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Published on: March 11, 2014
Evaluation of tissue-specific promoters in carcinomas of the cervix uteri
Daniel T Rein1, Martina Breidenbach, Dirk M Nettelbeck
1Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-2172, USA.
Background:
Gene therapy is a novel approach for treatment of patients with advanced, recurrent, or metastatic cervical cancer. One effective way to direct transgene expression to specific tissues or tumors is the use of tissue-specific-promoters (TSPs). In the context of adenovirus (Ad)-mediated cancer gene therapy it is rational to choose a TSP which is highly expressed in the tumor but has potentially low activity in non-tumor cells, especially the liver. In this study, we have investigated several promoters which fulfill these criteria. Candidate cervical cancer specific TSPs include promoters of the genes for secretory leukoprotease inhibitor (SLPI), cyclooxygenase-2 (COX-2), Midkine (MK), vascular endothelial growth factor receptor type 1 (flt-1), vascular endothelial growth factor (VEGF), Survivin and the receptor for chemokine SDS-1 (CXCR4).
Methods:
To evaluate the specific gene expression of the different promoters in the context of cervical cancer, we constructed a panel of E1-deleted Ads that express luciferase under the control of the promoters of interest. We investigated various established cervical cancer cell lines, as well as purified primary cancer cells and normal control cells from the cervix uteri.
Results:
In all cell lines tested, promoters for MK, VEGF and CXCR4 showed the highest activity. Both MK and VEGF promoters also resulted in a high activity in primary cervical cancer cells. Interestingly, gene expression profiles correlate with luciferase activity in both cell lines and primary cancer samples.
Conclusions:
Our study demonstrates that the promoters for MK and VEGF are active in cervical cancer. We believe that both promoters can be successfully employed as TSPs for gene therapy targeted to cervical cancer.
Insights
Midkine (MK) and vascular endothelial growth factor (VEGF) promoters show high activity in cervical cancer cells, making them promising for targeted gene therapy. These tissue-specific promoters offer potential for effective cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Gene therapy presents a novel treatment strategy for advanced, recurrent, or metastatic cervical cancer.
- Tissue-specific promoters (TSPs) are crucial for directing transgene expression to tumors while minimizing off-target effects, particularly in the liver.
- Several candidate TSPs, including those for Midkine (MK), vascular endothelial growth factor (VEGF), and CXCR4, were evaluated for cervical cancer specificity.
Purpose of the Study:
- To identify and evaluate the activity of cervical cancer-specific promoters for potential use in adenovirus (Ad)-mediated gene therapy.
- To compare the expression levels of various candidate TSPs in cervical cancer cell lines and primary tumor samples.
Main Methods:
- Constructed E1-deleted adenoviruses (Ads) expressing luciferase under the control of candidate TSPs.
- Assessed promoter activity using established cervical cancer cell lines, primary cancer cells, and normal cervical cells.
Main Results:
- Promoters for MK, VEGF, and CXCR4 exhibited the highest activity across tested cell lines.
- MK and VEGF promoters demonstrated significant activity in primary cervical cancer cells.
- Observed a correlation between gene expression profiles and luciferase activity in both cell lines and primary samples.
Conclusions:
- The study identified MK and VEGF promoters as highly active in cervical cancer.
- These promoters are suitable candidates for developing targeted gene therapy strategies for cervical cancer.
