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Tumor-targeting TRAIL expression mediated by miRNA response elements suppressed growth of uveal melanoma cells
1Institutes of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China.
Abstract:
Malignant uveal melanoma severely damages eye function and is prone to metastasize to other organs. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent to treat uveal melanoma because of its induction of apoptosis in cancer cells both at primary and metastatic sites. However, TRAIL therapy lacks tumor specificity in the current delivery systems for uveal melanoma treatment, thereby causing cytotoxiciy to normal tissues. To improve uveal melanoma specificity of adenovirus-based TRAIL introduction, we used miRNA response elements (MREs) of miR-34a, miR-137 and miR-182, which have been shown to have reduced expression in uveal melanoma cells, to regulate its expression. miR-34a, miR-137 and miR-182 all had lower expression levels in uveal melanoma cell lines, compared with normal cells. MREs-regulated luciferase activity was reduced in normal cell lines, but not significantly attenuated in uveal melanoma cells. The infection of MRE-regulated TRAIL-expressing adenoviral vector (Ad-TRAIL-3MREs) led to high level of TRAIL expression in uveal melanoma cell lines, but not in normal cells. Strong expression of TRAIL had a high anti-tumor capacity by inducing apoptosis in uveal melanoma cells. In contrast, Ad-TRAIL-3MREs had no cytotoxicity to normal cell lines. Animal experiments further confirmed tumor-suppressing effect of Ad-TRAIL-3MREs on uveal melanoma xenografts and its biosafety to hepatic tissues. Collectively, we constructed an MRE-directed TRAIL-expressing adenoviral vector and provided evidence that this vector possessed high anti-tumor activity and uveal melanoma specificity.
Insights
This study developed a targeted adenovirus therapy using miRNA response elements to deliver Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) specifically to uveal melanoma cells, enhancing treatment efficacy and safety.
Area of Science:
- Ophthalmology
- Oncology
- Gene Therapy
Background:
- Malignant uveal melanoma is an aggressive eye cancer with high metastatic potential.
- Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) shows promise for cancer treatment by inducing apoptosis, but current delivery methods lack specificity, causing toxicity to healthy tissues.
- Reduced expression of miR-34a, miR-137, and miR-182 is observed in uveal melanoma cells.
Purpose of the Study:
- To engineer an adenovirus-based TRAIL delivery system with enhanced specificity for uveal melanoma.
- To utilize miRNA response elements (MREs) of miR-34a, miR-137, and miR-182 to achieve tumor-specific TRAIL expression.
- To evaluate the anti-tumor activity and biosafety of the novel vector in vitro and in vivo.
Main Methods:
- Adenovirus vector construction expressing TRAIL regulated by MREs of miR-34a, miR-137, and miR-182 (Ad-TRAIL-3MREs).
- Assessment of MREs-regulated luciferase activity in normal and uveal melanoma cell lines.
- In vitro evaluation of TRAIL expression, apoptosis induction, and cytotoxicity in cancer and normal cells.
- In vivo studies using uveal melanoma xenografts in animals to assess tumor suppression and hepatic tissue safety.
Main Results:
- MREs significantly reduced luciferase activity in normal cells but not in uveal melanoma cells, indicating tumor-specific regulation.
- Ad-TRAIL-3MREs demonstrated high TRAIL expression and potent apoptosis induction in uveal melanoma cells, with minimal impact on normal cells.
- In vivo experiments confirmed Ad-TRAIL-3MREs' tumor-suppressing effect on uveal melanoma xenografts and its safety profile for hepatic tissues.
Conclusions:
- A novel MRE-directed adenoviral vector (Ad-TRAIL-3MREs) was successfully constructed for TRAIL delivery.
- This vector exhibits high specificity for uveal melanoma, leading to potent anti-tumor activity.
- The findings support the potential of this targeted gene therapy approach for treating malignant uveal melanoma with improved safety.
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