title: Prolonged and repetitive exposure to Porphyromonas gingivalis increases aggressiveness of oral cancer cells by promoting acquisition of cancer stem cell properties.
abstract: 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.
authors.affiliation: Department of Oral Pathology, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan-Si, Kyeongsangnam-Do, 626-870, South Korea.
authors.forename: Na Hee
authors.initials: NH
authors.lastname: Ha
authors.affiliation: Department of Oral Pathology, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan-Si, Kyeongsangnam-Do, 626-870, South Korea.
authors.forename: Bok Hee
authors.initials: BH
authors.lastname: Woo
authors.affiliation: Department of Oral Pathology, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan-Si, Kyeongsangnam-Do, 626-870, South Korea.
authors.forename: Da Jeong
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Department of Oral Pathology, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan-Si, Kyeongsangnam-Do, 626-870, South Korea.
authors.forename: Eun Sin
authors.initials: ES
authors.lastname: Ha
authors.affiliation: Department of Periodontology, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan, 626-870, South Korea.
authors.forename: Jeom Il
authors.initials: JI
authors.lastname: Choi
authors.affiliation: Department of Periodontology, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan, 626-870, South Korea.
authors.forename: Sung Jo
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Oral Anatomy, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan, 626-870, South Korea.
authors.forename: Bong Soo
authors.initials: BS
authors.lastname: Park
authors.affiliation: Department of Oral Pathology, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan-Si, Kyeongsangnam-Do, 626-870, South Korea.|Institute of Translational Dental Sciences, Pusan National University, 49 Busandaehak-Ro, Yangsan, 626-870, South Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Oral Pathology, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan-Si, Kyeongsangnam-Do, 626-870, South Korea. parkhr@pusan.ac.kr.|Institute of Translational Dental Sciences, Pusan National University, 49 Busandaehak-Ro, Yangsan, 626-870, South Korea. parkhr@pusan.ac.kr.
authors.forename: Hae Ryoun
authors.initials: HR
authors.lastname: Park
mesh_terms: D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D009062:Mouth Neoplasms / Q000150:complications / Q000382:microbiology / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000382:microbiology / Q000473:pathology*; D010518:Periodontitis / Q000150:complications / Q000382:microbiology / Q000473:pathology*; D016966:Porphyromonas gingivalis / Q000472:pathogenicity*
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: Cancer stem cell; Interleukin-8; Invasion; Matrix metalloproteinase; Oral cancer; Porphyromonas gingivalis