Abstract 143: CD24 induced miR-21 regulation is mainly mediated through Src, and both (CD24, Src) are post-transcriptionally downregulated by miR-34a

Abstract

Abstract Cancer is a complex disease and multi step process evolving from malfunctions of complex molecules and their networks which regulate this process. Understanding these networks will be essential to combat cancer. In this study, we focussed on key players in such networks. CD24, Src and miR-21 have been described as adverse prognostic markers in a panel of malignancies. CD24 interacts and co-localizes with Src in lipid rafts. Pdcd4 and miR-34a have been described as tumor suppressor genes which are down regulated in different tumor types. In a series of colon and breast cancer cell lines, we found that CD24 activates Src and inducing the activation of c-Jun and expression of c-Jun and c-Fos. Furthermore, we show here that it regulates the promoter activity of miR-21 and its expression, which leads to inhibition of miR-21 targeted tumor suppressor genes. Similar results were found for constitutively active src. Co-transfection of a CD24 expression construct and an si-RNA silencing of Src showed that CD24 mediated upregulation of miR-21 is mediated through Src. Taken together, our results suggest that CD24 expression upregulates miR-21 in a Src dependent manner. Furthermore, we found that miR-34a targets the CD24- and Src-3′UTR as shown by luciferase assays performed either with wild type or mutated miR-34a seed sequences within these 3′UTRs. MiR-34a post-transcriptional inhibition of CD24 and Src downregulated the activation of c-Jun and expression of c-Jun and c-Fos, inhibited miR-21 promoter activity and expression, and induced the expression of tumor suppressor genes Pdcd4 and PTEN significantly (p=0.05). Furthermore, miR-34a inhibited Src induced colony formation, migration and invasion. Our results revealed complex networking between essential players in the progression of solid tumors especially colorectal cancer. These findings could help to focus new therapeutic approaches to overcome this and further solid cancer entities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 143. doi:1538-7445.AM2012-143