Therapeutic potential of synthetic microRNA mimics based on the miR-15/107 consensus sequence

Our plain-English summary of Therapeutic potential of synthetic microRNA mimics based on the miR-15/107 consensus sequence, by G. Reid, M. Williams, Y.Y. Cheng, et al (Cancer Gene Therapy, 2025).

The study

• Authors: G. Reid, M. Williams, Y.Y. Cheng, K. Sarun, P. Winata, M.B. Kirschner, N. Mugridge, J. Weiss, M. Molloy, H. Brahmbhatt, J. MacDiarmid, N. van Zandwijk
• Journal: Cancer Gene Therapy
• Published: 2025;32(4):486-496
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2025. The Author(s).

In plain English

This laboratory study tested synthetic microRNA mimics, not people or asbestos exposure. The authors aligned seven microRNAs of the miR-15/107 group previously found downregulated in pleural mesothelioma (PM), derived a consensus sequence and made four mimics (107.1-107.4). These were transfected into PM, non-small cell lung (NSCLC), prostate, breast and colorectal cancer cell lines. In PM cells the consensus mimics were equal to or more active than a native miR-16 mimic, at least 2-fold more active; NSCLC and prostate lines were inhibited at concentrations at least 2-fold lower than those needed for miR-16; breast lines showed around two-fold greater activity; and the colorectal line was strongly inhibited by either mimic. Mimics 107.2 and 107.4 increased gemcitabine sensitivity in PM, lung, breast and prostate lines. Compared with miR-16, they reduced BCL2 mRNA similarly but suppressed CCND1 more, with lower predicted binding free energy. In nude-mouse xenografts of mesothelioma and NSCLC, EGFR-targeted nanocells loaded with con15/107.2 gave significant tumour growth inhibition versus saline or control mimic. The authors concluded such mimics have therapeutic potential across several cancer types.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: cancer cell line experiments in vitro plus mouse xenograft experiments in vivo
• Who was studied: Human cancer cell lines (mesothelioma, NSCLC, prostate, breast, colorectal) and athymic nude mice bearing subcutaneous MSTO-211H or A549 xenografts; work conducted in Sydney, Australia
• Exposure: Synthetic microRNA mimics based on the miR-15/107 consensus sequence (107.1-107.4) versus a native miR-16 mimic and control mimic, transfected at 5 nM or 0.039 to 10 nM, with or without gemcitabine; in vivo as EGFR-targeted EDV nanocells carrying consensus mimic 107.2
• Main results:
  • In the panel of PM cell lines, the consensus mimics were equal to or more active than the native miR-16 sequence when used at equimolar concentrations
  • Across a wider concentration range in PM cells, the consensus mimics were at least 2-fold more active than the native miR-16 mimic
  • Combining miR-15a and miR-16 mimics did not increase growth inhibition (data not shown)
  • In NSCLC (A549, H460, H1975) and prostate (PC-3, LNCaP) lines, the consensus mimics inhibited growth at concentrations at least 2-fold lower than required for native miR-16
  • Breast (MCF-7, MDA-MB-231) and colorectal (HCT-116) lines were strongly inhibited by miR-16 or the consensus mimics; for the breast lines the consensus mimics were around two-fold more growth inhibitory than the native sequence (no two-fold comparison was given for the colorectal line)
  • Target gene effects in PM cells: BCL2 mRNA reduced similarly by miR-16 and consensus mimics, CCND1 mRNA suppressed more by the consensus mimics
  • Predicted binding of the consensus mimics to two target sites in the CCND1 3'UTR had lower free energy than that of miR-16, which the authors took as indicative of enhanced binding
  • Proteomic (SWATH) analysis in MSTO cells showed similar numbers of up- and downregulated proteins for miR-16, 107.2 and 107.4 compared with control mimic
  • Both 107.2 and 107.4 increased gemcitabine sensitivity of cell lines derived from PM, lung, breast and prostate cancer compared with control mimic
  • In mice, nanocells loaded with conmiR-15/107.2 given four times per week produced significant tumour growth inhibition in both the mesothelioma and NSCLC xenograft models versus saline or control mimic
• The authors' conclusion: The authors concluded that a consensus mimic based on the miR-15/107 group showed enhanced activity compared with a mimic based on the endogenous miR-16 sequence, and suggested a similar strategy could be effective in other cancer types
• Limitations the authors state:
  • The authors stated that a full comparison of the targets of the consensus mimics versus the endogenous microRNAs was beyond the scope of the study
  • The authors stated the reason for the increased activity of the consensus mimics (alternative targets, enhanced hybridisation, or both) remained undetermined and was under continuing study
  • The authors noted that most proteins changed in pathways associated with cell death were not predicted targets of the consensus mimics by seed-based algorithms

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Colorectal Cancer, Gemcitabine, EGFR.

Related studies

• The analysis of novel microRNA mimic sequences in cancer cells reveals lack of specificity in stem-loop RT-qPCR-based microRNA detection — P. Winata, M. Williams, et al. (2017)
• miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma — M. Williams, M.B. Kirschner, et al. (2015)
• Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma — G. Reid, M.E. Pel, et al. (2013)
• A link between the fibroblast growth factor axis and the miR-16 family reveals potential new treatment combinations in mesothelioma — K. Schelch, M.B. Kirschner, et al. (2018)
• Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma — T.G. Johnson, K. Schelch, et al. (2018)
• MiR-score: a novel 6-microRNA signature that predicts survival outcomes in patients with malignant pleural mesothelioma — M.B. Kirschner, Y.Y. Cheng, et al. (2015)

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