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Cell-selective gene silencing in prostate cancer LNCap cells using prostate-specific membrane antigen promoter and enhancer in vitro and in vivo.
MedLine Citation:
PMID:  22612256     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
RNA interference (RNAi) has been widely used to silence specific genes. However, RNAi may also cause off-target silencing and elicit non-specific side effects. To achieve cell-specific gene silencing, a cell-selective promoter has to be used to drive RNAi expression. Furthermore, different terminators of cell-selective promoters may cause different silencing efficacies. In order to explore the best promoter and terminator combination and prove the cell-selective gene silencing effect of prostate-specific membrane antigen (PSMA) promoter (p) and enhancer (e). We first constructed three plasmids by using PSMA e/p and three different terminators (poly(A), minipoly(A), and poly(U)) to explore the cell-selective driving ability of PSMAp/e by targeting EGFP in LNCaP, PC-3, EJ and HEK293 cells. Then we chose nucleostemin (NS), an important endogenous gene of prostate cancer, and constructed the NS-targeting shRNA expression plasmid by using PSMAe/p-poly(A) combination. Cell proliferation, cell cycle and early apoptosis in vitro and xenograft tumor growth in BALB/c nude mice in vivo were detected after NS knockdown. Results showed that PSMAp/e can drive EGFP silencing in LNCaP, not in PC-3, EJ and HEK293 cells and PSMAe/p-poly(A) combination achieved the best silencing efficacy. Then PSMAe/p-shNS-poly(A) drives NS knockdown in LNCaP cells, not in PC-3, EJ and HEK293 cells. Furthermore, RNAi-mediated NS knockdown not only reduces cell proliferation rate, reduces the percentage of S-stage cells and increases the percentage of G1-stage cells and increases the early apoptosis ratio in LNCaP cells in vitro, but also inhibited the LNCaP xenograft tumor growth in BALB/c nude mice in vivo by intratumoral injection. In conclusion, Our study demonstrated that PSMAe/p-poly(A) combination is a promising delivery system for targeted RNAi gene therapy of prostate cancer. We showed one effective antitumor strategy by targeting NS protein, an important target in prostate cancer, with PSMAe/p-shNS-poly(A). These results serve as an important step for developing novel strategies to treat prostate cancer.
Authors:
Ranlu Liu; Jiantao Sun; Zhihong Zhang; Yong Xu
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-5-21
Journal Detail:
Title:  Cell biology international     Volume:  -     ISSN:  1095-8355     ISO Abbreviation:  -     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-5-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9307129     Medline TA:  Cell Biol Int     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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