title: Novel genes and pathways modulated by syndecan-1: implications for the proliferation and cell-cycle regulation of malignant mesothelioma cells.
abstract: Malignant pleural mesothelioma is a highly malignant tumor, originating from mesothelial cells of the serous cavities. In mesothelioma the expression of syndecan-1 correlates to epithelioid morphology and inhibition of growth and migration. Our previous data suggest a complex role of syndecan-1 in mesothelioma cell proliferation although the exact underlying molecular mechanisms are not completely elucidated. The aim of this study is therefore to disclose critical genes and pathways affected by syndecan-1 in mesothelioma; in order to better understand its importance for tumor cell growth and proliferation. We modulated the expression of syndecan-1 in a human mesothelioma cell line via both overexpression and silencing, and followed the transcriptomic responses with microarray analysis. To project the transcriptome analysis on the full-dimensional picture of cellular regulation, we applied pathway analysis using Ingenuity Pathway Analysis (IPA) and a novel method of network enrichment analysis (NEA) which elucidated signaling relations between differentially expressed genes and pathways acting via various molecular mechanisms. Syndecan-1 overexpression had profound effects on genes involved in regulation of cell growth, cell cycle progression, adhesion, migration and extracellular matrix organization. In particular, expression of several growth factors, interleukins, and enzymes of importance for heparan sulfate sulfation pattern, extracellular matrix proteins and proteoglycans were significantly altered. Syndecan-1 silencing had less powerful effect on the transcriptome compared to overexpression, which can be explained by the already low initial syndecan-1 level of these cells. Nevertheless, 14 genes showed response to both up- and downregulation of syndecan-1. The "cytokine - cytokine-receptor interaction", the TGF-β, EGF, VEGF and ERK/MAPK pathways were enriched in both experimental settings. Most strikingly, nearly all analyzed pathways related to cell cycle were enriched after syndecan-1 silencing and depleted after syndecan-1 overexpression. Syndecan-1 regulates proliferation in a highly complex way, although the exact contribution of the altered pathways necessitates further functional studies.
authors.affiliation: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden. tunde.szatmari@ki.se
authors.forename: Tünde
authors.initials: T
authors.lastname: Szatmári
authors.forename: Filip
authors.initials: F
authors.lastname: Mundt
authors.forename: Ghazal
authors.initials: G
authors.lastname: Heidari-Hamedani
authors.forename: Fang
authors.initials: F
authors.lastname: Zong
authors.forename: Elena
authors.initials: E
authors.lastname: Ferolla
authors.forename: Andrey
authors.initials: A
authors.lastname: Alexeyenko
authors.forename: Anders
authors.initials: A
authors.lastname: Hjerpe
authors.forename: Katalin
authors.initials: K
authors.lastname: Dobra
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D053668:Syndecan-1 / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
chemical_list: D053668:Syndecan-1