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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.

Identification of Pparγ-modulated miRNA hubs that target the fibrotic tumor microenvironment.

Author information

1
Department for Molecular Biology, Interfaculty Institute of Cell Biology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
2
German Cancer Consortium, German Cancer Research Center, 69120 Heidelberg, Germany.
3
International Max Planck Research School, 72076 Tübingen, Germany.
4
Applied Bioinformatics, Department of Computer Science, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
5
Cancer Epigenomics, German Cancer Research Center, 69120 Heidelberg, Germany.
6
Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo), 44139 Dortmund, Germany.
7
Experimental Gene Therapy and Clinical Chemistry, Institute of Molecular Pathobiochemistry, University Hospital Aachen, 52074 Aachen, Germany.
8
Biomolecular Interactions, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
9
Translational Bioinformatics, University Hospital Tübingen, 72076 Tübingen, Germany.
10
Genome Analytics Unit, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany.
11
Department for Molecular Biology, Interfaculty Institute of Cell Biology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; alfred.nordheim@uni-tuebingen.de.
12
Leibniz Institute on Aging, 07745 Jena, Germany.

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.

KEYWORDS:

PPARγ; fibrosis; hepatocellular carcinoma; microRNAs

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