S100P/RAGE signaling regulates microRNA-155 expression via AP-1 activation in colon cancer

BC Onyeagucha, ME Mercado-Pimentel… - Experimental cell …, 2013 - Elsevier
BC Onyeagucha, ME Mercado-Pimentel, J Hutchison, EK Flemington, MA Nelson
Experimental cell research, 2013Elsevier
Accumulating evidence indicates that elevated S100P promotes the pathogenesis of
cancers, including colon cancer. S100P exerts its effects by binding to and activating the
Receptor for Advance Glycation End-products (RAGE). The effects of up-regulated
S100P/RAGE signaling on cell functions are well documented. Despite these observations,
little is known about the downstream targets of S100P/RAGE signaling. In the present study,
we demonstrated for the first time that activation of RAGE by S100P regulates oncogenic …
Abstract
Accumulating evidence indicates that elevated S100P promotes the pathogenesis of cancers, including colon cancer. S100P exerts its effects by binding to and activating the Receptor for Advance Glycation End-products (RAGE). The effects of up-regulated S100P/RAGE signaling on cell functions are well documented. Despite these observations, little is known about the downstream targets of S100P/RAGE signaling. In the present study, we demonstrated for the first time that activation of RAGE by S100P regulates oncogenic microRNA-155 (miR-155) expression through Activator Protein-1 (AP-1) stimulation in colon cancer cells. Ectopic S100P up-regulated miR-155 levels in human colon cancer cells. Conversely, knockdown of S100P resulted in a decrease in miR-155 levels. Exogenous S100P induced miR-155 expression, but blockage of the RAGE with anti-RAGE antibody suppressed the induction of miR-155 by exogenous S100P. Attenuation of AP-1 activation through pharmacological inhibition of MEK activation or genetic inhibition of c-Jun activation using dominant negative c-Jun (TAM67) suppressed miR-155 induction by exogenous S100P. Also, S100P treatment stimulated the enrichment of c-Fos, an AP-1 family member, at the miR-155 host gene promoter site. Finally, a functional study demonstrated that miR-155 knockdown decreases colon cancer cell growth, motility, and invasion. Altogether, these data demonstrate that the expression of miR-155 is regulated by S100P and is dependent on RAGE activation and stimulation of AP-1.
Elsevier