miRNA-1246 induces pro-inflammatory responses in mesenchymal stem/stromal cells by regulating PKA and PP2A

// Alexander Bott 1 , Nese Erdem 1 , Shalom Lerrer 2 , Agnes Hotz-Wagenblatt 3 , Christian Breunig 1 , Khalid Abnaof 1 , Angelika Worner 1 , Heike Wilhelm 1 , Ewald Munstermann 1 , Adit Ben-Baruch 2 and Stefan Wiemann 1 1 Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany 2 Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel 3 Bioinformatics Group, Genomics & Proteomics Core Facility (GPCF), German Cancer Research Center (DKFZ), Heidelberg, Germany Correspondence to: Alexander Bott, email: alex.bott@gmx.de Stefan Wiemann, email: s.wiemann@dkfz.de Keywords: breast cancer, tumor microenvironment, mesenchymal stem/stromal cell, microRNA, NF-kappaB signaling Received: September 06, 2016     Accepted: December 26, 2016     Published: January 31, 2017 ABSTRACT The tumor microenvironment (TME) has an impact on breast cancer progression by creating a pro-inflammatory milieu within the tumor. However, little is known about the roles of miRNAs in cells of the TME during this process. We identified six putative oncomiRs in a breast cancer dataset, all strongly correlating with poor overall patient survival. Out of the six candidates, miR-1246 was upregulated in aggressive breast cancer subtypes and expressed at highest levels in mesenchymal stem/stroma cells (MSCs). Functionally, miR-1246 led to a p65-dependent increase in transcription and release of pro-inflammatory mediators IL-6, CCL2 and CCL5 in MSCs, and increased NF-κB activity. The pro-inflammatory phenotype of miR-1246 in MSCs was independent of TNFα stimulations and mediated by direct targeting of the tumor-suppressors PRKAR1A and PPP2CB. In vitro recapitulation of the TME revealed increased Stat3 phosphorylation in breast epithelial (MCF10A) and cancer cells (SK-BR-3, MCF7, T47D) upon incubation with conditioned medium (CM) of MSCs overexpressing miR-1246. Additionally, this stimulation enhanced proliferation of MCF10A cells, increased migration of MDA-MB-231 cells and induced attraction of THP-1 monocytic cells. Our data shows that miR-1246 acts as both key-enhancer of pro-inflammatory responses in MSCs and putative oncomiR in breast cancer, suggesting its influence on cancer-related inflammation and breast cancer progression.