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The autocrine glycosylated-GREM1 interacts with TGFB1 to suppress TGFβ/BMP/SMAD-mediated EMT partially by inhibiting MYL9 transactivation in urinary carcinoma

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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.

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Data availability

The raw data used to support the conclusions of this article will be made available by the corresponding author, without undue reservation to any qualified researcher.

Abbreviations

5-aza :

5-Aza-2’-deoxycytidine

AKT1 :

AKT serine/threonine kinase 1

AMH :

Anti-Mullerian hormone

bHLHs :

Basic HLHs

BLCA :

Bladder urothelial carcinoma

BMP :

Bone morphogenetic protein

BMPR2 :

Bone morphogenetic protein receptor type 2

BrdU :

5-Bromo-2'-deoxyuridine

BRE :

BMP responsive element

BTRC :

Beta-transducin repeat containing E3 ubiquitin protein

CDH1 :

Cadherin 1

CDKN1A :

Cyclin-dependent kinase inhibitor 1 A

DAPK1 :

Death-associated protein kinase 1

DSS :

Disease-specific survival

EMT :

Epithelial-mesenchymal transition

FN1 :

Fibronectin 1

GDF :

Growth differentiation factors

GEO :

Gene Expression Omnibus

GREM1 :

Gremlin 1, DAN family BMP antagonist

GSEA :

Gene Set Enrichment Analysis

HUVEC :

Human umbilical vein endothelial cells

ID1 :

Inhibitor of DNA binding 1

IKBKB :

Nuclear factor kappa B kinase subunit beta

MFS :

Metastasis-free survival

MGMT :

O-6-methylguanine-DNA methyltransferase

MLH1 :

MutL homolog 1

MMP :

Matrix metalloproteinase

MTT :

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

MYL9 :

Myosin light chain 9

NFκB :

Nuclear factor kappa B

NFKBIA :

NFKB inhibitor alpha

NGF :

Nerve growth factor

NODAL :

Nodal growth differentiation factor

PDAC :

Pancreatic ductal adenocarcinoma

PDGF :

Platelet-derived growth factor

PI3K :

Phosphoinositide 3-kinase

PIK3CA :

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

RELA :

RELA proto-oncogene

RPKM :

Read per kilobase per million

shRNA :

Small hairpin RNA

SNAI1 :

Snail family transcriptional repressor 1

SRE :

SMAD responsive element

TCGA :

The Cancer Genome Atlas

TGFβ :

Transforming growth factor beta

TGFBR :

Transforming growth factor beta receptor

TNF :

Tumor necrosis factor

TNFRSF1B :

TNF receptor superfamily member 1B

TP53 :

Tumor protein p53

TRAF1 :

TNF receptor-associated factor 1

TWIST1 :

Twist family bHLH transcription factor 1

UBUC :

Urinary bladder urothelial carcinoma

UC :

Urothelial carcinoma

UTUC :

Upper tract urothelial carcinoma

VIM :

Vimentin

ZEB1 :

Zinc finger E-box binding homeobox 1

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Acknowledgements

We sincerely appreciate the technical assistance from Ms. SZ Dehghanian and Dr. TJ Chen.

Funding

The National Science and Technology Council (MOST-107–2314-B-110-MY3), NSYSU-KMU Joint Research Project (#NSYSUKMU 109-I008), Kaohsiung Armed Forces General Hospital (KAFGH-A-108021 & -109038), and Kaohsiung Medical University Research Center (KMU-TC111A02-0) supported this research.

Author information

Author notes

  1. Ti-Chun Chan and Cheng-Tang Pan contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Research, Chi-Mei Medical Center, Tainan, 71004, Taiwan

    Ti-Chun Chan & Chien-Feng Li

  2. National Institute of Cancer Research, National Health Research Institutes, Tainan, 71004, Taiwan

    Ti-Chun Chan & Chien-Feng Li

  3. Institute of Precision Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan

    Cheng-Tang Pan, Hsin-Yu Hsieh, Chien-Feng Li & Yow-Ling Shiue

  4. Department of Mechanical and Electro-Mechanical Engineering, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan

    Cheng-Tang Pan

  5. Institute of Advanced Semiconductor Packaging and Testing, College of Semiconductor and Advanced Technology Research, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan

    Cheng-Tang Pan

  6. Institute of Biomedical Sciences, College of Medicine, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan

    Hsin-Yu Hsieh, Pichpisith Pierre Vejvisithsakul & Yow-Ling Shiue

  7. Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand

    Pichpisith Pierre Vejvisithsakul

  8. Department of Pathology, Kaohsiung Armed Forces General Hospital, Kaohsiung, 80284, Taiwan

    Ren-Jie Wei

  9. Institute of Medical Science and Technology, School of Medicine, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan

    Ren-Jie Wei

  10. Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung, 83102, Taiwan

    Ren-Jie Wei

  11. Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan

    Bi-Wen Yeh & Wen-Jeng Wu

  12. Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan

    Bi-Wen Yeh & Wen-Jeng Wu

  13. Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan

    Wen-Jeng Wu

  14. Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan

    Wen-Jeng Wu

  15. Division of Physiology, Livestock Research Institute, Tainan, 71246, Taiwan

    Lih-Ren Chen

  16. Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand

    Meng-Shin Shiao

Authors
  1. Ti-Chun Chan
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  2. Cheng-Tang Pan
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  3. Hsin-Yu Hsieh
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  9. Meng-Shin Shiao
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  10. Chien-Feng Li
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  11. Yow-Ling Shiue
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Contributions

CFL, WJW, YLS conceived the concepts; CFL, CTP, YLS designed the experiments; TCC, CTP, HYH, PV, RJW, BWY, LRC, and MSS performed the experiments; CTP and CFL analyzed the data. CFL, CTP and YLS wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Chien-Feng Li or Yow-Ling Shiue.

Ethics declarations

Human data and samples were obtained with informed consent, and the use was approved (IRB10207-001) by the Institutional Review Board of the Chi Mei Medical Center, Tainan, Taiwan. Animal treatments (#10626) were performed according to the Institutional Animal Care and Use Committee of National Sun Yat-sen University (NSYSU) Protocol, and NSYSU approved all protocols. This study does not contain any studies involving human participants performed by any of the authors.

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The authors declare no competing interests.

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Chan, TC., Pan, CT., Hsieh, HY. et al. The autocrine glycosylated-GREM1 interacts with TGFB1 to suppress TGFβ/BMP/SMAD-mediated EMT partially by inhibiting MYL9 transactivation in urinary carcinoma. Cell Oncol. 46, 933–951 (2023). https://doi.org/10.1007/s13402-023-00788-8

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