Endocrine Pathology

, Volume 30, Issue 1, pp 1–7 | Cite as

Increased Expression of GARP in Papillary Thyroid Carcinoma

  • Xiaoxu Zhang
  • Miao Guo
  • Jing Yang
  • Yuxiao Zheng
  • Yanjie Xiao
  • Wei LiuEmail author
  • Fu RenEmail author


Regulatory T cells (Tregs) are immunosuppressive immune cells that play an important role in tumor development. Suppression of Treg function is considered to be an effective strategy for cancer therapy. Glycoprotein A repetitions predominant (GARP) has been found on the surface of activated Tregs. GARP has been recently observed in only a few solid tumors including breast, colon, lung cancers, and melanoma. However, its function in cancers remains unknown. Here, we investigated the expression of GARP in human papillary thyroid carcinoma (PTC) and its prognostic significance. In this study, immunohistochemistry was performed to examine the expression of GARP and Foxp3 in 19 human PTC tissues (including 10 cases with and 9 cases without lymph node metastasis) and 20 benign thyroid diseases (including 10 cases with nodular goiter and 10 cases with adenoma). Compared with benign thyroid diseases, we found a significant increase in the expression of GARP in PTC. Increased GARP expression in PTC was positively correlated with increased expression of Foxp3, which is very important for development of Tregs. But, there is no significant association of elevated expression of GARP with lymph node metastasis in PTC. Our results indicate that GARP is implicated in the development of PTC and might be a potential novel target for anticancer therapy. In addition, our findings further support the existence of a positive-feedback loop between GARP and Foxp3.


GARP Foxp3 Papillary thyroid carcinoma Thyroid Cancer 



The authors thank Dr. Fengjie Qi for her confirmation of the pathological diagnosis of the patients. This study was supported by the high talent support program project of Jinzhou Medical University (2015RC011).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

The study was approved by the Ethics Committee of Jinzhou Medical University.


  1. 1.
    Chen, W., Zheng, R., Baade, P. D., Zhang, S., Zeng, H., Bray, F., Jemal, A., Yu, X. Q. & He, J. (2016) Cancer statistics in China, 2015, CA: a cancer journal for clinicians. 66, 115–132.Google Scholar
  2. 2.
    Siegel, R. L., Miller, K. D. & Jemal, A. (2016) Cancer statistics, 2016, CA: a cancer journal for clinicians. 66, 7–30.Google Scholar
  3. 3.
    Lim, H., Devesa, S. S., Sosa, J. A., Check, D. & Kitahara, C. M. (2017) Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013, JAMA. 317, 1338–1348.CrossRefGoogle Scholar
  4. 4.
    Davies, L., Morris, L. G., Haymart, M., Chen, A. Y., Goldenberg, D., Morris, J., Ogilvie, J. B., Terris, D. J., Netterville, J., Wong, R. J. & Randolph, G. (2015) American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: The Increasing Incidence of Thyroid Cancer, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 21, 686–696.CrossRefGoogle Scholar
  5. 5.
    Penna, G. C., Vaisman, F., Vaisman, M., Sobrinho-Simoes, M. & Soares, P. (2016) Molecular Markers Involved in Tumorigenesis of Thyroid Carcinoma: Focus on Aggressive Histotypes, Cytogenetic and genome research. 150, 194–207.CrossRefGoogle Scholar
  6. 6.
    Aliagas, E., Vidal, A., Texido, L., Ponce, J., Condom, E. & Martin-Satue, M. (2014) High expression of ecto-nucleotidases CD39 and CD73 in human endometrial tumors, Mediators of inflammation. 2014, 509027.CrossRefGoogle Scholar
  7. 7.
    Ruiz-Arguelles, G. J. & San Miguel, J. F. (1994) Cell surface markers in multiple myeloma, Mayo Clinic proceedings. 69, 684–690.CrossRefGoogle Scholar
  8. 8.
    Ryzhov, S. V., Pickup, M. W., Chytil, A., Gorska, A. E., Zhang, Q., Owens, P., Feoktistov, I., Moses, H. L. & Novitskiy, S. V. (2014) Role of TGF-beta signaling in generation of CD39+CD73+ myeloid cells in tumors, Journal of immunology. 193, 3155–3164.CrossRefGoogle Scholar
  9. 9.
    Hori, S., Nomura, T. & Sakaguchi, S. (2003) Control of regulatory T cell development by the transcription factor Foxp3, Science. 299, 1057–1061.CrossRefGoogle Scholar
  10. 10.
    Gavin, M. A., Torgerson, T. R., Houston, E., DeRoos, P., Ho, W. Y., Stray-Pedersen, A., Ocheltree, E. L., Greenberg, P. D., Ochs, H. D. & Rudensky, A. Y. (2006) Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development, Proceedings of the National Academy of Sciences of the United States of America. 103, 6659–6664.CrossRefGoogle Scholar
  11. 11.
    Ramsdell, F. & Ziegler, S. F. (2014) FOXP3 and scurfy: how it all began, Nature Reviews Immunology. 14, 343–349.CrossRefGoogle Scholar
  12. 12.
    Tran, D. Q., Ramsey, H. & Shevach, E. M. (2007) Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype, Blood. 110, 2983–2990.CrossRefGoogle Scholar
  13. 13.
    Ollendorff, V., Noguchi, T., deLapeyriere, O. & Birnbaum, D. (1994) The GARP gene encodes a new member of the family of leucine-rich repeat-containing proteins, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research. 5, 213–219.Google Scholar
  14. 14.
    Macaulay, I. C., Tijssen, M. R., Thijssen-Timmer, D. C., Gusnanto, A., Steward, M., Burns, P., Langford, C. F., Ellis, P. D., Dudbridge, F., Zwaginga, J. J., Watkins, N. A., van der Schoot, C. E. & Ouwehand, W. H. (2007) Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins, Blood. 109, 3260–3269.CrossRefGoogle Scholar
  15. 15.
    Metelli, A., Salem, M., Wallace, C. H., Wu, B. X., Li, A., Li, X. & Li, Z. (2018) Immunoregulatory functions and the therapeutic implications of GARP-TGF-beta in inflammation and cancer, Journal of hematology & oncology. 11, 24.CrossRefGoogle Scholar
  16. 16.
    Stockis, J., Colau, D., Coulie, P. G. & Lucas, S. (2009) Membrane protein GARP is a receptor for latent TGF-beta on the surface of activated human Treg, European Journal of Immunology. 39, 3315–3322.CrossRefGoogle Scholar
  17. 17.
    Tran, D. Q., Andersson, J., Wang, R., Ramsey, H., Unutmaz, D. & Shevach, E. M. (2009) GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3(+) regulatory T cells, Proceedings of the National Academy of Sciences of the United States of America. 106, 13445–13450.CrossRefGoogle Scholar
  18. 18.
    Wang, R., Wan, Q., Kozhaya, L., Fujii, H. & Unutmaz, D. (2008) Identification of a Regulatory T Cell Specific Cell Surface Molecule that Mediates Suppressive Signals and Induces Foxp3 Expression, Plos One. 3.Google Scholar
  19. 19.
    Wang, R., Kozhaya, L., Mercer, F., Khaitan, A., Fujii, H. & Unutmaz, D. (2009) Expression of GARP selectively identifies activated human FOXP3+regulatory T cells, Proceedings of the National Academy of Sciences of the United States of America. 106, 13439–13444.CrossRefGoogle Scholar
  20. 20.
    Miller, M. M., Fogle, J. E., Ross, P. & Tompkins, M. B. (2013) Feline glycoprotein A repetitions predominant anchors transforming growth factor beta on the surface of activated CD4(+)CD25(+) regulatory T cells and mediates AIDS lentivirus-induced T cell immunodeficiency, AIDS research and human retroviruses. 29, 641–651.CrossRefGoogle Scholar
  21. 21.
    Szepetowski, P., Ollendorff, V., Grosgeorge, J., Courseaux, A., Birnbaum, D., Theillet, C. & Gaudray, P. (1992) DNA amplification at 11q13.5-q14 in human breast cancer, Oncogene. 7, 2513–2517.PubMedGoogle Scholar
  22. 22.
    Metelli, A., Wu, B. X., Fugle, C. W., Rachidi, S., Sun, S., Zhang, Y., Wu, J., Tomlinson, S., Howe, P. H., Yang, Y., Garrett-Mayer, E., Liu, B. & Li, Z. (2016) Surface Expression of TGFbeta Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer, Cancer research. 76, 7106–7117.CrossRefGoogle Scholar
  23. 23.
    Hahn, S. A., Neuhoff, A., Landsberg, J., Schupp, J., Eberts, D., Leukel, P., Bros, M., Weilbaecher, M., Schuppan, D., Grabbe, S., Tueting, T., Lennerz, V., Sommer, C., Jonuleit, H. & Tuettenberg, A. (2016) A key role of GARP in the immune suppressive tumor microenvironment, Oncotarget. 7, 42996–43009.CrossRefGoogle Scholar
  24. 24.
    Guo, M., Liu, C., Qi, F. J., Zhang, X. M., Ren, L. L., Liu, Y. M., Meng, Z. C., Zhu, Z. T. & Xiao, J. Y. (2014) Elevated expression of nuclear protein kinase CK2alpha as a poor prognosis indicator in lymph node cancerous metastases of human thyroid cancers, Asian Pacific journal of cancer prevention : APJCP. 15, 7425–7432.CrossRefGoogle Scholar
  25. 25.
    Yu, W. R., Liu, T., Kiehl, T. R. & Fehlings, M. G. (2011) Human neuropathological and animal model evidence supporting a role for Fas-mediated apoptosis and inflammation in cervical spondylotic myelopathy, Brain : a journal of neurology. 134, 1277–1292.CrossRefGoogle Scholar
  26. 26.
    Probst-Kepper, M., Geffers, R., Kroger, A., Viegas, N., Erck, C., Hecht, H. J., Lunsdorf, H., Roubin, R., Moharregh-Khiabani, D., Wagner, K., Ocklenburg, F., Jeron, A., Garritsen, H., Arstila, T. P., Kekalainen, E., Balling, R., Hauser, H., Buer, J. & Weiss, S. (2009) GARP: a key receptor controlling FOXP3 in human regulatory T cells, Journal of cellular and molecular medicine. 13, 3343–3357.CrossRefGoogle Scholar
  27. 27.
    Probst-Kepper, M., Kroger, A., Garritsen, H. S. & Buer, J. (2009) Perspectives on Regulatory T Cell Therapies, Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie. 36, 302–308.CrossRefGoogle Scholar
  28. 28.
    Probst-Kepper, M. & Buer, J. (2010) FOXP3 and GARP (LRRC32): the master and its minion, Biology direct. 5, 8.CrossRefGoogle Scholar
  29. 29.
    Bates, G. J., Fox, S. B., Han, C., Leek, R. D., Garcia, J. F., Harris, A. L. & Banham, A. H. (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse, Journal of Clinical Oncology. 24, 5373–5380.CrossRefGoogle Scholar
  30. 30.
    Curiel, T. J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., Evdemon-Hogan, M., Conejo-Garcia, J. R., Zhang, L., Burow, M., Zhu, Y., Wei, S., Kryczek, I., Daniel, B., Gordon, A., Myers, L., Lackner, A., Disis, M. L., Knutson, K. L., Chen, L. & Zou, W. (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival, Nature medicine. 10, 942–949.CrossRefGoogle Scholar
  31. 31.
    Fu, J., Xu, D., Liu, Z., Shi, M., Zhao, P., Fu, B., Zhang, Z., Yang, H., Zhang, H., Zhou, C., Yao, J., Jin, L., Wang, H., Yang, Y., Fu, Y. X. & Wang, F. S. (2007) Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients, Gastroenterology. 132, 2328–2339.CrossRefGoogle Scholar
  32. 32.
    Cunha, L. L., Morari, E. C., Nonogaki, S., Soares, F. A., Vassallo, J. & Ward, L. S. (2012) Foxp3 expression is associated with aggressiveness in differentiated thyroid carcinomas, Clinics. 67, 483–488.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of AnatomyCollege of Basic Medical Sciences of Jinzhou Medical UniversityJinzhouChina
  2. 2.Department of Clinical LaboratoryThe First Affiliated Hospital of Jinzhou Medical UniversityJinzhouChina
  3. 3.Department of PathologyCollege of Basic Medical Sciences of Jinzhou Medical UniversityJinzhouChina
  4. 4.Department of Medical ImagingJinzhou Medical UniversityJinzhouChina
  5. 5.Department of EpidemiologyPublic Health College of Jinzhou Medical UniversityJinzhouChina
  6. 6.Institute of Biological AnthropologyJinzhou Medical UniversityJinzhouChina
  7. 7.Liaoning Province Key Laboratory of Chinese Physical Characteristics Research (LPKL-CPCR)JinzhouChina

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