title: Porphyromonas gingivalis promotes invasion of oral squamous cell carcinoma through induction of proMMP9 and its activation.
abstract: Recent epidemiological studies have revealed a significant association between periodontitis and oral squamous cell carcinoma (OSCC). Furthermore, matrix metalloproteinase 9 (MMP9) is implicated in the invasion and metastasis of tumour cells. We examined the involvement of Porphyromonas gingivalis, a periodontal pathogen, in OSCC invasion through induced expression of proMMP and its activation. proMMP9 was continuously secreted from carcinoma SAS cells, while P. gingivalis infection increased proenzyme expression and subsequently processed it to active MMP9 in culture supernatant, which enhanced cellular invasion. In contrast, Fusobacterium nucleatum, another periodontal organism, failed to demonstrate such activities. The effects of P. gingivalis were observed with highly invasive cells, but not with the low invasivetype. P. gingivalis also stimulated proteinase-activated receptor 2 (PAR2) and enhanced proMMP9 expression, which promoted cellular invasion. P. gingivalis mutants deficient in gingipain proteases failed to activate MMP9. Infected SAS cells exhibited activation of ERK1/2, p38, and NF-kB, and their inhibitors diminished both proMMP9-overexpression and cellular invasion. Together, our results show that P. gingivalis activates the ERK1/2-Ets1, p38/HSP27, and PAR2/NF-kB pathways to induce proMMP9 expression, after which the proenzyme is activated by gingipains to promote cellular invasion of OSCC cell lines. These findings suggest a novel mechanism of progression and metastasis of OSCC associated with periodontitis.
authors.affiliation: Department of Oral Frontier Biology, Center for Frontier Oral Science, Osaka University Graduate School of Dentistry, Suita, Osaka, 565-0871, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Inaba
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sugita
authors.forename: Masae
authors.initials: M
authors.lastname: Kuboniwa
authors.forename: Soichi
authors.initials: S
authors.lastname: Iwai
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hamada
authors.forename: Takeshi
authors.initials: T
authors.lastname: Noda
authors.forename: Ichijiro
authors.initials: I
authors.lastname: Morisaki
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lamont
authors.forename: Atsuo
authors.initials: A
authors.lastname: Amano
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000382:microbiology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D016967:Fusobacterium nucleatum / Q000254:growth & development; D015870:Gene Expression; D054884:Host-Pathogen Interactions; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000382:microbiology*; D016966:Porphyromonas gingivalis / Q000254:growth & development*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D020780:Matrix Metalloproteinase 9