title: Intravesical treatment of advanced urothelial bladder cancers with oncolytic HSV-1 co-regulated by differentially expressed microRNAs.
abstract: Urothelial bladder cancer is the most common malignancy of the urinary tract. Although most cases are initially diagnosed as non-muscle-invasive, more than 80% of patients will develop recurrent or metastatic tumors. No effective therapy exists currently for late-stage metastatic tumors. By intravesical application, local administration of oncolytic Herpes Simplex virus (oHSV-1) can provide a promising new therapy for this disease. However, its inherent neurotoxicity has been a perceived limitation for such application. In this study, we present a novel microRNA-regulatory approach to reduce HSV-1-induced neurotoxicity by suppressing viral replication in neurons while maintaining oncolytic selectivity toward urothelial tumors. Specifically, we designed a recombinant virus that utilizes differentially expressed endogenous microR143 (non-cancerous, ubiquitous) and microR124 (neural-specific) to regulate expression of ICP-4, a gene essential for HSV-1 replication. We found that expression of ICP-4 must be controlled by a combination of both miR143 and miR124 to achieve the most effective attenuation in HSV-1-induced toxicity while retaining maximal oncolytic capacity. These results suggest that interaction between miR143 and miR124 may be required to successfully regulate HSV-1 replication. Our resent study is the first proof-in-principle that miRNA combination can be exploited to fine-tune the replication of HSV-1 to treat human cancers.
authors.affiliation: The Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: K-X
authors.initials: KX
authors.lastname: Zhang
authors.affiliation: The Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Matsui
authors.affiliation: School of Medicine, University of Stanford, Stanford, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: O
authors.initials: O
authors.lastname: Osamu
authors.affiliation: The Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Skinner
authors.affiliation: Department of Anatomy and Histology, School of Basic Medical Science, Peking University, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: A
authors.initials: A
authors.lastname: So
authors.affiliation: The Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: P S
authors.initials: PS
authors.lastname: Rennie
authors.affiliation: Department of Surgery and Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: W W
authors.initials: WW
authors.lastname: Jia
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000627:therapeutic use; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000628:therapy*; D019459:Urothelium / Q000473:pathology; D014779:Virus Replication / Q000235:genetics
chemical_list: C509207:MIRN124 microRNA, human; C542359:MIRN143 microRNA, human; D035683:MicroRNAs