miRNA-1246 induces pro-inflammatory responses in mesenchymal stem/stromal cells by regulating PKA and PP2A
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Alexander Bott1, Nese Erdem1, Shalom Lerrer2, Agnes Hotz-Wagenblatt3, Christian Breunig1, Khalid Abnaof1, Angelika Wörner1, Heike Wilhelm1, Ewald Münstermann1, Adit Ben-Baruch2 and Stefan Wiemann1
1Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
2Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel
3Bioinformatics Group, Genomics & Proteomics Core Facility (GPCF), German Cancer Research Center (DKFZ), Heidelberg, Germany
Alexander Bott, email: firstname.lastname@example.org
Stefan Wiemann, email: email@example.com
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
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.
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