Skip to main content
SpringerLink
Log in

GRWD1 Over-Expression Promotes Gastric Cancer Progression by Activating Notch Signaling Pathway via Up-Regulation of ADAM17

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Glutamate-rich WD repeat containing 1 (GRWD1) is over-expressed in a variety of malignant tumors and is considered to be a potential oncogene. However, its mechanism of action in gastric cancer (GC) is still unclear.

Methods

Data analysis, Immunohistochemistry, and Western Blot (WB) were performed to verify the expression of GRWD1 in GC and para-cancerous tissues. The association between GRWD1 expression and tumor size, tissue differentiation, lymph node metastasis, TNM stage, and prognosis was analyzed according to the high and low expression levels of GRWD1. The relationship between GRWD1 and Notch pathway was verified by data analysis and WB. The effects of GRWD1 on the proliferation, migration, and invasion of GC cells were verified by cell proliferation, migration, and invasion assays. We confirmed that the high expression of GRWD1 promoted the proliferation of GC cells in vivo through the tumor formation assay in nude mice.

Results

The expression of GRWD1 was higher in GC tissues than in para-cancerous tissues, and its expression was positively correlated with tumor size, lymph node metastasis, and TNM stage, but negatively correlated with differentiation grade and prognosis. GRWD1 over-expression increased ADAM metallopeptidase domain 17 (ADAM17) expression and promoted Notch1 intracellular domain (NICD) release to promote GC cell proliferation, migration, and invasion in vitro. Results from animal studies have shown that high GRWD1 expression could promote GC cell proliferation in vivo by activating the Notch signaling pathway.

Conclusion

GRWD1 promotes GC progression through ADAM17-dependent Notch signaling, and GRWD1 may be a novel tumor marker and therapeutic target.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Torre LA, Siegel RL, Ward EM, Jemal A. Global Cancer Incidence and Mortality Rates and Trends—An Update. Cancer Epidemiology, Biomarkers & Prevention. 2016;25:16–27.

    Article  Google Scholar 

  2. Ferlay J, Colombet M, Soerjomataram I et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144:1941–1953.

    Article  CAS  PubMed  Google Scholar 

  3. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA:A Cancer Journal for Clinicians. 2015; 65: 87–108.

  4. Feng F, Tian Y, Xu G, et al. Diagnostic and prognostic value of CEA, CA19–9, AFP and CA125 for early gastric cancer. Bmc Cancer. 2017; 17.

  5. Takafuji T, Kayama K, Sugimoto N, Fujita M. GRWD1, a new player among oncogenesis-related ribosomal/nucleolar proteins. Cell Cycle. 2017;16:1397–1403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. van Nocker S, Ludwig P. The WD-repeat protein superfamily in Arabidopsis: conservation and divergence in structure and function. Bmc Genomics. 2003;4:50.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sugimoto N, Maehara K, Yoshida K et al. Cdt1-binding protein GRWD1 is a novel histone-binding protein that facilitates MCM loading through its influence on chromatin architecture. Nucleic Acids Res. 2015;43:5898–5911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wu Y, Wu X, Li Y et al. Comprehensive Analysis of Glutamate-Rich WD Repeat-Containing Protein 1 and Its Potential Clinical Significance for Pancancer. Biomed Res Int. 2021;2021:1–16.

    CAS  Google Scholar 

  9. Kayama K, Watanabe S, Takafuji T et al. GRWD1 negatively regulates p53 via the RPL11-MDM2 pathway and promotes tumorigenesis. Embo Rep. 2017;18:123–137.

    Article  CAS  PubMed  Google Scholar 

  10. Killian A, Sarafan-Vasseur N, Sesboüé R et al. Contribution of theBOP1 gene, located on 8q24, to colorectal tumorigenesis. Genes, Chromosomes and Cancer. 2006;45:874–881.

    Article  CAS  PubMed  Google Scholar 

  11. Zhou X, Shang J, Liu X et al. Clinical Significance and Oncogenic Activity of GRWD1 Overexpression in the Development of Colon Carcinoma. Onco Targets Ther. 2021;14:1565–1580.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Wang Q, Ren H, Xu Y et al. GRWD1 promotes cell proliferation and migration in non-small cell lung cancer by activating the Notch pathway. Exp Cell Res. 2020;387:111806.

    Article  CAS  PubMed  Google Scholar 

  13. Yao L, Tian F. GRWD1 affects the proliferation, apoptosis, invasion and migration of triple negative breast cancer through the Notch signaling pathway. Exp Ther Med. 2022;24:473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fabbri G, Rasi S, Rossi D et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011;208:1389–1401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mollen EWJ, Ient J, Tjan-Heijnen VCG, et al.. Moving Breast Cancer Therapy up a Notch. Front Oncol. 2018; 8.

  16. Robinson DR, Kalyana-Sundaram S, Wu Y et al. Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nat Med. 2011;17:1646–1651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lim JS, Ibaseta A, Fischer MM et al. Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer. Nature. 2017;545:360–364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Andersson ER, Lendahl U. Therapeutic modulation of Notch signalling — are we there yet? Nat Rev Drug Discov. 2014;13:357–378.

    Article  CAS  PubMed  Google Scholar 

  19. Niessen K, Fu Y, Chang L, Hoodless PA, McFadden D, Karsan A. Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J Cell Biol. 2008;182:315–325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137:216–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kalantari E, Saeidi H, Kia NS et al. Effect of DAPT, a gamma secretase inhibitor, on tumor angiogenesis in control mice. Adv Biomed Res. 2013;2:83.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Liu X, Xu Q, Xie W, Wang M. DAPT suppresses the proliferation of human glioma cell line SHG-44. Asian Pac j Trop Med. 2014;7:552–556.

    Article  CAS  PubMed  Google Scholar 

  23. Ichikawa MK, Saitoh M. Direct and indirect roles of GRWD1 in the inactivation of p53 in cancer. The Journal of Biochemistry. 2022;171:601–603.

    Article  CAS  PubMed  Google Scholar 

  24. Vousden KH, Prives C. Blinded by the Light: The Growing Complexity of p53. Cell. 2009;137:413–431.

    Article  CAS  PubMed  Google Scholar 

  25. Riley T, Sontag E, Chen P, Levine A. Transcriptional control of human p53-regulated genes. Nature reviews. Molecular Cell Biology. 2008;9:402–412.

    Article  CAS  PubMed  Google Scholar 

  26. Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009;9:749–758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Watanabe S, Fujiyama H, Takafuji T, et al.. Glutamate-rich WD40 repeat containing 1 regulates ribosomal protein L23 levels via the ubiquitin-proteasome system. J Cell Sci. 2018.

  28. Wang H, Zang C, Liu XS, Aster JC. The Role of Notch Receptors in Transcriptional Regulation. J Cell Physiol. 2015;230:982–988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang R, Li Y, Tsung A, et al.. iNOS promotes CD24+ CD133+ liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway. Proceedings of the National Academy of Sciences. 2018; 115.

  30. Delwig A, Rand MD. Kuz and TACE can activate Notch independent of ligand. Cell Mol Life Sci. 2008;65:2232–2243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Katoh M, Katoh M. WNT antagonist, DKK2, is a Notch signaling target in intestinal stem cells: augmentation of a negative regulation system for canonical WNT signaling pathway by the Notch-DKK2 signaling loop in primates. Int J Mol Med. 2007;19:197.

    CAS  PubMed  Google Scholar 

  32. Xu Y, Ren H, Jiang J et al. KIAA0247 inhibits growth, migration, invasion of non-small-cell lung cancer through regulating the Notch pathway. Cancer Sci. 2018;109:1055–1065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang Y, Zhong Y, Hou T, et al.. PM2.5 induces EMT and promotes CSC properties by activating Notch pathway in vivo and vitro. Ecotox Environ Safe. 2019; 178: 159–67.

  34. Zou Y, Yang R, Huang M, et al.. NOTCH2 negatively regulates metastasis and epithelial-Mesenchymal transition via TRAF6/AKT in nasopharyngeal carcinoma. J Exp Clin Canc Res. 2019; 38.

Download references

Acknowledgments

Thanks to the help of all members of Jingtao Lu Laboratory

Funding

This study was funded by the Key Research and Development Project of Anhui Provincial Department of Science and Technology (202004j07020036), Annual scientific research projects in Colleges and Universities of Anhui Provincial Department of Education (2022AH050779), and the Wu Jieping Medical Fund (320.6750.19092-19).

Author information

Author notes

  1. Huiming Ding and Zhenyou Feng are co-authors.

Authors and Affiliations

  1. Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, No. 218, Jixi Road, Shushan District, Hefei, 230022, China

    Huiming Ding, Zhenyou Feng & Kongwang Hu

  2. Department of General Surgery, Fuyang Hospital of Anhui Medical University, Fuyang, China

    Kongwang Hu

Authors
  1. Huiming Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhenyou Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kongwang Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Ding Huiming designed the study. Ding Huiming and Feng Zhenyou carried out data statistics, experimental verifi cation, and sorted out the data results. Hu Kongwang provided research ideas, participated in the research design, and determined the final research scheme. Hu Kongwang and Ding Huiming prepared the manuscript, and all authors have read and approved the final manuscript.

Corresponding author

Correspondence to Kongwang Hu.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest in this study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ding, H., Feng, Z. & Hu, K. GRWD1 Over-Expression Promotes Gastric Cancer Progression by Activating Notch Signaling Pathway via Up-Regulation of ADAM17. Dig Dis Sci 69, 821–834 (2024). https://doi.org/10.1007/s10620-023-08208-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-023-08208-5

Keywords

Search

Navigation