Lorand Vancza

All Publications

• Primary sclerosing cholangitis and the path to translation. The Journal of clinical investigation Váncza, L., Torok, N. J. 2023; 133 (17)

  View details for DOI 10.1172/JCI174218

  View details for PubMedID 37655665

• SPOCK1 Overexpression Suggests Poor Prognosis of Ovarian Cancer. Cancers Vancza, L., Horvath, A., Seungyeon, L., Rokusz, A., Dezso, K., Reszegi, A., Petovari, G., Gotte, M., Kovalszky, I., Baghy, K. 2023; 15 (7)

  Abstract

  PURPOSE: Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) has been found in a variety of malignant tumors and is associated with a poor prognosis. We aimed to explore the role of SPOCK1 in ovarian cancer.METHODS: Ovarian cancer cell lines SKOV3 and SW626 were transfected with SPOCK1 overexpressing or empty vector using electroporation. Cells were studied by immunostaining and an automated Western blotting system. BrdU uptake and wound healing assays assessed cell proliferation and migration. SPOCK1 expression in human ovarian cancer tissues and in blood samples were studied by immunostaining and ELISA. Survival of patients with tumors exhibiting low and high SPOCK1 expression was analyzed using online tools.RESULTS: Both transfected cell lines synthesized different SPOCK1 variants; SKOV3 cells also secreted the proteoglycan. SPOCK1 overexpression stimulated DNA synthesis and cell migration involving p21CIP1. Ovarian cancer patients had increased SPOCK1 serum levels compared to healthy controls. Tumor cells of tissues also displayed abundant SPOCK1. Moreover, SPOCK1 levels were higher in untreated ovarian cancer serum and tissue samples and lower in recipients of chemotherapy. According to in silico analyses, high SPOCK1 expression was correlated with shorter survival.CONCLUSION: Our findings suggest SPOCK1 may be a viable anti-tumor therapeutic target and could be used for monitoring ovarian cancer.

  View details for DOI 10.3390/cancers15072037

  View details for PubMedID 37046698

• STIFF MATRIX PROMOTES BILE DUCT CELL PROLIFERATION AND HYALURONIC ACID PRODUCTION IN PRIMARY SCLEROSING CHOLANGITIS Vancza, L., Kunimoto, K., Fan, W., Li, Y., Park, H., Nagy, N., Bollyky, P., Torok, N. J. WILEY. 2022: S1504

  View details for Web of Science ID 000870796604397

• EXTRACELLULAR MATRIX VISCOELASTICITY DRIVES LIVER CANCER PROGRESSION IN PRE-CIRRHOTIC NASH Fan, W., Li, Y., Adebowale, K., Kunimoto, K., Mozes, G., Vancza, L., Chen, D., Chaudhuri, O., Wells, R. G., Monga, S. S., Torok, N. J. WILEY. 2022: S98-S99

  View details for Web of Science ID 000870796600109

• Shc is implicated in calreticulin-mediated sterile inflammation in alcoholic hepatitis. Cellular and molecular gastroenterology and hepatology Li, Y., Jiang, J. X., Fan, W., Fish, S. R., Das, S., Gupta, P., Mozes, G., Vancza, L., Sarkar, S., Kunimoto, K., Chen, D., Park, H., Clemens, D., Tomilov, A., Cortopassi, G., Torok, N. J. 2022

  Abstract

  BACKGROUND: &Aims: Src homology and collagen (Shc) proteins are major adapters to extra-cellular signals however the regulatory role of Shc isoforms in sterile inflammatory responses in alcoholic hepatitis (AH) has not been fully investigated. We hypothesized that in an isoform-specific manner Shc modulates pre-apoptotic signals, calreticulin (CRT) membrane exposure and recruitment of inflammatory cells.METHODS: Liver biopsy samples from patients with AH vs. healthy subjects were studied for Shc expression using DNA microarray data and immunohistochemistry. ShcKD (hypomorph) and age-matched wild type (WT) mice were pair-fed according to the chronic-plus-binge alcohol (NIAAA) diet. To analyze hepatocyte-specific effects, AAV8-TBG-Cre (ShcHepKO)-mediated deletion was performed in fl/fl Shc mice. Lipid peroxidation, proinflammatory signals, redox radicals, NADH/NAD+ ratio, as well as cleaved caspase 8, BAP31, Bax, and Bak, in vivo. CRT translocation was studied in ethanol-exposed p46ShcẟSH2-transfected hepatocytes by membrane biotinylation in conjunction with p-Eif2alpha, BAP31, caspase 8, Bax/Bak. The effects of idebenone, a novel Shc inhibitor was studied in alcohol/pair-fed mice.RESULTS: Shc was significantly induced in patients with AH (p<0.01). ALT, NADH/NAD+ ratios, production of redox radicals, lipid peroxidation improved (p<0.05), and IL-1beta, MCP-1, and CXCL10 were reduced in ShcKD and ShcHepKO mice. In vivo, Shc-dependent induction, and in hepatocytes, p46Shc-dependent increase in pre-apoptotic proteins Bax/Bak, caspase 8, BAP31 cleavage and membrane translocation of CRT/Erp57 were seen. Idebenone protected against alcohol-mediated liver injury.CONCLUSION: Alcohol induces p46Shc-dependent activation of pre-apoptotic pathways and translocation of CRT to the membrane, where it acts as a DAMP, instigating immunogenicity. Shc inhibition could be a novel treatment strategy in AH.

  View details for DOI 10.1016/j.jcmgh.2022.09.005

  View details for PubMedID 36122677

• SPOCK1 with unexpected function. The start of a new career. American journal of physiology. Cell physiology Vancza, L., Tatrai, P., Reszegi, A., Baghy, K., Kovalszky, I. 2022

  Abstract

  SPOCK1, 2 and 3 are considered as matricellular proteoglycans without structural role. Their functions are only partly elucidated. SPOCK1 was detected in the brain as a member of the neural synapses, then in the neuromuscular junctions. It plays a role in the regulation of blood-brain barrier. Its best characterized activity was its oncogenic potential discovered in 2012. Its deleterious effect on tumor progression was detected on 36 different types of tumors by the end of 2020. However, its mode of actions is still not completely understood. Furthermore, even less was discovered about its physiological function. The fact that it was found to localize in the mitochondria and interfered with the lipid metabolism indicated, that the full discovery of SPOCK1 still waiting for us.

  View details for DOI 10.1152/ajpcell.00033.2022

  View details for PubMedID 35235422

• SPOCK1 Promotes the Development of Hepatocellular Carcinoma FRONTIERS IN ONCOLOGY Vancza, L., Karaszi, K., Peterfia, B., Turiak, L., Dezso, K., Sebestyen, A., Reszegi, A., Petovari, G., Kiss, A., Schaff, Z., Baghy, K., Kovalszky, I. 2022; 12: 819883

  Abstract

  The extracellular matrix proteoglycan SPOCK1 is increasingly recognized as a contributor to the development and progression of cancers. Here, we study how SPOCK1, which is present in non-tumorous hepatocytes at low concentrations, promotes the development and progression of malignant hepatocellular tumors. Although SPOCK1 is an extracellular matrix proteoglycan, its concentration increases in the cytoplasm of hepatocytes starting with very low expression in the normal cells and then appearing in much higher quantities in cells of cirrhotic human liver and hepatocellular carcinoma. This observation is similar to that observed after diethylnitrosamine induction of mouse hepatocarcinogenesis. Furthermore, syndecan-1, the major proteoglycan of the liver, and SPOCK1 are in inverse correlation in the course of these events. In hepatoma cell lines, the cytoplasmic SPOCK1 colocalized with mitochondrial markers, such as MitoTracker and TOMM20, a characteristic protein of the outer membrane of the mitochondrion and could be detected in the cell nucleus. SPOCK1 downregulation of hepatoma cell lines by siRNA inhibited cell proliferation, upregulated p21 and p27, and interfered with pAkt and CDK4 expression. A tyrosine kinase array revealed that inhibition of SPOCK1 in the liver cancer cells altered MAPK signaling and downregulated several members of the Sarc family, all related to the aggressivity of the hepatoma cell lines. These studies support the idea that SPOCK1 enhancement in the liver is an active contributor to human and rodent hepatocarcinogenesis and cancer progression. However, its mitochondrial localization raises the possibility that it has a currently unidentified physiological function in normal hepatocytes.

  View details for DOI 10.3389/fonc.2022.819883

  View details for Web of Science ID 000759874300001

  View details for PubMedID 35186754

  View details for PubMedCentralID PMC8853618

• Overexpression of Human Syndecan-1 Protects against the Diethylnitrosamine-Induced Hepatocarcinogenesis in Mice CANCERS Reszegi, A., Karaszi, K., Toth, G., Rada, K., Vancza, L., Turiak, L., Schaff, Z., Kiss, A., Szilak, L., Szabo, G., Petovari, G., Sebestyen, A., Dezso, K., Regos, E., Tatrai, P., Baghy, K., Kovalszky, I. 2021; 13 (7)

  Abstract

  Although syndecan-1 (SDC1) is known to be dysregulated in various cancer types, its implication in tumorigenesis is poorly understood. Its effect may be detrimental or protective depending on the type of cancer. Our previous data suggest that SDC1 is protective against hepatocarcinogenesis. To further verify this notion, human SDC1 transgenic (hSDC1+/+) mice were generated that expressed hSDC1 specifically in the liver under the control of the albumin promoter. Hepatocarcinogenesis was induced by a single dose of diethylnitrosamine (DEN) at an age of 15 days after birth, which resulted in tumors without cirrhosis in wild-type and hSDC1+/+ mice. At the experimental endpoint, livers were examined macroscopically and histologically, as well as by immunohistochemistry, Western blot, receptor tyrosine kinase array, phosphoprotein array, and proteomic analysis. Liver-specific overexpression of hSDC1 resulted in an approximately six month delay in tumor formation via the promotion of SDC1 shedding, downregulation of lipid metabolism, inhibition of the mTOR and the β-catenin pathways, and activation of the Foxo1 and p53 transcription factors that lead to the upregulation of the cell cycle inhibitors p21 and p27. Furthermore, both of them are implicated in the regulation of intermediary metabolism. Proteomic analysis showed enhanced lipid metabolism, activation of motor proteins, and loss of mitochondrial electron transport proteins as promoters of cancer in wild-type tumors, inhibited in the hSDC1+/+ livers. These complex mechanisms mimic the characteristics of nonalcoholic steatohepatitis (NASH) induced human liver cancer successfully delayed by syndecan-1.

  View details for DOI 10.3390/cancers13071548

  View details for Web of Science ID 000638358900001

  View details for PubMedID 33801718

  View details for PubMedCentralID PMC8037268

• Syndecan-1 Promotes Hepatocyte-Like Differentiation of Hepatoma Cells Targeting Ets-1 and AP-1 BIOMOLECULES Hollosi, P., Vancza, L., Karaszi, K., Dobos, K., Peterfia, B., Tatrai, E., Tatrai, P., Szarvas, T., Paku, S., Szilak, L., Kovalszky, I. 2020; 10 (10)

  Abstract

  Syndecan-1 is a transmembrane heparan sulfate proteoglycan which is indispensable in the structural and functional integrity of epithelia. Normal hepatocytes display strong cell surface expression of syndecan-1; however, upon malignant transformation, they may lose it from their cell surfaces. In this study, we demonstrate that re-expression of full-length or ectodomain-deleted syndecan-1 in hepatocellular carcinoma cells downregulates phosphorylation of ERK1/2 and p38, with the truncated form exerting an even stronger effect than the full-length protein. Furthermore, overexpression of syndecan-1 in hepatoma cells is associated with a shift of heparan sulfate structure toward a highly sulfated type specific for normal liver. As a result, cell proliferation and proteolytic shedding of syndecan-1 from the cell surface are restrained, which facilitates redifferentiation of hepatoma cells to a more hepatocyte-like phenotype. Our results highlight the importance of syndecan-1 in the formation and maintenance of differentiated epithelial characteristics in hepatocytes partly via the HGF/ERK/Ets-1 signal transduction pathway. Downregulation of Ets-1 expression alone, however, was not sufficient to replicate the phenotype of syndecan-1 overexpressing cells, indicating the need for additional molecular mechanisms. Accordingly, a reporter gene assay revealed the inhibition of Ets-1 as well as AP-1 transcription factor-induced promoter activation, presumably an effect of the heparan sulfate switch.

  View details for DOI 10.3390/biom10101356

  View details for Web of Science ID 000584100700001

  View details for PubMedID 32977498

  View details for PubMedCentralID PMC7598270