title: PDGF receptor-α promotes TGF-β signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-β receptors.
abstract: 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 of tumor cells, the role of PDGF receptors in TGF-β activation of HSCs has not been investigated. Here we report that PDGF receptor-α (PDGFR-α) is required for TGF-β signaling of cultured human HSCs although HSCs express both PDGF-α and -β receptors. PDGFR-α knockdown inhibits TGF-β-induced phosphorylation and nuclear accumulation of SMAD2 with no influence on AKT or ERK phosphorylation associated with noncanonical TGF-β signaling. PDGFR-α knockdown suppresses TGF-β receptor I (TβRI) but increases TβRII gene transcription. At the protein level, PDGFR-α is recruited to TβRI/TβRII complexes by TGF-β stimulation. PDGFR-α knockdown blocks TGF-β-mediated internalization of TβRII and induces accumulation of TβRII at the plasma membrane, thereby inhibiting TGF-β phosphorylation of SMAD2. Functionally, knockdown of PDGFR-α 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-α of HSCs. In summary, our finding that PDGFR-α knockdown inhibits SMAD-dependent TGF-β signaling by repressing TβRI transcriptionally and blocking endocytosis of TGF-β receptors highlights a convergence of PDGF and TGF-β signaling for HSC activation and PDGFR-α as a therapeutic target for liver metastasis and other settings of HSC activation.
authors.affiliation: GI Research Unit and Cancer Cell Biology Program, Mayo Clinic, Rochester, Minnesota;
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: GI Research Unit and Cancer Cell Biology Program, Mayo Clinic, Rochester, Minnesota; Tumor Microenvironment and Metastasis Section, the Hormel Institute/University of Minnesota, Austin, Minnesota; Department of Oncology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China;
authors.forename: Jiachu
authors.initials: J
authors.lastname: Li
authors.affiliation: Tumor Microenvironment and Metastasis Section, the Hormel Institute/University of Minnesota, Austin, Minnesota;
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Xiang
authors.affiliation: Tumor Microenvironment and Metastasis Section, the Hormel Institute/University of Minnesota, Austin, Minnesota;
authors.forename: Luyang
authors.initials: L
authors.lastname: Guo
authors.affiliation: GI Research Unit and Cancer Cell Biology Program, Mayo Clinic, Rochester, Minnesota; Department of Hepatobillary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Kangsheng
authors.initials: K
authors.lastname: Tu
authors.affiliation: GI Research Unit and Cancer Cell Biology Program, Mayo Clinic, Rochester, Minnesota;
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Liu
authors.affiliation: GI Research Unit and Cancer Cell Biology Program, Mayo Clinic, Rochester, Minnesota;
authors.forename: Vijay H
authors.initials: VH
authors.lastname: Shah
authors.affiliation: GI Research Unit and Cancer Cell Biology Program, Mayo Clinic, Rochester, Minnesota; Tumor Microenvironment and Metastasis Section, the Hormel Institute/University of Minnesota, Austin, Minnesota; nkang@hi.umn.edu.
authors.forename: Ningling
authors.initials: N
authors.lastname: Kang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D019073:HT29 Cells; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary; D016513:Mice, SCID; D019899:Paracrine Communication; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: colorectal liver metastasis; gene transcription; myofibroblasts; receptor endocytosis and trafficking; tumor microenvironment