Abstract:
There is compelling evidence that senescent cells, through the
senescence-associated secretory phenotype (SASP), can promote
malignant transformation and invasion. Interleukin-1 (IL-1) is a key
mediator of this cytokine network, but the control of its activity in the
senescence programme has not been elucidated. IL-1 signalling is
regulated by IL-1RA, which has four variants. Here, we show that
expression of intracellular IL-1RA type 1 (icIL-1RA1), which
competitively inhibits binding of IL-1 to its receptor, is progressively
lost during oral carcinogenesis ex vivo and that the pattern of
expression is associated with keratinocyte replicative fate in vitro. We
demonstrate that icIL-1RA1 is an important regulator of the SASP in
mortal cells, as CRISPR/Cas9-mediated icIL-1RA1 knockdown in
normal and mortal dysplastic oral keratinocytes is followed by
increased IL-6 and IL-8 secretion, and rapid senescence following
release from RhoA-activated kinase inhibition. Thus, we suggest that
downregulation of icIL-1RA1 in early stages of the carcinogenesis
process can enable the development of a premature and deregulated
SASP, creating a pro-inflammatory state in which cancer is more likely
to arise.
