期刊
ONCOTARGET
卷 8, 期 27, 页码 43897-43914出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.14915
关键词
breast cancer; tumor microenvironment; mesenchymal stem/stromal cell; microRNA; NF-kappaB signaling
资金
- Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ)
- Israel's Ministry of Science, Technology and Space (MOST) [Ca 153]
- German Federal Ministry of Education and Research [e: Med FKZ: 031A429]
- Baden-Wurttemberg Stiftung [BWST_NCRNA_035]
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-kappa B activity. The pro-inflammatory phenotype of miR-1246 in MSCs was independent of TNFa 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 keyenhancer 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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