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PDGF receptor-? promotes TGF-? signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-? receptors.

ABSTRACT: Platelet-derived growth factor (PDGF) and transforming growth factor-? (TGF-?) signaling are required for hepatic stellate cell (HSC) activation under pathological conditions such as liver metastatic tumor growth. These two signaling pathways are functionally divergent; PDGF signaling promotes proliferation and migration of HSCs, and TGF-? induces transdifferentiation of quiescent HSCs into myofibroblasts. Although PDGF signaling is implicated in TGF-?-mediated epithelial mesenchymal transition of tumor cells, the role of PDGF receptors in TGF-? activation of HSCs has not been investigated. Here we report that PDGF receptor-? (PDGFR-?) is required for TGF-? signaling of cultured human HSCs although HSCs express both PDGF-? and -? receptors. PDGFR-? knockdown inhibits TGF-?-induced phosphorylation and nuclear accumulation of SMAD2 with no influence on AKT or ERK phosphorylation associated with noncanonical TGF-? signaling. PDGFR-? knockdown suppresses TGF-? receptor I (T?RI) but increases T?RII gene transcription. At the protein level, PDGFR-? is recruited to T?RI/T?RII complexes by TGF-? stimulation. PDGFR-? knockdown blocks TGF-?-mediated internalization of T?RII and induces accumulation of T?RII at the plasma membrane, thereby inhibiting TGF-? phosphorylation of SMAD2. Functionally, knockdown of PDGFR-? reduces paracrine effects of HSCs on colorectal cancer cell proliferation and migration in vitro. In mice and patients, colorectal cancer cell invasion of the liver induces upregulation of PDGFR-? of HSCs. In summary, our finding that PDGFR-? knockdown inhibits SMAD-dependent TGF-? signaling by repressing T?RI transcriptionally and blocking endocytosis of TGF-? receptors highlights a convergence of PDGF and TGF-? signaling for HSC activation and PDGFR-? as a therapeutic target for liver metastasis and other settings of HSC activation.

SUBMITTER: Liu C

PROVIDER: S-EPMC4187064 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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PDGF receptor-α promotes TGF-β signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-β receptors.

Liu Chunsheng C Li Jiachu J Xiang Xiaoyu X Guo Luyang L Tu Kangsheng K Liu Qinghua Q Shah Vijay H VH Kang Ningling N

American journal of physiology. Gastrointestinal and liver physiology 20140828 7

Platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) signaling are required for hepatic stellate cell (HSC) activation under pathological conditions such as liver metastatic tumor growth. These two signaling pathways are functionally divergent; PDGF signaling promotes proliferation and migration of HSCs, and TGF-β induces transdifferentiation of quiescent HSCs into myofibroblasts. Although PDGF signaling is implicated in TGF-β-mediated epithelial mesenchymal transition ...[more]

PMID: 25169976

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Project description:BACKGROUND:Hepatic fibrosis is caused by chronic liver injury and may progress toward liver cirrhosis, and even hepatocellular carcinoma. However, current treatment is not satisfactory. Therefore, there is a mandate to find novel therapeutic targets to improve therapy, and biomarkers to monitor therapeutic response. METHODS:Liver fibrosis was induced by carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild type (WT) or CTHRC1-/- mice, followed by immunofluorescence and immunohistochemical analyses. CTHRC1 monoclonal antibody (mAb) was used to abrogate the effect of CTHRC1 in vitro and in vivo. RESULTS:Here, we reported that collagen triple helix repeat containing 1 (CTHRC1), a secreted protein derived from hepatic stellate cells (HSCs), was significantly up-regulated in fibrotic liver tissues. CTHRC1 promoted HSCs transformation from a quiescent to an activated state, and enhanced migratory or contractile capacities of HSCs by activating TGF-? signaling. Meanwhile, CTHRC1 competitively bound to Wnt noncononical receptor and promoted the contractility but not activation of HSCs. CCl4 or TAA-induced liver fibrosis was attenuated in CTHRC-/- mice compared with littermate control, while a monoclonal antibody of CTHRC1 suppressed liver fibrosis in WT mice treated with CCl4 or TAA. INTERPRETATION:We demonstrated that CTHRC1 is a new regulator of liver fibrosis by modulating TGF-? signaling. Targeting CTHRC1 could be a promising therapeutic approach, which can suppress TGF-? signaling and avoid the side effects caused by directly targeting TGF-?. CTHRC1 could also be a potential biomarker for monitoring response to anti-fibrotic therapy. FUND: This study was supported by the National Natural Science Foundation of China (ID 81672358, 81871923, 81872242, 81802890), the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (ID 20181708), the Natural Science Foundation of Shanghai (ID 17ZR1428300, 18ZR1436900), and Shanghai Municipal Health Bureau (ID 2018BR32). The funders did not play a role in manuscript design, data collection, data analysis, interpretation nor writing of the manuscript.

Dataset Information

PDGF receptor-? promotes TGF-? signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-? receptors.

Publications

PDGF receptor-α promotes TGF-β signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-β receptors.

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