title: Integrated analysis of the prostate cancer small-nucleolar transcriptome reveals SNORA55 as a driver of prostate cancer progression.
abstract: Metastasis is the primary cause of death in prostate cancer (PCa) patients. Small nucleolar RNAs (snoRNAs) have long been considered "housekeeping" genes with no relevance for cancer biology. Emerging evidence has challenged this assumption, suggesting that snoRNA expression is frequently modulated during cancer progression. Despite this, no study has systematically addressed the prognostic and functional significance of snoRNAs in PCa. We performed RNA Sequencing on paired metastatic/non-metastatic PCa xenografts derived from clinical specimens. The clinical significance of differentially expressed snoRNAs was further investigated in two independent primary PCa cohorts (131 and 43 patients, respectively). The snoRNA demonstrating the strongest association with clinical outcome was quantified in PCa patient-derived serum samples and its functional relevance was investigated in PCa cells via gene expression profiling, pathway analysis and gene silencing. Our comparison revealed 21 differentially expressed snoRNAs in the metastatic vs. non-metastatic xenografts. Of those, 12 were represented in clinical databases and were further analyzed. SNORA55 emerged as a predictor of shorter relapse-free survival (results confirmed in two independent databases). SNORA55 was reproducibly detectable in serum samples from PCa patients. SNORA55 silencing in PCa cell lines significantly inhibited cell proliferation and migration. Pathway analysis revealed that SNORA55 expression is significantly associated with growth factor signaling and pro-inflammatory cytokine expression in PCa. Our results demonstrate that SNORA55 up-regulation predicts PCa progression and that silencing this non-coding gene affects PCa cell proliferation and metastatic potential, thus positioning it as both a novel biomarker and therapeutic target.
authors.affiliation: Experimental Therapeutics, BC Cancer Agency Cancer Research Centre, Vancouver BC, Canada; The Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver BC, Canada; Department of Life, Health, and Chemical Sciences, The Open University, Milton Keynes, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Crea
authors.affiliation: Molecular Pathology Unit, Institute of Pathology University Hospital Basel, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Quagliata
authors.affiliation: Oncology, FHMS, School of Biosciences and Medicine, University of Surrey, UK.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Michael
authors.affiliation: Experimental Therapeutics, BC Cancer Agency Cancer Research Centre, Vancouver BC, Canada.
authors.forename: Hui Hsuan
authors.initials: HH
authors.lastname: Liu
authors.affiliation: Karolinska Institutet, Institute of Environmental Medicine, Unit of Biostatistics, Stockholm, Sweden.
authors.forename: Paolo
authors.initials: P
authors.lastname: Frumento
authors.affiliation: Medical Oncology, BC Cancer Agency Vancouver Cancer Centre, Vancouver BC, Canada.
authors.forename: Arun A
authors.initials: AA
authors.lastname: Azad
authors.affiliation: Experimental Therapeutics, BC Cancer Agency Cancer Research Centre, Vancouver BC, Canada.
authors.forename: Hui
authors.initials: H
authors.lastname: Xue
authors.affiliation: Genetics Unit, Integrative Oncology, BC Cancer Agency Cancer Research Centre, Vancouver BC, Canada.
authors.forename: Larissa
authors.initials: L
authors.lastname: Pikor
authors.affiliation: Experimental Therapeutics, BC Cancer Agency Cancer Research Centre, Vancouver BC, Canada; The Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver BC, Canada.
authors.forename: Akira
authors.initials: A
authors.lastname: Watahiki
authors.affiliation: Cancer Center ZeTuP AG St.Gallen, St.Gallen, Switzerland.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Morant
authors.affiliation: Molecular Pathology Unit, Institute of Pathology University Hospital Basel, Switzerland.
authors.forename: Serenella
authors.initials: S
authors.lastname: Eppenberger-Castori
authors.affiliation: Experimental Therapeutics, BC Cancer Agency Cancer Research Centre, Vancouver BC, Canada.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Experimental Therapeutics, BC Cancer Agency Cancer Research Centre, Vancouver BC, Canada.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Parolia
authors.affiliation: Integrated DNA Technologies, Coralville, IA, USA.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Lennox
authors.affiliation: Genetics Unit, Integrative Oncology, BC Cancer Agency Cancer Research Centre, Vancouver BC, Canada.
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
authors.affiliation: The Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver BC, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.affiliation: The Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver BC, Canada; Medical Oncology, BC Cancer Agency Vancouver Cancer Centre, Vancouver BC, Canada.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Chi
authors.affiliation: Oncology, FHMS, School of Biosciences and Medicine, University of Surrey, UK.
authors.forename: Hardev
authors.initials: H
authors.lastname: Pandha
authors.affiliation: Experimental Therapeutics, BC Cancer Agency Cancer Research Centre, Vancouver BC, Canada; The Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver BC, Canada. Electronic address: ywang@bccrc.ca.
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Experimental Therapeutics, BC Cancer Agency Cancer Research Centre, Vancouver BC, Canada. Electronic address: chelgaso@bccrc.ca.
authors.forename: Cheryl D
authors.initials: CD
authors.lastname: Helgason
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D020537:RNA, Small Nucleolar / Q000235:genetics*; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D020537:RNA, Small Nucleolar
keywords: Antisense oligonucleotide; Next generation sequencing; Non-coding RNAs; Patient-derived xenograft; Prostate cancer; SNORA55
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