Journal
AGING-US
Volume 8, Issue 8, Pages 1608-1635Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.100987
Keywords
miR-335; PTEN; fibroblast; CAF; SASP; COX-2
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Funding
- University of Sheffield
- Pathological Society London
- University of Otago-Dunedin
- Development and Promotion of Science and Technology Talents Project, The Royal Thai Government
- University of Malaya-MOHE High Impact Research grant [UM.C/625/1/HIR/MOHE/DENT/22]
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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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