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Therapeutic potential of synthetic microRNA mimics based on the miR-15/107 consensus sequence
Glen Reid1,2,3, Marissa Williams4,5, Yuen Yee Cheng4,5,6
1Asbestos and Dust Diseases Research Institute (ADDRI), Sydney, NSW, Australia. glen.reid@otago.ac.nz.
Abstract:
MicroRNA expression is frequently suppressed in cancer, and previously we demonstrated coordinate downregulation of multiple related microRNAs of the miR-15/107 group in malignant pleural mesothelioma (PM). From an alignment of the miR-15 family and the related miR-103/107, we derived a consensus sequence and used this to generate synthetic mimics. The synthetic mimics displayed tumour suppressor activity in PM cells in vitro, which was greater than that of a mimic based on the native miR-16 sequence. These mimics were also growth inhibitory in cells from non-small cell lung (NSCLC), prostate, breast and colorectal cancer, and sensitised all cell lines to the chemotherapeutic drug gemcitabine. The increased activity corresponded to enhanced inhibition of the expression of target genes and was associated with an increase in predicted binding to target sites, and proteomic analysis revealed a strong effect on proteins involved in RNA and DNA processes. Applying the novel consensus mimics to xenograft models of PM and NSCLC in vivo using EGFR-targeted nanocells loaded with mimic led to tumour growth inhibition. These results suggest that mimics based on the consensus sequence of the miR-15/107 group have therapeutic potential in a range of cancer types.
Insights
Synthetic microRNA mimics targeting the miR-15/107 group show significant tumor suppressor activity across multiple cancer types. These mimics demonstrate therapeutic potential in preclinical models, inhibiting tumor growth and enhancing chemotherapy response.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- MicroRNA (miRNA) expression is often suppressed in various cancers, including malignant pleural mesothelioma (PM).
- Previous research indicated coordinated downregulation of the miR-15/107 miRNA group in PM.
- This downregulation suggests a potential role for these miRNAs in cancer development.
Purpose of the Study:
- To develop and evaluate synthetic miRNA mimics based on a consensus sequence of the miR-15/107 group.
- To assess the therapeutic potential of these mimics as anti-cancer agents.
- To investigate their efficacy in various cancer cell lines and preclinical models.
Main Methods:
- Derived a consensus sequence from aligned miR-15 family and miR-103/107 sequences.
- Generated synthetic miRNA mimics based on the consensus sequence.
- Tested mimics in vitro for tumor suppressor activity in cancer cell lines (PM, NSCLC, breast, prostate, colorectal) and in vivo using xenograft models.
Main Results:
- Consensus mimics exhibited greater tumor suppressor activity than native miR-16 mimics in PM cells.
- Mimics inhibited growth in multiple cancer cell lines and sensitized them to gemcitabine.
- In vivo studies showed significant tumor growth inhibition in PM and NSCLC xenografts.
Conclusions:
- Consensus miR-15/107 mimics demonstrate potent anti-cancer activity across diverse cancer types.
- These mimics offer a promising therapeutic strategy for various cancers.
- Further development of these mimics holds potential for novel cancer treatments.
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