The autocrine glycosylated-GREM1 interacts with TGFB1 to suppress TGFβ/BMP/SMAD-mediated EMT partially by inhibiting MYL9 transactivation in urinary carcinoma
Issued Date
2023-01-01
Resource Type
ISSN
22113428
eISSN
22113436
Scopus ID
2-s2.0-85149954488
Journal Title
Cellular Oncology
Rights Holder(s)
SCOPUS
Bibliographic Citation
Cellular Oncology (2023)
Suggested Citation
Chan T.C., Pan C.T., Hsieh H.Y., Vejvisithsakul P.P., Wei R.J., Yeh B.W., Wu W.J., Chen L.R., Shiao M.S., Li C.F., Shiue Y.L. The autocrine glycosylated-GREM1 interacts with TGFB1 to suppress TGFβ/BMP/SMAD-mediated EMT partially by inhibiting MYL9 transactivation in urinary carcinoma. Cellular Oncology (2023). doi:10.1007/s13402-023-00788-8 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/82324
Title
The autocrine glycosylated-GREM1 interacts with TGFB1 to suppress TGFβ/BMP/SMAD-mediated EMT partially by inhibiting MYL9 transactivation in urinary carcinoma
Author's Affiliation
School of Medicine
Chi Mei Medical Center
Taiwan Livestock Research Institute
Kaohsiung Medical University Chung-Ho Memorial Hospital
Military Kaohsiung General Hospital Taiwan
Faculty of Medicine Ramathibodi Hospital, Mahidol University
Kaohsiung Medical University
National Sun Yat-Sen University
College of Medicine
National Health Research Institutes Taiwan
Fooyin University Taiwan
Chi Mei Medical Center
Taiwan Livestock Research Institute
Kaohsiung Medical University Chung-Ho Memorial Hospital
Military Kaohsiung General Hospital Taiwan
Faculty of Medicine Ramathibodi Hospital, Mahidol University
Kaohsiung Medical University
National Sun Yat-Sen University
College of Medicine
National Health Research Institutes Taiwan
Fooyin University Taiwan
Other Contributor(s)
Abstract
Purpose: Urothelial carcinoma (UC) is a common disease in developed counties. This study aimed to identify autocrine roles and signaling pathways of gremlin 1, DAN family BMP antagonist (GREM1), which inhibits tumor growth and epithelial-mesenchymal transition (EMT) in UC. Methods: Systematic in vitro and in vivo studies using genetic engineering, different urinary bladder urothelial carcinoma (UBUC)-derived cell lines, and mouse models were performed, respectively. Further, primary upper tract urothelial carcinoma (UTUC) and UBUC specimens were evaluated by immunohistochemistry. Results: GREM1 protein levels conferred better disease-specific and metastasis-free survival rates and played an independent prognostic factor in UTUC and UBUC. Hypermethylation is the primary cause of low GREM1 levels. In different UBUC-derived cell lines, the autocrine/secreted and glycosylated GREM1 interacted with transforming growth factor beta 1 (TGFB1) and inhibited TGFβ/BMP/SMAD signaling and myosin light chain 9 (MYL9) transactivation, subsequently cell proliferation and epithelial-mesenchymal transition (EMT). Secreted and glycosylated GREM1 also suppressed tumor growth, metastasis, and MYL9 levels in the mouse model. Instead, cytosolic GREM1 promoted cell proliferation and EMT by activating the tumor necrosis factor (TNF)/AKT/nuclear factor kappa B (NFκB) axis. Conclusions: Clinical associations, animal models, and in vitro indications provided solid evidence to show that the epithelial autocrine GREM1 is a novel tumor suppressor in UCs. The glycosylated-GREM1 hampered cell proliferation, migration, invasion, and in vitro angiogenesis through interaction with TGFB1 to inactivate TGFβ/BMP/SMAD-mediated EMT in an autocrine manner.