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Multiple-Gene Regulation for Enhanced Antitumor Efficacy with Branch-PCR-Assembled TP53 and MYC Gene Nanovector
Longhuai Cheng1, Liqing Lu1, Ziyi Chen1
1State Key Laboratory of Elemento-Organic Chemistry, Department of Chemical Biology, National Pesticide Engineering Research Center, Collaborative Innovation Center of Chemical Science and Engineering, College of Chemistry, Nankai University, Tianjin 300071, China.
Abstract:
Multiple proteins are involved in network regulation through the crosstalk of different signaling pathways in cancers. Here, we propose a novel strategy of genome therapy with branch-PCR-assembled gene nanovectors to perform network-based gene regulation at multiple levels for cancer therapy. To validate network-based multiplex-gene regulation for genome therapy, we chose to simultaneously target one tumor suppressor gene (TP53) and one oncogene (MYC) in two different signaling pathways. The results showed that, compared to gene nanovectors targeting single genes (NP-TP53 and NP-shMYC), branch-PCR-assembled gene nanovectors simultaneously expressing p53 proteins and MYC shRNA arrays (NP-TP53-shMYC) showed enhanced antitumor efficacy in both MDA-MB-231 cancer cells and an MDA-MB-231-tumor-bearing mouse model. These findings indicate the feasibility and effectiveness of genome therapy in cancer therapy.
Insights
This study introduces a new genome therapy using gene nanovectors to regulate multiple cancer-related genes simultaneously. This network-based approach demonstrated enhanced antitumor efficacy compared to single-gene targeting.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Cancer involves complex protein network regulation via signaling pathway crosstalk.
- Current therapies often target single genes, limiting efficacy in complex diseases.
- Network-based gene regulation offers a promising strategy for enhanced cancer treatment.
Purpose of the Study:
- To develop and validate a novel genome therapy using branch-PCR-assembled gene nanovectors.
- To investigate network-based, multi-level gene regulation for cancer therapy.
- To simultaneously target the tumor suppressor gene TP53 and the oncogene MYC.
Main Methods:
- Development of branch-PCR-assembled gene nanovectors for multiplex-gene delivery.
- Simultaneous delivery of p53 protein expression and MYC shRNA using nanovectors (NP-TP53-shMYC).
- Evaluation of antitumor efficacy in MDA-MB-231 cancer cells and a xenograft mouse model.
Main Results:
- Branch-PCR-assembled nanovectors (NP-TP53-shMYC) showed superior antitumor efficacy compared to single-gene targeting nanovectors (NP-TP53, NP-shMYC).
- Enhanced efficacy was observed in both in vitro (MDA-MB-231 cells) and in vivo (tumor-bearing mouse model) settings.
- Demonstrated successful simultaneous regulation of TP53 and MYC pathways.
Conclusions:
- Network-based multiplex-gene regulation via novel gene nanovectors is feasible for cancer therapy.
- This approach offers enhanced antitumor efficacy by targeting multiple key genes.
- The developed genome therapy strategy holds significant potential for future cancer treatment applications.
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