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

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 developme...

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Published inAging (Albany, NY.) Vol. 8; no. 8; pp. 1608 - 1635
Main Authors Kabir, Tasnuva D, Leigh, Ross J, Tasena, Hataitip, Mellone, Massimiliano, Coletta, Ricardo D, Parkinson, Eric K, Prime, Stephen S, Thomas, Gareth J, Paterson, Ian C, Zhou, Donghui, McCall, John, Speight, Paul M, Lambert, Daniel W
Format Journal Article
LanguageEnglish
Published United States Impact Journals LLC 01.08.2016
Subjects
Cancer-Associated Fibroblasts - drug effects
Cancer-Associated Fibroblasts - metabolism
Celecoxib - pharmacology
Cell Movement - drug effects
Cell Movement - physiology
Cellular Senescence - physiology
Coculture Techniques
Cyclooxygenase 2 - metabolism
Dinoprostone - metabolism
Humans
MicroRNAs - metabolism
Phenotype
PTEN Phosphohydrolase - metabolism
Research Paper
Signal Transduction - drug effects
Signal Transduction - physiology
Up-Regulation
PTEN
CAF
miR-335
fibroblast
COX-2
SASP
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Summary: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.
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ISSN:1945-4589
1945-4589
DOI:10.18632/aging.100987