title: S100P/RAGE signaling regulates microRNA-155 expression via AP-1 activation in colon cancer.
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.
authors.affiliation: Department of Cancer Biology Graduate Interdisciplinary Program, The University of Arizona, Tucson, AZ, United States; Department of Pathology, The University of Arizona, Tucson, AZ, United States.
authors.forename: Benjamin Chidi
authors.initials: BC
authors.lastname: Onyeagucha
authors.affiliation: Department of Pathology, The University of Arizona, Tucson, AZ, United States; Arizona Cancer Center, The University of Arizona, Tucson, AZ, United States.
authors.forename: Melania E
authors.initials: ME
authors.lastname: Mercado-Pimentel
authors.affiliation: Department of Pathology, The University of Arizona, Tucson, AZ, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hutchison
authors.affiliation: Louisiana Cancer Research Consortium, New Orleans, LA, United States; Tulane Cancer Center and Department of Pathology Tulane University, New Orleans, LA, United States.
authors.forename: Erik K
authors.initials: EK
authors.lastname: Flemington
authors.affiliation: Department of Cancer Biology Graduate Interdisciplinary Program, The University of Arizona, Tucson, AZ, United States; Department of Pathology, The University of Arizona, Tucson, AZ, United States; Arizona Cancer Center, The University of Arizona, Tucson, AZ, United States. Electronic address: mnelson@pathology.arizona.edu.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Nelson
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D002135:Calcium-Binding Proteins; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C103003:S100P protein, human; D018808:Transcription Factor AP-1
keywords: AP-1; Colon cancer; RAGE; S100P; miR-155; miR-155 sponge