Abstract
Metastatic prostate cancer (PCa) is still an incurable disease. Long non-coding RNAs (lncRNAs) may be an overlooked source of cancer biomarkers and therapeutic targets. We therefore performed RNA sequencing on paired metastatic/non-metastatic PCa xenografts derived from clinical specimens. The most highly up-regulated transcript was LOC728606, a lncRNA now designated PCAT18. PCAT18 is specifically expressed in the prostate compared to 11 other normal tissues (p<0.05) and up-regulated in PCa compared to 15 other neoplasms (p<0.001). Cancer-specific up-regulation of PCAT18 was confirmed on an independent dataset of PCa and benign prostatic hyperplasia samples (p<0.001). PCAT18 was detectable in plasma samples and increased incrementally from healthy individuals to those with localized and metastatic PCa (p<0.01). We identified a PCAT18-associated expression signature (PES), which is highly PCa-specific and activated in metastatic vs. primary PCa samples (p<1E-4, odds ratio>2). The PES was significantly associated with androgen receptor (AR) signalling. Accordingly, AR activation dramatically up-regulated PCAT18 expression in vitro and in vivo. PCAT18 silencing significantly (p<0.001) inhibited PCa cell proliferation and triggered caspase 3/7 activation, with no effect on non-neoplastic cells. PCAT18 silencing also inhibited PCa cell migration (p<0.01) and invasion (p<0.01). These results position PCAT18 as a potential therapeutic target and biomarker for metastatic PCa.
Highlights
The vast majority of prostate cancer (PCa)-related deaths are attributed to the progression from localized disease to metastatic castration-resistant PCa [1]
As the goal of this project was to identify previously uncharacterized Long non-coding RNAs (lncRNAs) associated with PCa metastasis, we performed RNA sequencing analysis on our patient-derived PCa xenografts using the strategy outlined in Suppl
PCa samples are often composed of multi-clonal subpopulations, each with a different mutational spectrum and metastatic potential[29]
Summary
The vast majority of prostate cancer (PCa)-related deaths are attributed to the progression from localized disease to metastatic castration-resistant PCa (mCRPC) [1]. Estimates suggest the number of human lncRNAs rivals that of protein-coding genes, ranging from 10,000 to 20,000 [6] Despite these large numbers, only a handful of lncRNAs have been characterized. While the clinical utility of PCGEM1 has yet to be determined, PCA3 is present in urine samples from PCa patients and is able to detect the disease with 77.5% sensitivity and 57.1% specificity [10]. For this reason, a PCA3 test has been approved by the Food and Drug Administration as a diagnostic tool. Functional data on PCA3 and PCGEM1 are still incomplete or are emerging in very recent publications [11,12,13], so it is not clear that either of them is a viable therapeutic target
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