Transfection with Plasmid-Encoding lncRNA-SLERCC nanoparticle-mediated delivery suppressed tumor progression in renal
Weipu Mao1,2, Keyi Wang1, Wentao Zhang1
1Department of Urology, School of Medicine, Shanghai Tenth People's Hospital, Tongji University, No. 301, Yanchang Road, Jing'an District, Shanghai, 200072, P. R. China.
Background:
The accumulating evidence confirms that long non-coding RNAs (lncRNAs) play a critical regulatory role in the progression of renal cell carcinoma (RCC). But, the application of lncRNAs in gene therapy remains scarce. Here, we investigated the efficacy of a delivery system by introducing the plasmid-encoding tumor suppressor lncRNA-SLERCC (SLERCC) in RCC cells.
Methods:
We performed lncRNAs expression profiling in paired cancer and normal tissues through microarray and validated in our clinical data and TCGA dataset. The Plasmid-SLERCC@PDA@MUC12 nanoparticles (PSPM-NPs) were tested in vivo and in vitro, including cellular uptake, entry, CCK-8 assay, tumor growth inhibition, histological assessment, and safety evaluations. Furthermore, experiments with nude mice xenografts model were performed to evaluate the therapeutic effect of PSPM-NPs nanotherapeutic system specific to the SLERCC.
Results:
We found that the expression of SLERCC was downregulated in RCC tissues, and exogenous upregulation of SLERCC could suppress metastasis of RCC cells. Furthermore, high expression DNMT3A was recruited at the SLERCC promoter, which induced aberrant hypermethylation, eventually leading to downregulation of SLERCC expression in RCC. Mechanistically, SLERCC could directly bind to UPF1 and exert tumor-suppressive effects through the Wnt/β-catenin signaling pathway, thereby inhibiting progression and metastasis in RCC. Subsequently, the PSPM-NPs nanotherapeutic system can effectively inhibit the growth of RCC metastases in vivo.
Conclusions:
Our findings suggested that SLERCC is a promising therapeutic target and that plasmid-encapsulated nanomaterials targeting transmembrane metastasis markers may open a new avenue for the treatment in RCC.
Insights
This study shows that the tumor suppressor long non-coding RNA SLERCC is downregulated in renal cell carcinoma (RCC). Restoring SLERCC expression via a novel nanoparticle delivery system effectively suppressed RCC progression and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Nanomedicine
Background:
- Long non-coding RNAs (lncRNAs) are critical regulators in renal cell carcinoma (RCC) progression.
- The therapeutic application of lncRNAs in RCC remains limited.
- This study investigates the potential of lncRNA-SLERCC as a therapeutic target in RCC.
Purpose of the Study:
- To investigate the role of lncRNA-SLERCC in RCC.
- To develop and evaluate a novel nanoparticle-based delivery system for SLERCC in RCC treatment.
- To explore the therapeutic efficacy of SLERCC delivery in an RCC xenograft model.
Main Methods:
- lncRNA expression profiling in RCC tissues and public datasets (TCGA).
- Development and in vitro/in vivo evaluation of Plasmid-SLERCC@PDA@MUC12 nanoparticles (PSPM-NPs).
- Assessment of cellular uptake, tumor growth inhibition, and safety in a nude mice xenograft model.
Main Results:
- SLERCC expression is downregulated in RCC, and its upregulation suppresses RCC cell metastasis.
- DNMT3A-mediated hypermethylation contributes to SLERCC downregulation in RCC.
- SLERCC directly interacts with UPF1, inhibiting the Wnt/β-catenin pathway and suppressing RCC progression.
- PSPM-NPs effectively inhibit RCC metastasis in vivo.
Conclusions:
- SLERCC is a potential therapeutic target for RCC.
- Plasmid-encapsulated nanomaterials targeting metastasis markers offer a novel treatment strategy for RCC.
