Abstract
Francesco Crea1, Akira Watahiki1,2, Luca Quagliata3, Hui Xue1, Larissa Pikor4, Abhijit Parolia1,5, Yuwei Wang1, Dong Lin1,2, Wan L. Lam4, William L. Farrar6, Takao Isogai7, Rudolf Morant8, Serenella Castori-Eppenberger3, Kim N. Chi2,9, Yuzhuo Wang1,2, and Cheryl D. Helgason1
1 Experimental Therapeutics, BC Cancer Agency Cancer Research Centre, Vancouver BC, Canada.
2 The Vancouver prostate Centre, Vancouver General Hospital, Vancouver BC, Canada.
3 Molecular Pathology Unit, Institute of Pathology, University Hospital Basel, Switzerland
4 Genetics Unit, Integrative Oncology, BC Cancer Agency Cancer Research Centre, Vancouver BC, Canada.
5 Honours Biotechnology, Department of Microbiology and Immunology, University of British Columbia, Vancouver BC, Canada
6 Cancer Stem Cell Section, National Laboratory at Frederick, MD, USA.
7 Translational Research Center, Fukushima Medical University, Fukushima, Japan
8 Cancer Center, ZeTuP AG St.Gallen, St.Gallen, Switzerland
9 Medical Oncology, BC Cancer Agency Vancouver Cancer Centre, Vancouver BC, Canada.
Correspondence:
Cheryl D. Helgason, email:
Francesco Crea, email:
Keywords: long non-coding RNA, prostate cancer, metastasis, androgen receptor, cancer biomarkers.
Received: January 15, 2014 Accepted: February 4, 2014 Published: February 6, 2014
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.
