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      Ficolin-2 and ficolin-3 in women with malignant and benign ovarian tumours

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          Abstract

          Ficolins are serum pattern recognition molecules. They have opsonic properties and are able to activate complement via the lectin pathway. This paper reports investigations concerning ficolin-2 and ficolin-3 in ovarian cancer (OC). Their serum levels, single nucleotide polymorphisms of the corresponding FCN2 and FCN3 genes and specific mRNA expression in ovarian sections were investigated in 128 patients suffering from primary OC and 197 controls operated on for reasons other than malignancies. The latter consisted of two reference groups: those with benign tumours ( n = 123) and those with normal ovaries (NO) ( n = 74). Serum ficolin-2 and ficolin-3 concentrations were higher among patients with malignant disease when compared with either of the reference groups. A significant correlation between ficolin-2 and ficolin-3 concentrations was found, while no correlations with CA125 antigen or CRP were observed. No differences in the frequency of single nucleotide polymorphisms at sites −64, −4 (promoter), +6359, or +6424 (exon 8) ( FCN2 gene) nor in the frame-shift mutation 1637delC ( FCN3 gene) were found between investigated groups. In contrast to serum concentrations, the expression of FCN2 gene (reported for the first time in ovarian sections) was significantly lower in women with OC in comparison with patients with NO but not with benign ovarian tumours. In case of FCN3 gene, its expression levels in OC group inversely correlated with serum ficolin-3 and were lower in comparison with controls.

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          The online version of this article (doi:10.1007/s00262-013-1445-3) contains supplementary material, which is available to authorized users.

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          Most cited references39

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          Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas.

          This study analyzed gene expression patterns and global genomic alterations in hepatocellular carcinomas (HCC), hepatoblastomas (HPBL), tissue adjacent to HCC and normal liver tissue derived from normal livers and hepatic resections. We found that HCC and adjacent non-neoplastic cirrhotic tissue have considerable overlap in gene expression patterns compared to normal liver. Several genes including Glypican 3, spondin-2, PEG10, EDIL3 and Osteopontin are over-expressed in HCC vs. adjacent tissue whereas Ficolin 3 is the most consistently under-expressed gene. HCC can be subdivided into three clusters based on gene expression patterns. HCC and HPBL have clearly different patterns of gene expression, with genes IGF2, Fibronectin, DLK1, TGFb1, MALAT1 and MIG6 being over-expressed in HPBL versus HCC. In addition, specific areas of the genome appear unstable in HCC, with the same regions undergoing either deletion or increased gene dosage in all HCC. In conclusion, a set of specific genes and areas of genomic instability are found across the board in liver neoplasia.
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            Polymorphisms in the FCN2 gene determine serum variation and function of Ficolin-2.

            The ficolin 1, 2 and 3 (derived from the FCN1, 2 and 3 genes, respectively) are homologous soluble pattern recognition molecules of importance for innate immunity, comprising collagen-like and fibrinogen-like domains, binding to sugar groups on different types of microorganisms. Serum concentration of Ficolin-2 varies considerably in healthy individuals. Thus, we speculated whether this could be due to variations in the FCN2 gene. We sequenced the promoter region and the exons and intron-exon boundaries of FCN2 in Danish Caucasians. For comparison, FCN1 and FCN3 were also investigated. Ficolin-2 concentrations were measured in serum and the functional relevance of amino acid substituting polymorphisms in FCN2 was investigated by binding to and recovery from N-acetylglucosamine (GlcNAc). Both FCN1 and FCN2 contained polymorphisms in the promoters and structural parts of the genes, but only polymorphisms in FCN2 resulted in amino acid exchanges. FCN2 promoter polymorphisms were associated with marked changes in the Ficolin-2 serum concentration, whereas two polymorphisms clustered in the exon encoding the fibrinogen-like domain were associated with increased and decreased GlcNAc binding, respectively. In FCN3, only a single frame-shift deletion in exon 5 was detected. These results show that the FCN genes are polymorphic and that particularly FCN2 harbors functional polymorphic sites that regulate both the expression as well as the function of Ficolin-2, which may have pathophysiological implications for innate immunity.
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              Serum concentrations of lectin-pathway components in healthy neonates, children and adults: mannan-binding lectin (MBL), M-, L-, and H-ficolin, and MBL-associated serine protease-2 (MASP-2).

              This study aimed to measure serum concentrations of five lectin-pathway components, mannan-binding lectin (MBL), M-ficolin, L-ficolin, H-ficolin, and MBL-associated serine protease-2 (MASP-2), in healthy neonates and children, to determine if they change with age and to compare them with serum concentrations in healthy adults. Concentrations were measured in 141 preterm and 30 term neonates, in 120 children including infants and adolescents, and in 350 adults (97 for L-ficolin) by inhouse time-resolved immunofluorometric assays or commercially available enzyme-linked immunosorbent assays. The adjacent categories method applying Wilcoxon-Mann-Whitney tests was used to determine age categories where concentrations differed significantly. Displaying serum concentration vs. age, an inverted-U shape (higher concentrations in children than in neonates and adults) was found for MBL and the ficolins, and an S-shape for MASP-2. Serum concentrations of all five lectin-pathway components were significantly lower in preterm neonates 1 yr and H-ficolin in term neonates and in children were found to be comparable with adult values. MBL, M-, L-, and H-ficolin, and MASP-2 serum concentrations show important changes with age. The respective normal ranges for adults should not be used in the pediatric population. The age-specific pediatric ranges established here may be used instead. © 2011 John Wiley & Sons A/S.
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                Author and article information

                Contributors
                +4842-2723607 , +4842-2723630 , mcedzynski@cbm.pan.pl
                Journal
                Cancer Immunol Immunother
                Cancer Immunol. Immunother
                Cancer Immunology, Immunotherapy
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0340-7004
                1432-0851
                7 June 2013
                7 June 2013
                August 2013
                : 62
                : 8
                : 1411-1419
                Affiliations
                [ ]Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
                [ ]Chair and Department of Gynaecology, Oncologic Gynaecology and Gynaecologic Endocrinology, Medical University of Gdansk, Kliniczna 1a, 80-402 Gdańsk, Poland
                [ ]Department of Biochemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland
                [ ]Institute of Microbiology, Immunology and Biotechnology, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
                [ ]Department of Clinical Pathomorphology, Polish Mother`s Memorial Hospital Research Institute, Rzgowska 281/289, 93-338 Lodz, Poland
                [ ]Department of Immunochemistry, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wroclaw, Poland
                [ ]Scottish National Blood Transfusion Service, National Science Laboratory, Ellen’s Glen Road, Edinburgh, EH17 7QT Scotland UK
                [ ]Department of Applied Biochemistry, Tokai University, 4-1-1 Kitakaname, Hiratsuka-shi, Kanagawa 259-1292 Japan
                Article
                1445
                10.1007/s00262-013-1445-3
                3717161
                23744477
                b36dfeef-cc5a-4630-acaf-2f9f11731447
                © The Author(s) 2013

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                : 25 April 2013
                : 27 May 2013
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2013

                Oncology & Radiotherapy
                ovarian cancer, benign ovarian tumours, ficolin-3 (h-ficolin), ficolin-2 (l-ficolin),fcn2 gene,fcn3 gene

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