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    ABSTRACT: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological cancers; the majority of EOC is the serous histotype and diagnosed at advanced stage. IL6 is the cytokine that has been found most frequently associated with carcinogenesis and progression of serous EOCs. IL6 is a growth-promoting and anti-apoptotic factor, and high plasma levels of IL6 in advanced stage EOCs correlate with poor prognosis. The objective of the present study was to identify IL6 co-regulated genes and gene network/s in EOCs. We applied bioinformatics tools on 7 publicly available data sets containing the gene expression profiles of 1262 EOC samples. By Pearson's correlation analysis we identified, in EOCs, an IL6-correlated gene signature containing 40 genes mainly associated with proliferation. 33 of 40 genes were also significantly correlated in low malignant potential (LMP) EOCs, while 7 genes, named C5AR1, FPR1, G0S2, IL8, KLF2, MMP19, and THBD were IL6-correlated only in advanced stage EOCs. Among the 40-gene signature EGFR ligand HBEGF, genes of the EGR family members and genes encoding for negative feedback regulators of growth factor signaling were included. The results obtained by Gene Set Enrichment and Ingenuity Pathway Analyses enabled the identification, respectively, of gene sets associated with 'early growth factor response' for the 40-gene signature, and a biological network related to 'thrombosis and cardiovascular disease' for the 7-gene signature. In agreement with these results, selected genes from the identified signatures were validated in vitro by real time RT-PCR in serous EOC cell lines upon stimulation with EGF. Serous EOCs, independently of their aggressiveness, co-regulate IL6 expression together with that of genes associated to growth factor signaling, arguing for the hypothesis that common mechanism/s driven by EGFR ligands characterize both advanced-stage and LMP EOCs. Only advanced-stage EOCs appeared to be characterized by a scenario that involves genes which are so far associated with thrombosis and cardiovascular disease, thus suggesting that this pathway is implicated in the growth and/or spread of more aggressive tumors. We have discovered novel activated signaling pathways that drive the expression of IL6 and of co-regulated genes and are possibly involved in the pathobiology of EOCs.
    BMC Genomics 07/2013; 14(1):508. · 4.04 Impact Factor
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    ABSTRACT: Cold atmospheric plasma (CAP) has the potential to interact with tissue or cells leading to fast, painless and efficient disinfection and furthermore has positive effects on wound healing and tissue regeneration. For clinical implementation it is necessary to examine how CAP improves wound healing and which molecular changes occur after the CAP treatment. In the present study we used the second generation MicroPlaSter ß® in analogy to the current clinical standard (2 min treatment time) in order to determine molecular changes induced by CAP using in vitro cell culture studies with human fibroblasts and an in vivo mouse skin wound healing model. Our in vitro analysis revealed that the CAP treatment induces the expression of important key genes crucial for the wound healing response like IL-6, IL-8, MCP-1, TGF-ß1, TGF-ß2, and promotes the production of collagen type I and alpha-SMA. Scratch wound healing assays showed improved cell migration, whereas cell proliferation analyzed by XTT method, and the apoptotic machinery analyzed by protein array technology, was not altered by CAP in dermal fibroblasts. An in vivo wound healing model confirmed that the CAP treatment affects above mentioned genes involved in wound healing, tissue injury and repair. Additionally, we observed that the CAP treatment improves wound healing in mice, no relevant side effects were detected. We suggest that improved wound healing might be due to the activation of a specified panel of cytokines and growth factors by CAP. In summary, our in vitro human and in vivo animal data suggest that the 2 min treatment with the MicroPlaSter ß® is an effective technique for activating wound healing relevant molecules in dermal fibroblasts leading to improved wound healing, whereas the mechanisms which contribute to these observed effects have to be further investigated.
    PLoS ONE 11/2013; 8(11):e79325. · 3.53 Impact Factor
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    ABSTRACT: Significance: A highly interactive serine protease/plasmin/matrix metalloproteinase axis regulates stromal remodeling in the wound microenvironment. Current findings highlight the importance of stringent controls on protease expression and their topographic activities in cell proliferation, migration, and tissue homeostasis. Targeting elements in this cascading network may lead to novel therapeutic approaches for fibrotic diseases and chronic wounds. Recent Advances: Matrix-active proteases and their inhibitors orchestrate wound site tissue remodeling, cell migration, and proliferation. Indeed, the serine proteases urokinase plasminogen activator and tissue-type plasminogen activator (uPA/tPA) and their major phsyiological inhibitor, plasminogen activator inhibitor-1 (PAI-1; serine protease inhibitor clade E member 1 [SERPINE1]), are upregulated in several cell types during injury repair. Coordinate expression of proteolytic enzymes and their inhibitors in the wound bed provides a mechanism for fine control of focal proteolysis to facilitate matrix restructuring and cell motility in complex environments. Critical Issues: Cosmetic and tissue functional consequences of wound repair anomalies affect the quality of life of millions of patients in the United States alone. The development of novel therapeutics to manage individuals most affected by healing anomalies will likely derive from the identification of critical, translationally accessible, control elements in the wound site microenvironment. Future Directions: Activation of the PAI-1 gene early after wounding, its prominence in the repair transcriptome and varied functions suggest a key role in the global cutaneous injury response program. Targeting PAI-1 gene expression and/or PAI-1 function with molecular genetic constructs, neutralizing antibodies or small molecule inhibitors may provide a novel, therapeutically relevant approach, to manage the pathophysiology of wound healing disorders associated with deficient or excessive PAI-1 levels.
    Advances in wound care. 03/2014; 3(3):281-290.

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