Abstract
To date, only a few prostate-specific vector genes have been tested for prostate targeting in gene therapy of prostate cancer (CaP). Current clinical trials of gene therapy of CaP utilize the only two available vector genes with a combination of a rat probasin promoter and a human PSA promoter sequence in an adenovirus vector to target CaP. There is an urgent need to establish additional vector gene systems to sustain and propagate the current research. Since PSP94 (prostate secretory protein of 94 amino acids) is one of the three most abundant proteins secreted from the human prostate and is generally considered to be prostate tissue-specific in both human and rodents, we performed a transgenic experiment to assess the promoter/enhancer region of PSP94 gene-directed prostate targeting. Firstly, a series of progressive deletion mutants of a 3.84 kb PSP94 gene promoter/enhancer region (including parts of the intron 1 sequence) linked with a reporter LacZ gene was constructed and assessed in vitro in cell culture. Next, transgenic mice were generated with two transgene constructs using the SV40 early region (Tag oncogene) as a selection marker. PSP94 gene promoter/enhancer region-directed SV40 Tag expression specifically in the mouse was demonstrated in three breeding lines (A, B, C, n = 374) by immunohistochemistry staining of Tag expression. Specific targeting to the prostate in the PSP94 gene-directed transgenic CaP model was characterized histologically by correlation of SV40 Tag-induced tumorigenesis (tumor grading) with puberty and age (10–32 weeks). Prostatic hyperplasia was observed as early as 10 weeks of age, with subsequent emergence of prostatic intraepithelial neoplasia (PIN) and eventually high grade carcinoma in the prostate. The PSP94 transgenic mouse CaP model was further characterized by its tumor progression and metastatic tendency at 20 weeks of age and also by its responsiveness and refractoriness to androgen manipulation. This study indicates that the PSP94 gene promoter/enhancer has the potential for prostate specific targeting and may ultimately be of use in gene therapy of CaP.
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Acknowledgements
The authors would greatly appreciate Dr Robert J Matusik and Dr Norman Greenberg for their help and support and for their critical review of the manuscript. This work was supported by grants from the Medical Research Council of Canada (MT-15390), The Kidney Foundation of Canada, The Prostate Cancer Research Foundation of Canada, an RGC Earmarked Research Grant (CUHK 4131/00M to FLC), a grant-in-aid (No.11671562) from the Ministry of Education, Science, Sports and Culture of Japan, and also from Procyon Biopharma Inc. (Montreal, Quebec, Canada).
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Gabril, M., Onita, T., Ji, P. et al. Prostate targeting: PSP94 gene promoter/enhancer region directed prostate tissue-specific expression in a transgenic mouse prostate cancer model. Gene Ther 9, 1589–1599 (2002). https://doi.org/10.1038/sj.gt.3301895
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DOI: https://doi.org/10.1038/sj.gt.3301895
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