The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

Abstract

Matricellular proteins mediate pleiotropic effects during tissue injury and repair. CCN1 is a matricellular protein that has been implicated in angiogenesis, inflammation, and wound repair. In this study, we identified CCN1 as a gene that is differentially up-regulated in alveolar mesenchymal cells of human subjects with rapidly progressive idiopathic pulmonary fibrosis (IPF). Elevated levels of CCN1 mRNA were confirmed in lung tissues of IPF subjects undergoing lung transplantation, and CCN1 protein was predominantly localized to fibroblastic foci. CCN1 expression in ex vivo IPF lung fibroblasts correlated with gene expression of the extracellular matrix proteins, collagen (Col)1a1, Col1a2, and fibronectin as well as the myofibroblast marker, a-smooth muscle actin. RNA interference (RNAi)-mediated knockdown of CCN1 down-regulated the constitutive expression of these profibrotic genes in IPF fibroblasts. TGF-b1, a known mediator of tissue fibrogenesis, induces gene and protein expression of CCN1 via a mothers against decapentaplegic homolog 3 (SMAD3)-dependent mechanism. Importantly, endogenous CCN1 potentiates TGF-b1-induced SMAD3 activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In vivo RNAi-mediated silencing of CCN1 attenuates fibrogenic responses to bleomycin-induced lung injury. These studies support previously unrecognized, cooperative interaction between the CCN1 matricellular protein and canonical TGF-b1/SMAD3 signaling that promotes lung

YAP1 is an independent prognostic marker in pancreatic cancer and associated with extracellular matrix remodeling

“…To understand the biological role of YAP1 in pancreatic cancer, we performed bioinformatic analyses of protein networks. The results revealed that YAP1 is directly connected to secreted AREG, CTGF, CYR61, FGF1 and MSLN that are involved in fibrosis and other key signaling pathways involved in the tumor-stroma interactions [27][28][29][30][31].…”

GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

“…Interestingly, all 7 genes that were classified as synergistic were YAP/TAZ targets (Fig 1F, S2 Table) and 9/13 of the genes classified as additive (Fig 1F, S2 Table) were also shown to be regulated by YAP/TAZ [13,[46][47][48][49][50]. Among these genes, CTGF [51,52], IL11 [53], EDN1 [54], SERPINE1/PAI-1 [55], F3/tissue factor [56], CYR61 [57], KLF10 [58], ATF3 [59], FZD8/Frizzled-8 [59] and RUNX1 [60] have been shown to be important profibrotic mediators. Gene expression profiles of these genes are shown in Fig 1G. These results suggested that LPA and TGFβ1 signalling converges on YAP/TAZ and that YAP/TAZ could represent a central node to regulate fibrotic responses.…”

Therapeutic targets in fibrotic pathways

“…Additionally, research has shown several genetic hotspots, such as the MUC5B promoter, associate with a worsened phenotype (3). Extra-cellular matrix proteins such as integrins and matricellular proteins have been associated with fibrosis (4, 5). Most saliently important is the cytokine Transforming Growth Factor β (TGF-β), which is well accepted as a driver of cellular fibrosis (5, 6).…”