Antisense Oligonucleotides Targeting Y-Box Binding Protein-1 Inhibit Tumor Angiogenesis by Downregulating Bcl-xL-VEGFR2/-Tie Axes

Kiyoko Setoguchi, Lin Cui, Nobutaka Hachisuka, Sumalee Obchoei, Kentaro Shinkai, Fuminori Hyodo, Kiyoko Kato, Fumito Wada, Tsuyoshi Yamamoto, Mariko Harada-Shiba, Satoshi Obika, Kenji Nakano

Research output: Contribution to journalArticle

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Abstract

Y-box binding protein-1 (YB-1), involved in cancer progression and chemoradiation resistance, is overexpressed in not only cancer cells but also tumor blood vessels. In this study, we investigated the potential value of amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting YB-1 (YB-1 ASOA) as an antiangiogenic cancer therapy. YB-1 ASOA was superior to natural DNA-based ASO or locked nucleic acid (LNA)-modified YB-1 ASO in both knockdown efficiency and safety, the latter assessed by liver function. YB-1 ASOA administered i.v. significantly inhibited YB-1 expression in CD31-positive angiogenic endothelial cells, but not in cancer cells, in the tumors. With regard to the mechanism of its antiangiogenic effects, YB-1 ASOA downregulated both Bcl-xL/VEGFR2 and Bcl-xL/Tie signal axes, which are key regulators of angiogenesis, and induced apoptosis in vascular endothelial cells. In the xenograft tumor model that had low sensitivity to anti-VEGF antibody, YB-1 ASOA significantly suppressed tumor growth; not only VEGFR2 but also Tie2 expression was decreased in tumor vessels. In conclusion, YB-1/Bcl-xL/VEGFR2 and YB-1/Bcl-xL/Tie signal axes play pivotal roles in tumor angiogenesis, and YB-1 ASOA may be feasible as an antiangiogenic therapy for solid tumors.

Original languageEnglish
Pages (from-to)170-181
Number of pages12
JournalMolecular Therapy - Nucleic Acids
Volume9
DOIs
Publication statusPublished - Dec 2017

Fingerprint

Y-Box-Binding Protein 1
Antisense Oligonucleotides
Down-Regulation
Neoplasms
Endothelial Cells
Vascular Tissue Neoplasms
Heterografts
Nucleic Acids
Vascular Endothelial Growth Factor A
Anti-Idiotypic Antibodies

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Antisense Oligonucleotides Targeting Y-Box Binding Protein-1 Inhibit Tumor Angiogenesis by Downregulating Bcl-xL-VEGFR2/-Tie Axes. / Setoguchi, Kiyoko; Cui, Lin; Hachisuka, Nobutaka; Obchoei, Sumalee; Shinkai, Kentaro; Hyodo, Fuminori; Kato, Kiyoko; Wada, Fumito; Yamamoto, Tsuyoshi; Harada-Shiba, Mariko; Obika, Satoshi; Nakano, Kenji.

In: Molecular Therapy - Nucleic Acids, Vol. 9, 12.2017, p. 170-181.

Research output: Contribution to journalArticle

Setoguchi, K, Cui, L, Hachisuka, N, Obchoei, S, Shinkai, K, Hyodo, F, Kato, K, Wada, F, Yamamoto, T, Harada-Shiba, M, Obika, S & Nakano, K 2017, 'Antisense Oligonucleotides Targeting Y-Box Binding Protein-1 Inhibit Tumor Angiogenesis by Downregulating Bcl-xL-VEGFR2/-Tie Axes', Molecular Therapy - Nucleic Acids, vol. 9, pp. 170-181. https://doi.org/10.1016/j.omtn.2017.09.004
Setoguchi, Kiyoko ; Cui, Lin ; Hachisuka, Nobutaka ; Obchoei, Sumalee ; Shinkai, Kentaro ; Hyodo, Fuminori ; Kato, Kiyoko ; Wada, Fumito ; Yamamoto, Tsuyoshi ; Harada-Shiba, Mariko ; Obika, Satoshi ; Nakano, Kenji. / Antisense Oligonucleotides Targeting Y-Box Binding Protein-1 Inhibit Tumor Angiogenesis by Downregulating Bcl-xL-VEGFR2/-Tie Axes. In: Molecular Therapy - Nucleic Acids. 2017 ; Vol. 9. pp. 170-181.
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