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

• Published in: Experimental cell research 2013-08, Vol.319 (13), p.2081-2090
• Main Authors: Onyeagucha, Benjamin Chidi, Mercado-Pimentel, Melania E., Hutchison, Jennifer, Flemington, Erik K., Nelson, Mark A.
• Format: Article
• Language: English
• Subjects: AP-1; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Calcium-Binding Proteins - physiology; Cellular biology; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; HEK293 Cells; Humans; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miR-155; miR-155 sponge; Models, Biological; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasm Proteins - physiology; RAGE; Receptor for Advanced Glycation End Products; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Receptors, Immunologic - physiology; S100P; Signal transduction; Signal Transduction - genetics; Signal Transduction - physiology; Transcription Factor AP-1 - metabolism; Transcriptional Activation; Tumor Cells, Cultured
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2013.05.009

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. [Display omitted] •The S100P/RAGE receptor signaling pathway induces expression of the oncogenic miR-155.•The activator protein -1 (AP-1) complex is involved in the induction of miR-155 by S100P/RAGE receptor signaling.•Loss of miR-55 function by a miR-155 sponge decrease colon cancer cell growth, motility, and invasion in vitro.