MicroRNA regulation of oncolytic herpes simplex virus-1 for selective killing of prostate cancer cells.
OBJECTIVE
Advanced castration-resistant prostate cancer, for which there are few treatment options, remains one of the leading causes of cancer death. MicroRNAs (miRNA) have provided a new opportunity for more stringent regulation of tumor-specific viral replication. The purpose of this study was to provide a proof-of-principle that miRNA-regulated oncolytic herpes simplex virus-1 (HSV-1) virus can selectively target cancer cells with reduced toxicity to normal tissues.


METHODS
We incorporated multiple copies of miRNA complementary target sequences (for miR-143 or miR-145) into the 3'-untranslated region (3'-UTR) of an HSV-1 essential viral gene, ICP4, to create CMV-ICP4-143T and CMV-ICP4-145T amplicon viruses and tested their targeting specificity and efficacy both in vitro and in vivo.


RESULTS
Although miR-143 and miR-145 are highly expressed in normal tissues, they are significantly down-regulated in prostate cancer cells. We further showed that miR-143 and miR-145 inhibited the expression of the ICP4 gene at the translational level by targeting the corresponding 3'-UTR in a dose-dependent manner. This enabled selective viral replication in prostate cancer cells. When mice bearing LNCaP human prostate tumors were treated with these miRNA-regulated oncolytic viruses, a >80% reduction in tumor volume was observed, with significantly attenuated virulence to normal tissues in comparison with control amplicon viruses not carrying these 3'-UTR sequences.


CONCLUSIONS
Our study is the first to show that inclusion of specific miRNA target sequences into the 3'-UTR of an essential HSV-1 gene is a viable strategy for restricting viral replication and oncolysis to cancer cells while sparing normal tissues.
Lee
Cleo Y F
CY
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Rennie
Paul S
PS
Jia
William W G
WW
D000818:Animals; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018390:Gene Targeting / Q000379:methods; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D009928:Organ Specificity / Q000235:genetics; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome; D014709:Vero Cells; D014779:Virus Replication / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D035683:MicroRNAs