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High Expression of GRP78 Promotes Invasion and Metastases in Patients with Esophageal Squamous Cell Carcinoma

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Abstract

Background

Esophageal squamous cell carcinoma (ESCC) has a poor prognosis due to its high frequency of metastasis and invasion. Recent studies have suggested glucose-regulated protein 78KD (GRP78) may play important roles in progression and development of malignant tumors. However, the mechanisms of invasion and metastasis of ESCC in relation to GRP78 still remain obscure.

Aim

The aim of this study was to investigate the effect of GRP78 on invasion and metastasis of ESCC and to explore its potential mechanism.

Methods

GRP78 expression levels in ESCC tissues were examined by immunohistochemistry. RT-PCR and western blot were used to test the relative expression of GRP78 in non-metastatic and high-metastatic ESCC cells. In vitro and in vivo studies were both performed to investigate the role of GRP78 in invasion and metastasis of ESCC cells. The expression of metastasis-related proteins was examined by western blot in GRP78-depleted cells.

Results

The expression of GRP78 is correlated with invasion, metastasis and poor prognosis in ESCC patients. GRP78 expression was significantly higher in highly metastatic cells compared with ESCC non-metastatic cells. In addition, down-regulation of GRP78 significantly inhibited the metastatic potential of ESCC cells in both in vitro and in vivo studies. The expression of MMP-2 and MMP-9 were down-regulated in GRP78-depleted ESCC cells.

Conclusions

The present study demonstrated that GRP78 plays important roles in invasion and metastasis of ESCC, indicating that GRP78 might be used as a potential prognostic and therapeutic marker in patients with ESCC by modulating the expression of MMP-2 and MMP-9.

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Abbreviations

ESCC:

Esophageal squamous cell carcinoma

siRNA:

Small interfering RNA

NC:

Negative control

GRP78:

Glucose-regulated protein 78KD

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Eloubeidi MA, Desmond R, Arguedas MR, Reed CE, Wilcox CM. Prognostic factors for the survival of patients with esophageal carcinoma in the US: the importance of tumor length and lymph node status. Cancer. 2002;95:1434–1443.

    Article  PubMed  Google Scholar 

  3. Lin DC, Du XL, Wang MR. Protein alterations in ESCC and clinical implications: a review. Dis Esophagus. 2009;22:9–20.

    Article  PubMed  Google Scholar 

  4. Kwong KF. Molecular biology of esophageal cancer in the genomics era. Surg Clin N Am. 2005;85:539–553.

    Article  PubMed  Google Scholar 

  5. Ye Q, Yan Z, Liao X, et al. Muc1 induces metastasis in esophageal squamous cell carcinoma by upregulating matrix metalloproteinase 13. Lab Invest. 2011;91:778–787.

    Article  CAS  PubMed  Google Scholar 

  6. Koyama H, Iwata H, Kuwabara Y, Iwase H, Kobayashi S, Fujii Y. Gelatinolytic activity of matrix metalloproteinase-2 and -9 in oesophageal carcinoma. A study using in situ zymography. Eur J Cancer. 2000;36:2164–2170.

    Article  CAS  PubMed  Google Scholar 

  7. Uchikado Y, Natsugoe S, Okumura H, et al. Slug expression in the e-cadherin preserved tumors is related to prognosis in patients with esophageal squamous cell carcinoma. Clin Cancer Res. 2005;11:1174–1180.

    CAS  PubMed  Google Scholar 

  8. Cao J, Chiarelli C, Richman O, Zarrabi K, Kozarekar P, Zucker S. Membrane type 1 matrix metalloproteinase induces epithelial-to-mesenchymal transition in prostate cancer. J Biol Chem. 2008;283:6232–6240.

    Article  CAS  PubMed  Google Scholar 

  9. Su R, Li Z, Li H, et al. GRP78 promotes the invasion of hepatocellular carcinoma. BMC Cancer. 2010;10:20.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Xing X, Lai M, Wang Y, Xu E, Huang Q. Overexpression of glucose-regulated protein 78 in colon cancer. Clin Chim Acta. 2006;364:308–315.

    Article  CAS  PubMed  Google Scholar 

  11. Uramoto H, Sugio K, Oyama T, et al. Expression of endoplasmic reticulum molecular chaperone GRP78 in human lung cancer and its clinical significance. Lung Cancer. 2005;49:55–62.

    Article  PubMed  Google Scholar 

  12. Zhang J, Jiang Y, Jia Z, et al. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin Exp Metastasis. 2006;23:401–410.

    Article  PubMed  Google Scholar 

  13. Daneshmand S, Quek ML, Lin E, et al. Glucose-regulated protein GRP78 is up-regulated in prostate cancer and correlates with recurrence and survival. Hum Pathol. 2007;38:1547–1552.

    Article  CAS  PubMed  Google Scholar 

  14. Du XL, Hu H, Lin DC, et al. Proteomic profiling of proteins dysregulted in chinese esophageal squamous cell carcinoma. J Mol Med (Berl). 2007;85:863–875.

    Article  CAS  Google Scholar 

  15. Dong D, Stapleton C, Luo B, et al. A critical role for GRP78/bip in the tumor microenvironment for neovascularization during tumor growth and metastasis. Cancer Res. 2011;71:2848–2857.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Li H, Song H, Luo J, Liang J, Zhao S, Su R. Knockdown of glucose-regulated protein 78 decreases the invasion, metalloproteinase expression and ECM degradation in hepatocellular carcinoma cells. J Exp Clin Cancer Res. 2012;31:39.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Kraljevic PS, Sedic M, Bosnjak H, Spaventi S, Pavelic K. Metastasis: new perspectives on an old problem. Mol Cancer. 2011;10:22.

    Article  Google Scholar 

  18. Li Z, Li Z. Glucose regulated protein 78: a critical link between tumor microenvironment and cancer hallmarks. Biochim Biophys Acta. 2012;1826:13–22.

    CAS  PubMed  Google Scholar 

  19. Dong D, Ni M, Li J, et al. Critical role of the stress chaperone GRP78/bip in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res. 2008;68:498–505.

    Article  CAS  PubMed  Google Scholar 

  20. Baumeister P, Dong D, Fu Y, Lee AS. Transcriptional induction of GRP78/bip by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor-induced apoptosis. Mol Cancer Ther. 2009;8:1086–1094.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Zhang LC, Wang JR, Zhao L, et al. GRP78 upregulation-induced increase in cisplatin sensitivity of spca1 lung cancer cells. Chin Med J (Engl). 2011;124:3341–3346.

    CAS  Google Scholar 

  22. Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med. 2006;12:895–904.

    Article  CAS  PubMed  Google Scholar 

  23. Zucker S, Vacirca J. Role of matrix metalloproteinases (MMPS) in colorectal cancer. Cancer Metastasis Rev. 2004;23:101–117.

    Article  CAS  PubMed  Google Scholar 

  24. Pellikainen JM, Ropponen KM, Kataja VV, Kellokoski JK, Eskelinen MJ, Kosma VM. Expression of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer with a special reference to activator protein-2, her2, and prognosis. Clin Cancer Res. 2004;10:7621–7628.

    Article  CAS  PubMed  Google Scholar 

  25. Li Y, Ma J, Guo Q, et al. Overexpression of MMP-2 and MMP-9 in esophageal squamous cell carcinoma. Dis Esophagus. 2009;22:664–667.

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors thank Dr. Qingchuan Zhao for his help in collection of the esophageal squamous cell carcinoma specimens and Prof. Zengshan Li for his help in analyzing the results of HE staining of paraffin sections.

Conflict of interest

None.

Author information

Author notes

    Authors and Affiliations

    1. State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 Changle Western Road, Xi’an, 710032, Shaanxi Province, China

      Guohong Zhao, Guanghui Xu, Lei Yang, Hui Zhang, Ying Wang, Yongzhan Nie, Kaichun Wu, Daiming Fan, Hongbo Zhang & Dexin Zhang

    2. Department of Endocrinology, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, Shanxi Province, China

      Guohong Zhao & Kai Jiao

    3. Department of Pediatrics, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, Shanxi Province, China

      Jianqin Kang

    4. Department of Digestive, General Hospital of Chengdu Military Command, Chengdu, 610083, Sichuan Province, China

      Shanhong Tang

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    1. Guohong Zhao
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    2. Jianqin Kang
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    13. Dexin Zhang
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    Corresponding author

    Correspondence to Dexin Zhang.

    Additional information

    Guohong Zhao, Jianqin Kang, Kai Jiao and Guanghui Xu contributed equally to this work.

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    Cite this article

    Zhao, G., Kang, J., Jiao, K. et al. High Expression of GRP78 Promotes Invasion and Metastases in Patients with Esophageal Squamous Cell Carcinoma. Dig Dis Sci 60, 2690–2699 (2015). https://doi.org/10.1007/s10620-015-3689-6

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    • DOI: https://doi.org/10.1007/s10620-015-3689-6

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