Adeno-associated virus–delivered short hairpin-structured RNA for androgen receptor gene silencing induces tumor eradication of prostate cancer xenografts in nude mice: A preclinical study

Authors

  • Aijing Sun,

    1. Department of Pathology, Shaoxing People's Hospital and the First Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China
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  • Jianxi Tang,

    1. Department of Urology, The University of Kansas Medical Center, Kansas City, Kansas
    Current affiliation:
    1. Department of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong 519000, China
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  • Paul F. Terranova,

    1. Department of Molecular and Integrated Physiology, The University of Kansas Medical Center, Kansas City, Kansas
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  • Xiaoming Zhang,

    1. Department of Anatomy and Cell Biology, The University of Kansas Medical Center, Kansas City, Kansas
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  • James Brantley Thrasher,

    1. Department of Urology, The University of Kansas Medical Center, Kansas City, Kansas
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  • Benyi Li

    Corresponding author
    1. Department of Pathology, Shaoxing People's Hospital and the First Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China
    2. Department of Urology, The University of Kansas Medical Center, Kansas City, Kansas
    3. Department of Molecular and Integrated Physiology, The University of Kansas Medical Center, Kansas City, Kansas
    • KUMC Urology, 3901 Rainbow Blvd, MS# 3035, Kansas City, KS 66160, USA
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    • Fax: +1-913-5884756


Abstract

The androgen receptor (AR) is the most critical factor in prostate cancer progression. We previously demonstrated that silencing the AR using 2 unique small interfering RNAs (no. 8 and no. 31 AR siRNA) induces apoptotic cell death in AR-positive prostate cancer cells. To develop this AR siRNA technique into a therapy for prostate cancers, we generated an adeno-associated virus (AAV) vector to stably express a short hairpin-structured RNA (shRNA) against the AR gene in vivo. In addition to the no. 8 AR shRNA (ARHP8), we also screened a group of AR shRNAs with different sequences and identified a less effective AR shRNA (ARHP4) that was used as an shRNA control. An empty AAV vector (AAV-GFP) was used as a negative control. Intratumoral injection of AAV-ARHP8 viruses significantly suppressed tumor growth of xenografts derived from either androgen-responsive or castration-resistant prostate cancer cells. Most interestingly, systemic delivery of the AAV-ARHP8 but not AAV-ARHP4 or AAV-GFP viruses via tail vein injection eliminated xenografts within 10 days. Further analysis revealed that AAV-ARHP8 viruses dramatically reduced the expression of AR-regulated cellular survival genes and caused a dramatic apoptotic response. Taken together, our data strongly suggest that AAV-ARHP8 viruses induced a strong AR gene silencing in vivo and that systemic delivery of ARHP8 siRNA via an AAV vector or any other means might be considered as novel gene therapy for prostate cancers.

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