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

Yuxia Wang; Shiyu Liu; Bolei Li; Yaling Jiang; Xinxuan Zhou; Jing Chen; Mingyun Li; Biao Ren; Xian Peng; Xuedong Zhou; Lei Cheng

doi:10.1080/20002297.2019.1643205

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

J Oral Microbiol. 2019 Jul 22;11(1):1643205. doi: 10.1080/20002297.2019.1643205. eCollection 2019.

Authors

Yuxia Wang^{1

2

3}, Shiyu Liu^{1

2}, Bolei Li^{1

2}, Yaling Jiang^{1

2}, Xinxuan Zhou¹, Jing Chen^{1

2}, Mingyun Li¹, Biao Ren¹, Xian Peng¹, Xuedong Zhou^{1

2}, Lei Cheng^{1

2}

Affiliations

¹ State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China.
² Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
³ Department of Cariology and Endodontics, Hospital of Stomatology, Nankai University, Tianjin, China.

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, tnfrsf1β, and il1β) 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.

Keywords: COX-2; Staphylococcus aureus; malignant transformation; oral keratinocytes; proliferation.

Grants and funding

This study was supported by the National Key Research and Development Program of China 2017YFC0840107 (L.C.); National Natural Science Foundation of China grant 81870759 (L.C.), 81600858 (B.R.), and 81430011 (X.Z.). The Youth Grant of the Science and Technology Department of the Sichuan Province, China 2017JQ0028 (L.C.). Innovative Research Team Program of Sichuan Province (L.C).