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Argonaute2 is a potential target for siRNA-based cancer therapy for HT1080 human fibrosarcoma

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Abstract

Small interfering RNAs (siRNAs) are small RNA molecules that have a potent, sequence-specific gene silencing effect and therefore show promise for therapeutic use as molecular-targeted drugs for the treatment of various genetic diseases, including cancer. The aim of the present study was to evaluate whether Argonaute2 (Ago2) is a therapeutically effective target for siRNA-based cancer therapy. Ago2 is the key protein in mammalian RNAi and is also known as the only member of the Ago family that mediates the microRNA (miRNA)-dependent cleavage of targeted mRNAs. It is assumed that these unique properties of the Ago2 protein can play a central role in the regulation of the miRNA pathway and subsequent translational inhibition of miRNA-targeted mRNAs, including cell survival and cancer progression. To assess its therapeutic effect, siRNA against Ago2 (Ago2-siRNA) was transfected into HT1080 human fibrosarcoma cells, which are malignant cancer cells. Ago2 gene silencing resulted in the inhibition of cell growth and the induction of apoptosis and G0/G1 arrest in the cell cycle. In addition, Ago2 knockdown induced morphological changes and actin stress fiber formation in the cells. The results of a microarray study showed that Ago2 suppression stimulated several crucial genes related to apoptosis, the cell cycle, immune response, cell adhesion, metabolism, etc. Repeated intratumoral injection of Ago2-siRNA/cationic liposome complex induced tumor growth suppression in an HT1080 xenograft model. These results suggest that the suppression of the Ago2 gene may be useful for the inhibition of cancer progression and that Ago2 may be a desirable target for siRNA-based cancer therapy.

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Acknowledgments

The authors thank Dr. James L. McDonald for his helpful advice in improving the manuscript. This research was supported by Research on Advanced Medical Technology in Health and Labor Science Research Grants, Ministry of Health, Labor and Welfare, Japan.

Conflict of interest

Authors declare no conflict.

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Author notes

  1. Tatsuaki Tagami

    Present address: Ontario Institute for Cancer Research, MaRS Centre, South Tower, 101 College Street, Suite 800, Toronto, ON, Canada, M5G 0A3

  2. Jose Mario Barichello

    Present address: Laboratory of Nanotechnology, School of Pharmacy, Universidade Federal de Ouro Preto (UFOP), 35400-000, Ouro Preto, Minas Gerais, Brazil

Authors and Affiliations

  1. Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan

    Tatsuaki Tagami, Takuya Suzuki, Kiyomi Hirose, Jose Mario Barichello, Tatsuhiro Ishida & Hiroshi Kiwada

  2. Japan Association for the Advancement of Medical Equipment, Tokyo, Japan

    Jose Mario Barichello

  3. Department of Medicinal Biochemistry, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, Tokushima, Japan

    Naoshi Yamazaki

  4. Department of Medical Biochemistry, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka, 422-8526, Japan

    Tomohiro Asai & Naoto Oku

  5. Global COE Program, University of Shizuoka, Suruga-ku, Shizuoka, Japan

    Tomohiro Asai & Naoto Oku

Authors
  1. Tatsuaki Tagami
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Correspondence to Tatsuhiro Ishida.

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Tagami, T., Suzuki, T., Hirose, K. et al. Argonaute2 is a potential target for siRNA-based cancer therapy for HT1080 human fibrosarcoma. Drug Deliv. and Transl. Res. 1, 277–288 (2011). https://doi.org/10.1007/s13346-011-0025-3

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