title: Apple- and Hop-Polyphenols Inhibit Porphyromonas gingivalis-Mediated Precursor of Matrix Metalloproteinase-9 Activation and Invasion of Oral Squamous Cell Carcinoma Cells.
abstract: Recent epidemiologic studies have revealed a significant association between periodontitis and oral squamous cell carcinoma (OSCC). Furthermore, periodontitis is markedly associated with orodigestive cancer mortality, whereas Porphyromonas gingivalis (Pg) infection has been identified as a specific and potentially independent microbial factor related to increased risk of orodigestive cancer death. The authors previously reported that Pg induced the precursor form of matrix metalloproteinase-9 (proMMP-9) production via proteinase-activated receptor (PAR)-related pathways, after which proMMP-9 was activated by gingipains to enhance cellular invasion of SAS cells. In the present study, effects of selected polyphenols as inhibitors of cellular invasion caused by Pg gingipains in SAS cells are examined.
  
  
  
  OSCC cells were infected with Pg strains including gingipain mutants. To evaluate effects of inhibitors: 1) apple polyphenol (AP); 2) hop bract polyphenol (HBP); 3) high-molecular-weight fractions of HBP (HMW-HBP); 4) low-molecular-weight fractions of HBP (LMW-HBP); 5) epigallocatechin gallate (EGCg); 6) KYT-1 (Arg-gingipain inhibitor); and KYT-36 (Lys-gingipain inhibitor) in combination are used. PAR2 and PAR4 mRNA expressions are examined using real-time reverse transcription polymerase chain reaction, and signaling pathways are evaluated by western blotting analysis.
  
  
  
  KYT-1/KYT-36, AP, HBP, and HMW-HBP significantly inhibited PAR2 and PAR4 mRNA expressions, proMMP-9 activation, and cellular invasion. Furthermore, AP, HBP, and HMW-HBP reduced activation of heat shock protein 27 and Ets1 and nuclear translocation of nuclear factor-kappa B, whereas EGCg and LMW-HBP did not.
  
  
  
  These results suggest that AP, HBP, HMW-HBP are potent inhibitors of proMMP-9 activation and cellular invasion mediated with Pg in OSCC cells.
authors.affiliation: Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Inaba
authors.affiliation: Research and Development-Production Headquarters, Asahi Breweries Limited, Ibaraki, Japan.
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Tagashira
authors.affiliation: Research and Development-Production Headquarters, Asahi Breweries Limited, Ibaraki, Japan.
authors.forename: Tomomasa
authors.initials: T
authors.lastname: Kanda
authors.affiliation: Department of Oral Microbiology, Asahi University School of Dentistry, Hozumi, Gifu, Japan.
authors.forename: Yukitaka
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Department of Preventive Dentistry, Osaka University Graduate School of Dentistry, Suita-Osaka, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Amano
authors.affiliation: Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Matsumoto-Nakano
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D006801:Humans; D027845:Malus / Q000737:chemistry*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009062:Mouth Neoplasms / Q000188:drug therapy*; D059808:Polyphenols; D016966:Porphyromonas gingivalis / Q000737:chemistry*
chemical_list: D059808:Polyphenols; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Carcinoma; Porphyromonas gingivalis; cell biology; matrix metalloproteinases; microbiology; polyphenols