TGF-β signaling promotes desmoid tumor formation via CSRP2 upregulation.

Autor: Li Y; Division of Pathophysiology, Aichi Cancer Center Research Institute, Nagoya, Japan.; Department of Plastic Reconstructive Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan., Fujishita T; Division of Pathophysiology, Aichi Cancer Center Research Institute, Nagoya, Japan., Mishiro-Sato E; Division of Pathophysiology, Aichi Cancer Center Research Institute, Nagoya, Japan.; Molecular Structure Center, Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya, Japan., Kojima Y; Division of Pathophysiology, Aichi Cancer Center Research Institute, Nagoya, Japan., Niu Y; Division of Pathophysiology, Aichi Cancer Center Research Institute, Nagoya, Japan., Taketo MM; Colon Cancer Project, Kyoto University Hospital-iACT, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Urano Y; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Sakai T; Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan., Enomoto A; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Nishida Y; Department of Rehabilitation, Nagoya University Hospital, Nagoya, Japan., Aoki M; Division of Pathophysiology, Aichi Cancer Center Research Institute, Nagoya, Japan.; Department of Cancer Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Jazyk: angličtina
Zdroj: Cancer science [Cancer Sci] 2024 Feb; Vol. 115 (2), pp. 401-411. Date of Electronic Publication: 2023 Dec 01.
DOI: 10.1111/cas.16037
Abstrakt: 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.
(© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
Databáze: MEDLINE
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