Identification of Ppar <i>γ</i> -modulated miRNA hubs that target the fibrotic tumor microenvironment
Identification of Ppar <i>γ</i> -modulated miRNA hubs that target the fibrotic tumor microenvironment
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.
Extracellular Matrix/pathology [MeSH] ; PPAR gamma/metabolism [MeSH] ; Carcinoma, Hepatocellular/pathology ; Liver/pathology [MeSH] ; Lung Neoplasms/genetics [MeSH] ; Epigenesis, Genetic ; Breast Neoplasms/pathology ; Lung Neoplasms/genetics ; Carcinoma, Hepatocellular/genetics ; Liver Cirrhosis/pathology [MeSH] ; Extracellular Matrix/pathology ; Liver/cytology [MeSH] ; Liver/pathology ; MicroRNAs/genetics [MeSH] ; Disease Models, Animal [MeSH] ; Female [MeSH] ; DNA Methylation ; Humans [MeSH] ; Breast Neoplasms/genetics [MeSH] ; Lung Neoplasms/pathology ; CpG Islands/genetics ; Animals [MeSH] ; Gene Expression Regulation, Neoplastic ; Disease Models, Animal ; Datasets as Topic ; CpG Islands/genetics [MeSH] ; Liver/cytology ; Lung Neoplasms/pathology [MeSH] ; Promoter Regions, Genetic/genetics ; Hepatic Stellate Cells/pathology ; MicroRNAs/genetics ; Tumor Microenvironment/genetics [MeSH] ; Gene Expression Regulation, Neoplastic [MeSH] ; Breast Neoplasms/genetics ; Liver Neoplasms/genetics ; Tumor Microenvironment/genetics ; Female ; Liver Cirrhosis/pathology ; Mice ; Liver Neoplasms/pathology [MeSH] ; RNA-Seq [MeSH] ; Primary Cell Culture [MeSH] ; Liver Neoplasms/genetics [MeSH] ; Breast Neoplasms/pathology [MeSH] ; Liver Neoplasms/pathology ; Humans ; PPAR gamma/metabolism ; Datasets as Topic [MeSH] ; RNA-Seq ; Carcinoma, Hepatocellular/pathology [MeSH] ; Epigenesis, Genetic [MeSH] ; Promoter Regions, Genetic/genetics [MeSH] ; Mice [MeSH] ; Carcinoma, Hepatocellular/genetics [MeSH] ; DNA Methylation [MeSH] ; Hepatic Stellate Cells/pathology [MeSH] ; Animals ; Primary Cell Culture
Extracellular Matrix/pathology [MeSH] ; PPAR gamma/metabolism [MeSH] ; Carcinoma, Hepatocellular/pathology ; Liver/pathology [MeSH] ; Lung Neoplasms/genetics [MeSH] ; Epigenesis, Genetic ; Breast Neoplasms/pathology ; Lung Neoplasms/genetics ; Carcinoma, Hepatocellular/genetics ; Liver Cirrhosis/pathology [MeSH] ; Extracellular Matrix/pathology ; Liver/cytology [MeSH] ; Liver/pathology ; MicroRNAs/genetics [MeSH] ; Disease Models, Animal [MeSH] ; Female [MeSH] ; DNA Methylation ; Humans [MeSH] ; Breast Neoplasms/genetics [MeSH] ; Lung Neoplasms/pathology ; CpG Islands/genetics ; Animals [MeSH] ; Gene Expression Regulation, Neoplastic ; Disease Models, Animal ; Datasets as Topic ; CpG Islands/genetics [MeSH] ; Liver/cytology ; Lung Neoplasms/pathology [MeSH] ; Promoter Regions, Genetic/genetics ; Hepatic Stellate Cells/pathology ; MicroRNAs/genetics ; Tumor Microenvironment/genetics [MeSH] ; Gene Expression Regulation, Neoplastic [MeSH] ; Breast Neoplasms/genetics ; Liver Neoplasms/genetics ; Tumor Microenvironment/genetics ; Female ; Liver Cirrhosis/pathology ; Mice ; Liver Neoplasms/pathology [MeSH] ; RNA-Seq [MeSH] ; Primary Cell Culture [MeSH] ; Liver Neoplasms/genetics [MeSH] ; Breast Neoplasms/pathology [MeSH] ; Liver Neoplasms/pathology ; Humans ; PPAR gamma/metabolism ; Datasets as Topic [MeSH] ; RNA-Seq ; Carcinoma, Hepatocellular/pathology [MeSH] ; Epigenesis, Genetic [MeSH] ; Promoter Regions, Genetic/genetics [MeSH] ; Mice [MeSH] ; Carcinoma, Hepatocellular/genetics [MeSH] ; DNA Methylation [MeSH] ; Hepatic Stellate Cells/pathology [MeSH] ; Animals ; Primary Cell Culture
selected citations These citations are derived from selected sources.This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).0 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Average influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Average
Citations provided by BIP!Popularity provided by BIP!