miRNA-1246 induces pro-inflammatory responses in mesenchymal stem/stromal cells by regulating PKA and PP2A.
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.
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Alexander
A
Bott
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Nese
N
Erdem
Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel.
Shalom
S
Lerrer
Bioinformatics Group, Genomics & Proteomics Core Facility (GPCF), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Agnes
A
Hotz-Wagenblatt
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Christian
C
Breunig
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Khalid
K
Abnaof
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Angelika
A
Wörner
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Heike
H
Wilhelm
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ewald
E
Münstermann
Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel.
Adit
A
Ben-Baruch
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Stefan
S
Wiemann
D020413:3' Untranslated Regions; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020413:3' Untranslated Regions; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C577700:MIRN1246 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C517834:PRKAR1A protein, human; D014409:Tumor Necrosis Factor-alpha; D017868:Cyclic AMP-Dependent Protein Kinases; C517190:PPP2CB protein, human; D054648:Protein Phosphatase 2
NF-kappaB signaling; breast cancer; mesenchymal stem/stromal cell; microRNA; tumor microenvironment