ABSTRACT
Hippo signaling pathway is considered a key regulator of tissue homeostasis, cell proliferation, apoptosis and it is involved in cancer development. In skeletal muscle, YAP, a downstream target of the Hippo pathway, is an important player in myoblast proliferation, atrophy/hypertrophy regulation, and in mechano-trasduction, transferring mechanical signals into transcriptional responses. We studied components of Hippo pathway in muscle specimens from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy type 2A and type 2B and healthy subjects. Only DMD muscles had decreased YAP1 protein expression, increased LATS1/2 kinase activity, low Survivin mRNA expression and high miR-21 expression. In light of our novel results, a schematic model is postulated: low levels of YOD1 caused by increased inhibition by miR-21 lead to an increase of LATS1/2 activity which in turn augments phosphorylation of YAP. Reduced amount of active YAP, which is also a target of increased miR-21, causes decreased nuclear expression of YAP-mediated target genes. Since it is known that YAP has beneficial roles in promoting tissue repair and regeneration after injury so that its activation may be therapeutically useful, our results suggest that some components of Hippo pathway could become novel therapeutic targets for DMD treatment.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , MicroRNAs/metabolism , Muscular Dystrophy, Duchenne/metabolism , Phosphoproteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Survivin/metabolism , Adolescent , Adult , Animals , Cell Cycle Proteins , Child , Child, Preschool , Humans , Mice, Inbred C57BL , Mice, Transgenic , Middle Aged , Muscle, Skeletal/metabolism , Muscular Dystrophies, Limb-Girdle/metabolism , RNA, Messenger/metabolism , Signal Transduction , Transcription Factors , YAP-Signaling Proteins , Young AdultABSTRACT
Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer and is among the leading causes of cancer-related mortality worldwide. Although the dysregulation of microRNAs (miRNAs or miRs) has often been reported in HCC, the precise molecular mechanisms by which miRNAs modulate the process of tumorigenesis and the behavior of cancer cells are not yet clearly understood. In this study, we identified a novel threemiRNA signature, including miR371-5p, miR373 and miR543, that appears to orchestrate programmed cell necrosis in HCC by directly targeting the caspase8 gene (Casp8). Our results demonstrated that miR371-5p, miR373 and miR543 were overexpressed in HCC tissues compared with paired adjacent normal tissues. The upregulation of these miRNAs specifically and markedly downregulated the expression of Casp8, as well as significantly enhanced the Z-VAD/TNFα-induced necroptosis of HCC cells. By contrast, the selective knockdown of miRNA expression led to a significant increase in Casp8 levels and a marked reduction in programmed cell necrosis. Intriguingly, the sustained overexpression of Casp8 reversed the pronecroptotic effects exerted by miRNA mimics. Finally, a strong inverse association between the level of miR223 and the expression levels of nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing-3 inflammasome was observed in our HCC specimens. On the whole, the present study revealed a molecular link between the threemiRNA signature, comprising miR371-5p, miR373 and miR543, and the negative necroptotic regulator Casp8, and presents evidence for its employment as a novel potential diagnostic, prognostic and therapeutic target in HCC.
