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MicroRNA-21 is immunosuppressive and pro-metastatic via separate mechanisms

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posted on 2022-10-20, 22:52 authored by Lap Hing Chi, RSN Cross, Richard RedversRichard Redvers, M Davis, S Hediyeh-zadeh, Suresh MathivananSuresh Mathivanan, M Samuel, EC Lucas, Kellie MouchemoreKellie Mouchemore, PA Gregory, Cameron JohnstoneCameron Johnstone, Robin AndersonRobin Anderson
MiR-21 was identified as a gene whose expression correlated with the extent of metastasis of murine mammary tumours. Since miR-21 is recognised as being associated with poor prognosis in cancer, we investigated its contribution to mammary tumour growth and metastasis in tumours with capacity for spontaneous metastasis. Unexpectedly, we found that suppression of miR-21 activity in highly metastatic tumours resulted in regression of primary tumour growth in immunocompetent mice but did not impede growth in immunocompromised mice. Analysis of the immune infiltrate of the primary tumours at the time when the tumours started to regress revealed an influx of both CD4+ and CD8+ activated T cells and a reduction in PD-L1+ infiltrating monocytes, providing an explanation for the observed tumour regression. Loss of anti-tumour immune suppression caused by decreased miR-21 activity was confirmed by transcriptomic analysis of primary tumours. This analysis also revealed reduced expression of genes associated with cell cycle progression upon loss of miR-21 activity. A second activity of miR-21 was the promotion of metastasis as shown by the loss of metastatic capacity of miR-21 knockdown tumours established in immunocompromised mice, despite no impact on primary tumour growth. A proteomic analysis of tumour cells with altered miR-21 activity revealed deregulation of proteins known to be associated with tumour progression. The development of therapies targeting miR-21, possibly via targeted delivery to tumour cells, could be an effective therapy to combat primary tumour growth and suppress the development of metastatic disease.

Funding

This project was supported by a National Health and Medical Research Council of Australia (NHMRC) Project Grant (APP1020280) and from the Austin Medical Research Fund (2018). RLA was supported by a senior fellowship from NBCF. LHC is supported by a graduate research scholarship from La Trobe University. Olivia Newton-John Cancer Research Institute (Heidelberg, Australia) acknowledges the support of the Operational Infrastructure Program of Victorian Government.

History

Publication Date

2022-07-11

Journal

Oncogenesis

Volume

11

Article Number

38

Pagination

12p.

Publisher

Springer Nature

ISSN

2157-9024

Rights Statement

© The Author(s) 2022 This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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