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Title: MicroRNA-21 is immunosuppressive and pro-metastatic via separate mechanisms.
Austin Authors: Chi, Lap Hing;Cross, Ryan S N;Redvers, Richard P;Davis, Melissa;Hediyeh-Zadeh, Soroor;Mathivanan, Suresh;Samuel, Monisha;Lucas, Erin C;Mouchemore, Kellie;Gregory, Philip A;Johnstone, Cameron N ;Anderson, Robin L 
Affiliation: Olivia Newton-John Cancer Research Institute
Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia..
Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia..
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia..
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia..
Division of Immunology and Allergy, Department of Medicine, Karolinska Institute, Solna, Sweden..
School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia..
Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia..
Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia..
Peter MacCallum Cancer Centre, Parkville, VIC, Australia..
Issue Date: 11-Jul-2022
Date: 2022
Publication information: Oncogenesis 2022; 11(1): 38
Abstract: 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.
DOI: 10.1038/s41389-022-00413-7
ORCID: 0000-0002-6464-8661
Journal: Oncogenesis
PubMed URL: 35821197
ISSN: 2157-9024
Type: Journal Article
Appears in Collections:Journal articles

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