The cyclo-oxygenase 2 promoter is induced in nontarget cells following adenovirus infection, but an AU-rich 3′-untranslated region destabilization element can increase specificity

Authors

  • Merja Särkioja,

    1. Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory, University of Helsinki, Helsinki, Finland
    2. Laboratory of Transplantation Pathology, HUSLAB, Helsinki University Central Hospital (HUCH), Helsinki, Finland
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  • Tanja Hakkarainen,

    1. Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory, University of Helsinki, Helsinki, Finland
    2. Laboratory of Transplantation Pathology, HUSLAB, Helsinki University Central Hospital (HUCH), Helsinki, Finland
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  • Minna Eriksson,

    1. Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory, University of Helsinki, Helsinki, Finland
    2. Laboratory of Transplantation Pathology, HUSLAB, Helsinki University Central Hospital (HUCH), Helsinki, Finland
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  • Ari Ristimäki,

    1. Department of Pathology, HUCH, Helsinki, Finland
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  • Renee A. Desmond,

    1. Division of Biostatistics and Bioinformatics, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
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  • Anna Kanerva,

    1. Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory, University of Helsinki, Helsinki, Finland
    2. Laboratory of Transplantation Pathology, HUSLAB, Helsinki University Central Hospital (HUCH), Helsinki, Finland
    3. Department of Obstetrics and Gynecology, HUCH, Helsinki, Finland
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  • Akseli Hemminki

    Corresponding author
    1. Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory, University of Helsinki, Helsinki, Finland
    2. Laboratory of Transplantation Pathology, HUSLAB, Helsinki University Central Hospital (HUCH), Helsinki, Finland
    • Cancer Gene Therapy Group, Biomedicum Helsinki, PO Box 63, 00014 University of Helsinki, Finland.
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Abstract

Background

Cyclo-oxygenase 2 (Cox-2) is expressed in many types of tumors, but typically undetectable in normal tissues. However, Cox-2 is known to be induced following infection by many microbial agents, which might threaten the tumor selectivity of the Cox-2 promoter in the context of virotherapy or viral gene delivery. Cox-2 expression is regulated in part post-transcriptionally by stimulation or inhibition of mRNA degradation by 3′-untranslated region (3′-UTR) AU-rich elements. In the present study, we investigated the induction of the Cox-2 promoter both in normal and tumor cells after adenovirus infection and explored the utility of AU-rich elements for regaining promoter selectivity.

Methods

Nontumor and tumor cells were transfected in vitro and in vivo with plasmids containing the Cox-2 or cytomegalovirus immediate early promoter driving luciferase (with or without 3′-UTR elements) followed by adenoviral infection. Selectivity and activity of the promoters and 3′-UTR elements were analysed by luciferase assay and in-vivo imaging.

Results

The Cox-2 promoter was induced in both normal and tumor cells following infection with E1 containing replicative adenoviruses but not in the absence of E1. Utilization of AU-rich elements counteracted promoter induction in vitro and in vivo in nonmalignant cells but not in cancer cells, thus increasing the selectivity of the approach ten-fold without loss of potency.

Conclusions

Adenoviral infection induces the Cox-2 promoter in normal and tumor cells, which might compromise specificity of the promoter. Utilization of AU-rich destabilization elements can rescue the tumor selectivity of the promoter. Copyright © 2008 John Wiley & Sons, Ltd.

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