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New highly potent and specific E6 and E7 siRNAs for treatment of HPV16 positive cervical cancer

Cancer Gene Therapy volume 15, pages 140–153 (2008)Cite this article

Abstract

Persistent infection by high-risk types of human papillomaviruses (HPV) is a necessary cause of cervical cancer, with HPV16 the most prevalent, accounting for more than 50% of reported cases. The virus encodes the E6 and E7 oncoproteins, whose expression is essential for maintenance of the malignant phenotype. To select efficacious siRNAs applicable to RNAi therapy for patients with HPV16+ cervical cancer, E6 and E7 siRNAs were designed using siDirect computer software, after which 10 compatible with all HPV16 variants were selected, and then extensively examined for RNAi activity and specificity using HPV16+ and HPV16−cells. Three siRNAs with the highest RNAi activities toward E6 and E7 expression, as well as specific and potent growth suppression of HPV16+ cancer cells as low as 1 nM were chosen. Growth suppression was accompanied by accumulation of p53 and p21WAF1/CIP1, as well as morphological and cytochemical changes characteristic of cellular senescence. Antitumor activity of one of the selected siRNAs was confirmed by retarded tumor growth of HPV16+ cells in NOD/SCID mice when locally injected in a complex with atelocollagen. Our results demonstrate that these E6 and E7 siRNAs are promising therapeutic agents for treatment of virus-related cancer.

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Acknowledgements

We thank Dr Hideki Matsui and Dr Kazuhito Tomizawa (Okayama University) for their helpful discussion and suggestions. This work was supported in part by Grants-in-aid for Scientific Research (C) from Japan Society for the Promotion of Science [15591749 (MY), 19592169 (KY)].

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Authors and Affiliations

  1. Molecular Cellular Oncology and Microbiology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

    K Yamato

  2. Division of Pathology, Keio University, School of Medicine, Tokyo, Japan

    T Yamada

  3. Division of Hematology, Keio University, School of Medicine, Tokyo, Japan

    M Kizaki & Y Ikeda

  4. Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan

    K Ui-Tei & K Saigo

  5. RNAi Company Ltd., Tokyo, Japan

    Y Natori & M Fujino

  6. Department of Oral Microbiology, Kyushu Dental College, Fukuoka, Japan

    T Nishihara

  7. Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama, Japan

    Y Nasu

  8. Department of Physiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama, Japan

    M Yoshinouchi

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Yamato, K., Yamada, T., Kizaki, M. et al. New highly potent and specific E6 and E7 siRNAs for treatment of HPV16 positive cervical cancer. Cancer Gene Ther 15, 140–153 (2008). https://doi.org/10.1038/sj.cgt.7701118

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