title: Innate immune signaling through differential RIPK1 expression promote tumor progression in head and neck squamous cell carcinoma.
abstract: Head and neck squamous cell carcinoma (HNSCC) is a devastating disease for which new treatments, such as immunotherapy are needed. Synthetic double-stranded RNAs, which activate toll-like receptor 3 (TLR3), have been used as potent adjuvants in cancer immunotherapy by triggering a proapoptotic response in cancer cells. A better understanding of the mechanism of TLR3-mediated apoptosis and its potential involvement in controlling tumor metastasis could lead to improvements in current treatment. Using paired, autologous primary and metastatic HNSCC cells we previously showed that metastatic, but not primary tumor-derived cells, were unable to activate prosurvival NF-κB in response to p(I):p(C) resulting in an enhanced apoptotic response. Here, we show that transcriptional downregulation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in metastatic HNSCC cells causes a loss of TLR3-mediated NF-κB signaling, resulting in enhanced apoptosis. Loss of RIPK1 strongly correlates with metastatic disease in a cohort of HNSCC patients. This downregulation of RIPK1 is possibly mediated by enhanced methylation of the RIPK1 promoter in tumor cells and enhances protumorigenic properties such as cell migration. The results described here establish a novel mechanism of TLR3-mediated apoptosis in metastatic cells and may create new opportunities for using double stranded RNA to target metastatic tumor cells.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, Cancer Virology Program and.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: McCormick
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, Cancer Virology Program and.
authors.forename: Arundhati
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Sumita
authors.initials: S
authors.lastname: Trivedi
authors.affiliation: Department of Pathology.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, Cancer Virology Program and.
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Coyne
authors.affiliation: Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA, Department of Otolaryngology and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, Cancer Virology Program and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA saumen@pitt.edu.
authors.forename: Saumendra N
authors.initials: SN
authors.lastname: Sarkar
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015536:Down-Regulation; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012330:RNA, Double-Stranded / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D051196:Toll-Like Receptor 3 / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D012330:RNA, Double-Stranded; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases