title: A miR-335/COX-2/PTEN axis regulates the secretory phenotype of senescent cancer-associated fibroblasts.
abstract: Senescent cancer-associated fibroblasts (CAF) develop a senescence-associated secretory phenotype (SASP) that is believed to contribute to cancer progression. The mechanisms underlying SASP development are, however, poorly understood. Here we examined the functional role of microRNA in the development of the SASP in normal fibroblasts and CAF. We identified a microRNA, miR-335, up-regulated in the senescent normal fibroblasts and CAF and able to modulate the secretion of SASP factors and induce cancer cell motility in co-cultures, at least in part by suppressing the expression of phosphatase and tensin homologue (PTEN). Additionally, elevated levels of cyclo-oxygenase 2 (PTGS2; COX-2) and prostaglandin E2 (PGE2) secretion were observed in senescent fibroblasts, and inhibition of COX-2 by celecoxib reduced the expression of miR-335, restored PTEN expression and decreased the pro-tumourigenic effects of the SASP. Collectively these data demonstrate the existence of a novel miRNA/PTEN-regulated pathway modulating the inflammasome in senescent fibroblasts.
authors.affiliation: Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, S10 2TA, UK.|Department of Surgical Sciences, Dunedin Medical School, Dunedin, University of Otago, Dunedin Hospital, Dunedin 9016, New Zealand.
authors.forename: Tasnuva D
authors.initials: TD
authors.lastname: Kabir
authors.affiliation: Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, S10 2TA, UK.
authors.forename: Ross J
authors.initials: RJ
authors.lastname: Leigh
authors.affiliation: Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, S10 2TA, UK.
authors.forename: Hataitip
authors.initials: H
authors.lastname: Tasena
authors.affiliation: Faculty of Medicine Cancer Sciences Unit, Southampton University, Somers Building, Southampton SO16 6YD, UK.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mellone
authors.affiliation: Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil.
authors.forename: Ricardo D
authors.initials: RD
authors.lastname: Coletta
authors.affiliation: Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, UK.
authors.forename: Eric K
authors.initials: EK
authors.lastname: Parkinson
authors.affiliation: Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, UK.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Prime
authors.affiliation: Faculty of Medicine Cancer Sciences Unit, Southampton University, Somers Building, Southampton SO16 6YD, UK.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Thomas
authors.affiliation: Department of Oral and Craniofacial Sciences, and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, Malaya, Malaysia.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Paterson
authors.affiliation: Department of Biochemistry, School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
authors.forename: Donghui
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Surgical Sciences, Dunedin Medical School, Dunedin, University of Otago, Dunedin Hospital, Dunedin 9016, New Zealand.
authors.forename: John
authors.initials: J
authors.lastname: McCall
authors.affiliation: Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, S10 2TA, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Speight
authors.affiliation: Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, S10 2TA, UK.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lambert
mesh_terms: D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D000068579:Celecoxib / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology*; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C556347:MIRN335 microRNA, human; D035683:MicroRNAs; D051546:Cyclooxygenase 2; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000068579:Celecoxib; D015232:Dinoprostone
keywords: CAF; COX-2; PTEN; SASP; fibroblast; miR-335