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MUC1-Driven Guanylin Gene Delivery via Succinylated PEI-9 Nanocarrier for Colorectal Cancer Treatment: An in Silico
Pouria Samadi1,2, Fatemeh Rahbarizadeh3, Fatemeh Nouri4
1Poursina Hakim Digestive Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
Purpose:
Addressing colorectal cancer (CRC) poses a significant challenge, demanding the precise delivery of therapeutic agents to eliminate cancer cells while minimizing the impact on healthy cells. The strategic selection of therapeutic targets, the utilization of nanocarriers with optimal efficacy and low toxicity, and the development of gene constructs with targeted expression in cancer cells are crucial aspects of this pursuit.
Methods:
This study employed a systems biology approach to comprehensively investigate the guanylin hormone-encoding gene (GUCA2A). Exploration encompassed expression patterns across tissues and single cells, clinical endpoints, methylation profiles, mutations, and immune and functional analyses. Subsequently, GUCA2A was identified as a potential target for gain of function studies, leading to its amplification and cloning into gene constructs featuring both a robust CMV promoter and a cancer-specific MUC1 promoter. The succinylated PEI-9, characterized by low toxicity and high gene transfer efficiency, was then fabricated and characterized on HCT-116 cancer cells and normal Vero cell lines.
Results:
systems biology studies revealed guanylin's aberrant expression patterns, methylation variations, and mutational changes as well as its remarkable association with immune engagement and poor survival outcomes in CRC. Moreover, SPEI-9 was introduced as a highly efficient and safe nanocarrier for gene delivery purposes. Additionally, in vitro studies revealed that both guanylin-expressing gene constructs exhibited the potential to inhibit cell growth and proliferation, inducing apoptosis, suppressing cell migration, and curtailing colony formation. Notably, these effects were more robust but non-specific in cancer cells treated with constructs containing the CMV general promoter, while induction via the MUC1 promoter was more specific.
Conclusion:
A genetic construct featuring strong universal CMV and specific MUC1 promoter, expressing the guanylin peptide hormone, demonstrated highly effective and specific anticancer effects when transfected with nanocarriers characterized by high efficiency and low cytotoxicity. This nano-system holds promising implications for future targeted CRC therapy clinical trials.
Insights
This study developed a novel gene therapy for colorectal cancer (CRC) using guanylin hormone and efficient nanocarriers. The MUC1 promoter-driven construct showed specific, potent anti-cancer effects, offering a promising new CRC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Nanotechnology
Background:
- Colorectal cancer (CRC) necessitates targeted therapies to improve efficacy and reduce side effects.
- Gene therapy and nanocarrier systems offer potential for precise cancer treatment delivery.
- Understanding gene expression and function in CRC is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the guanylin hormone-encoding gene (GUCA2A) as a therapeutic target for colorectal cancer.
- To develop and evaluate a novel gene delivery system using succinylated PEI-9 (SPEI-9) nanocarriers.
- To assess the anti-cancer efficacy of GUCA2A gene constructs with cancer-specific (MUC1) and universal (CMV) promoters.
Main Methods:
- A systems biology approach was used to analyze GUCA2A expression, methylation, mutations, and clinical associations in CRC.
- GUCA2A was amplified and cloned into gene constructs with CMV and MUC1 promoters.
- Succinyl PEI-9 (SPEI-9) nanocarriers were synthesized and characterized for low toxicity and high gene transfer efficiency.
- In vitro studies were conducted on HCT-116 cancer cells and normal Vero cell lines.
Main Results:
- Systems biology analysis revealed aberrant GUCA2A expression and its association with poor CRC survival and immune engagement.
- SPEI-9 demonstrated high efficiency and low toxicity for gene delivery.
- Both CMV and MUC1 promoter-driven GUCA2A constructs inhibited cancer cell growth, proliferation, migration, and colony formation.
- The MUC1 promoter-driven construct exhibited more specific anti-cancer effects in cancer cells compared to the CMV promoter.
Conclusions:
- A targeted gene therapy system using guanylin peptide hormone, delivered via SPEI-9 nanocarriers, shows significant potential for CRC treatment.
- The MUC1 promoter enhances the specificity of gene expression, leading to targeted anti-cancer effects.
- This nano-system provides a promising platform for future clinical trials in targeted CRC therapy.
