YAP1/Twist promotes fibroblast activation and lung fibrosis that conferred by miR-15a loss in IPF

Cell Death Differ. 2019 Sep;26(9):1832-1844. doi: 10.1038/s41418-018-0250-0. Epub 2019 Jan 15.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic parenchymal lung disease of unknown etiology and lack effective interventions. Using a combination of in vitro and in vivo studies, we found that overexpression of YAP1, a key effector in the Hippo pathway, promoted cell proliferation, migration, and collagen production in lung fibroblasts. Furthermore, the pro-fibrotic action of YAP1 was mediated by transcriptional activation of Twist1 through interacting with its partner TEAD. In contrast, knockdown of YAP1 inhibited extracellular matrix (ECM) deposition, which ultimately ameliorated lung fibrosis in vitro and in vivo. Additionally, we constructed a dysregulated miRNA regulatory network that affects the expression of the Hippo pathway effectors in IPF and identified miR-15a, which is significantly down-regulated in IPF patients, as one of the most essential miRNAs regulating this pathway. Moreover, knockdown of miR-15a resulted in fibroblast activation and lung fibrosis through promoting Twist expression by targeting inhibition of YAP1. In contrast, therapeutic restoration of miR-15a inhibits fibrogenesis in lung fibroblast and abrogated BLM-induced lung fibrosis in mice. These results highlight a role for miR-15a/YAP1/Twist axis in IPF that offer novel strategies for the prevention and treatment of lung fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Bleomycin / toxicity
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Differentiation / genetics
  • Cell Proliferation / genetics
  • Databases, Nucleic Acid
  • Disease Models, Animal
  • Extracellular Matrix / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibrosis
  • Humans
  • Idiopathic Pulmonary Fibrosis / chemically induced
  • Idiopathic Pulmonary Fibrosis / genetics
  • Idiopathic Pulmonary Fibrosis / metabolism*
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • RNA, Small Interfering
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta1 / metabolism
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • MIRN15 microRNA, human
  • MicroRNAs
  • Mirn15a microRNA, mouse
  • RNA, Small Interfering
  • Transcription Factors
  • Transforming Growth Factor beta1
  • Twist-Related Protein 1
  • YAP1 protein, human
  • Yap1 protein, mouse
  • Bleomycin