Prolonged and repetitive exposure to Porphyromonas gingivalis increases aggressiveness of oral cancer cells by promoting acquisition of cancer stem cell properties
- 627 Downloads
Periodontitis is the most common chronic inflammatory condition occurring in the human oral cavity, but our knowledge on its contribution to oral cancer is rather limited. To define crosstalk between chronic periodontitis and oral cancer, we investigated whether Porphyromonas gingivalis, a major pathogen of chronic periodontitis, plays a role in oral cancer progression. To mimic chronic irritation by P. gingivalis in the oral cavity, oral squamous cell carcinoma (OSCC) cells were infected with P. gingivalis twice a week for 5 weeks. Repeated infection of oral cancer cells by P. gingivalis resulted in morphological changes of host cancer cells into an elongated shape, along with the decreased expression of epithelial cell markers, suggesting acquisition of an epithelial-to-mesenchymal transition (EMT) phenotype. The prolonged exposure to P. gingivalis also promoted migratory and invasive properties of OSCC cells and provided resistance against a chemotherapeutic agent, all of which are described as cellular characteristics undergoing EMT. Importantly, long-term infection by P. gingivalis induced an increase in the expression level of CD44 and CD133, well-known cancer stem cell markers, and promoted the tumorigenic properties of infected cancer cells compared to non-infected controls. Furthermore, increased invasiveness of P. gingivalis-infected OSCC cells was correlated with enhanced production of matrix metalloproteinase (MMP)-1 and MMP-10 that was stimulated by interleukin-8 (IL-8) release. This is the first report demonstrating that P. gingivalis can increase the aggressiveness of oral cancer cells via epithelial-mesenchymal transition-like changes and the acquisition of stemness, implicating P. gingivalis as a potential bacterial risk modifier.
KeywordsPorphyromonas gingivalis Oral cancer Cancer stem cell Interleukin-8 Matrix metalloproteinase Invasion
This work was supported by Basic Science Research Program through National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A1A2A16050554).
Conflicts of interest
- 1.Beaugerie L, Svrcek M, Seksik P, Bouvier AM, Simon T, Allez M, et al. Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease. Gastroenterology. 2013;145(1):166–75. doi: 10.1053/j.gastro.2013.03.044.CrossRefPubMedGoogle Scholar
- 19.Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A. 2007;104(3):973–8. doi: 10.1073/pnas.0610117104.CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Horikawa T, Yang J, Kondo S, Yoshizaki T, Joab I, Furukawa M, et al. Twist and epithelial-mesenchymal transition are induced by the EBV oncoprotein latent membrane protein 1 and are associated with metastatic nasopharyngeal carcinoma. Cancer Res. 2007;67(5):1970–8. doi: 10.1158/0008-5472.CAN-06-3933.CrossRefPubMedGoogle Scholar
- 36.Yin Y, Grabowska AM, Clarke PA, Whelband E, Robinson K, Argent RH, et al. Helicobacter pylori potentiates epithelial:mesenchymal transition in gastric cancer: links to soluble HB-EGF, gastrin and matrix metalloproteinase-7. Gut. 2010;59(8):1037–45. doi: 10.1136/gut.2009.199794.CrossRefPubMedPubMedCentralGoogle Scholar
- 41.Kong QL, Hu LJ, Cao JY, Huang YJ, Xu LH, Liang Y, et al. Epstein-Barr virus-encoded LMP2A induces an epithelial-mesenchymal transition and increases the number of side population stem-like cancer cells in nasopharyngeal carcinoma. PLoS Pathog. 2010;6(6), e1000940. doi: 10.1371/journal.ppat.1000940.CrossRefPubMedPubMedCentralGoogle Scholar