Joonas H Kauppila1,2,3,4, Johanna Korvala3,5, Kristiina Siirilä5, Marika Manni1, Laura K Mäkinen6,7, Jaana Hagström8,9, Timo Atula6,7, Caj Haglund10, Katri S Selander11, Juha Saarnio2,3,4, Tuomo J Karttunen1,3,4, Petri P Lehenkari2,3,4,12, Tuula Salo3,4,5,8. 1. Department of Pathology, University of Oulu, Oulu, Finland. 2. Department of Surgery, University of Oulu, Oulu, Finland. 3. Medical Research Center Oulu, Oulu, Finland. 4. Oulu University Hospital, Oulu, Finland. 5. Department of Dentistry, University of Oulu, Oulu, Finland. 6. Department of Otorhinolaryngology and Head and Neck Surgery, University of Helsinki, Helsinki, Finland. 7. Department of Otorhinolaryngology and Head and Neck Surgery, Helsinki University Hospital, Helsinki, Finland. 8. Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland. 9. Huslab, Helsinki, Finland. 10. Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland. 11. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. 12. Anatomy and Cell biology, University of Oulu, Oulu, Finland.
Abstract
BACKGROUND: Toll-like receptor 9 (TLR9) is a cellular receptor, which recognizes bacterial and host-derived DNA. Stimulation of TLR9 induces cellular invasion via matrix metalloproteinase 13 (MMP-13). The aim of this study was to evaluate the role of TLR9 in invasion of oral tongue squamous cell carcinoma (OTSCC). METHODS: The effects of TLR9 ligands on oral squamous cell carcinoma cell lines were studied with invasion and migration assays, as well as in a myoma organotypic model. RESULTS: The TLR9 ligand, CpG-ODN, increased invasion and migration in OTSCC lines. These effects were reduced by TLR9 siRNA or inhibition with TLR9 antibodies. Immunohistochemical analysis of tissues from 195 patients with OTSCC revealed that TLR9 was expressed in 181/195 carcinomas. The expression of TLR9 was higher in the malignant cells than in the normal epithelium. High TLR9 expression was associated with high MMP-13 expression and poor differentiation. High TLR9 expression was also identified as an independent predictor of poor prognosis (HR 1.810, 95% CI [1.053-3.112]). CONCLUSION: Toll-like receptor 9 mediates OTSCC invasion and migration in vitro and is an independent prognostic factor of OTSCC. Inhibition of TLR9 may be a novel therapeutic opportunity in oral cancer.
BACKGROUND:Toll-like receptor 9 (TLR9) is a cellular receptor, which recognizes bacterial and host-derived DNA. Stimulation of TLR9 induces cellular invasion via matrix metalloproteinase 13 (MMP-13). The aim of this study was to evaluate the role of TLR9 in invasion of oral tongue squamous cell carcinoma (OTSCC). METHODS: The effects of TLR9 ligands on oral squamous cell carcinoma cell lines were studied with invasion and migration assays, as well as in a myoma organotypic model. RESULTS: The TLR9 ligand, CpG-ODN, increased invasion and migration in OTSCC lines. These effects were reduced by TLR9 siRNA or inhibition with TLR9 antibodies. Immunohistochemical analysis of tissues from 195 patients with OTSCC revealed that TLR9 was expressed in 181/195 carcinomas. The expression of TLR9 was higher in the malignant cells than in the normal epithelium. High TLR9 expression was associated with high MMP-13 expression and poor differentiation. High TLR9 expression was also identified as an independent predictor of poor prognosis (HR 1.810, 95% CI [1.053-3.112]). CONCLUSION:Toll-like receptor 9 mediates OTSCC invasion and migration in vitro and is an independent prognostic factor of OTSCC. Inhibition of TLR9 may be a novel therapeutic opportunity in oral cancer.
Authors: Joni Leppänen; Olli Helminen; Heikki Huhta; Joonas H Kauppila; Joel Isohookana; Kirsi-Maria Haapasaari; Petri Lehenkari; Juha Saarnio; Tuomo J Karttunen Journal: Virchows Arch Date: 2017-02-12 Impact factor: 4.064