Journal
EXPERIMENTAL CELL RESEARCH
Volume 319, Issue 13, Pages 2081-2090Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2013.05.009
Keywords
Colon cancer; S100P; RAGE; miR-155; AP-1; miR-155 sponge
Categories
Funding
- Cancer Biology Training grant [T32 CA09213]
- SPORE Developmental Research Program (Pilot Grant) [P50 CA 95060]
- More Graduate Education at Mountain States Alliance (MGE@MSA) Alliance for Graduate Education and the Professoriate (AGEP) National Science Foundation (NSF) [HRD-0450137]
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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. (C) 2013 Elsevier Inc. All rights reserved.
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