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Staphylococcus aureus induces COX-2-dependent proliferation and malignant transformation in oral keratinocytes.

ABSTRACT: The COX-2/PGE2 axis can play roles in mediating the progression of tumor. COX-2 induction was observed in oral cancer. In our previous study, we found Staphylococcus aureus, a pathogen prevalent in oral cancer, can activate the COX-2/PGE2 pathway in human oral keratinocyte (HOK) cells. Here, we investigated the proliferation of HOK cells affected by COX-2 induction and the role of COX-2 induction in the malignant transformation of HOK cells. We found S. aureus was able to facilitate HOK cell proliferation through upregulating COX-2 expression. With the induction of COX-2, expression of oral cancer-associated genes cyclin D1 was upregulated and p16 was downregulated. Transcriptome analysis showed that the "NF-kappa B signaling pathway" and "TNF signaling pathway" had the highest enrichment of differentially expressed genes (DEGs) with COX-2 over-expression. Seven upregulated genes (jun, tlr4, cxcl1, lif, cxcl3, tnfrsf1?, and il1?) in these two pathways were critical for the increased proliferation of HOK cells and might be associated with COX-2. Malignant transformation of cells was evaluated by soft agar colony formation assay and S. aureus infection promoted HOK cell colony formation. These results suggest the potential of S. aureus to induce the infection-associated malignant transformation of oral epitheliums through COX-2 activation.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6691923 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Staphylococcus aureus induces COX-2-dependent proliferation and malignant transformation in oral keratinocytes.

Wang Yuxia Y Liu Shiyu S Li Bolei B Jiang Yaling Y Zhou Xinxuan X Chen Jing J Li Mingyun M Ren Biao B Peng Xian X Zhou Xuedong X Cheng Lei L

Journal of oral microbiology 20190722 1

The COX-2/PGE2 axis can play roles in mediating the progression of tumor. COX-2 induction was observed in oral cancer. In our previous study, we found Staphylococcus aureus, a pathogen prevalent in oral cancer, can activate the COX-2/PGE2 pathway in human oral keratinocyte (HOK) cells. Here, we investigated the proliferation of HOK cells affected by COX-2 induction and the role of COX-2 induction in the malignant transformation of HOK cells. We found S. aureus ...[more]

PMID: 31448061

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Project description:Skin is the most common site of Staphylococcus aureus infection. While most of these infections are self-limited, recurrent infections are common. Keratinocytes and recruited immune cells participate in skin defense against infection. We postulated that S. aureus is able to adapt to the milieu within human keratinocytes to avoid keratinocyte-mediated clearance. From a collection of S. aureus isolated from chronically infected patients with atopic dermatitis, we noted 22% had an agr mutant-like phenotype. Using several models of human skin infection, we demonstrate that toxin-deficient, agr mutants of methicillin-resistant S. aureus (MRSA) USA300 are able to persist within keratinocytes by stimulating autophagy and evading caspase-1 and inflammasome activation. MRSA infection induced keratinocyte autophagy, as evidenced by galectin-8 and LC3 accumulation. Autophagy promoted the degradation of inflammasome components and facilitated staphylococcal survival. The recovery of more than 58% agr or RNAIII mutants (P < 0.0001) of an inoculum of wild-type (WT) MRSA from within wortmannin-treated keratinocytes compared to control keratinocytes reflected the survival advantage for mutants no longer expressing agr-dependent toxins. Our results illustrate the dynamic interplay between S. aureus and keratinocytes that can result in the selection of mutants that have adapted specifically to evade keratinocyte-mediated clearance mechanisms. Human skin is a major site of staphylococcal infection, and keratinocytes actively participate in eradication of these pathogens. We demonstrate that methicillin-resistant Staphylococcus aureus (MRSA) is ingested by keratinocytes and activates caspase-1-mediated clearance through pyroptosis. Toxin-deficient MRSA mutants are selected within keratinocytes that fail to induce caspase-1 activity and keratinocyte-mediated clearance. These intracellular staphylococci induce autophagy that enhances their intracellular survival by diminishing inflammasome components. These findings suggest that S. aureus mutants, by exploiting autophagy, can persist within human keratinocytes.

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Staphylococcus aureus induces COX-2-dependent proliferation and malignant transformation in oral keratinocytes.

Publications

<i>Staphylococcus aureus</i> induces COX-2-dependent proliferation and malignant transformation in oral keratinocytes.

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