Several long non-coding RNAs (lncRNAs) have been identified to play key, rate-limiting roles in malignancies, and the mechanisms involved are now being elucidated. This study addressed the roles of NEAT1 and MIAT lncRNAs, in breast cancer. The short isoform NEAT1 _1 was found to be significantly up-regulated in advanced stages of breast cancer samples and in the ER/PR +ve and HER –ve molecular subtype, where its expression correlated positively with that of its neighbouring gene, MALAT1. NEAT1 transcripts in breast cancer cell lines were detected in both nuclear and cytoplasmic compartments. Silencing of cytoplasmic NEAT1 led to an increase in the expression of nuclear NEAT1, where such overexpression inhibited apoptosis and increased cell survival. Consistent with this, siRNA and ASO mediated knockdown of NEAT1 transcript levels decreased cell survival and migration and promoted cell death induced by different apoptotic stimuli including chemotherapeutic agents and UV-C irradiation. Reduced NEAT1 expression levels were also associated with changes in the expression of genes involved in the regulation of cell proliferation and survival. More importantly, it was found that NEAT1_1 regulates gene expression in cis and trans. MIAT expression levels were significantly increased in triple negative breast cancer samples and its expression correlated with NEAT1 expression. In breast cancer cell lines, MIAT expression was found to correlate with the expression of the transcription factor Oct4. MIAT down-regulation in breast cancer cells enhanced the basal apoptosis level and inhibited short and long-term survival. Induction of cell death by UV-C irradiation and chemotherapeutic drugs was also augmented in cells transfected with MIAT specific siRNA. Taken together, the outcome of this study reveals important roles for NEAT1 and MIAT lncRNAs in breast cancer. Future work should explore the potential of these lncRNAs in the development of therapeutic drugs and as diagnostic and prognostic markers.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:739437 |
| Date | January 2018 |
| Creators | Al-Mnaseer, Zainab Ahmed Mustafa |
| Publisher | Keele University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.keele.ac.uk/4541/ |
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