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A miR-335/COX-2/PTEN axis regulates the secretory phenotype of senescent cancer-associated fibroblasts

Kabir TD 1 , Leigh RJ 1 , Tasena H 1 , Mellone M 2 , Coletta RD 3 , Parkinson EK 4 Show all authors , Prime SS 4 , Thomas GJ 2 , Paterson IC 5 , Zhou D 6 , McCall J 7 , Speight PM 1 , Lambert DW 1

Affiliations 

  • 1 Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, S10 2TA, UK
  • 2 Faculty of Medicine Cancer Sciences Unit, Southampton University, Somers Building, Southampton SO16 6YD, UK
  • 3 Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil
  • 4 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
  • 5 Department of Oral and Craniofacial Sciences, and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, Malaya, Malaysia
  • 6 Department of Biochemistry, School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand
  • 7 Department of Surgical Sciences, Dunedin Medical School, Dunedin, University of Otago, Dunedin Hospital, Dunedin 9016, New Zealand
Aging (Albany NY), 2016 08;8(8):1608-35.
PMID: 27385366 DOI: 10.18632/aging.100987

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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