Identification of a long non-coding RNA as a novel biomarker and potential therapeutic target for metastatic prostate cancer

Abstract

// Francesco Crea 1 , Akira Watahiki 1,2 , Luca Quagliata 3 , Hui Xue 1 , Larissa Pikor 4 , Abhijit Parolia 1,5 , Yuwei Wang 1 , Dong Lin 1,2 , Wan L. Lam 4 , William L. Farrar 6 , Takao Isogai 7 , Rudolf Morant 8 , Serenella Castori-Eppenberger 3 , Kim N. Chi 2,9 , Yuzhuo Wang 1,2 , and Cheryl D. Helgason 1 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.