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Virus Res. 2017 Aug 15;240:207-214. doi: 10.1016/j.virusres.2017.08.016. Epub 2017 Sep 1.

Targeting human breast cancer cells by an oncolytic adenovirus using microRNA-targeting strategy.

Author information

1
Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 1471613151, Iran.
2
Department of Microbiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
3
Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada; Cellular & Molecular Research Center (CMRC), Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences (AJUMS), Ahvaz, 6135715794, Iran.
4
Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 1471613151, Iran. Electronic address: Mokhtari@sina.tums.ac.ir.

Abstract

MicroRNA-targeting strategy is a promising approach that enables oncolytic viruses to replicate in tumor cells but not in normal cells. In this study, we targeted adenoviral replication toward breast cancer cells by inserting ten complementary binding sites for miR-145-5p downstream of E1A gene. In addition, we evaluated the effect of increasing miR-145 binding sites on inhibition of virus replication. Ad5-control and adenoviruses carrying five or ten copies of miR145-5p target sites (Ad5-5miR145T, Ad5-10miR145T) were generated and inoculated into MDA-MB-453, BT-20, MCF-7 breast cancer cell lines and human mammary epithelial cells (HMEpC). Titer of Ad5-10miR145T in HMEpC was significantly lower than Ad5-control titer. Difference between the titer of these two viruses at 12, 24, 36, and 48h after infection was 1.25, 2.96, 3.06, and 3.77 log TCID50. No significant difference was observed between the titer of both adenoviruses in MDA-MB-453, BT-20 and MCF-7 cells. The infectious titer of adenovirus containing 10 miR-145 binding sites in HMEpC cells at 24, 36, and 48h post-infection was 1.7, 2.08, and 4-fold, respectively, lower than the titer of adenovirus carrying 5 miR-145 targets. Our results suggest that miR-145-targeting strategy provides selectivity for adenovirus replication in breast cancer cells. Increasing the number of miRNA binding sites within the adenoviral genome confers more selectivity for viral replication in cancer cells.

KEYWORDS:

Adenovirus; Breast cancer; MicroRNAs; Oncolytic virotherapy; Virus replication

PMID:
28867494
DOI:
10.1016/j.virusres.2017.08.016
[Indexed for MEDLINE]

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