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Identification of Ppar-modulated miRNA hubs that target the fibrotic tumor microenvironment.
Winkler, Ivana Bitter, Catrin Winkler, Sebastian Weichenhan, Dieter Thavamani, Abhishek Hengstler, Jan G Borkham-Kamphorst, Erawan Kohlbacher, Oliver Plass, Christoph Geffers, Robert
Winkler, Ivana
Bitter, Catrin
Winkler, Sebastian
Weichenhan, Dieter
Thavamani, Abhishek
Hengstler, Jan G
Borkham-Kamphorst, Erawan
Kohlbacher, Oliver
Plass, Christoph
Geffers, Robert
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2020-01-07
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Abstract
Liver fibrosis interferes with normal liver function and facilitates hepatocellular carcinoma (HCC) development, representing a major threat to human health. Here, we present a comprehensive perspective of microRNA (miRNA) function on targeting the fibrotic microenvironment. Starting from a murine HCC model, we identify a miRNA network composed of 8 miRNA hubs and 54 target genes. We show that let-7, miR-30, miR-29c, miR-335, and miR-338 (collectively termed antifibrotic microRNAs [AF-miRNAs]) down-regulate key structural, signaling, and remodeling components of the extracellular matrix. During fibrogenic transition, these miRNAs are transcriptionally regulated by the transcription factor Pparγ and thus we identify a role of Pparγ as regulator of a functionally related class of AF-miRNAs. The miRNA network is active in human HCC, breast, and lung carcinomas, as well as in 2 independent mouse liver fibrosis models. Therefore, we identify a miRNA:mRNA network that contributes to formation of fibrosis in tumorous and nontumorous organs of mice and humans.
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Proc Natl Acad Sci U S A. 2020 Jan 7;117(1):454-463. doi: 10.1073/pnas.1909145117. Epub 2019 Dec 23.
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1091-6490
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Attribution-NonCommercial-ShareAlike 4.0 International