Oncolytic potential of an E4-deficient adenovirus that can recognize the stabilization of AU-rich element containing mRNA in cancer cells

Yanagawa-Matsuda,Aya; Mikawa,Yohei; Habiba,Umma; Kitamura,Tetsuya; Yasuda,Motoaki; Towfik-Alam,Mohammad; Kitagawa,Yoshimasa; Minowa,Kazuyuki; Shindoh,Masanobu; Higashino,Fumihiro

doi:10.3892/or.2018.6865

Oncolytic potential of an E4-deficient adenovirus that can recognize the stabilization of AU-rich element containing mRNA in cancer cells

Authors:
- Aya Yanagawa-Matsuda
- Yohei Mikawa
- Umma Habiba
- Tetsuya Kitamura
- Motoaki Yasuda
- Mohammad Towfik-Alam
- Yoshimasa Kitagawa
- Kazuyuki Minowa
- Masanobu Shindoh
- Fumihiro Higashino
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Affiliations: Department of Oral Pathology and Biology, Hokkaido University Faculty of Dental Medicine and Graduate School of Dental Medicine,Sapporo 060-8586, Japan, Oral Molecular Microbiology, Hokkaido University Faculty of Dental Medicine and Graduate School of Dental Medicine,Sapporo 060-8586, Japan, Department of Oral Diagnosis and Medicine, Hokkaido University Faculty of Dental Medicine and Graduate School of Dental Medicine,Sapporo 060-8586, Japan, Department of Dental Radiology, Hokkaido University Faculty of Dental Medicine and Graduate School of Dental Medicine,Sapporo 060-8586, Japan
Published online on: November 12, 2018 https://doi.org/10.3892/or.2018.6865
Pages: 954-960

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Abstract

AU-rich elements (AREs) are RNA elements that enhance the rapid decay of mRNA. The fate of ARE-mRNA is controlled by ARE-binding proteins. HuR, a member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins, is involved in the export and stabilization of ARE-mRNA. In the vast majority of cancer cells, HuR constitutively relocates to the cytoplasm, resulting in the stabilization of ARE-mRNA. Previously, we described that the adenovirus gene product, E4orf6, which is necessary for virus replication, participates in ARE-mRNA export and stabilization. In the present study, we showed the oncolytic potential of E4orf6-deleted adenovirus dl355, which is expected to be replicated selectively in cancer cells. Virus production and cytolytic activity of dl355 were higher in cancer cells than in normal cells. HuR-depletion downregulated dl355 replication, demonstrating that ARE-mRNA stabilization is required for the production of this virus. Tumor growth was inhibited in nude mice by an intratumoral injection of dl355. Furthermore, dl355 had a stronger oncolytic effect than E1B55k-deleted adenovirus. These results indicate that dl355 has potential as an oncolytic adenovirus for a large number of cancers where ARE-mRNA is stabilized.

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