Single bioengineered ncRNA molecule for dual-targeting toward the control of non-small cell lung cancer patient-derived xenograft tumor growth
| Autor: | Hannah Petrek, Mei Juan Tu, Jing Xin Qiu, Neelu Batra, Qianyu Zhang, Pui Yan Ho, Aiming Yu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Lung Neoplasms RNA Untranslated Mice SCID NSCLC Biochemistry Mice 0302 clinical medicine Carcinoma Non-Small-Cell Lung Pharmacology & Pharmacy Non-Small-Cell Lung Lung Cancer biology Lung Cancer Untranslated Pharmacology and Pharmaceutical Sciences Middle Aged Non-coding RNA 5.1 Pharmaceuticals 030220 oncology & carcinogenesis Gene Targeting Development of treatments and therapeutic interventions Dual-targeting Biotechnology RNA therapy Bioengineering SCID Article 03 medical and health sciences Patient-derived xenograft microRNA Genetics medicine Animals Humans Viability assay Lung cancer miRNA Pharmacology Carcinoma RNA medicine.disease Xenograft Model Antitumor Assays Oncolytic virus 030104 developmental biology biology.protein Cancer research Cyclin-dependent kinase 6 Biochemistry and Cell Biology |
| Zdroj: | Biochem Pharmacol |
| Popis: | Lung cancer remains the leading cause of cancer deaths worldwide and accounts for more than 22% of all cancer-related deaths in the US. Developing new therapies is essential to combat against deadly lung cancer, especially the most common type, non-small cell lung cancer (NSCLC). With the discovery of genome-derived functional small noncoding RNA (ncRNA), namely microRNAs (miRNA or miR), restoration of oncolytic miRNAs lost or downregulated in NSCLC cells represents a new therapeutic strategy. Very recently, we have developed a novel technology that achieves in vivo fermentation production of bioengineered miRNA agents (BERA) for research and development. In this study, we aimed at simultaneously introducing two miRNAs into NSCLC cells by using single recombinant "combinatorial BERA" (CO-BERA) molecule. Our studies show that single CO-BERA molecule (e.g., let-7c/miR-124) was successfully processed to two miRNAs (e.g., let-7c-5p and miR-124-3p) to combinatorially regulate the expression of multiple targets (e.g., RAS, VAMP3 and CDK6) in human NSCLC cells, exhibiting greater efficacy than respective BERA miRNAs in the inhibition of cell viability and colony formation. Furthermore, we demonstrate that CO-BERA let-7c/miR-124-loaded lipopolyplex nanomedicine was the most effective among tested RNAs in the control of tumor growth in NSCLC patient-derived xenograft mouse models. The anti-tumor activity of CO-BERA let-7c/miR-124 was associated with the suppression of RAS and CDK6 expression, and enhancement of apoptosis. These results support the concept to use single ncRNA agent for dual-targeting and offer insight into developing new RNA therapeutics for the treatment of lethal NSCLC. |
| Databáze: | OpenAIRE |
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