Recombinant adenovirus infection suppresses hTERT expression through virus-associated RNA-mediated induction of type 1 interferon.

Abstract

Adenovirus vector is one of the most widely used vectors in gene therapy applications for the treatment of diverse human diseases including cancer. In this study, we showed that infection with E1E3-deleted recombinant human adenovirus serotype 5 reduced human telomerase reverse transcriptase (hTERT) mRNA levels in hepatoma cell lines. We defined the mechanisms by which the recombinant adenovirus vector reduces hTERT mRNA levels as follows: Using the virus-associated RNA I/II (VAI/II) expression construct, we demonstrated that the expression of VAI and VAII RNAs led to an increase in IFN-α2 level, and IFN-α2 induction was responsible for the decrease in hTERT mRNA levels. We showed that the effects of VA RNAs were specific for the replication-incompetent E1E3-deleted adenovirus vector, because wild-type adenovirus affected neither IFN-α2 nor hTERT mRNA levels. Moreover, we demonstrated that adenovirus vector-mediated delivery of the hTERT-targeting anti-cancer reagent could additively reduce the levels of hTERT mRNA that were specifically overexpressed in most of the cancer cells. This study showed that E1E3-deleted adenovirus vector system reduced hTERT mRNA levels through VA RNA-mediated induction of type 1 interferon; hence the recombinant adenovirus itself could have anti-cancer activity. These results indicate that recombinant adenovirus vector could be an effective means to deliver anti-cancer reagents for combating cancerous cells more effectively.

• Authors: Chang Ho Lee, Hee Won Kim, Taehyeong Kim, Seong-Wook Lee
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 458 Issue 4 Pg. 830-5 (Mar 20 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 25689720 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Interferon-alpha
• RNA, Messenger
• RNA, Viral
• adenovirus associated RNA
• TERT protein, human
• Telomerase

Topics

• Adenoviridae (genetics)
• Carcinoma, Hepatocellular (genetics, therapy)
• Cell Line, Tumor
• Down-Regulation
• Genetic Therapy (methods)
• Genetic Vectors (genetics, therapeutic use)
• Humans
• Interferon-alpha (genetics)
• Liver Neoplasms (genetics, therapy)
• RNA, Messenger (genetics)
• RNA, Viral (genetics)
• Telomerase (genetics)
• Up-Regulation