Abstract
The long noncoding RNA myocardial infarction associated transcript (MIAT) is involved in a number of diseases, including myocardial infarction and diabetic retinopathy. Emerging evidence suggests that MIAT expression levels are increased in different type of cancers, including breast cancer. In the present study, we further evaluated the role of MIAT in breast cancer and investigated the consequences of its silencing on breast cancer response to chemotherapeutic agents. Expression levels of MIAT mRNA in breast cancer were determined using TissueScan™ Breast Cancer cDNA Arrays. Breast cancer cell lines were transfected with MIAT specific siRNAs, with silencing confirmed using RT-qPCR and the effects on breast cancer cell survival and response to different apoptotic stimuli determined. MIAT transcript levels were significantly elevated in breast cancer samples. Such increase was specific to the early stages of the disease, ER, PR +ve, HER –ve, and triple negative breast cancer samples. Silencing of MIAT induced growth arrest and increased basal apoptosis. Reduced levels of MIAT augmented the apoptotic response of breast cancer cells to a wide range of apoptotic stimuli. Our results also showed that MIAT down-regulation was associated with a decrease in OCT4 mRNA, suggesting the existence of a MIAT/OCT4 regulatory loop, similar to that observed in malignant mature B cells. Taken together with the recent demonstration of oncogene characteristics, our observations suggest that MIAT plays an important role in breast tumorigenesis. Strategies to decrease MIAT expression levels may improve sensitivity to therapy in breast cancer by enhancing the apoptotic responses to conventional chemotherapies.
Highlights
The term long noncoding RNA is regularly used to describe the class of RNA transcripts longer than 200 nucleotides, which do not encode a protein [1,2]
The results revealed that the overall mean of myocardial infarction associated transcript (MIAT) expression level was significantly higher in breast tumor compared with the mean of MIAT expression levels in normal breast tissue (Figure 1A)
To further confirm our observations that silencing MIAT is associated with an increase in apoptosis levels in breast cancer cells, we examine the influence of MIAT silencing on the cell survival of another triple negative breast cancer (TNBC) cell line Hs58T
Summary
The term long noncoding RNA (lncRNA) is regularly used to describe the class of RNA transcripts longer than 200 nucleotides, which do not encode a protein [1,2]. Similar to mRNAs, lncRNAs are RNA polymerase II transcripts, processed via capping at the 5 end, polyadenylated at the 3 end and spliced Their strong cell-type specific and temporal expression has confirmed their importance and several of these lncRNAs have been characterized to play key roles in the control of multiple biological processes, such as gene expression, epigenetic regulation, and chromatin remodeling [3,4]. Classes of lncRNAs include long intergenic ncRNAs, natural antisense transcripts to protein coding genes, pseudogene-derived transcripts, and intronic lncRNAs [5,6]. These transcripts are known to regulate gene expression, guide chromatin-modifying complexes to specific loci, and RNA splicing by acting as signals, scaffolds, guides, or decoys [7].
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