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DNA Polymerases as targets for gene therapy of hepatocellular carcinoma.
- Source :
-
BMC cancer [BMC Cancer] 2015 Apr 29; Vol. 15, pp. 325. Date of Electronic Publication: 2015 Apr 29. - Publication Year :
- 2015
-
Abstract
- Background: Hepatocyte carcinoma (HCC) is one of the most common malignancies worldwide. Despite many achievements in diagnosis and treatment, HCC mortality remains high due to the malignant nature of the disease. Novel approaches, especially for targeted therapy, are being extensively explored. Gene therapy is ideal for such purpose for its specific expression of exogenous genes in HCC cells driven by tissue-specific promoter. However strategies based on correction of mutations or altered expressions of genes responsible for the development/progression of HCC have limitations because these aberrant molecules are not presented in all cancerous cells. In the current work, we adopted a novel strategy by targeting the DNA replication step which is essential for proliferation of every cancer cell.<br />Methods: A recombinant adenovirus with alpha fetoprotein (AFP) promoter-controlled expressions of artificial microRNAs targeting DNA polymerases α, δ, ε and recombinant active Caspase 3, namely Ad/AFP-Casp-AFP-amiR, was constructed.<br />Results: The artificial microRNAs could efficiently inhibit the expression of the target polymerases in AFP-positive HCC cells at both RNA and protein levels, and HCC cells treated with the recombinant virus Ad/AFP-Casp-AFP-amiR exhibited significant G0/1 phase arrest. The proliferation of HCC cells were significantly inhibited by Ad/AFP-Casp-AFP-amiR with increased apoptosis. On the contrary, the recombinant adenovirus Ad/AFP-Casp-AFP-amiR did not inhibit the expression of DNA polymerases α, δ or ε in AFP-negative human normal liver cell HL7702, and showed no effect on the cell cycle progression, proliferation or apoptosis.<br />Conclusions: Inhibition of DNA polymerases α, δ and ε by AFP promoter-driven artificial microRNAs may lead to effective growth arrest of AFP-positive HCC cells, which may represent a novel strategy for gene therapy by targeting the genes that are essential for the growth/proliferation of cancer cells, avoiding the limitations set by any of the individually altered gene.
- Subjects :
- Adenoviridae genetics
Animals
Apoptosis genetics
Carcinoma, Hepatocellular pathology
Carcinoma, Hepatocellular therapy
Cell Line, Tumor
DNA Polymerase I antagonists & inhibitors
DNA Polymerase II antagonists & inhibitors
DNA Polymerase III antagonists & inhibitors
Genetic Therapy
Humans
Liver Neoplasms pathology
Liver Neoplasms therapy
Mice
MicroRNAs genetics
Molecular Targeted Therapy
Promoter Regions, Genetic
Xenograft Model Antitumor Assays
Carcinoma, Hepatocellular genetics
DNA Polymerase I genetics
DNA Polymerase II genetics
DNA Polymerase III genetics
Liver Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1471-2407
- Volume :
- 15
- Database :
- MEDLINE
- Journal :
- BMC cancer
- Publication Type :
- Academic Journal
- Accession number :
- 25924900
- Full Text :
- https://doi.org/10.1186/s12885-015-1339-1