Activation of TGF-β1-CD147 positive feedback loop in hepatic stellate cells promotes liver fibrosis

Abstract

Activation of hepatic stellate cells (HSCs) by transforming growth factor-β1 (TGF-β1) initiates HBV-associated fibrogenesis. The mechanism of TGF-β1 modulating HSC activation is not fully uncovered. We hypothesized a positive feedback signaling loop of TGF-β1-CD147 promoting liver fibrogenesis by activation of HSCs. Human HSC cell line LX-2 and spontaneous liver fibrosis model derived from HBV transgenic mice were used to evaluate the activation of molecules in the signaling loop. Wound healing and cell contraction assay were performed to detect the CD147-overexpressed HSC migration and contraction. The transcriptional regulation of CD147 by TGF-β1/Smad4 was determined using dual-luciferase reporter assay and chromatin immunoprecipitation. We found that a positive reciprocal regulation between TGF-β1 and CD147 mediated HSC activation. CD147 over-expression promoted HSC migration and accelerated TGF-β1-induced cell contraction. Phosphorylation of Smad2 and Smad3 in cooperation with Smad4 mediated the TGF-β1-regulated CD147 expression. Smad4 activated the transcription by direct interaction with CD147 promoter. Meanwhile, CD147 modulated the activated phenotype of HSCs through the ERK1/2 and Sp1 which up-regulated α-SMA, collagen I, and TGF-β1 synthesis. These findings indicate that TGF-β1-CD147 loop plays a key role in regulating the HSC activation and combination of TGF-β receptor inhibitor and anti-CD147 antibody might be promised to reverse fibrogenesis.

TGF-β signaling controls FSHR signaling-reduced ovarian granulosa cell apoptosis through the SMAD4/miR-143 axis

“…It has been recently reported that the TGF- β 1-activated SMAD4 complex may upregulate CD147 expression by directly interacting with a specific SBE in the CD147 promoter, thereby controlling HSC migration. 52 Here, we identified two SBEs in the miR-143 promoter and demonstrated that SMAD4 decreased miR-143 expression in pGCs by binding to SBE2 in its promoter. Interestingly, a recent study demonstrated that blockade of TGF- β signaling decreases the miR-143 level in smooth muscle cells.…”

“…49, 50 SMAD4 can complete extracellular TGF- β signal transmission by combining with SBEs of target promoters. 51, 52 TGF- β signaling has an important role during epithelial–mesenchymal transition. Specifically, binding of SMAD4 to the SBE within the promoter region of the CAR gene in breast epithelial cells 50 and the CDH2 gene in human pancreatic ductal epithelium 53 and non-small cell lung cancer cells 51 is necessary for TGF- β -stimulated transcription.…”

Targeting Mechanotransduction at the Transcriptional Level: YAP and BRD4 Are Novel Therapeutic Targets for the Reversal of Liver Fibrosis

“…Through autocrine and paracrine mechanisms, extracellular matrix components such as MMPs, fibrillary collagens and proteoglycans promote growth factor (mainly PDGF) and cytokine signaling. This signaling, particularly through the transforming growth factor-beta (TGF-β) and Wnt pathways, further activates HSCs, thus creating a positive, profibrotic feedback loop (Figure 1, Karsdal et al, 2015; Li et al, 2015). Ultimately, mechanotransduction- and growth factor-induced gene regulation by transcriptional regulators such as YAP and BRD4 mediate fibroproliferative disease and represents a unique target for pharmacological intervention for patients with liver fibrosis.…”

Aberrant SSEA-4 upregulation mediates myofibroblast activity to promote pre-cancerous oral submucous fibrosis

“…Numerous key profibrotic cytokines components of EMT have been identified, such as transforming growth factor-β (TGF-β), platelet-derived growth factor, and IGF-132. TGF-β, a multifunction cytokine, plays crucial roles in EMT program and fibrosis33343536. Arecoline could promote the transdifferentiation of human BMFs into myofibroblasts through activating integrin αvβ6/TGF-β1 signaling8.…”