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Concomitant high expression of ERα36, GRP78 and GRP94 is associated with aggressive papillary thyroid cancer behavior

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Abstract

Purpose

Papillary thyroid cancer (PTC) is more common in women than in men. It has been suggested that estrogen may be involved in its development, as has previously been shown for breast, endometrial and ovarian cancer. The purpose of this study was to assess correlations between the expression of the estrogen receptor alpha36 (ERα36) and the glucose regulated proteins GRP78 and GRP94 (chaperones involved in glycoprotein folding) and various PTC clinicopathological features, as well as to evaluate the potential usefulness of these three potential oncogenic proteins in the prediction of aggressive PTC behavior.

Methods

ERα36, GRP78 and GRP94 protein expression in 218 primary PTC tissues and PTC-derived BCPAP cells was examined using immunohistochemistry, Western blotting and immunocytochemistry. The proliferative, invasive and migrative capacities of BCPAP cells in which the respective genes were either exogenously over-expressed or silenced were assessed using BrdU incorporation and Transwell assays, respectively.

Results

We found that ERα36, GRP78 and GRP94 protein expression was upregulated in the primary PTC tissues tested. We also found that ERα36, GRP78 and GRP94 expression modulation affected the proliferation, invasion and migration of PTC-derived BCPAP cells. A positive correlation and a positive feedback loop were noted between ERα36, GRP78 and GRP94 protein expression in the primary PTC tissues and in BCPAP cells, respectively. High ERα36 expression in combination with a high GRP78/ GRP94 expression was found to have a stronger correlation with extrathyroid extension (ETE), lymph node metastasis (LNM), distant metastasis (DM) and high TNM stage than high ERα36 expression in combination with either high GRP78 or high GRP94 expression (p = 0.028 for ETE, p = 0.002 for DM and p ≤ 0.001 for LNM and high TNM stage) or high ERα36 expression alone (p < 0.001 for ETE, LNM, DM and high TNM stage).

Conclusions

From our data we conclude that a concomitant high expression of ERα36, GRP78 and GRP94 is strongly associated with aggressive PTC behavior and may be used as a predictor for ETE, LNM, DM and high TNM stage.

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References

  1. H. Li, J. Li, Thyroid disorders in women. Minerva Med. 106, 109–114 (2015)

    PubMed  CAS  Google Scholar 

  2. S. Hima, S. Sreeja, Modulatory role of 17β-estradiol in the tumor microenvironment of thyroid cancer. IUBMB Life 68, 85–96 (2016). https://doi.org/10.1002/iub.1462

    Article  PubMed  CAS  Google Scholar 

  3. E. Przybylik-Mazurek, A. Hubalewska-Dydejczyk, A. Fedorowicz, D. Pach, Factors connected with the female sex seem to play an important role in differentiated thyroid cancer. Gynecol. Endocrinol. 28, 150–155 (2012). https://doi.org/10.3109/09513590.2011.563909

    Article  PubMed  CAS  Google Scholar 

  4. S. Caini, B. Gibelli, D. Palli, C. Saieva, M. Ruscica, S. Gandini, Menstrual and reproductive history and use of exogenous sex hormones and risk of thyroid cancer among women: A meta-analysis of prospective studies. Cancer Causes Control 26, 511–518 (2015). https://doi.org/10.1007/s10552-015-0546-z

    Article  PubMed  Google Scholar 

  5. M.C. Pike, C.L. Pearce, A.H. Wu, Prevention of cancers of the breast, endometrium and ovary. Oncogene 23, 6379–6391 (2004). https://doi.org/10.1038/sj.onc.1207899

    Article  PubMed  CAS  Google Scholar 

  6. C. Busonero, S. Leone, F. Acconcia, Emetine induces estrogen receptor alpha degradation and prevents 17β-estradiol-induced breast cancer cell proliferation. Cell. Oncol. 40, 299–301 (2017). https://doi.org/10.1007/s13402-017-0322-z

    Article  CAS  Google Scholar 

  7. Z. Wang, X. Zhang, P. Shen, B.W. Loggie, Y. Chang, T.F. Deuel, Identification, cloning, and expression of human estrogen receptor-alpha36, a novel variant of human estrogen receptor-alpha66. Biochem. Biophys. Res. Commun. 336, 1023–1027 (2005). https://doi.org/10.1016/j.bbrc.2005.08.226

    Article  PubMed  CAS  Google Scholar 

  8. Z.Y. Wang, L. Yin, Estrogen receptor alpha-36 (ER-α36): A new player in human breast cancer. Mol. Cell. Endocrinol. 418, 193–206 (2015). https://doi.org/10.1016/j.mce.2015.04.017

    Article  PubMed  CAS  Google Scholar 

  9. S.L. Lin, L.Y. Yan, X.W. Liang, Z.B. Wang, Z.Y. Wang, J. Qiao, H. Schatten, Q.Y. Sun, A novel variant of ER-alpha, ER-alpha36 mediates testosterone-stimulated ERK and Akt activation in endometrial cancer Hec1A cells. Reprod. Biol. Endocrinol. 7, 1–8 (2009)

    Article  CAS  Google Scholar 

  10. X. Zhang, Z.Y. Wang, Estrogen receptor-α variant, ER-α36, is involved in tamoxifen resistance and estrogen hypersensitivity. Endocrinology 154, 1990–1998 (2013). https://doi.org/10.1210/en.2013-1116

    Article  PubMed  CAS  Google Scholar 

  11. J. Cao, L. Teng, Estrogen receptor-α36 is involved in development of acquired tamoxifen resistance via regulating the growth status switch in breast cancer cells. Mol. Oncol. 7, 611–624 (2013)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Z. Wang, X. Zhang, P. Shen, B.W. Loggie, Y. Chang, T.F. Deuel, A variant of estrogen receptor-{alpha}, hER-{alpha}36: Transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling. Proc. Natl. Acad. Sci. U. S. A. 103, 9063–9068 (2006). https://doi.org/10.1073/pnas.0603339103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. S.L. Lin, L.Y. Yan, X.T. Zhang, J. Yuan, M. Li, J. Qiao, Z.Y. Wang, Q.Y. Sun, ER-alpha36, a variant of ER-alpha, promotes tamoxifen agonist action in endometrial cancer cells via the MAPK/ERK and PI3K/Akt pathways. PLoS One 5, e9013 (2010). https://doi.org/10.1371/journal.pone.0009013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. J.S. Tong, Q.H. Zhang, Z.B. Wang, S. Li, C.R. Yang, X.Q. Fu, Y. Hou, Z.Y. Wang, J. Sheng, Q.Y. Sun, ER-α36, a novel variant of ER-α, mediates estrogen-stimulated proliferation of endometrial carcinoma cells via the PKCδ/ERK pathway. PLoS One 5, e15408 (2010). https://doi.org/10.1371/journal.pone.0015408

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. X.T. Zhang, L. Ding, L.G. Kang, Z.Y. Wang, Involvement of ER-α36, Src, EGFR and STAT5 in the biphasic estrogen signaling of ER-negative breast cancer cells. Oncol. Rep. 27, 2057–2065 (2012). https://doi.org/10.3892/or.2012.1722

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. X.T. Zhang, L.G. Kang, L. Ding, S. Vranic, Z. Gatalica, Z.Y. Wang, A positive feedback loop of ER-α36/EGFR promotes malignant growth of ER-negative breast cancer cells. Oncogene 30, 770–780 (2011). https://doi.org/10.1038/onc.2010.458

    Article  PubMed  CAS  Google Scholar 

  17. L.M. Lee, J. Cao, H. Deng, P. Chen, Z. Gatalica, Z.Y. Wang, ER-alpha36, a novel variant of ER-alpha, is expressed in ER-positive and -negative human breast carcinomas. Anticancer Res. 28, 479–483 (2008)

    PubMed  PubMed Central  CAS  Google Scholar 

  18. B.B. Tu, S.L. Lin, L.Y. Yan, Z.Y. Wang, Q.Y. Sun, J. Qiao, ER-α36, a novel variant of estrogen receptor α, is involved in EGFR-related carcinogenesis in endometrial cancer. Am. J. Obstet. Gynecol. 205, e1–e6 (2011)

    Article  Google Scholar 

  19. H. Deng, X. Huang, J. Fan, L. Wang, Q. Xia, X. Yang, Z. Wang, L. Liu, A variant of estrogen receptor-alpha, ER-alpha36 is expressed in human gastric cancer and is highly correlated with lymph node metastasis. Oncol. Rep. 24, 171–176 (2010)

    PubMed  PubMed Central  CAS  Google Scholar 

  20. A.S. Lee, The glucose-regulated proteins: Stress induction and clinical applications. Trends Biochem. Sci. 26, 504–510 (2001). https://doi.org/10.1016/S0968-0004(01)01908-9

    Article  PubMed  CAS  Google Scholar 

  21. A.S. Lee, Glucose-regulated proteins in cancer: Molecular mechanisms and therapeutic potential. Nat. Rev. Cancer 14, 263–276 (2014). https://doi.org/10.1038/nrc3701

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. A. Altmeyer, R.G. Maki, A.M. Feldweg, M. Heike, V.P. Protopopov, S.K. Masur, P.K. Srivastava, Tumor-specific cell surface expression of the-KDEL containing, endoplasmic reticular heat shock protein gp96. Int. J. Cancer 69, 340–349 (1996). https://doi.org/10.1002/(SICI)1097-0215(19960822)69:4<340::AID-IJC18>3.0.CO;2-9

    Article  PubMed  CAS  Google Scholar 

  23. K. Melendez, E.S. Wallen, B.S. Edwards, C.D. Mobarak, D.G. Bear, P.L. Moseley, Heat shock protein 70 and glycoprotein 96 are differentially expressed on the surface of malignant and nonmalignant breast cells. Cell Stress Chaperones 11, 334–342 (2006). https://doi.org/10.1379/CSC-187.1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. J.G. Kiang, I.D. Gist, G.C. Tsokos, 17 beta-estradiol-induced increases in glucose-regulated protein 78kD and 94kD protect human breast cancer T47-D cells from thermal injury. Chin. J. Phys. 40, 213–219 (1997)

    CAS  Google Scholar 

  25. P. Scriven, S. Coulson, R. Haines, S. Balasubramanian, S. Cross, L. Wyld, Activation and clinical significance of the unfolded protein response in breast cancer. Br. J. Cancer 101, 1692–1698 (2009). https://doi.org/10.1038/sj.bjc.6605365

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Y.Z. Zheng, Z.G. Cao, X. Hu, Z.M. Shao, The endoplasmic reticulum stress markers GRP78 and CHOP predict disease-free survival and responsiveness to chemotherapy in breast cancer. Breast Cancer Res. Treat. 145, 349–358 (2014). https://doi.org/10.1007/s10549-014-2967-x

    Article  PubMed  CAS  Google Scholar 

  27. J.H. Parmar, K.L. Cook, A.N. Shajahan-Haq, P.A. Clarke, I. Tavassoly, R. Clarke, J.J. Tyson, W.T. Baumann, Modelling the effect of GRP78 on anti-oestrogen sensitivity and resistance in breast cancer. Interface Focus 3, 20130012 (2013). https://doi.org/10.1098/rsfs.2013.0012

    Article  PubMed  PubMed Central  Google Scholar 

  28. N. Dejeans, C. Glorieux, S. Guenin, R. Beck, B. Sid, R. Rousseau, B. Bisig, P. Delvenne, P. Buc Calderon, J. Verrax, Overexpression of GRP94 in breast cancer cells resistant to oxidative stress promotes high levels of cancer cell proliferation and migration: Implications for tumor recurrence. Free Radic. Biol. Med. 52, 993–1002 (2012)

    Article  PubMed  CAS  Google Scholar 

  29. G. Calì, L. Insabato, D. Conza, G. Bifulco, L. Parrillo, P. Mirra, F. Fiory, C. Miele, G.A. Raciti, B. Di Jeso, G. Terrazzano, F. Beguinot, L. Ulianich, GRP78 mediates cell growth and invasiveness in endometrial cancer. J. Cell. Physiol. 229, 1417–1426 (2014). https://doi.org/10.1002/jcp.24578

    Article  PubMed  CAS  Google Scholar 

  30. F. Delie, P. Petignat, M. Cohen, GRP78 protein expression in ovarian cancer patients and perspectives for a drug-targeting approach. J. Oncol. 2012, 468615 (2012)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. H.C. Zheng, H. Takahashi, X.H. Li, T. Hara, S. Masuda, Y.F. Guan, Y. Takano, Overexpression of GRP78 and GRP94 are markers for aggressive behavior and poor prognosis in gastric carcinomas. Hum. Pathol. 39, 1042–1049 (2008). https://doi.org/10.1016/j.humpath.2007.11.009

    Article  PubMed  CAS  Google Scholar 

  32. H. Takahashi, J.P. Wang, H.C. Zheng, S. Masuda, Y. Takano, Overexpression of GRP78 and GRP94 is involved in colorectal carcinogenesis. Histol. Histopathol. 26, 663–671 (2011). https://doi.org/10.14670/HH-26.663

    Article  PubMed  Google Scholar 

  33. N. Wang, H.J. Luo, G.B. Dong, M. Xu, G.G. Chen, Z.M. Liu, Overexpression of HIF-2α, TWIST, and CXCR4 is associated with lymph node metastasis in papillary thyroid carcinoma. Clin. Dev. Immunol. 2013, 589423 (2013)

    PubMed  PubMed Central  Google Scholar 

  34. J. Matthews, J.A. Gustafsson, Estrogen signaling: A subtle balance between ER alpha and ER beta. Mol. Interv. 3, 281–292 (2003). https://doi.org/10.1124/mi.3.5.281

    Article  PubMed  CAS  Google Scholar 

  35. J. Hou, M. Deng, X. Li, W. Liu, X. Chu, J. Wang, F. Chen, S. Meng, Chaperone gp96 mediates ER-α36 cell membrane expression. Oncotarget 6, 31857–31867 (2015). https://doi.org/10.18632/oncotarget.5273

    Article  PubMed  PubMed Central  Google Scholar 

  36. A.E. Dhamad, Z. Zhou, J. Zhou, Y. Du, Systematic proteomic identification of the heat shock proteins (Hsp) that interact with estrogen receptor alpha (ERα) and biochemical characterization of the ERα-Hsp70 interaction. PLoS One 11, e0160312 (2016). https://doi.org/10.1371/journal.pone.0160312

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Y.S. Guo, Z. Sun, J. Ma, W. Cui, B. Gao, H.Y. Zhang, Y.H. Han, H.M. Hu, L. Wang, J. Fan, L. Yang, J. Tang, Z.J. Luo, 17β-estradiol inhibits ER stress-induced apoptosis through promotion of TFII-I-dependent Grp78 induction in osteoblasts. Lab. Investig. 94, 906–916 (2014). https://doi.org/10.1038/labinvest.2014.63

    Article  PubMed  CAS  Google Scholar 

  38. Z. Fu, H. Zhen, F. Zou, X. Wang, Y. Chen, L. Liu, Involvement of the Akt signaling pathway in ER-α36/GRP94-mediated signaling in gastric cancer. Oncol. Lett. 8, 2077–2080 (2014). https://doi.org/10.3892/ol.2014.2514

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Z. Fu, H. Deng, X. Wang, X. Yang, Z. Wang, L. Liu, Involvement of ER-α36 in the malignant growth of gastric carcinoma cells is associated with GRP94 overexpression. Histopathology 63, 325–333 (2013). https://doi.org/10.1111/his.12171

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 81272937).

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Author notes

  1. Yu-Jie Dai and Yi-Bo Qiu contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, China

    Yu-Jie Dai, Yi-Bo Qiu, Ling-Yao Liao & Zhi-Min Liu

  2. Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China

    Rong Jiang & Man Xu

  3. Department of Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T, Hong Kong, China

    George G. Chen

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  1. Yu-Jie Dai
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Dai, YJ., Qiu, YB., Jiang, R. et al. Concomitant high expression of ERα36, GRP78 and GRP94 is associated with aggressive papillary thyroid cancer behavior. Cell Oncol. 41, 269–282 (2018). https://doi.org/10.1007/s13402-017-0368-y

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