TGF-β signaling promotes desmoid tumor formation via CSRP2 upregulation.
Yu LiTeruaki FujishitaEmi Mishiro-SatoYasushi KojimaYanqing NiuMakoto Mark TaketoYuya UranoTomohisa SakaiAtsushi EnomotoYoshihiro NishidaMasahiro AokiPublished in: Cancer science (2023)
Desmoid tumors (DTs), also called desmoid-type fibromatoses, are locally aggressive tumors of mesenchymal origin. In the present study, we developed a novel mouse model of DTs by inducing a local mutation in the Ctnnb1 gene, encoding β-catenin in PDGFRA-positive stromal cells, by subcutaneous injection of 4-hydroxy-tamoxifen. Tumors in this model resembled histologically clinical samples from DT patients and showed strong phosphorylation of nuclear SMAD2. Knockout of SMAD4 in the model significantly suppressed tumor growth. Proteomic analysis revealed that SMAD4 knockout reduced the level of Cysteine-and-Glycine-Rich Protein 2 (CSRP2) in DTs, and treatment of DT-derived cells with a TGF-β receptor inhibitor reduced CSRP2 RNA levels. Knockdown of CSRP2 in DT cells significantly suppressed their proliferation. These results indicate that the TGF-β/CSRP2 axis is a potential therapeutic target for DTs downstream of TGF-β signaling.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- induced apoptosis
- signaling pathway
- cell cycle arrest
- mouse model
- end stage renal disease
- chronic kidney disease
- ejection fraction
- bone marrow
- prognostic factors
- oxidative stress
- gene expression
- single cell
- cell death
- genome wide
- peritoneal dialysis
- copy number
- climate change
- patient reported outcomes
- combination therapy
- small molecule
- estrogen receptor
- fluorescent probe
- patient reported
- positive breast cancer
- nucleic acid
- human health