Abstract
It is now appreciated that long non-coding RNAs (lncRNAs) are important players in orchestrating cancer progression. In this study we characterized GHSROS, a human lncRNA gene on the opposite DNA strand (antisense) to the ghrelin receptor gene, in prostate cancer. The lncRNA was upregulated by prostate tumors from different clinical datasets. Transcriptome data revealed that GHSROS alters the expression of cancer-associated genes. Functional analyses in vitro showed that GHSROS mediates tumor growth, migration and survival, and resistance to the cytotoxic drug docetaxel. Increased cellular proliferation of GHSROS-overexpressing PC3, DU145, and LNCaP prostate cancer cell lines in vitro was recapitulated in a subcutaneous xenograft model. Conversely, in vitro antisense oligonucleotide inhibition of the lncRNA reciprocally regulated cell growth and migration, and gene expression. Notably, GHSROS modulates the expression of PPP2R2C, the loss of which may drive androgen receptor pathway-independent prostate tumor progression in a subset of prostate cancers. Collectively, our findings suggest that GHSROS can reprogram prostate cancer cells toward a more aggressive phenotype and that this lncRNA may represent a potential therapeutic target.
Highlights
The human genome yields a multitude of RNA transcripts with no obvious protein-coding ability, collectively termed non-coding RNAs (Mattick & Rinn, 2015)
Interrogation of exon arrays harboring four different strand-specific probes against GHSROS demonstrated that the long non-coding RNAs (lncRNAs) is actively transcribed, expressed at low levels in cancer cell lines and tissues (Fig. S1), consistent with previous observations from Northern blotting and RT-PCR experiments (Whiteside et al, 2013)
To expand on these observations, we examined an independent cohort of eight normal prostate tissue specimens and 28 primary tumors with high Gleason scores (18 of which had metastases at biopsy)
Summary
The human genome yields a multitude of RNA transcripts with no obvious protein-coding ability, collectively termed non-coding RNAs (ncRNAs) (Mattick & Rinn, 2015). A decade of intensive research has revealed that many ncRNAs greater than 200 nucleotides in length have expression patterns and functions as diverse as protein-coding RNAs (Mattick & Rinn, 2015; Huarte, 2015). These long non-coding RNAs (lncRNAs) have emerged as important regulators of gene expression, acting on nearby (cis) or distant (trans) protein-coding genes (Huarte, 2015). We provide evidence that this lncRNA reprograms prostate cancer cells toward a more aggressive phenotype, possibly by repressing the expression of the tumor suppressor PPP2R2C to allow androgen-independent growth
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