Abstract
Aberrant expression of long non-coding RNAs (lncRNAs) has been regarded as a critical component in bladder cancer (BC) and lncRNAs have been associated with BC development and progression although their overall expression and functional significance is still unclear. The aim of our study was to identify novel lncRNAs with a functional role in BC carcinogenesis. RNA-sequencing was used to identify aberrantly expressed lncRNAs in 8 normal and 72 BC samples. We identified 89 lncRNAs that were significantly dys-regulated in BC. Five lncRNAs; LINC00958, LINC01296, LINC00355, LNC-CMC1-1 and LNC-ALX1-2 were selected for further analyses. Silencing of LINC00958 or LINC01296 in vitro reduced both cell viability and migration. Knock-down of LINC00958 also affected invasion and resistance to anoikis. These cellular effects could be linked to direct/indirect regulation of protein coding mRNAs involved in cell death/survival, proliferation and cellular movement. Finally, we showed that LINC00958 binds proteins involved in regulation and initiation of translation and in post-transcriptional modification of RNA, including Metadherin, which has previously been associated with BC. Our analyses identified novel lncRNAs in BC that likely act as oncogenic drivers contributing to an aggressive cancerous phenotype likely through interaction with proteins involved in initiation of translation and/or post-transcriptional modification of RNA.
Highlights
The human genome contains ~20,000 protein coding genes, covering less than 2% of the total genome sequence[1]
Using CuffDiff[232] we identified 89 significantly dysregulated lincRNAs in Bladder cancer (BC) when compared to normal bladder tissue (p < 0.01; multiple testing correction; Fig. 1b,c)
We focused our attention on lincRNAs up-regulated in BC and selected five of the most differentially expressed for detailed functional characterization (Fig. 1c, d)
Summary
The human genome contains ~20,000 protein coding genes, covering less than 2% of the total genome sequence[1]. It has recently become clear that more than 80% of the genome is actively transcribed and the vast majority of the transcribed genes are non-protein coding[2]. H19, was found to be up-regulated in two independent BC patient cohorts, and increased expression levels were significantly correlated with either high risk of early tumor recurrence or risk of metastasis[18, 19]. Using loss of function studies we showed that LINC00958 and LINC01296 exhibit oncogenic functions in BC cell lines by regulating mRNAs associated with pathways related to cell death/ survival and cellular movement. RNA pull-down and RNA immunoprecipitation (RIP) showed that LINC00958 interacts with proteins related to regulation and initiation of translation and/or post-transcriptional modification of RNA, consistent with potential oncogenic functions in BC
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