04/21/2022] [Accepted: 04/22/2022] [Indexed: 02/04/2023] Open
Abstract
The squamous cell carcinoma antigen (SCCA) is a tumor marker that has gained increasing attention for its biological functions and significance in normal physiological and pathological processes. Not only SCCA but also circulating immune complexes of SCCA and immunoglobulin M (IgM) are involved in normal physiological and pathological processes, providing a background for numerous clinical studies aimed at assessing the potential role of SCCA, SCCA–IgM, and SCCA isoform complexes in clinical practice. Previous studies support the clinical value of SCCA as a tumor marker for either diagnosing squamous cancers or monitoring the response to radiotherapy or chemotherapy, tumor relapse, and treatment failure. However, these studies show contrasting results, making the diagnostic or prognostic value of SCCA controversial. To reduce clinical heterogeneity across studies and achieve a more accurate and reliable comparison of results, a standardized detection method, scoring system, and cutoff level need to be established. Moreover, despite the fact that performances of different methods are comparable, the dynamic observation of tumor marker kinetics should be conducted under the same method.
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Correnti M, Cappon A, Pastore M, Piombanti B, Lori G, Oliveira DVPN, Munoz‐Garrido P, Lewinska M, Andersen JB, Coulouarn C, Sulpice L, Peraldo Neia C, Cavalloni G, Quarta S, Biasiolo A, Fassan M, Ramazzotti M, Parri M, Recalcati S, di Tommaso L, Campani C, Invernizzi P, Torzilli G, Marra F, Pontisso P, Raggi C. The protease-inhibitor SerpinB3 as a critical modulator of the stem-like subset in human cholangiocarcinoma. Liver Int 2022; 42:233-248. [PMID: 34478594 PMCID: PMC9290104 DOI: 10.1111/liv.15049] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 08/07/2021] [Accepted: 08/25/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Cholangiocarcinoma (CCA) is a form of primary liver cancer with limited therapeutic options. Recently, cancer stem cells (CSCs) have been proposed as a driving force of tumour initiation and dissemination, thus representing a crucial therapeutic target. The protease inhibitor SerpinB3 (SB3) has been identified in several malignancies including hepatocellular carcinoma. SB3 has been involved in the early events of hepatocarcinogenesis and is highly expressed in hepatic progenitor cells and in a mouse model of liver progenitor cell activation. However, only limited information on the possible role of SB3 in CCA stem-like compartment is available. METHODS Enrichment of CCA stem-like subset was performed by sphere culture (SPH) in CCA cell lines (CCLP1, HUCCT1, MTCHC01 and SG231). Quantitative RT-PCR and Western blotting were used to detect SB3 in both SPH and parental monolayer (MON) cells. Acquired CSC-like features were analysed using an endogenous and a paracrine in vitro model, with transfection of SB3 gene or addition of recombinant SB3 to cell medium respectively. SB3 tumorigenic role was explored in an in vivo mouse model of CCA by subcutaneous injection of SB3-transfected MON (MONSB3+ ) cells in immune-deficient NOD-SCID/IL2Rgnull (NSG) mice. SB3 expression in human CCA sections was investigated by immunohistochemistry. Overall survival (OS) and time to recurrence (TTR) analyses were carried out from a transcriptome database of 104 CCA patients. RESULTS SB3, barely detected in parental MON cells, was overexpressed in the same CCA cells grown as 3D SPH. Notably, MONSB3+ showed significant overexpression of genes associated with stemness (CD24, CD44, CD133), pluripotency (c-MYC, NOTCH1, STAT3, YAP, NANOG, BMI1, KLF4, OCT4, SOX2), epithelial mesenchymal transition (β-catenin, SLUG) and extracellular matrix remodelling (MMP1, MMP7, MMP9, ADAM9, ADAM10, ADAM17, ITGB3). SB3-overexpressing cells showed superior spherogenic capacity and invasion ability compared to control. Importantly, MONSB3+ exhibited activation of MAP kinases (ERK1/2, p38, JNK) as well as phosphorylation of NFκB (p65) in addition to up-regulation of the proto-oncogene β-catenin. All these effects were reversed after transient silencing of SB3. According to the in vitro finding, MONSB3+ cells retained high tumorigenic potential in NSG mice. SB3 overexpression was observed in human CCA tissues and analysis of OS as well as TTR indicated a worse prognosis in SB3+ CCA patients. CONCLUSION These findings indicate a SB3 role in mediating malignant phenotype of CCA and identify a new therapeutic target.
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Affiliation(s)
- Margherita Correnti
- Center for Autoimmune Liver DiseasesHumanitas Clinical and Research CenterRozzanoItaly
- Department of Biomedical Sciences for HealthUniversity of MilanMilanItaly
| | - Andrea Cappon
- Animal Care‐Polo Vallisneri University of PaduaPaduaItaly
| | - Mirella Pastore
- Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
| | - Benedetta Piombanti
- Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
| | - Giulia Lori
- Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
| | | | | | - Monika Lewinska
- Biotech Research and Innovation CentreUniversity of CopenhagenCopenhagenDenmark
| | - Jesper B. Andersen
- Biotech Research and Innovation CentreUniversity of CopenhagenCopenhagenDenmark
| | - Cédric Coulouarn
- CHU RennesService de Chirurgie Hépatobiliaire et DigestiveInsermUniv RennesCOSS (Chemistry, Oncogenesis Stress Signaling)UMR_S 1242Centre de Lutte contre le Cancer Eugène MarquisRennesFrance
| | - Laurent Sulpice
- CHU RennesService de Chirurgie Hépatobiliaire et DigestiveINSERM 1241Université de RennesRennesFrance
| | | | - Giuliana Cavalloni
- Division of Medical OncologyCandiolo Cancer InstituteFPO‐IRCCSCandiolo, TorinoItaly
| | - Santina Quarta
- Department of Medicine‐DIMEDUniversity of PaduaPaduaItaly
| | | | - Matteo Fassan
- Department of Medicine‐DIMEDUniversity of PaduaPaduaItaly
| | - Matteo Ramazzotti
- Department of Experimental and Clinical Biomedical SciencesUniversity of FlorenceFlorenceItaly
| | - Matteo Parri
- Department of Experimental and Clinical Biomedical SciencesUniversity of FlorenceFlorenceItaly
| | - Stefania Recalcati
- Department of Biomedical Sciences for HealthUniversity of MilanMilanItaly
| | - Luca di Tommaso
- Department of PathologyHumanitas Clinical and Research CenterRozzanoItaly
- Department of Biomedical SciencesHumanitas UniversityRozzanoItaly
| | - Claudia Campani
- Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver DiseasesDepartment of Medicine and SurgeryUniversity of Milano‐BicoccaMonzaItaly
- European Reference Network on Hepatological Diseases (ERN RARE‐LIVER)San Gerardo HospitalMonzaItaly
| | - Guido Torzilli
- Department of Hepatobiliary and General SurgeryHumanitas UniversityHumanitas Clinical and Research CenterIRCCS, RozzanoMilanItaly
| | - Fabio Marra
- Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
| | | | - Chiara Raggi
- Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
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Low P66shc with High SerpinB3 Levels Favors Necroptosis and Better Survival in Hepatocellular Carcinoma. BIOLOGY 2021; 10:biology10050363. [PMID: 33922660 PMCID: PMC8145214 DOI: 10.3390/biology10050363] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/13/2021] [Accepted: 04/16/2021] [Indexed: 12/14/2022]
Abstract
Simple Summary Cell proliferation and escape from apoptosis are important pathological features of hepatocellular carcinoma, one of the tumors with the highest mortality rate worldwide. The aim of the study was to evaluate the expression of the pro-apoptotic p66shc and the anti-apoptotic SerpinB3 molecules in relation to clinical outcome in patients with hepatocellular carcinoma and to evaluate their effect on cell fate and tumor growth. In patients with hepatocellular carcinoma the best survival was observed in the subgroup with p66shc levels below median values and SerpinB3 levels above median values. Mice p66shc knockout showed high levels of SerpinB3, while in hepatoma cells overexpressing SerpinB3, p66shc expression was trivial. Hepatoma cells overexpressing SerpinB3 were more prone to die after oxidizing treatments. These cells injected in nude mice developed tumors five times smaller than those from controls. Tumors originating from hepatoma cells overexpressing SerpinB3 showed typical features of necroptosis. In conclusion, in patients affected by hepatocellular carcinoma, the pattern characterized by p66shc downregulation and elevated SerpinB3 levels was associated with markedly better survival. This pattern favored necroptosis in experimental high-stress conditions. Abstract Cell proliferation and escape from apoptosis are important pathological features of hepatocellular carcinoma (HCC), one of the tumors with the highest mortality rate worldwide. The aim of the study was to evaluate the expression of the pro-apoptotic p66shc and the anti-apoptotic SerpinB3 in HCCs in relation to clinical outcome, cell fate and tumor growth. p66shc and SerpinB3 were evaluated in 67 HCC specimens and the results were correlated with overall survival. Proliferation and cell death markers were analyzed in hepatoma cells overexpressing SerpinB3, under different stress conditions. p66shc−/− mice and xenograft models were also used to assess the effects of p66shc and SerpinB3 on tumor growth. In patients with HCC, the best survival was observed in the subgroup with p66shc levels below median values and SerpinB3 levels above median values. Mice p66shc−/− showed high levels of SerpinB3, while in HepG2 cells overexpressing SerpinB3, p66shc expression was trivial. HepG2 overexpressing SerpinB3 cells were more prone to die after oxidizing treatments, such as diamide or high concentration H2O2. These cells injected in nude mice developed tumors five times smaller than those from control HepG2 cells. Tumors originating from HepG2 overexpressing SerpinB3 cells showed decreased activated Caspase-8, with concomitant increase of RIP3K and decreased levels of cleaved RIP3K, typical features of necroptosis. In conclusion, in patients affected by HCC, the pattern characterized by p66shc downregulation and elevated SerpinB3 levels was associated with markedly better survival. This pattern favored necroptosis in experimental high-stress conditions.
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Moldogazieva NT, Mokhosoev IM, Zavadskiy SP, Terentiev AA. Proteomic Profiling and Artificial Intelligence for Hepatocellular Carcinoma Translational Medicine. Biomedicines 2021; 9:biomedicines9020159. [PMID: 33562077 PMCID: PMC7914649 DOI: 10.3390/biomedicines9020159] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/27/2021] [Accepted: 02/02/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver with high morbidity and mortality rates worldwide. Since 1963, when alpha-fetoprotein (AFP) was discovered as a first HCC serum biomarker, several other protein biomarkers have been identified and introduced into clinical practice. However, insufficient specificity and sensitivity of these biomarkers dictate the necessity of novel biomarker discovery. Remarkable advancements in integrated multiomics technologies for the identification of gene expression and protein or metabolite distribution patterns can facilitate rising to this challenge. Current multiomics technologies lead to the accumulation of a huge amount of data, which requires clustering and finding correlations between various datasets and developing predictive models for data filtering, pre-processing, and reducing dimensionality. Artificial intelligence (AI) technologies have an enormous potential to overcome accelerated data growth, complexity, and heterogeneity within and across data sources. Our review focuses on the recent progress in integrative proteomic profiling strategies and their usage in combination with machine learning and deep learning technologies for the discovery of novel biomarker candidates for HCC early diagnosis and prognosis. We discuss conventional and promising proteomic biomarkers of HCC such as AFP, lens culinaris agglutinin (LCA)-reactive L3 glycoform of AFP (AFP-L3), des-gamma-carboxyprothrombin (DCP), osteopontin (OPN), glypican-3 (GPC3), dickkopf-1 (DKK1), midkine (MDK), and squamous cell carcinoma antigen (SCCA) and highlight their functional significance including the involvement in cell signaling such as Wnt/β-catenin, PI3K/Akt, integrin αvβ3/NF-κB/HIF-1α, JAK/STAT3 and MAPK/ERK-mediated pathways dysregulated in HCC. We show that currently available computational platforms for big data analysis and AI technologies can both enhance proteomic profiling and improve imaging techniques to enhance the translational application of proteomics data into precision medicine.
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Affiliation(s)
- Nurbubu T. Moldogazieva
- Laboratory of Bioinformatics, Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia
- Correspondence: or
| | - Innokenty M. Mokhosoev
- Department of Biochemistry and Molecular Biology, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (I.M.M.); (A.A.T.)
| | - Sergey P. Zavadskiy
- Department of Pharmacology, A.P. Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
| | - Alexander A. Terentiev
- Department of Biochemistry and Molecular Biology, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (I.M.M.); (A.A.T.)
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Wang L, Huang L, Xi L, Zhang SC, Zhang JX. High expression of squamous cell carcinoma antigen in poorly differentiated adenocarcinoma of the stomach: A case report. World J Clin Cases 2020; 8:4572-4578. [PMID: 33083420 PMCID: PMC7559675 DOI: 10.12998/wjcc.v8.i19.4572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/11/2020] [Accepted: 09/05/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Squamous cell carcinoma antigen (SCCA) is regarded as a specific indicator of epithelial malignancies and is widely used in the diagnosis of squamous cell carcinoma (SCC). However, the expression of SCCA in gastric adenocarcinoma has not been studied in detail. CASE SUMMARY A 52-year-old man was admitted to our hospital for a 2.5 cm × 2.5 cm ulcer at the antrum-body junction with dull pain and fullness in the upper abdomen for 2 mo. His pre-surgery serological testing results showed 0.51 ng/mL SCCA (reference interval, < 1.5 ng/mL) and 9.9 ng/mL carcinoembryonic antigen (reference range, < 4.7 ng/mL). He underwent radical distal gastrectomy and Roux-en Y anastomosis and was diagnosed with poorly differentiated mucinous adenocarcinoma (Lauren classification: Diffuse) by pathological examination of the resected lesion. Immunohistochemistry showed that SCCA was highly expressed in the cytoplasm of cancer cells. After surgery, the patient received an S-1 adjuvant chemotherapy regimen for six cycles containing tegafur, gimeracil, and oteracil potassium. He showed no sign of recurrence or metastasis within 24-mo follow-up. CONCLUSION This is a frontal report of SCCA overexpression in poorly differentiated adenocarcinoma of the stomach.
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Affiliation(s)
- Lin Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Lei Huang
- Department of Laboratory Medicine, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Lei Xi
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Shi-Chang Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Jie-Xin Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
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Pelizzaro F, Soldà F, Cardin R, Imondi A, Sartori A, Penzo B, Sammarco A, Aliberti C, Vitale A, Cillo U, Farinati F. SCCA-IgM in hepatocellular carcinoma patients treated with transarterial chemoembolization: gender-related differences. Biomark Med 2020; 14:855-867. [PMID: 32808827 DOI: 10.2217/bmm-2019-0564] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 05/18/2020] [Indexed: 02/06/2023] Open
Abstract
Aim: Squamous cell carcinoma antigen immune complexed with immunoglobulin M (SCCA-IgM) is a useful but not completely satisfactory biomarker of hepatocellular carcinoma (HCC). Considering its gender-specific behavior in preclinical models, we investigated gender-related differences of SCCA-IgM as a prognostic marker in HCC. Patients & methods: Two hundred and eight prospectively recruited patients treated with transarterial chemoembolization in a single tertiary care hospital were retrospectively evaluated. Correlations between SCCA-IgM levels, clinical characteristics and survival were assessed according to gender. Results: When the disease was advanced, SCCA-IgM was higher in males and lower in females. Levels below 130 AU/ml predicted a significantly longer survival in males (p = 0.007) and a shorter survival in females (p = 0.01). Conclusion: In predicting the prognosis of HCC patients, the interpretation of SCCA-IgM should consider gender as a relevant variable.
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Affiliation(s)
- Filippo Pelizzaro
- Department of Surgery, Oncology & Gastroenterology, Gastroenterology Unit, University of Padova, Padova, Italy
| | - Federica Soldà
- Department of Surgery, Oncology & Gastroenterology, Gastroenterology Unit, University of Padova, Padova, Italy
| | - Romilda Cardin
- Department of Surgery, Oncology & Gastroenterology, Gastroenterology Unit, University of Padova, Padova, Italy
| | - Angela Imondi
- Department of Surgery, Oncology & Gastroenterology, Gastroenterology Unit, University of Padova, Padova, Italy
| | - Anna Sartori
- Department of Surgery, Oncology & Gastroenterology, Gastroenterology Unit, University of Padova, Padova, Italy
| | - Barbara Penzo
- Department of Surgery, Oncology & Gastroenterology, Gastroenterology Unit, University of Padova, Padova, Italy
| | - Ambra Sammarco
- Department of Surgery, Oncology & Gastroenterology, Gastroenterology Unit, University of Padova, Padova, Italy
| | - Camillo Aliberti
- Department of Radiology, Radiology Unit, Azienda Ospedale-Università di Padova, Padova, Italy
| | - Alessandro Vitale
- Department of Surgery, Oncology & Gastroenterology, Hepatobiliary Surgery & Liver Transplantation Unit, University of Padova, Padova, Italy
| | - Umberto Cillo
- Department of Surgery, Oncology & Gastroenterology, Hepatobiliary Surgery & Liver Transplantation Unit, University of Padova, Padova, Italy
| | - Fabio Farinati
- Department of Surgery, Oncology & Gastroenterology, Gastroenterology Unit, University of Padova, Padova, Italy
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Autophagy Is Deficient and May be Negatively Regulated by SERPINB3 in Middle Ear Cholesteatoma. Otol Neurotol 2020; 41:e881-e888. [PMID: 32569142 DOI: 10.1097/mao.0000000000002690] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
HYPOTHESIS Whereas autophagy has been linked to various human diseases, whether it also plays a role in cholesteatoma is virtually unknown. This study aimed to investigate the activity and regulation of autophagy in cholesteatoma. BACKGROUND The treatment of middle ear cholesteatoma has been challenging due to an insufficient understanding of the underlying disease mechanism. METHODS Expression of microtubule-associated protein 1A/1B-light chain 3 (LC3), the autophagy protein marker, and phosphorylated Akt (p-Akt), and mammalian target of rapamycin (p-mTOR), the known autophagy regulators, in fresh retroauricular skin and cholesteatoma tissue samples was analyzed by immunoblotting. The results were further confirmed by immunohistochemistry and statistical analyses. Cell proliferation of primary retroauricular skin- and cholesteatoma-derived fibroblasts was evaluated by methyl thiazol tetrazolium (MTT) assay. Ectopic expression of serine proteinase inhibitor, clade B, member 3 (SERPINB3) in the fibroblasts was achieved by electroporation and the expression was detected by immunoblotting. RESULTS LC3 expression was significantly decreased in cholesteatoma in most of the 15 paired retroauricular skin/cholesteatoma tissue samples. However, p-Akt and p-mTOR expression in the cholesteatoma samples was not significantly different from that in the control subjects. Immunohistochemical studies further demonstrated an inverse correlation between LC3 expression and cholesteatoma. The cholesteatoma fibroblasts proliferated faster than the retroauricular skin fibroblasts, and had higher SERPINB3 but lower LC3 expression. Furthermore, overexpression of SERPINB3 in the retroauricular skin fibroblasts enhanced cell proliferation and downregulated LC3 expression. CONCLUSION Autophagy is significantly suppressed in cholesteatoma tissues, which may not involve the Akt/mTOR signaling pathway. More importantly, SERPINB3 may promote cell proliferation and negatively regulate autophagy in cholesteatoma fibroblasts. Together, these findings warrant further investigation into the pathogenic mechanism of cholesteatoma.
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Squamous cell carcinoma antigen-IgM (SCCA-IgM) is associated with interstitial lung disease in systemic sclerosis. Joint Bone Spine 2020; 87:331-335. [PMID: 32087361 DOI: 10.1016/j.jbspin.2020.02.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 02/12/2020] [Indexed: 11/20/2022]
Abstract
OBJECTIVE Interstitial lung disease (ILD) is the major determinant of prognosis in patients with systemic sclerosis (SSc). Squamous Cell Carcinoma Antigen (SCCA1) is a serin protease inhibitor which plays a pivotal role in inflammation and fibrosis. SCCA1 is overexpressed in pulmonary tissue of patients with idiopathic pulmonary fibrosis and can be detectable in serum as circulating immune complex bound to IgM (SCCA-IgM). We aimed to investigate the association between SCCA-IgM and clinical features of patients with SSc. METHODS Ninety-seven patients with SSc (ACR/EULAR criteria) were consecutively enrolled in the study. Clinical and serological variables and organ involvement were recorded. Pulmonary involvement was investigated by high-resolution CT (HRCT) and respiratory function tests. SCCA-IgM serum levels were measured by a validated ELISA assay (Hepa-IC, Xeptagen, Venice, Italy). We set the cut-off value for serum levels of SCCA-IgM >200 AU/ml, calculated as mean+3 standard deviations in 100 healthy subjects. RESULTS Forty-one (42.3%) patients were affected with ILD. SCCA-IgM values were significantly higher in patients with ILD than in those without: 218 (80-402) vs. 87.5 (59-150) AU/mL, P=0.003. Patients with positive SCCA-IgM had more frequently ILD (69.7% vs. 28.1%, P≤0.0001) and a lower total lung capacity (TLC) (P=0.024) compared with negative ones. No differences were found in any other clinical and serological features. At multivariate analysis, SCCA-IgM was found to be associated with ILD diagnosis (OR 10.6, IC 2.9-38.4, P=0.001). CONCLUSION SCCA-IgM is associated with interstitial lung disease in scleroderma patients and might be used in the assessment of SSc-ILD.
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Khattab FM, Samir MA. Measurement of squamous cell carcinoma antigen 2 in lichen planus patients. J Cosmet Dermatol 2019; 19:1780-1784. [PMID: 31815365 DOI: 10.1111/jocd.13216] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 10/22/2019] [Indexed: 01/11/2023]
Abstract
BACKGROUND Lichen planus (LP) is an autoinflammatory mucocutaneous skin disorder with a multifactorial pathogenesis. Squamous cell carcinoma antigen (SCCA) is a tumor marker recognized as a part of the ovalbumin-serpin family. In patients' serum and skin, SCCA expression is increased with inflammatory skin diseases as psoriasis. AIM This study aimed to estimate serum SCCA2 levels in patients with LP and to assess its relationship with disease severity and types. PATIENTS AND METHODS We included 34 adult patients with LP and 20 healthy adults as control. The total score of LP activity, area, and severity index was calculated for all patients, whereas serum SCCA2 levels were measured in all participants using enzyme-linked immunosorbent assay. RESULTS The mean serum SCCA2 levels were significantly higher in patients than their healthy controls (P < .001) and in female patients than male patients (P < .01). The mean serum SCCA2 levels in patients with eruptive LP were significantly higher compared to those with localized (P < .05) and hypertrophic (P < .01) forms. In ROC analysis, when LPAASI = 5 was taken as the limit, an ideal SCCA2 endpoint was discovered at 0.45 ng/mL with the upper Youden index. CONCLUSION Serum SCCA2 might be a potential biomarker for LP as it was elevated in patients with LP and was associated with disease severity. Further studies are needed to assess the therapeutic effect of its blockade, which could be a way to improve outcome in LP patients.
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Affiliation(s)
- Fathia M Khattab
- Department of Dermatology, Venereology, and Andrology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Mai A Samir
- Department of Dermatology, Venereology, and Andrology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Cannito S, Foglia B, Villano G, Turato C, C Delgado T, Morello E, Pin F, Novo E, Napione L, Quarta S, Ruvoletto M, Fasolato S, Zanus G, Colombatto S, Lopitz-Otsoa F, Fernández-Ramos D, Bussolino F, Sutti S, Albano E, Martínez-Chantar ML, Pontisso P, Parola M. SerpinB3 Differently Up-Regulates Hypoxia Inducible Factors -1α and -2α in Hepatocellular Carcinoma: Mechanisms Revealing Novel Potential Therapeutic Targets. Cancers (Basel) 2019; 11:1933. [PMID: 31817100 PMCID: PMC6966556 DOI: 10.3390/cancers11121933] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 11/29/2019] [Accepted: 12/02/2019] [Indexed: 12/15/2022] Open
Abstract
SerpinB3 (SB3) is a hypoxia and hypoxia-inducible factor (HIF)-2α-dependent cysteine-protease inhibitor up-regulated in hepatocellular carcinoma (HCC), released by cancer cells and able to stimulate proliferation and epithelial-to-mesenchymal-transition. Methods: In the study we employed transgenic and knock out SerpinB3 mice, liver cancer cell line, human HCC specimens, and mice receiving diethyl-nitrosamine (DEN) administration plus choline-deficient L-amino acid refined (CDAA) diet (DEN/CDAA protocol). Results: We provide detailed and mechanistic evidence that SB3 can act as a paracrine mediator able to affect the behavior of surrounding cells by differentially up-regulating, in normoxic conditions, HIF-1α and HIF-2α. SB3 acts by (i) up-regulating HIF-1α transcription, facilitating cell survival in a harsh microenvironment and promoting angiogenesis, (ii) increasing HIF-2α stabilization via direct/selective NEDDylation, promoting proliferation of liver cancer cells, and favoring HCC progression. Moreover (iii) the highest levels of NEDD8-E1 activating enzyme (NAE1) mRNA were detected in a subclass of HCC patients expressing the highest levels of HIF-2α transcripts; (iv) mice undergoing DEN/CDAA carcinogenic protocol showed a positive correlation between SB3 and HIF-2α transcripts with the highest levels of NAE1 mRNA detected in nodules expressing the highest levels of HIF-2α transcripts. Conclusions: These data outline either HIF-2α and NEDDylation as two novel putative therapeutic targets to interfere with the procarcinogenic role of SerpinB3 in the development of HCC.
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Affiliation(s)
- Stefania Cannito
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine & Clinical Pathology, University of Torino, 10125 Torino, Italy; (S.C.); (B.F.); (E.M.); (F.P.); (E.N.)
| | - Beatrice Foglia
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine & Clinical Pathology, University of Torino, 10125 Torino, Italy; (S.C.); (B.F.); (E.M.); (F.P.); (E.N.)
| | - Gianmarco Villano
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (G.V.); (M.R.); (S.F.)
| | - Cristian Turato
- Veneto Institute of Oncology IOV—IRCCS, 35128 Padova, Italy;
| | - Teresa C Delgado
- Liver Disease and Metabolism Laboratory, CIC bioGUNE, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain; (T.C.D.); (F.L.-O.); (D.F.-R.); (M.L.M.-C.)
| | - Elisabetta Morello
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine & Clinical Pathology, University of Torino, 10125 Torino, Italy; (S.C.); (B.F.); (E.M.); (F.P.); (E.N.)
| | - Fabrizio Pin
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine & Clinical Pathology, University of Torino, 10125 Torino, Italy; (S.C.); (B.F.); (E.M.); (F.P.); (E.N.)
| | - Erica Novo
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine & Clinical Pathology, University of Torino, 10125 Torino, Italy; (S.C.); (B.F.); (E.M.); (F.P.); (E.N.)
| | - Lucia Napione
- Department of Applied Science and Technology, Politecnico di Torino, 10129 Torino, Italy;
- Laboratory of Vascular Oncology Candiolo Cancer Institute—FPO IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), 10060 Candiolo, Italy;
| | - Santina Quarta
- Department of Medicine, University of Padova, 35128 Padova, Italy; (S.Q.); (P.P.)
| | - Mariagrazia Ruvoletto
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (G.V.); (M.R.); (S.F.)
| | - Silvano Fasolato
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (G.V.); (M.R.); (S.F.)
| | - Giacomo Zanus
- Hepatobiliary Surgery, University of Padova, 35128 Padova, Italy;
| | | | - Fernando Lopitz-Otsoa
- Liver Disease and Metabolism Laboratory, CIC bioGUNE, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain; (T.C.D.); (F.L.-O.); (D.F.-R.); (M.L.M.-C.)
| | - David Fernández-Ramos
- Liver Disease and Metabolism Laboratory, CIC bioGUNE, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain; (T.C.D.); (F.L.-O.); (D.F.-R.); (M.L.M.-C.)
| | - Federico Bussolino
- Laboratory of Vascular Oncology Candiolo Cancer Institute—FPO IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), 10060 Candiolo, Italy;
- Department of Oncology, University of Torino, 10125 Torino, Italy;
| | - Salvatore Sutti
- Department of Health Sciences and Interdisciplinary Research Center for Autoimmune Diseases, University Amedeo Avogadro of East Piedmont, 28100 Novara, Italy; (S.S.); (E.A.)
| | - Emanuele Albano
- Department of Health Sciences and Interdisciplinary Research Center for Autoimmune Diseases, University Amedeo Avogadro of East Piedmont, 28100 Novara, Italy; (S.S.); (E.A.)
| | - Maria Luz Martínez-Chantar
- Liver Disease and Metabolism Laboratory, CIC bioGUNE, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain; (T.C.D.); (F.L.-O.); (D.F.-R.); (M.L.M.-C.)
| | - Patrizia Pontisso
- Department of Medicine, University of Padova, 35128 Padova, Italy; (S.Q.); (P.P.)
| | - Maurizio Parola
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine & Clinical Pathology, University of Torino, 10125 Torino, Italy; (S.C.); (B.F.); (E.M.); (F.P.); (E.N.)
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Brustolin L, Pettenuzzo N, Nardon C, Quarta S, Marchiò L, Biondi B, Pontisso P, Fregona D. Au(iii)-Proline derivatives exhibiting selective antiproliferative activity against HepG2/SB3 apoptosis-resistant cancer cells. Dalton Trans 2019; 48:16017-16025. [PMID: 31599279 DOI: 10.1039/c9dt03036k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
This paper deals with the combination of a proline-based moiety with biologically active gold centers in the oxidation states +1 and +3. In particular, six Au(i)/(iii)-proline dithiocarbamato (DTC) complexes with general formulae [Au(DTC)2] and [AuIIIX2(DTC)] (X = Cl, Br) are reported here. After the synthesis of the ligand and the complexes, all derivatives were characterized via several techniques and tested for their stability in DMSO/water media. This study was focused on the demonstration of a peculiar behavior of Au(iii)-DTC species in solution. Finally, the complexes were screened for their antiproliferative activity against 2 human cancer cell lines, namely HepG2 and HepG2/SB3, taken as models of hepatocellular carcinoma. The latter, chosen for its aggressiveness due to the upregulation of the anti-apoptotic protein SerpinB3, was selectively inhibited in terms of growth by some Au(iii)-DTC complexes.
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Affiliation(s)
- L Brustolin
- Department of Chemical Sciences, University of Padova, Via F. Marzolo 1, 35131 Padova, Italy. and Department of Surgical, Oncologic and Gastroenterological Sciences, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - N Pettenuzzo
- Department of Chemical Sciences, University of Padova, Via F. Marzolo 1, 35131 Padova, Italy. and Department of Surgical, Oncologic and Gastroenterological Sciences, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - C Nardon
- Department of Chemical Sciences, University of Padova, Via F. Marzolo 1, 35131 Padova, Italy.
| | - S Quarta
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - L Marchiò
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze, 17/A - 43124, Parma, Italy
| | - B Biondi
- CNR, Padova Unit, Inst Biomol Chem, Via Marzolo 1, I-35131 Padua, Italy
| | - P Pontisso
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - D Fregona
- Department of Chemical Sciences, University of Padova, Via F. Marzolo 1, 35131 Padova, Italy.
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Sebastião MJ, Serra M, Pereira R, Palacios I, Gomes-Alves P, Alves PM. Human cardiac progenitor cell activation and regeneration mechanisms: exploring a novel myocardial ischemia/reperfusion in vitro model. Stem Cell Res Ther 2019; 10:77. [PMID: 30845956 PMCID: PMC6407246 DOI: 10.1186/s13287-019-1174-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 02/12/2019] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Numerous studies from different labs around the world report human cardiac progenitor cells (hCPCs) as having a role in myocardial repair upon ischemia/reperfusion (I/R) injury, mainly through auto/paracrine signaling. Even though these cell populations are already being investigated in cell transplantation-based clinical trials, the mechanisms underlying their response are still poorly understood. METHODS To further investigate hCPC regenerative process, we established the first in vitro human heterotypic model of myocardial I/R injury using hCPCs and human-induced pluripotent cell-derived cardiomyocytes (hiPSC-CMs). The co-culture model was established using transwell inserts and evaluated in both ischemia and reperfusion phases regarding secretion of key cytokines, hiPSC-CM viability, and hCPC proliferation. hCPC proteome in response to I/R was further characterized using advanced liquid chromatography mass spectrometry tools. RESULTS This model recapitulates hallmarks of I/R, namely hiPSC-CM death upon insult, protective effect of hCPCs on hiPSC-CM viability (37.6% higher vs hiPSC-CM mono-culture), and hCPC proliferation (approximately threefold increase vs hCPCs mono-culture), emphasizing the importance of paracrine communication between these two populations. In particular, in co-culture supernatant upon injury, we report higher angiogenic functionality as well as a significant increase in the CXCL6 secretion rate, suggesting an important role of this chemokine in myocardial regeneration. hCPC whole proteome analysis allowed us to propose new pathways in the hCPC-mediated regenerative process, including cell cycle regulation, proliferation through EGF signaling, and reactive oxygen species detoxification. CONCLUSION This work contributes with new insights into hCPC biology in response to I/R, and the model established constitutes an important tool to study the molecular mechanisms involved in the myocardial regenerative process.
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Affiliation(s)
- Maria J. Sebastião
- Animal Cell Technology Unit, iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
- ITQB-NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Margarida Serra
- Animal Cell Technology Unit, iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
- ITQB-NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Rute Pereira
- Animal Cell Technology Unit, iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
- ITQB-NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Itziar Palacios
- Coretherapix, S.L.U (Tigenix Group, Takeda), Parque Tecnológico de Madrid, Madrid, Spain
| | - Patrícia Gomes-Alves
- Animal Cell Technology Unit, iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
- ITQB-NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Paula M. Alves
- Animal Cell Technology Unit, iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
- ITQB-NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
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Turato C, Fornari F, Pollutri D, Fassan M, Quarta S, Villano G, Ruvoletto M, Bolondi L, Gramantieri L, Pontisso P. MiR-122 Targets SerpinB3 and Is Involved in Sorafenib Resistance in Hepatocellular Carcinoma. J Clin Med 2019; 8:171. [PMID: 30717317 PMCID: PMC6406326 DOI: 10.3390/jcm8020171] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 01/11/2019] [Accepted: 01/29/2019] [Indexed: 12/12/2022] Open
Abstract
The only first-line treatment approved for advanced hepatocellular carcinoma (HCC) is sorafenib. Since many patients experience drug resistance, the discovery of more effective therapeutic strategies represents an unmet clinical need. MicroRNA (MiR)-122 is downregulated in most HCCs, while oncogenic SerpinB3 is upregulated. Here, we assessed the relationship between miR-122 and SerpinB3 and their influence on cell phenotype and sorafenib resistance in HCC. A bioinformatics analysis identified SerpinB3 among hypothetical miR-122 targets. In SerpinB3-overexpressing HepG2 cells, miR-122 transfection decreased SerpinB3 mRNA and protein levels, whereas miR-122 inhibition increased SerpinB3 expression. Luciferase assay demonstrated the interaction between miR-122 and SerpinB3 mRNA. In an HCC rat model, high miR-122 levels were associated with negative SerpinB3 expression, while low miR-122 levels correlated with SerpinB3 positivity. A negative correlation between miR-122 and SerpinB3 or stem cell markers was found in HCC patients. Anti-miR-122 transfection increased cell viability in sorafenib-treated Huh-7 cells, while miR-122 overexpression increased sorafenib sensitivity in treated cells, but not in those overexpressing SerpinB3. In conclusion, we demonstrated that miR-122 targets SerpinB3, and its low levels are associated with SerpinB3 positivity and a stem-like phenotype in HCC. MiR-122 replacement therapy in combination with sorafenib deserves attention as a possible therapeutic strategy in SerpinB3-negative HCCs.
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Affiliation(s)
- Cristian Turato
- Venetian Institute of Oncology (IOV-IRCCS), 35128 Padua, Italy.
| | - Francesca Fornari
- Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
| | - Daniela Pollutri
- Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
| | - Matteo Fassan
- Department of Medicine, University of Padua, 35128 Padua, Italy.
| | - Santina Quarta
- Department of Medicine, University of Padua, 35128 Padua, Italy.
| | - Gianmarco Villano
- Department of Surgical, Gastroenterological and Oncological Sciences, University of Padua, 35128 Padua, Italy.
| | | | - Luigi Bolondi
- Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
| | - Laura Gramantieri
- Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
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Dynamic matrisome: ECM remodeling factors licensing cancer progression and metastasis. Biochim Biophys Acta Rev Cancer 2018; 1870:207-228. [DOI: 10.1016/j.bbcan.2018.09.002] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 09/07/2018] [Accepted: 09/30/2018] [Indexed: 01/04/2023]
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Kwon OK, Jeon JM, Sung E, Na AY, Kim SJ, Lee S. Comparative Secretome Profiling and Mutant Protein Identification in Metastatic Prostate Cancer Cells by Quantitative Mass Spectrometry-based Proteomics. Cancer Genomics Proteomics 2018; 15:279-290. [PMID: 29976633 DOI: 10.21873/cgp.20086] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 06/04/2018] [Accepted: 06/06/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Secreted proteins play an important role in promoting cancer (PCa) cell migration and invasion. Proteogenomics helps elucidate the mechanism of diseases, discover therapeutic targets, and generate biomarkers for diagnosis through protein variations. MATERIALS AND METHODS We carried out mass a spectrometry-based proteomic analysis of the conditioned media (CM) from two human prostate cancer cell lines, belonging to different metastatic sites, to identify potential metastatic and/or aggressive factors. RESULTS We identified a total of 598 proteins, among which 561 were quantified based on proteomic analysis. Among the quantified proteins, 128 were up-regulated and 83 were down-regulated in DU145/PC3 cells. Six mutant peptides were identified in the CM of prostate cancer cell lines using proteogenomics approach. CONCLUSION This is the first proteogenomics study in PCa aiming at exploring a new type of metastatic factor, which are mutant peptides, predicting a novel biomarker of metastatic PCa for diagnosis, prognosis and drug targeting.
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Affiliation(s)
- Oh Kwang Kwon
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics-based Creative Drug Research Team, Kyungpook National University, Daegu, Republic of Korea
| | - Ju Mi Jeon
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics-based Creative Drug Research Team, Kyungpook National University, Daegu, Republic of Korea
| | - Eunji Sung
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics-based Creative Drug Research Team, Kyungpook National University, Daegu, Republic of Korea
| | - Ann-Yea Na
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics-based Creative Drug Research Team, Kyungpook National University, Daegu, Republic of Korea
| | - Sun Joo Kim
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics-based Creative Drug Research Team, Kyungpook National University, Daegu, Republic of Korea
| | - Sangkyu Lee
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics-based Creative Drug Research Team, Kyungpook National University, Daegu, Republic of Korea
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Suratanee A, Plaimas K. Network-based association analysis to infer new disease-gene relationships using large-scale protein interactions. PLoS One 2018; 13:e0199435. [PMID: 29949603 PMCID: PMC6021074 DOI: 10.1371/journal.pone.0199435] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 06/07/2018] [Indexed: 01/02/2023] Open
Abstract
Protein-protein interactions integrated with disease-gene associations represent important information for revealing protein functions under disease conditions to improve the prevention, diagnosis, and treatment of complex diseases. Although several studies have attempted to identify disease-gene associations, the number of possible disease-gene associations is very small. High-throughput technologies have been established experimentally to identify the association between genes and diseases. However, these techniques are still quite expensive, time consuming, and even difficult to perform. Thus, based on currently available data and knowledge, computational methods have served as alternatives to provide more possible associations to increase our understanding of disease mechanisms. Here, a new network-based algorithm, namely, Disease-Gene Association (DGA), was developed to calculate the association score of a query gene to a new possible set of diseases. First, a large-scale protein interaction network was constructed, and the relationship between two interacting proteins was calculated with regard to the disease relationship. Novel plausible disease-gene pairs were identified and statistically scored by our algorithm using neighboring protein information. The results yielded high performance for disease-gene prediction, with an F-measure of 0.78 and an AUC of 0.86. To identify promising candidates of disease-gene associations, the association coverage of genes and diseases were calculated and used with the association score to perform gene and disease selection. Based on gene selection, we identified promising pairs that exhibited evidence related to several important diseases, e.g., inflammation, lipid metabolism, inborn errors, xanthomatosis, cerebellar ataxia, cognitive deterioration, malignant neoplasms of the skin and malignant tumors of the cervix. Focusing on disease selection, we identified target genes that were important to blistering skin diseases and muscular dystrophy. In summary, our developed algorithm is simple, efficiently identifies disease–gene associations in the protein-protein interaction network and provides additional knowledge regarding disease-gene associations. This method can be generalized to other association studies to further advance biomedical science.
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Affiliation(s)
- Apichat Suratanee
- Department of Mathematics, Faculty of Applied Science, King Mongkut’s University of Technology North Bangkok, Bangkok, Thailand
- * E-mail: (AS); (KP)
| | - Kitiporn Plaimas
- Advanced Virtual and Intelligent Computing (AVIC) Center, Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
- * E-mail: (AS); (KP)
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Fasolato S, Trevellin E, Ruvoletto M, Granzotto M, Zanus G, Boscaro E, Babetto E, Terrin L, Battocchio MA, Ciscato F, Turato C, Quarta S, Cillo U, Pontisso P, Vettor R. SerpinB3 induces dipeptidyl-peptidase IV/CD26 expression and its metabolic effects in hepatocellular carcinoma. Life Sci 2018. [DOI: 10.1016/j.lfs.2018.03.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Izuhara K, Yamaguchi Y, Ohta S, Nunomura S, Nanri Y, Azuma Y, Nomura N, Noguchi Y, Aihara M. Squamous Cell Carcinoma Antigen 2 (SCCA2, SERPINB4): An Emerging Biomarker for Skin Inflammatory Diseases. Int J Mol Sci 2018; 19:E1102. [PMID: 29642409 PMCID: PMC5979376 DOI: 10.3390/ijms19041102] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 04/04/2018] [Accepted: 04/05/2018] [Indexed: 12/19/2022] Open
Abstract
Squamous cell carcinoma antigens 1 and 2 (SCCA1 and 2, SERPIN B3 and B4), members of the ovalbumin serpin (ov-serpin)/clade B serpin family, were originally discovered as tumor-specific antigens and are used as tumor markers for various kinds of squamous cell carcinomas. Recently, our understanding of the underlying mechanisms of how SCCA1/2 enhance tumor growth has greatly increased. Moreover, it has been shown that SCCA1/2 are involved in the pathogenesis of several inflammatory diseases: asthma, psoriasis, and atopic dermatitis (AD). IL-22 and IL-17, signature cytokines of type 17 inflammation, as well as IL-4 and IL-13, signature cytokines of type 2 inflammation, both of which are positively correlated with the pathogenesis of psoriasis and allergic diseases, respectively, can induce expression of SCCA1/2 in airway epithelial cells and/or keratinocytes, leading to high expression of SCCA1/2 in these diseases. Based on these findings, several trials have been performed to examine the potential of applying SCCA1/2 to biomarkers for these diseases. The findings show that SCCA2 is useful to aid diagnosis, estimate clinical severity and disease type, and assess responses to treatment in psoriasis and AD. These results suggest that SCCA2 has emerged as a novel biomarker for skin inflammatory diseases.
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Affiliation(s)
- Kenji Izuhara
- Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan.
| | - Yukie Yamaguchi
- Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
| | - Shoichiro Ohta
- Department of Medical Technology and Sciences, School of Health Sciences at Fukuoka, International University of Health and Welfare, Okawa 831-8501, Japan.
| | - Satoshi Nunomura
- Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan.
| | - Yasuhiro Nanri
- Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan.
| | | | | | | | - Michiko Aihara
- Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
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Maddalo G, Fassan M, Cardin R, Piciocchi M, Marafatto F, Rugge M, Zaninotto G, Pozzan C, Castoro C, Ruol A, Biasiolo A, Farinati F. Squamous Cellular Carcinoma Antigen Serum Determination as a Biomarker of Barrett Esophagus and Esophageal Cancer: A Phase III Study. J Clin Gastroenterol 2018; 52:401-406. [PMID: 28422774 DOI: 10.1097/mcg.0000000000000790] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
GOAL To evaluate the potential role of the determination of the immunocomplexed form of squamous cell carcinoma antigen [SCCA-immunoglobulin (Ig)M] for the screening of Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). BACKGROUND The cost-effectiveness of surveillance in BE is still debated and the use of biomarkers in screening and surveillance still not recommended. No information is available regarding SCCA-IgM determination in BE. STUDY SCCA-IgM levels were determined (enzyme-linked immunosorbent assay) in 231 patients prospectively recruited, 71 with BE, 53 with EAC, and 107 controls, including 42 blood donors and 65 patients with gastroesophageal reflux. SCCA-IgM cutoffs between BE/EAC and controls and for BE "at risk" versus short nondysplastic BE were calculated by receiver operating characteristic curves. Immunostaining for SCCA-IgM was obtained in a subgroup of patients. RESULTS Median SCCA-IgM values were significantly higher in BE and EAC than in controls (P=0.0001). Patients with SCCA-IgM levels above the cutoff had a 33 times higher relative risk of harboring BE or EAC (P=0.0001). Patients "at risk," with long or dysplastic BE had SCCA-IgM levels significantly higher than those with short nondysplastic BE (P=0.035) and patients with SCCA-IgM above the cutoff had a 8 times higher relative risk of having BE "at risk." SCCA was expressed in Barrett mucosa but not in cardiac metaplasia. CONCLUSIONS Serum SCCA-IgM determination allows the identification of patients at risk for BE/EAC and the stratification of BE patients in subgroups with different cancer risk. Because of the still limited number of controls, large, prospective studies are required to confirm this evidence.
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Affiliation(s)
- Gemma Maddalo
- Departments of Surgery, Oncology and Gastroenterology
| | | | | | | | | | | | - Giovanni Zaninotto
- Department of Surgery and Cancer, Imperial College, St Mary's Hospital, London, UK
| | | | - Carlo Castoro
- Surgical Oncology Unit, Veneto Institute of Oncology (IOV-IRCCS), Padova, Italy
| | - Alberto Ruol
- Departments of Surgery, Oncology and Gastroenterology
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Yang H, Hu H, Gou Y, Hu Y, Li H, Zhao H, Wang B, Li P, Zhang Z. Combined detection of Twist1, Snail1 and squamous cell carcinoma antigen for the prognostic evaluation of invasion and metastasis in cervical squamous cell carcinoma. Int J Clin Oncol 2017; 23:321-328. [PMID: 29101499 DOI: 10.1007/s10147-017-1210-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 10/17/2017] [Indexed: 01/05/2023]
Abstract
BACKGROUND Cervical cancer is one of the most common malignant tumours of the female reproductive system, ranking second only to breast cancer in morbidity worldwide. Essential features of the progression of cervical cancer are invasion and metastasis, which are closely related to disease prognosis and mortality rate. At the present time there is no effective method to evaluate cancer invasion and metastasis before surgery. Here we report our study on molecular changes in biopsy tissue for the prognostic evaluation of cancer invasion and metastasis. PATIENTS AND METHODS Expression of the epithelial-mesenchymal transition-inducing transcription factors Twist1 and Snail1 was detected by immunohistochemistry in 32 normal, 36 low-grade squamous intraepithelial neoplasia (LSIL), 54 high-grade squamous intraepithelial neoplasia (HSIL) and 320 cervical squamous cell carcinoma (CSCC) samples. The correlation between the expression of Twist1, Snail1 and squamous cell carcinoma antigen (SCCA) in CSCC tissues and clinical pathology results was evaluated. A transwell migration and invasion assay was used to explore the roles of Twist1 and Snail1 in the invasion of cancer cells. Lymph node metastasis and lymphovascular space invasion (LVSI) rates for the following groups were analysed: SCCA(+) group, Twist1(+) group, Snail1(+) group, Twist1(+)Snail1(+)group, Twist1(+)SCCA(+)group, Snail1(+)SCCA(+)group and Twist1(+)Snail1(+)SCCA(+) group. RESULTS The expression of Twist1 and Snail1 was significantly upregulated in HSIL and CSCC (p < 0.05). Twist1 and Snail1 expression levels were associated with LVSI, lymph node metastasis and histological grade (p < 0.05) but not with age or FIGO stage (p > 0.05). The expression of SCCA was associated with LVSI, lymph node metastasis, FIGO stage and histological grade (p < 0.05) but not with age (p > 0.05). Twist1 was an independent factor contributing to the invasion ability of cervical cancer cells. In addition, the positive rate of lymph node metastasis and LVSI was higher in the Twist1(+)Snail1(+)SCCA(+) group than in the SCCA(+) group, Twist1(+) group and Snail1(+) group, respectively (p < 0.05). CONCLUSION Combined detection of Twist1 and Snail1 in SCCA-positive biopsy specimens may be a potential method for evaluating the invasion and metastasis of CSCC prior to surgery.
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Affiliation(s)
- Huilun Yang
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.,Department of Obstetrics and Gynecology, The First People's Hospital of Yangzhou, Yangzhou, 225000, China
| | - Haiyang Hu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.,Department of Obstetrics and Gynecology, Affiliated Hospital of Jining Medical University, Jining, 272000, China
| | - Yanling Gou
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Yuhong Hu
- Department of Obstetrics and Gynecology, The First Hospital Affiliated to Jiamusi University, Jiamusi, China
| | - Hui Li
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Hongwei Zhao
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Beidi Wang
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Peiling Li
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Zongfeng Zhang
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
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Turato C, Balasso A, Carloni V, Tiribelli C, Mastrotto F, Mazzocca A, Pontisso P. New molecular targets for functionalized nanosized drug delivery systems in personalized therapy for hepatocellular carcinoma. J Control Release 2017; 268:184-197. [PMID: 29051062 DOI: 10.1016/j.jconrel.2017.10.027] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 10/12/2017] [Accepted: 10/14/2017] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma, the most frequent solid tumor of the liver, has a very poor prognosis, being the second most common cause of death from cancer worldwide. The incidence and mortality of this liver tumor are increasing in most areas of the world as a consequence of aging and the emerging of new risk factors such as the metabolic syndrome, beside the recognized role of hepatitis B and C viral infections and alcohol abuse. Despite the increasing knowledge on the molecular mechanisms underlying hepatic carcinogenesis, effective therapeutic strategies are still an unmet clinical need. Efforts have been made to develop selective drugs as well as effective targeted drug delivery systems. The development of novel drug carriers for therapeutic molecules can indeed offer a valuable strategy to ameliorate the efficacy of HCC treatment. In this review, we discuss recent drug delivery strategies for HCC treatment based on the exploitation of targeted nanoparticles (NPs). Indeed, a few of these platforms have achieved an advanced stage of preclinical development. Here, we review the most promising drug nanovehicles based on both synthetic and natural polymers, including polysaccharides that have emerged for their biocompatibility and biodegradability. To maximize site-selectivity and therapeutic efficacy, drug delivery systems should be functionalized with ligands which can specifically recognize and bind targets expressed by HCC, namely cell membrane associated antigens, receptors or biotransporters. Cell surface and intracellular molecular targets are exploited either to selectively deliver drug-loaded nanovehicles or to design novel selective therapeutics. In conclusion, the combination of novel and safe drug delivery strategies based on site-specific targeted drug nanovehicles with therapeutic molecular targets may significantly improve the pharmacological efficacy for the treatment of HCC.
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Affiliation(s)
| | - Anna Balasso
- Department of Pharmaceutical & Pharmacological Sciences, University of Padova, Padova, Italy
| | - Vinicio Carloni
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | | | - Francesca Mastrotto
- Department of Pharmaceutical & Pharmacological Sciences, University of Padova, Padova, Italy
| | - Antonio Mazzocca
- Interdisciplinary Department of Medicine, University of Bari, Bari, Italy.
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Turato C, Kent P, Sebastiani G, Cannito S, Morello E, Terrin L, Biasiolo A, Simonato D, Parola M, Pantopoulos K, Pontisso P. Serpinb3 is overexpressed in the liver in presence of iron overload. J Investig Med 2017; 66:32-38. [PMID: 28935635 DOI: 10.1136/jim-2017-000473] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2017] [Indexed: 11/04/2022]
Abstract
Iron overload results in cellular toxicity, tissue injury, organ fibrosis and increased risk of neoplastic transformation. SerpinB3 is a serine protease inhibitor overexpressed in the liver in oxidative stress conditions, able to induce fibrosis and increased risk of malignant transformation. Aim of the present study was to assess the effect of iron overload on SerpinB3 expression in the liver using in vivo and in vitro models.The expression of Serpinb3 was assessed in the liver of hemojuvelin knockout mice (Hjv-/-), an established model of hereditary hemochromatosis, and of wild type control mice, following dietary or pharmacological iron manipulation. To assess the direct effect of iron in vitro, cell lines were treated with different concentration of hemin or with an iron chelator.Hepatic Serpinb3 mRNA and protein were highly expressed in Hjv-/- mice, but not in wild type controls fed with a standard diet. Serpinb3 became detectable in wild type mice fed with a high iron diet or injected with iron dextran; these treatments further induced Serpinb3 expression in Hjv-/- mice. Livers expressing Serpinb3 showed a positive staining also for HIF-2α in the same areas. Hemin promoted induction of SerpinB3 mRNA in HeLa and HA22T/VGH cells, but a mild stimulation of SerpinB3 promoter activity in HeLa and Huh7 cells. In conclusion, Serpinb3 is strongly induced by iron in the mouse liver. The molecular link between iron, ROS and SerpinB3 seems to be HIF-2α, which is induced by iron overload and was previously found capable of up-regulating SerpinB3 at the transcriptional level.
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Affiliation(s)
| | | | | | - Stefania Cannito
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Elisabetta Morello
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Liliana Terrin
- Department of Medicine, University of Padova, Padova, Italy
| | | | | | - Maurizio Parola
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
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36
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Terrin L, Agostini M, Ruvoletto M, Martini A, Pucciarelli S, Bedin C, Nitti D, Pontisso P. SerpinB3 upregulates the Cyclooxygenase-2 / β-Catenin positive loop in colorectal cancer. Oncotarget 2017; 8:15732-15743. [PMID: 28178650 PMCID: PMC5362519 DOI: 10.18632/oncotarget.14997] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 01/03/2017] [Indexed: 12/30/2022] Open
Abstract
Colorectal cancer is characterized by aberrant Cyclooxigenase-2 (COX-2) and β-Catenin pathways. Recently, the protease inhibitor SerpinB3 has been described overexpressed in more advanced stages of this tumor. Aim of the study was to explore the possible relationship between these molecules in this setting. We evaluated colorectal cancer specimens from 105 patients and a positive correlation between SerpinB3, COX-2 and β-Catenin expression was observed, with higher levels in tumor than in adjacent tissue. The highest levels were associated with pathologic parameters of poor prognosis, including vascular invasion, lymph node metastasis and perineural invasion. The molecular and protein profiles of COX-2 and β-Catenin were analyzed in cell lines with different expression of SerpinB3. In those with high expression of SerpinB3, COX-2 and β-Catenin were higher than in controls. Cells with high levels of SerpinB3 showed higher proliferation and invasion compared to controls. In conclusion, in colorectal cancer SerpinB3, COX-2 and β-Catenin are positively correlated and associated with more advanced tumor stage. The in vitro experimental results support a driving role of SerpinB3 in the upregulation of COX-2/ β-Catenin positive loop, associated with a more aggressive cellular phenotype.
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Affiliation(s)
| | - Marco Agostini
- Surgery Branch, Department of Surgery Oncology and Gastroenterology, University of Padua, Italy.,Nano-Inspired Biomedicine Laboratory, Istituto di Ricerca Pediatrica - Città della Speranza, Padua, Italy.,Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, TX, USA
| | | | | | - Salvatore Pucciarelli
- Surgery Branch, Department of Surgery Oncology and Gastroenterology, University of Padua, Italy
| | - Chiara Bedin
- Nano-Inspired Biomedicine Laboratory, Istituto di Ricerca Pediatrica - Città della Speranza, Padua, Italy
| | - Donato Nitti
- Surgery Branch, Department of Surgery Oncology and Gastroenterology, University of Padua, Italy
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Sung E, Kwon OK, Lee JM, Lee S. Proteomics approach to identify novel metastatic bone markers from the secretome of PC-3 prostate cancer cells. Electrophoresis 2017. [PMID: 28627741 DOI: 10.1002/elps.201700052] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Prostate cancer is the leading type of cancer diagnosed, and the most frequent cause of worldwide male cancer-related deaths annually. The limitations of current prostate cancer screening tests demand the identification of novel biomarkers for the early diagnosis of prostate cancer bone metastasis. In the present study, we performed a proteomic analysis of secreted proteins from the prostate cancer bone metastasis cell line, PC-3, and the normal prostate cell line, RWPE-1. We thus quantified 917 proteins, of which 68 were found to be secreted at higher levels by PC-3 than by RWPE-1 cells via LC-MS/MS. To characterize the highly secreted proteins in the PC-3 cell line and thereby identify biomarker proteins, we divided the quantifiable proteins into four quantitative categories (Q1-Q4). The KEGG lysine degradation and osteoclast differentiation pathways were demonstrated to be enriched in the highly secreted Q4 protein group. Transforming growth factor (TGF) beta family proteins related to osteoclast differentiation were identified as key regulators of PC-3 cell proliferation. Immunoblotting was used to confirm the observed high level of pentraxin, follistatin, TGF-beta family members, and serpin B3 secretion by PC-3 cells. From the collective results of the present study, we suggest that serpin B3 is a promising novel biomarker candidate for the diagnosis of prostate cancer bone metastasis.
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Affiliation(s)
- EunJi Sung
- BK21 Plus KNU Multi-Omics-based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Oh Kwang Kwon
- BK21 Plus KNU Multi-Omics-based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Jae-Mok Lee
- Department of Periodontology, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea
| | - Sangkyu Lee
- BK21 Plus KNU Multi-Omics-based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
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Guarino M, Di Costanzo GG, Gallotta A, Tortora R, Paneghetti L, Auriemma F, Tuccillo C, Fassina G, Caporaso N, Morisco F. Circulating SCCA-IgM complex is a useful biomarker to predict the outcome of therapy in hepatocellular carcinoma patients. Scandinavian Journal of Clinical and Laboratory Investigation 2017; 77:448-453. [PMID: 28609160 DOI: 10.1080/00365513.2017.1336569] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) develops in about 3-4% of cirrhotic patients every year. The squamous cell carcinoma antigen (SCCA) has been found elevated in liver cancer specimens by immunohistochemistry, and detected in complex with IgM (SCCA-IgM) in the serum of patients with HCC. The aim of this study was to evaluate the ability of serological SCCA-IgM levels to predict the efficacy of HCC therapy. MATERIALS AND METHODS From April 2012 to April 2014, 131 patients with a new diagnosis of HCC were enrolled. The HCC diagnosis was made according to the EASL guidelines. The patients were staged and treated according to the BCLC Staging System: BCLC stages A and B were treated with locoregional therapy, and BCLC stage C was treated with Sorafenib. Response to therapy was evaluated according to the mRECIST criteria. Serum SCCA-IgM levels were determined by a commercially available ELISA kit at basal time (T0) and after one month of treatment (T1). RESULTS At baseline and one month into therapy, SCCA-IgM levels were significantly lower (p value <.05) in patients who responded to therapy compared to those who did not respond (median SCCA-IgM level [25th + 75th percentile] at T0:115.1 AU/mL [50.0 + 174.4] vs. 149.1 AU/mL [111.3 + 198.8]; median SCCA-IgM level [25th + 75th percentile] at T1: 113.4 AU/mL [50.0 + 194.2] vs. 170.6 AU/mL [111.7 + 344.2]). CONCLUSION Our study suggests that the SCCA-IgM determination could be helpful in predicting the response to therapy in patients with HCC.
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Affiliation(s)
- Maria Guarino
- a Department of Clinical Medicine and Surgery, Gastroenterology Unit , University of Naples Federico II , Naples , Italy
| | | | | | - Raffaella Tortora
- a Department of Clinical Medicine and Surgery, Gastroenterology Unit , University of Naples Federico II , Naples , Italy
| | | | - Francesco Auriemma
- a Department of Clinical Medicine and Surgery, Gastroenterology Unit , University of Naples Federico II , Naples , Italy
| | - Concetta Tuccillo
- d Department of Clinical and Experimental Medicine 'F. Magrassi and A. Lanzara', Gastroenterology Unit , Second University of Naples , Naples , Italy
| | | | - Nicola Caporaso
- a Department of Clinical Medicine and Surgery, Gastroenterology Unit , University of Naples Federico II , Naples , Italy
| | - Filomena Morisco
- a Department of Clinical Medicine and Surgery, Gastroenterology Unit , University of Naples Federico II , Naples , Italy
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Novo E, Villano G, Turato C, Cannito S, Paternostro C, Busletta C, Biasiolo A, Quarta S, Morello E, Bocca C, Miglietta A, David E, Sutti S, Plebani M, Albano E, Parola M, Pontisso P. SerpinB3 Promotes Pro-fibrogenic Responses in Activated Hepatic Stellate Cells. Sci Rep 2017; 7:3420. [PMID: 28611447 PMCID: PMC5469760 DOI: 10.1038/s41598-017-03744-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 05/05/2017] [Indexed: 01/15/2023] Open
Abstract
SerpinB3 is a hypoxia- and hypoxia-inducible factor-2α-dependent cystein protease inhibitor that is up-regulated in hepatocellular carcinoma and in parenchymal cells during chronic liver diseases (CLD). SerpinB3 up-regulation in CLD patients has been reported to correlate with the extent of liver fibrosis and the production of transforming growth factor-β1, but the actual role of SerpinB3 in hepatic fibrogenesis is still poorly characterized. In the present study we analyzed the pro-fibrogenic action of SerpinB3 in cell cultures and in two different murine models of liver fibrosis. "In vitro" experiments revealed that SerpinB3 addition to either primary cultures of human activated myofibroblast-like hepatic stellate cells (HSC/MFs) or human stellate cell line (LX2 cells) strongly up-regulated the expression of genes involved in fibrogenesis and promoted oriented migration, but not cell proliferation. Chronic liver injury by CCl4 administration or by feeding a methionine/choline deficient diet to transgenic mice over-expressing human SerpinB3 in hepatocytes confirmed that SerpinB3 over-expression significantly increased the mRNA levels of pro-fibrogenic genes, collagen deposition and αSMA-positive HSC/MFs as compared to wild-type mice, without affecting parenchymal damage. The present study provides for the first time evidence that hepatocyte release of SerpinB3 during CLD can contribute to liver fibrogenesis by acting on HSC/MFs.
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Affiliation(s)
- Erica Novo
- Department Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Torino, Italy
| | | | | | - Stefania Cannito
- Department Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Torino, Italy
| | - Claudia Paternostro
- Department Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Torino, Italy
| | - Chiara Busletta
- Department Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Torino, Italy
| | | | - Santina Quarta
- Department of Medicine, University of Padova, Padova, Italy
| | - Elisabetta Morello
- Department Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Torino, Italy
| | - Claudia Bocca
- Department Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Torino, Italy
| | - Antonella Miglietta
- Department Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Torino, Italy
| | - Ezio David
- Pathology Unit, S. Giovanni Battista Hospital, Torino, Italy
| | - Salvatore Sutti
- Department of Health Sciences, University "A. Avogadro" of East Piedmont, Novara, Italy
| | - Mario Plebani
- Department of Medicine, University of Padova, Padova, Italy
| | - Emanuele Albano
- Department of Health Sciences, University "A. Avogadro" of East Piedmont, Novara, Italy
| | - Maurizio Parola
- Department Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Torino, Italy.
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Re-programming pullulan for targeting and controlled release of doxorubicin to the hepatocellular carcinoma cells. Eur J Pharm Sci 2017; 103:104-115. [DOI: 10.1016/j.ejps.2017.02.016] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/03/2017] [Accepted: 02/08/2017] [Indexed: 02/07/2023]
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41
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Fassan M, Realdon S, Vianello L, Quarta S, Ruol A, Castoro C, Scarpa M, Zaninotto G, Guzzardo V, Sileni VC, Pontisso P, Rugge M. Squamous cell carcinoma antigen (SCCA) is up-regulated during Barrett's carcinogenesis and predicts esophageal adenocarcinoma resistance to neoadjuvant chemotherapy. Oncotarget 2017; 8:24372-24379. [PMID: 28042960 PMCID: PMC5421854 DOI: 10.18632/oncotarget.14108] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 11/22/2016] [Indexed: 12/15/2022] Open
Abstract
Squamous Cell Carcinoma Antigen (SCCA) is consistently overexpressed in many different solid tumors, and has been associated with both tumor aggressiveness and chemoresistance. No data, however, is currently available on SCCA expression during esophageal Barrett's carcinogenesis, nor on SCCA expression's role on esophageal adenocarcinoma chemoresistance. The SCCA immunohistochemical expression was assessed in a series of 100 biopsy samples covering the whole histological spectrum of Barrett's oncogenesis. Squamous native mucosa was characterized by a moderate to strong cytoplasmic and nuclear SCCA expression in suprabasal, medium, and superficial layers. On the other hand, almost half of the considered lesions did not express SCCA; the other half featured weak to moderate SCCA expression. The relationship between SCCA protein expression and tumor response to neoadjuvant chemotherapy was assessed in 90 esophageal adenocarcinoma specimens (40 biopsy and 50 surgery specimens), stratified according to Mandard tumor regression grade. As observed in other settings, the presence of SCCA expression clustered in the group of tumors characterized by a lower responsiveness to neoadjuvant treatments. The present results suggest an involvement of SCCA in a subset of Barrett-related tumors, and prompt to consider the SCCA-protein expression as response-predictive marker of neoadjuvant therapy in esophageal adenocarcinomas.
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Affiliation(s)
- Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy
| | - Stefano Realdon
- Gastroenterology Unit, Istituto Oncologico Veneto, IOV-IRCCS, Padua, Italy
| | - Luca Vianello
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy
| | - Santina Quarta
- Department of Medicine (DIMED), 5th Medical Clinic, University of Padua, Padua, Italy
| | - Alberto Ruol
- Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), 3rd Surgical Clinic, University of Padua, Padua, Italy
| | - Carlo Castoro
- Esophageal and Digestive Tract Surgical Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Marco Scarpa
- Esophageal and Digestive Tract Surgical Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Giovanni Zaninotto
- Imperial College London, Department of Surgery and Cancer, Division of Surgery, London, UK
| | - Vincenza Guzzardo
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy
| | - Vanna Chiarion Sileni
- Melanoma & Esophageal Oncology Unit, Istituto Oncologico Veneto, IOV-IRCCS, Padua, Italy
| | - Patrizia Pontisso
- Department of Medicine (DIMED), 5th Medical Clinic, University of Padua, Padua, Italy
| | - Massimo Rugge
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy
- Veneto Tumour Registry, Veneto Region, Padua, Italy
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Jha S, Ramadori F, Quarta S, Biasiolo A, Fabris E, Baldan P, Guarino G, Ruvoletto M, Villano G, Turato C, Gatta A, Mancin F, Pontisso P, Scrimin P. Binding and Uptake into Human Hepatocellular Carcinoma Cells of Peptide-Functionalized Gold Nanoparticles. Bioconjug Chem 2017; 28:222-229. [PMID: 27771945 PMCID: PMC5247774 DOI: 10.1021/acs.bioconjchem.6b00441] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 10/17/2016] [Indexed: 01/15/2023]
Abstract
One of the most daunting challenges of nanomedicine is the finding of appropriate targeting agents to deliver suitable payloads precisely to cells affected by malignancies. Even more complex is the ability to ensure that the nanosystems enter those cells. Here, we use 2 nm (metal core) gold nanoparticles to target human hepatocellular carcinoma (HepG2) cells stably transfected with the SERPINB3 (SB3) protein. The nanoparticles were coated with a 85:15 mixture of thiols featuring, respectively, a phosphoryl choline (to ensure water solubility and biocompatibility) and a 28-mer peptide corresponding to the amino acid sequence 21-47 of the hepatitis B virus-PreS1 protein (PreS1(21-47)). Conjugation of the peptide was performed via the maleimide-thiol reaction in methanol, allowing the use of a limited amount of the targeting molecule. This is an efficient procedure also in the perspective of selecting libraries of new targeting agents. The rationale behind the selection of the peptide is that SB3, which is undetectable in normal hepatocytes, is overexpressed in hepatocellular carcinoma and in hepatoblastoma and has been proposed as a target of the hepatitis B virus (HBV). For the latter, the key recognition element is the PreS1(21-47) peptide, which is a fragment of one of the proteins composing the viral envelope. The ability of the conjugated nanoparticles to bind the target protein SB3, expressed in liver cancer cells, was investigated by surface plasmon resonance analysis and in vitro via cellular uptake analysis followed by atomic absorption analysis of digested samples. The results showed that the PreS1(21-47) peptide is a suitable targeting agent for cells overexpressing the SB3 protein. Even more important is the evidence that the gold nanoparticles are internalized by the cells. The comparison between the surface plasmon resonance analysis and the cellular uptake studies suggests that the presentation of the protein on the cell surface is critical for efficient recognition.
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Affiliation(s)
- Satadru Jha
- Dipartimento
di Scienze Chimiche, Università di
Padova, via Marzolo 1, 35131, Padova, Italy
| | - Federico Ramadori
- Dipartimento
di Scienze Chimiche, Università di
Padova, via Marzolo 1, 35131, Padova, Italy
| | - Santina Quarta
- Dipartimento
di Medicina, Univeristà di Padova, via Giustiniani, 2, 35128 Padova, Italy
| | - Alessandra Biasiolo
- Dipartimento
di Medicina, Univeristà di Padova, via Giustiniani, 2, 35128 Padova, Italy
| | - Enrica Fabris
- Dipartimento
di Scienze Chimiche, Università di
Padova, via Marzolo 1, 35131, Padova, Italy
| | - Paola Baldan
- Dipartimento
di Scienze Chimiche, Università di
Padova, via Marzolo 1, 35131, Padova, Italy
| | - Gaetano Guarino
- Dipartimento
di Scienze Chimiche, Università di
Padova, via Marzolo 1, 35131, Padova, Italy
| | - Mariagrazia Ruvoletto
- Dipartimento
di Medicina, Univeristà di Padova, via Giustiniani, 2, 35128 Padova, Italy
| | - Gianmarco Villano
- Dipartimento
di Medicina, Univeristà di Padova, via Giustiniani, 2, 35128 Padova, Italy
| | - Cristian Turato
- Dipartimento
di Medicina, Univeristà di Padova, via Giustiniani, 2, 35128 Padova, Italy
| | - Angelo Gatta
- Dipartimento
di Medicina, Univeristà di Padova, via Giustiniani, 2, 35128 Padova, Italy
| | - Fabrizio Mancin
- Dipartimento
di Scienze Chimiche, Università di
Padova, via Marzolo 1, 35131, Padova, Italy
| | - Patrizia Pontisso
- Dipartimento
di Medicina, Univeristà di Padova, via Giustiniani, 2, 35128 Padova, Italy
| | - Paolo Scrimin
- Dipartimento
di Scienze Chimiche, Università di
Padova, via Marzolo 1, 35131, Padova, Italy
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Sun Y, Sheshadri N, Zong WX. SERPINB3 and B4: From biochemistry to biology. Semin Cell Dev Biol 2016; 62:170-177. [PMID: 27637160 DOI: 10.1016/j.semcdb.2016.09.005] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Revised: 09/08/2016] [Accepted: 09/12/2016] [Indexed: 12/15/2022]
Abstract
Human SERPINB3 and SERPINB4 are evolutionary duplicated serine/cysteine protease inhibitors. Genomic analysis indicates that these paralogous genes were encoded from independent loci arising from tandem gene duplication. Although the two molecules share 92% identity of their amino acid sequences, they are distinct in the Reactive Center Loop (RCL) including a hinge region and catalytic sequences which accounts for altered substrate specificity. Elevated expression of the two molecules has been reported to contribute to numerous pathological conditions such as inflammatory diseases and cancer. In this review, we focus on summarizing the biochemical features of SERPINB3/B4 and discussing the mechanistic basis for their biological functions and implications in human diseases.
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Affiliation(s)
- Yu Sun
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
| | - Namratha Sheshadri
- National Cancer Institute, Center for Cancer Research, Frederick, MD 21702, United States
| | - Wei-Xing Zong
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, United States.
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Systems-level effects of ectopic galectin-7 reconstitution in cervical cancer and its microenvironment. BMC Cancer 2016; 16:680. [PMID: 27558259 PMCID: PMC4997669 DOI: 10.1186/s12885-016-2700-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 08/09/2016] [Indexed: 12/20/2022] Open
Abstract
Background Galectin-7 (Gal-7) is negatively regulated in cervical cancer, and appears to be a link between the apoptotic response triggered by cancer and the anti-tumoral activity of the immune system. Our understanding of how cervical cancer cells and their molecular networks adapt in response to the expression of Gal-7 remains limited. Methods Meta-analysis of Gal-7 expression was conducted in three cervical cancer cohort studies and TCGA. In silico prediction and bisulfite sequencing were performed to inquire epigenetic alterations. To study the effect of Gal-7 on cervical cancer, we ectopically re-expressed it in the HeLa and SiHa cervical cancer cell lines, and analyzed their transcriptome and SILAC-based proteome. We also examined the tumor and microenvironment host cell transcriptomes after xenotransplantation into immunocompromised mice. Differences between samples were assessed with the Kruskall-Wallis, Dunn’s Multiple Comparison and T tests. Kaplan–Meier and log-rank tests were used to determine overall survival. Results Gal-7 was constantly downregulated in our meta-analysis (p < 0.0001). Tumors with combined high Gal-7 and low galectin-1 expression (p = 0.0001) presented significantly better prognoses (p = 0.005). In silico and bisulfite sequencing assays showed de novo methylation in the Gal-7 promoter and first intron. Cells re-expressing Gal-7 showed a high apoptosis ratio (p < 0.05) and their xenografts displayed strong growth retardation (p < 0.001). Multiple gene modules and transcriptional regulators were modulated in response to Gal-7 reconstitution, both in cervical cancer cells and their microenvironments (FDR < 0.05 %). Most of these genes and modules were associated with tissue morphogenesis, metabolism, transport, chemokine activity, and immune response. These functional modules could exert the same effects in vitro and in vivo, even despite different compositions between HeLa and SiHa samples. Conclusions Gal-7 re-expression affects the regulation of molecular networks in cervical cancer that are involved in diverse cancer hallmarks, such as metabolism, growth control, invasion and evasion of apoptosis. The effect of Gal-7 extends to the microenvironment, where networks involved in its configuration and in immune surveillance are particularly affected. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2700-8) contains supplementary material, which is available to authorized users.
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45
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Biasiolo A, Trotta E, Fasolato S, Ruvoletto M, Martini A, Gallotta A, Fassina G, Angeli P, Gatta A, Pontisso P. Squamous cell carcinoma antigen-IgM is associated with hepatocellular carcinoma in patients with cirrhosis: A prospective study. Dig Liver Dis 2016; 48:197-202. [PMID: 26614642 DOI: 10.1016/j.dld.2015.10.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 09/29/2015] [Accepted: 10/23/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Squamous cell carcinoma antigen (SCCA)-IgM complex has been described as a promising tool to identify patients with progressive liver disease at higher risk of hepatocellular carcinoma (HCC) development in retrospective studies. AIM To assess the clinical value of this biomarker in patients with cirrhosis in a prospective study. METHODS Patients with overt cirrhosis were prospectively evaluated at 6-month intervals for HCC development and decompensation with clinical examination, liver ultrasound, α-fetoprotein measurement. SCCA-IgM was measured in serum by immunoenzymatic assay. Median follow-up duration was 52 months (range 12-68 months). RESULTS 70 patients (26% male; mean age 56±10 years) were enrolled. The main aetiological factors were alcohol (44%) and hepatitis C (34%). Baseline values of SCCA-IgM were significantly higher in patients who developed HCC. Positivity of the biomarker at baseline was associated with a significantly shorter HCC-free survival, while α-fetoprotein (cut off >20 ng/ml) was not significant. SCCA-IgM positivity and hepatitis C were significant prognostic factors for HCC development. The biomarker was not associated with the development of clinical complications of cirrhosis. CONCLUSION This prospective study demonstrates that in patients with cirrhosis SCCA-IgM is associated with HCC development and may be useful for clinical management of cirrhotic patients at higher risk of HCC development.
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Affiliation(s)
| | - Elisa Trotta
- Department of Medicine, University of Padua, Italy
| | | | | | | | | | | | - Paolo Angeli
- Department of Medicine, University of Padua, Italy
| | - Angelo Gatta
- Department of Medicine, University of Padua, Italy
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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. Hypoxia up-regulates SERPINB3 through HIF-2α in human liver cancer cells. Oncotarget 2016; 6:2206-21. [PMID: 25544768 PMCID: PMC4385846 DOI: 10.18632/oncotarget.2943] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 12/09/2014] [Indexed: 02/04/2023] Open
Abstract
SERPINB3 is a cysteine-proteases inhibitor up-regulated in a significant number of cirrhotic patients carrying hepatocellular carcinoma (HCC) and recently proposed as a prognostic marker for HCC early recurrence. SERPINB3 has been reported to stimulate proliferation, inhibit apoptosis and, similar to what reported for hypoxia, to trigger epithelial-to-mesenchymal transition (EMT) and increased invasiveness in liver cancer cells. This study has investigated whether SERPINB3 expression is regulated by hypoxia-related mechanisms in liver cancer cells. Exposure of HepG2 and Huh7 cells to hypoxia up-regulated SERPINB3 transcription, protein synthesis and release in the extracellular medium. Hypoxia-dependent SERPINB3 up-regulation was selective (no change detected for SERPINB4) and operated through hypoxia inducible factor (HIF)-2α (not HIF-1α) binding to SERPINB3 promoter, as confirmed by chromatin immuno-precipitation assay and silencing experiments employing specific siRNAs. HIF-2α-mediated SERPINB3 up-regulation under hypoxic conditions required intracellular generation of ROS. Immuno-histochemistry (IHC) and transcript analysis, performed in human HCC specimens, revealed co-localization of the two proteins in liver cancer cells and the existence of a positive correlation between HIF-2α and SERPINB3 transcript levels, respectively. Hypoxia, through HIF-2α-dependent and redox-sensitive mechanisms, up-regulates the transcription, synthesis and release of SERPINB3, a molecule with a high oncogenic potential.
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Affiliation(s)
- Stefania Cannito
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Interuniversity Center for Liver Pathophysiology, University of Torino, Italy
| | | | - Claudia Paternostro
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Interuniversity Center for Liver Pathophysiology, University of Torino, Italy
| | | | | | - Irene Cambieri
- Department of Plastic Surgery and Burn Unit Skin Bank, CTO Hospital, Torino, Italy
| | | | - Erica Novo
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Interuniversity Center for Liver Pathophysiology, University of Torino, Italy
| | - Elisabetta Morello
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Interuniversity Center for Liver Pathophysiology, University of Torino, Italy
| | | | | | - Tiziana Musso
- Department of Public Health and Pediatric Sciences, University of Torino, Italy
| | - Ezio David
- Pathology Unit, San Giovanni Battista Hospital, Torino, Italy
| | - Ignazia Tusa
- Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Firenze, Italy
| | - Elisabetta Rovida
- Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Firenze, Italy
| | - Riccardo Autelli
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Interuniversity Center for Liver Pathophysiology, University of Torino, Italy
| | - Antonina Smedile
- Gastroenterology and Hepatology Division, San Giovanni Battista Hospital, Torino, Italy
| | - Umberto Cillo
- Unit of Hepatobiliary Surgery and Liver Transplantation, University of Padova, Italy
| | | | - Maurizio Parola
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Interuniversity Center for Liver Pathophysiology, University of Torino, Italy
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Martini A, Gallotta A, Pontisso P, Fassina G. Clinical applications of squamous cell carcinoma antigen-immunoglobulins M to monitor chronic hepatitis C. World J Hepatol 2015; 7:2913-2919. [PMID: 26689503 PMCID: PMC4678378 DOI: 10.4254/wjh.v7.i29.2913] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 09/30/2015] [Accepted: 12/02/2015] [Indexed: 02/06/2023] Open
Abstract
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.
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48
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Turato C, Cannito S, Simonato D, Villano G, Morello E, Terrin L, Quarta S, Biasiolo A, Ruvoletto M, Martini A, Fasolato S, Zanus G, Cillo U, Gatta A, Parola M, Pontisso P. SerpinB3 and Yap Interplay Increases Myc Oncogenic Activity. Sci Rep 2015; 5:17701. [PMID: 26634820 PMCID: PMC4669520 DOI: 10.1038/srep17701] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 10/29/2015] [Indexed: 01/03/2023] Open
Abstract
SerpinB3 has been recently described as an early marker of liver carcinogenesis, but the potential mechanistic role of this serpin in tumor development is still poorly understood. Overexpression of Myc often correlates with more aggressive tumour forms, supporting its involvement in carcinogenesis. Yes-associated protein (Yap), the main effector of the Hippo pathway, is a central regulator of proliferation and it has been found up-regulated in hepatocellular carcinomas. The study has been designed to investigate and characterize the interplay and functional modulation of Myc by SerpinB3 in liver cancer. Results from this study indicate that Myc was up-regulated by SerpinB3 through calpain and Hippo-dependent molecular mechanisms in transgenic mice and hepatoma cells overexpressing human SerpinB3, and also in human hepatocellular carcinomas. Human recombinant SerpinB3 was capable to inhibit the activity of Calpain in vitro, likely reducing its ability to cleave Myc in its non oncogenic Myc-nick cytoplasmic form. SerpinB3 indirectly increased the transcription of Myc through the induction of Yap pathway. These findings provide for the first time evidence that SerpinB3 can improve the production of Myc through direct and indirect mechanisms that include the inhibition of generation of its cytoplasmic form and the activation of Yap pathway.
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Affiliation(s)
| | - Stefania Cannito
- Dept. of Clinical and Biological Sciences, Unit of Experimental Medicine and Interuniversity Center for Liver Pathophysiology, University of Torino, Italy
| | | | | | - Elisabetta Morello
- Dept. of Clinical and Biological Sciences, Unit of Experimental Medicine and Interuniversity Center for Liver Pathophysiology, University of Torino, Italy
| | | | | | | | | | | | | | - Giacomo Zanus
- Unit of Hepatobiliary Surgery and Liver Transplantation, University of Padova, Italy
| | - Umberto Cillo
- Unit of Hepatobiliary Surgery and Liver Transplantation, University of Padova, Italy
| | | | - Maurizio Parola
- Dept. of Clinical and Biological Sciences, Unit of Experimental Medicine and Interuniversity Center for Liver Pathophysiology, University of Torino, Italy
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Randall DR, Park PS, Chau JK. Identification of altered protein abundances in cholesteatoma matrix via mass spectrometry-based proteomic analysis. J Otolaryngol Head Neck Surg 2015; 44:50. [PMID: 26608071 PMCID: PMC4660678 DOI: 10.1186/s40463-015-0104-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 11/10/2015] [Indexed: 11/20/2022] Open
Abstract
Background Cholesteatoma are cyst-like structures lined with a matrix of differentiated squamous epithelium overlying connective tissue. Although epithelium normally exhibits self-limited growth, cholesteatoma matrix erodes mucosa and bone suggesting changes in matrix protein constituents that permit destructive behaviour. Differential proteomic studies can measure and compare the cholesteatoma proteome to normal tissues, revealing protein alterations that may propagate the destructive process. Methods Human cholesteatoma matrix, cholesteatoma-involved ossicles, and normal middle ear mucosa, post-auricular skin, and non-involved ossicles were harvested. These tissues were subjected to multiplex peptide labeling followed by liquid chromatography and tandem mass spectrometry analysis. Relative protein abundances were compared and evaluated for ontologic function and putative involvement in cholesteatoma. Results Our methodology detected 10 764 peptides constituting 1662 unique proteins at 95 % confidence or greater. Twenty-nine candidate proteins were identified in soft tissue analysis, with 29 additional proteins showing altered abundances in bone samples. Ontologic functions and known relevance to cholesteatoma are discussed, with several candidates highlighted for their roles in epithelial integrity, evasion of apoptosis, and immunologic function. Conclusion This study produced an extensive cholesteatoma proteome and identified 58 proteins with altered abundances contributing to disease pathopathysiology. As well, potential biomarkers of residual disease were highlighted. Further investigation into these proteins may provide useful options for novel therapeutics or monitoring disease status.
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Affiliation(s)
- Derrick R Randall
- Section of Otolaryngology - Head & Neck Surgery, Department of Surgery, University of Calgary, Calgary, Foothills Medical Centre, 1403 - 29 Street NW, Calgary, AB, T2N 2T9, Canada
| | - Phillip S Park
- Section of Otolaryngology - Head & Neck Surgery, Department of Surgery, University of Calgary, Calgary, Foothills Medical Centre, 1403 - 29 Street NW, Calgary, AB, T2N 2T9, Canada
| | - Justin K Chau
- Section of Otolaryngology - Head & Neck Surgery, Department of Surgery, University of Calgary, Calgary, Foothills Medical Centre, 1403 - 29 Street NW, Calgary, AB, T2N 2T9, Canada.
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50
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Martini A, Fattovich G, Guido M, Bugianesi E, Biasiolo A, Ieluzzi D, Gallotta A, Fassina G, Merkel C, Gatta A, Negro F, Pontisso P. 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. [PMID: 25611978 DOI: 10.1111/jvh.12394] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 12/07/2014] [Indexed: 12/13/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) enhances the risk of progressive liver disease. In chronic hepatitis C (CHC), liver steatosis is frequent, especially in genotype 3, but its clinical significance is debated. As squamous cell carcinoma antigen (SCCA)-IgM has been associated with advanced liver disease and risk of tumour development, we evaluated its occurrence in CHC and the possible relation with NASH at liver biopsy. Using a validated ELISA, serum SCCA-IgM was measured in 91 patients with CHC at the time of liver biopsy performed before antiviral treatment, at the end of treatment and 6 months thereafter, and in 93 HCV-negative patients with histological diagnosis of nonalcoholic fatty liver disease, as controls. SCCA-IgM was detected in 33% of CHC patients and in 4% of controls. This biomarker was found more elevated in CHC patients with histological NASH, and at multivariate analysis, SCCA-IgM and HCV genotype 3 were independently associated with NASH [OR (95% CI): 6.94 (1.21-40) and 27.02 (4.44-166.6)]. As predictors of NASH, HCV genotype 3 and SCCA-IgM had a specificity and a sensitivity of 97% and 44%, and of 95% and 27%, respectively. PPV and NPV were 80% and 86% for HCV genotype 3 vs 73% and 72% for SCCA-IgM. In patients with sustained virologic response to therapy, SCCA-IgM levels decreased significantly, while these remained unchanged in nonresponders. In conclusion, SCCA-IgM is detectable in one-third of patients with CHC and significantly correlates with histological NASH.
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Affiliation(s)
- A Martini
- Department of Medicine, University of Padua, Padua, Italy
| | - G Fattovich
- Division of Gastroenterology and Endoscopy, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.,Department of Medicine, University of Verona, Verona, Italy
| | - M Guido
- Department of Medicine, University of Padua, Padua, Italy
| | - E Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Torino, Torino, Italy
| | - A Biasiolo
- Department of Medicine, University of Padua, Padua, Italy
| | - D Ieluzzi
- Division of Gastroenterology and Endoscopy, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | | | | | - C Merkel
- Department of Medicine, University of Padua, Padua, Italy
| | - A Gatta
- Department of Medicine, University of Padua, Padua, Italy
| | - F Negro
- Division of Clinical Pathology, University Hospitals of Geneva, Geneva, Switzerland.,Division Gastroenterology and Hepatology, University Hospitals of Geneva, Geneva, Switzerland
| | - P Pontisso
- Department of Medicine, University of Padua, Padua, Italy
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