Identification of Ppar γ -modulated miRNA hubs that target the fibrotic tumor microenvironment

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.

Network and systems based re-engineering of dendritic cells with non-coding RNAs for cancer immunotherapy

“…Among the identified miRNAs there were several, such as miR-15a-5p, miR-16-5p, miR-20a-5p, and miR-424-5p, which target a considerable number of genes. Such hubs have been shown to be important regulators, as they represent sites of signalling convergence in gene regulatory networks and coordinate cell development and function (87)(88)(89). In contrast, other DE miRNAs, such as miR-15a-3p and miR-9-3p, exert a narrow function by regulating the expression of specific protein-coding genes in the caIKK-DCs.…”

Non-Coding RNAs: Regulating Disease Progression and Therapy Resistance in Hepatocellular Carcinoma

“…Similarly let-7 family was also shown to be downregulated in HCV-associated HCC [110]. The let-7 family was identified as a component of a miRNA hub that are transcriptionally regulated by PPARγ and target fibrogenic genes [111]. During liver fibrosis these miRNAs are downregulated and thus were collectively termed as anti-fibrotic miRNAs.…”

Molecular Mechanisms to Target Cellular Senescence in Hepatocellular Carcinoma

“…Since chronic liver injury triggers inflammatory and wound-healing processes and in consequence hepatic fibrosis that may progress to cirrhosis if not treated successfully, it essentially contributes to hepatocarcinogenesis [119][120][121]. There is mounting evidence that SRF and MRTFs play an important role in liver fibrosis as HCC tumor tissue derived from livers of SRF-VP16 iHep mice expressing a constitutively active variant of SRF shows a stronger fibrotic microenvironment with increased collagen depositions than the precancerous nodular tissue [122]. From this murine HCC model, a crucial function of miRNAs in controlling liver fibrosis was recently uncovered [122].…”

“…There is mounting evidence that SRF and MRTFs play an important role in liver fibrosis as HCC tumor tissue derived from livers of SRF-VP16 iHep mice expressing a constitutively active variant of SRF shows a stronger fibrotic microenvironment with increased collagen depositions than the precancerous nodular tissue [122]. From this murine HCC model, a crucial function of miRNAs in controlling liver fibrosis was recently uncovered [122]. A network of miRNAs was revealed to regulate remodeling, signaling and structural components of the fibrotic extracellular matrix (ECM) [122].…”

“…From this murine HCC model, a crucial function of miRNAs in controlling liver fibrosis was recently uncovered [122]. A network of miRNAs was revealed to regulate remodeling, signaling and structural components of the fibrotic extracellular matrix (ECM) [122]. ECM remodeling triggers a positive feedback loop that leads to nuclear translocation of MRTFs and the transcriptional coactivator Yes-associated protein (YAP), resulting in increased expression of MRTF/YAP dependent target genes [123].…”