Spliceosome-Associated MicroRNAs Identified in Breast Cancer Cells Act on Nuclear Targets and Are Potential Indicators for Tumorigenicity

Abstract

MicroRNAs (miRNAs) act as negative regulators of gene expression in the cytoplasm. Previous studies identified miRNAs associated with the spliceosome. Here we study three breast-derived cell-lines with increased tumorigenicity (from MCF-10A to MCF-7 and MDA-MB-231) and compared their miRNA sequences at the spliceosome fraction (SF). We report that the SF-miRNAs expression, identity, and pre-miRNA segmental composition vary across these cell-lines. The expression of the majority of the abundant SF-miRNAs (e.g. miR-100, miR-30a, and let-7 members) shows an opposite trend in view of the literature and breast cancer large cohorts. The results suggest that SF-miRNAs act in the nucleus on alternative targets than in the cytoplasm. One such miRNA is miR-7704 whose genomic position overlaps HAGLR, a cancer-related lncRNA. We found an inverse expression of miR-7704 and HAGLR in the tested cell lines. Moreover, inhibition of miR-7704 caused an increase in HAGLR expression. Furthermore, increasing miR-7704 levels attenuated the MDA-MB-231 cell-division rate. While miR-7704 acts as oncomiR in breast cancer patients, it has a tumor-suppressing function in SF, with HAGLR being its nuclear target. Manipulating miR-7704 levels is a potential lead for altering tumorigenicity. Altogether, we report on the potential of manipulating SF-miRNAs as an unexplored route for breast cancer therapeutics.