Abstract 1806: AP-1 transcriptionally regulates expression of miR-155 in colon cancer cells.

Accumulating evidence indicates 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 overwhelming evidences, 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. Both S100P and miR-155 expressions are up-regulated in colon tumor specimens. Ectopic S100P expression leads to elevation of miR-155 level. Conversely, knockdown of S100P results in a decrease in miR-155 levels. Exogenous S100P induces miR-155 expression, but blockage of the RAGE receptor with anti-RAGE antibody suppresses the induction of miR-155 by exogenous S100P. Attenuation Blockage of AP-1 activation by S100P, through pharmacological inhibition of MEK activation or genetic inhibition of c-Jun activation using dominant negative c-Jun (TAM67) suppresses miR-155 induction by exogenous S100P. Exogenous S100P treatment stimulates the enrichment of c-Fos, an AP-1 family member at the miR-155 promoter site. Finally, functional study shows that miR-155 knockdown decreases colon cancer cell cell cell growtholon formation and motilityotility in S100P stably transfected cells and parental cells. Taken together, these data demonstrate that the expression of miR-155 is regulated by S100P is dependent on RAGE activation and stimulation of AP-1. Furthermore, the results show that miR-155 is a downstream target of S100P/RAGE signaling and a critical player in S100P functions in colon cancer cells. Citation Format: Benjamin C. Onyeagucha, Melania Mercado-Pimentel, Erik Flemington, Mark A. Nelson. AP-1 transcriptionally regulates expression of miR-155 in colon cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1806. doi:10.1158/1538-7445.AM2013-1806