Cell-specific expression of artificial microRNAs targeting essential genes exhibit potent antitumor effect on hepatocellular carcinoma cells
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Chenyu Mao1,4, Hao Liu2, Ping Chen3, Jingjia Ye1, Lisong Teng4, Zhenyu Jia2 and Jiang Cao1
1 Clinical Research Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China
2 Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, P. R. China
3 Sir Run Run Shaw Institute of Clinical Medicine, Zhejiang University, Hangzhou, Zhejiang, P. R. China
4 Cancer Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China
Zhenyu Jia, email:
Jiang Cao, email:
Keywords: Hepatocelluar Carcinoma; Gene Therapy; Artificial MicroRNA; RNA Interference
Received: December 03, 2014 Accepted: January 02, 2015 Published: January 21, 2015
To achieve specific and potent antitumor effect of hepatocyte carcinoma cells, replication defective adenoviral vectors, namely rAd/AFP-amiRG, rAd/AFP-amiRE and rAd/AFP-amiRP, were constructed which were armed with artificial microRNAs (amiRs) targeting essential functional genes glyceraldehyde-3-phosphate dehydrogenase, eukaryotic translation initiation factor 4E and DNA polymerase α respectively under the control of a recombinant promoter comprised of human α-fetoprotein enhancer and basal promoter. The AFP enhancer/promoter showed specific high transcription activity in AFP-positive HCC cells Hep3B, HepG2 and SMMC7721, while low in AFP-negative cell Bcap37. All artificial microRNAs exhibited efficient knockdown of target genes. Decreased ATP production and protein synthesis was observed in rAd/AFP-amiRG and rAd/AFP-amiRE treated HCC cells. All three recombinant adenoviruses showed efficient blockage of cell cycle progression and significant suppression of HCC cells in vitro. In nude mice model bearing Hep3B xenograft, administration of rAd/AFP-amiRG showed potent antitumor effect. The strategy of tumor-specific knockdown of genes essential for cell survival and proliferation may suggest a novel promising approach for HCC gene therapy.
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