Qi L, Higgins SP, Lu Q, Samarakoon R, Wilkins-Port CE, Ye Q et al.SERPINE1 (PAI-1) is a prominent member of the early G0 G1 transition "wound repair" transcriptome in p53 mutant human keratinocytes. J Invest Dermatol 128:749-753

Journal of Investigative Dermatology (Impact Factor: 7.22). 04/2008; 128(3):749-53. DOI: 10.1038/sj.jid.5701068
Source: PubMed


Abbreviations: FBS, fetal bovine serum

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    • "NFkB also emerged to be a possible transcriptional regulator of 13 out of 40 genes according to the reported informations [35], data which might further indicate that a growth factor-dependent NFkB signaling is activated in a subset of EOC. It is noteworthy that IL6 and 19 of the 40 correlated genes were found up-modulated upon 2 hr serum stimulation of quiescent keratinocytes [36]. We can therefore argue that the activation of growth factor activated signaling can either directly or indirectly induce the expression of IL6 and genes which likely play a role in the growth of EOCs. "
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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. DOI:10.1186/1471-2164-14-508 · 3.99 Impact Factor
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    • "Expression of genes for the major Has enzymes (Has1-3) and HA-degrading enzymes (Hyal1-3) was measured in injured REK 3-D cultures, and Has2 and Has3 were upregulated whereas expression of the hyaluronidases remained unchanged after injury (Fig. 6). Interestingly, the fact that Has3 is induced more than Has2 in our system is consistent with reports that Has3 is preferentially induced over Has2 in human keratinocytes exposed to cytokines (Sayo et al., 2002) or to serum in order to stimulate the " wound repair transcriptome " (Qi et al., 2008). From these data we conclude that the soluble factor (HB-EGF) induces overall HA production by increasing Has gene expression. "
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    ABSTRACT: Hyaluronic acid (HA), a glycosaminoglycan located between keratinocytes in the epidermis, accumulates dramatically following skin wounding. To study inductive mechanisms, a rat keratinocyte organotypic culture model that faithfully mimics HA metabolism was used. Organotypic cultures were needle-punctured 100 times, incubated for up to 24 hours, and HA analyzed by histochemical and biochemical methods. Within 15 minutes post-injury, HA levels had elevated two-fold, increasing to four-fold by 24 hours. HA elevations far from the site of injury suggested the possible involvement of a soluble HA-inductive factor. Media transfer experiments (from wounded cultures to unwounded cultures) confirmed the existence of a soluble factor. From earlier evidence, we hypothesized that an EGF-like growth factor might be responsible. This was confirmed as follows: (1) EGFR kinase inhibitor (AG1478) completely prevented wounding-induced HA accumulation. (2) Rapid tyrosine-phosphorylation of EGFR correlated well with the onset of increased HA synthesis. (3) A neutralizing antibody that recognizes heparin binding EGF-like growth factor (HB-EGF) blocked wounding-induced HA synthesis by > or =50%. (4) Western analyses showed that release of activated HB-EGF (but neither amphiregulin nor EGF) occured after wounding. In summary, rapid HA accumulation after epidermal wounding occurs through a mechanism requiring cleavage of HB-EGF and activation of EGFR signaling.
    Journal of Investigative Dermatology 02/2009; 129(8):2046-58. DOI:10.1038/jid.2009.9 · 7.22 Impact Factor
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    • "Microarray of the EMT transcriptome in several clinically relevant model systems has provided insights into the specific repertoire of " plasticity " genes. Plasminogen activator inhibitor type-1 (PAI-1; SERPINE1), the major physiologic regulator of the pericellular plasmin-generating cascade, is a prominent member of the subset of TGF-β1-induced, EMT-associated genes in human malignant keratinocytes [21] [26] [27]. In epithelial cells undergoing a mesenchymallike conversion in response to the E-cadherin transcriptional repressors Snail, Slug or E47, PAI-1 upregulation appears to be an essential characteristic of the plastic phenotype [28]. "
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    ABSTRACT: Increased transforming growth factor-beta (TGF-beta) expression and epidermal growth factor receptor (EGFR) amplification accompany the emergence of highly aggressive human carcinomas. Cooperative signaling between these two growth factor/receptor systems promotes cell migration and synthesis of stromal remodeling factors (i.e., proteases, protease inhibitors) that, in turn, regulate tumor invasion, neo-angiogenesis and inflammation. ranscript profiling of transformed human cells revealed that genes encoding wound healing, matrix remodeling and cell cycle proteins (i.e., the "tissue repair" transcriptome) are significantly up-regulated early after growth factor stimulation. The major inhibitor of plasmin generation, plasminogen activator inhibitor-1 (PAI-1), is among the most highly induced transcripts during the phenotypic transition initiated by TGF-beta maximal expression requires EGFR signaling. PAI-1 induction occurs early in the progression of incipient epidermal squamous cell carcinoma (SCC) and is a significant indicator of poor prognosis in epithelial malignancies. Mouse modeling and molecular genetic analysis of complex systems indicates that PAI-1 regulates the temporal/spatial control of pericellular proteolysis, promotes epithelial plasticity, inhibits capillary regression and facilitates stromal invasion. Defining TGF-beta1-initiated signaling events that cooperate with an activated EGFR to impact the protease-protease inhibitor balance in the tumor microenvironment is critical to the development of novel therapies for the clinical management of human cancers.
    Journal of Oncology 02/2009; 2009:342391. DOI:10.1155/2009/342391
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