Cell-specific expression of artificial microRNAs targeting essential genes exhibit potent antitumor effect on hepatocellular carcinoma cells.

Abstract	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.
Authors	Chenyu Mao, Hao Liu, Ping Chen, Jingjia Ye, Lisong Teng, Zhenyu Jia, Jiang Cao
Journal	Oncotarget (Oncotarget) Vol. 6 Issue 8 Pg. 5707-19 (Mar 20 2015) ISSN: 1949-2553 [Electronic] United States
PMID	25691059 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	AFP protein, human MicroRNAs PHB2 protein, human Phb2 protein, mouse Prohibitins alpha-Fetoproteins
Topics	Animals Carcinoma, Hepatocellular (genetics, metabolism, pathology, therapy) Cell Line, Tumor Cell Survival (genetics) Gene Knockdown Techniques (methods) Genes, Essential Genetic Therapy (methods) Hep G2 Cells Humans Liver Neoplasms (genetics, metabolism, pathology, therapy) Mice Mice, Inbred BALB C MicroRNAs (administration & dosage, biosynthesis, genetics) Prohibitins Promoter Regions, Genetic RNA Interference Random Allocation Transcription, Genetic Transfection Xenograft Model Antitumor Assays alpha-Fetoproteins (genetics)

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