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Human microRNA similarity in breast cancer.

ABSTRACT: MicroRNAs (miRNAs) play important roles in a variety of human diseases, including breast cancer. A number of miRNAs are up- and down-regulated in breast cancer. However, little is known about miRNA similarity and similarity network in breast cancer. Here, a collection of 272 breast cancer-associated miRNA precursors were utilized to calculate similarities of sequences, target genes, pathways and functions and construct a combined similarity network. Well-characterized miRNAs and their similarity network were highlighted. Interestingly, miRNA sequence-dependent similarity networks were not identified in spite of sequence-target gene association. Similarity networks with minimum and maximum number of miRNAs originate from pathway and mature sequence, respectively. The breast cancer-associated miRNAs were divided into 7 functional classes (classes I-VII) followed by disease enrichment analysis and novel miRNA-based disease similarities were found. The finding would provide insight into miRNA similarity, similarity network and disease heterogeneity in breast cancer.

SUBMITTER: Jing Y

PROVIDER: S-EPMC8529337 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RNA editing by RNA specific adenosine deaminase acting on RNA (ADAR) is increasingly being found to alter microRNA (miRNA) regulation. Editing of miRNA transcripts can affect their processing, as well as which messenger RNAs (mRNAs) they target. Further, editing of target mRNAs can also affect their complementarity to miRNAs. Notably, ADAR editing is often increased in malignancy with the effect of these RNA changes being largely unclear. In addition, numerous reports have now identified an array of miRNAs that directly contribute to various malignancies although the majority of their targets remain largely undefined. Here we propose that modulating the targets of miRNAs via mRNA editing is a frequent occurrence in cancer and an underappreciated participant in pathology. In order to more accurately characterize the relationship between these two regulatory processes, this study examined RNA editing events within mRNA sequences of two breast cancer cell lines (MCF-7 and MDA-MB-231) and determined whether or not these edits could modulate miRNA associations. Computational analyses of RNA-Seq data from these two cell lines identified over 50,000 recurrent editing sites within human mRNAs, and many of these were located in 3' untranslated regions (UTRs). When these locations were screened against the list of currently-annotated miRNAs we discovered that editing caused a subset (~9%) to have significant alterations to mRNA complementarity. One miRNA in particular, miR-140-3p, is known to be misexpressed in many breast cancers, and we found that mRNA editing allowed this miRNA to directly target the apoptosis inducing gene DFFA in MCF-7, but not in MDA-MB-231 cells. As these two cell lines are known to have distinct characteristics in terms of morphology, invasiveness and physiological responses, we hypothesized that the differential RNA editing of DFFA in these two cell lines could contribute to their phenotypic differences. Indeed, we confirmed through western blotting that inhibiting miR-140-3p increases expression of the DFFA protein product in MCF-7, but not MDA-MB-231, and further that inhibition of miR-140-3p also increases cellular growth in MCF-7, but not MDA-MB-231. Broadly, these results suggest that the creation of miRNA targets may be an underappreciated function of ADAR and may help further elucidate the role of RNA editing in tumor pathogenicity.

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Human microRNA similarity in breast cancer.

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