title: CD24 induces expression of the oncomir miR-21 via Src, and CD24 and Src are both post-transcriptionally downregulated by the tumor suppressor miR-34a.
abstract: Cancer is a complex disease process that evolves as a consequence of multiple malfunctions in key regulatory molecular networks. Understanding these networks will be essential to combat cancer. In this study, we focussed on central players in such networks. In a series of colon and breast cancer cell lines, we found that CD24 activates Src, and induces the activation of c-Jun and expression of c-Jun and c-Fos. Thereby CD24 increases the promoter activity and expression of miR-21, which in turn suppresses expression of Pdcd4 and PTEN. Co-transfection of a CD24 expression construct and an siRNA that silences Src showed that CD24-dependent upregulation of miR-21 is mediated by Src. Additionally, we found that miR-34a post-transcriptionally downregulates CD24 and Src expression, leading to the deactivation of c-Jun, reduced expression of c-Jun and c-Fos, inhibition of miR-21, and upregulation of Pdcd4 and PTEN. Furthermore, miR-34a-mediated inhibition of Src expression reduced migration and invasion of colorectal cancer cells. Resected tumor tissues from 26 colorectal patients showed significantly lower expression of Pdcd4 and miR-34a, and higher expression of CD24, Src and miR-21 compared to the corresponding normal tissues. Moreover, CD24 positively correlated with the amount of Src protein in tumor tissues, and a trend towards an inverse correlation between miR-34a and Src protein levels was also observed. Our results reveal essential players in the complex networks that regulate the progression of solid tumors such as colorectal cancer. These findings therefore identify novel therapeutic approaches for combating tumor growth and progression.
authors.affiliation: Department of Experimental Surgery, University of Heidelberg, Mannheim and Molecular Oncology of Solid Tumors, DKFZ, Heidelberg, Germany.
authors.forename: Santoshi
authors.initials: S
authors.lastname: Muppala
authors.forename: Giridhar
authors.initials: G
authors.lastname: Mudduluru
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Leupold
authors.forename: Daniel
authors.initials: D
authors.lastname: Buergy
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Sleeman
authors.forename: Heike
authors.initials: H
authors.lastname: Allgayer
mesh_terms: D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*
chemical_list: D051927:CD24 Antigen; C524940:MIRN21 microRNA, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016392:Proto-Oncogene Proteins pp60(c-src)