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The essential roles of CCR7 in epithelial-to-mesenchymal transition induced by hypoxia in epithelial ovarian carcinomas

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Tumor Biology

Abstract

The chemokine receptor CCR7 and its ligands CCL19/21 mediate the tumor mobility, invasion, and metastasis (Wu et al. Curr Pharm Des. 15:742–57, 2009). Hypoxia induced epithelial-to-mesenchymal transition (EMT) to facilitate the tumor biology. Here, we addressed the roles of CCR7 in epithelial ovarian carcinoma tissues and hypoxia-induced serous papillary cystic adenocarcinoma (SKOV-3) EMT. The expression level of CCR7 protein was analyzed by immunohistochemistry in 30 specimens of epithelial ovarian carcinomas. Western blot was used to investigate the expression of hypoxia-induced CCR7, HIF-1α, and EMT markers (N-cadherin, Snail, MMP-9). In addition, wound healing and Transwell assay were introduced to observe the capacity of migration and invasiveness. Our data showed CCR7 expression was observed in 22 cases of tissues and closely associated with lymph node metastasis and FIGO stage (III + IV). At 6, 12, 24, and 36 h following hypoxia, CCR7 and HIF-1α proteins were both obviously upregulated in a time-dependent method, compared with normal oxygen. In vitro, SKOV-3 expressed N-cadherin, Snail, and MMP-9 once either CCL21 stimulation or hypoxia induction, while hypoxia accompanied with CCL21 induction exhibited strongest upregulation of N-cadherin, Snail, and MMP-9 proteins. Besides, wound healing and Transwell assay further identified that hypoxia with CCL21 stimulation can remarkably promote cell migration and invasiveness. Taken together, CCR7 can constitutively express in epithelial ovarian carcinomas and be induced rapidly in response to hypoxia, which indeed participates in EMT development and prompts the cell migration and invasion. Thus, this study suggested that the epithelial ovarian cancer invasion and metastasis can be inhibited by antagonizing CCR7.

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References

  1. Wu X, Lee VC, Chevalier E, Hwang ST. Chemokine receptors as targets for cancer therapy. Curr Pharm Des. 2009;15:742–57.

  2. Menon U, Gentry-Maharaj A, Jacobs I. Ovarian cancer screening and mortality. JAMA. 2011;306:1544.

    Article  CAS  Google Scholar 

  3. Bandera CA. Advances in the understanding of risk factors for ovarian cancer. J Reprod Med. 2005;50:399–406.

    PubMed  Google Scholar 

  4. Huang RY, Chung VY, Thiery JP. Targeting pathways contributing to epithelial-mesenchymal transition (EMT) in epithelial ovarian cancer. Curr Drug Targets. 2012;13:1649–53.

    Article  CAS  Google Scholar 

  5. Sánchez-Sánchez N, Riol-Blanco L, Rodríguez-Fernández JL. The multiple personalities of the chemokine receptor CCR7 in dendritic cells. J Immunol. 2006;176:5153–9.

    Article  Google Scholar 

  6. Kochetkova M, Kumar S, McColl SR. Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells. Cell Death Differ. 2009;16:664–73.

    Article  CAS  Google Scholar 

  7. Ouyang G, Wang Z, Fang X, Liu J, Yang CJ. Molecular signaling of the epithelial to mesenchymal transition in generating and maintaining cancer stem cells. Cell Mol Life Sci. 2010;67:2605–18.

    Article  CAS  Google Scholar 

  8. Naber HP, Drabsch Y, Snaar-Jagalska BE, ten Dijke P, van Laar T. Snail and Slug, key regulators of TGF-β-induced EMT, are sufficient for the induction of single-cell invasion. Biochem Biophys Res Commun. 2013;435:58–63.

    Article  CAS  Google Scholar 

  9. de Herreros AG, Peiro S, Nassour M, Savagner P. Snail family regulation and epithelial mesenchymal transitions in breast cancer progression. J Mammary Gland Biol Neoplasia. 2010;15:135–47.

    Article  Google Scholar 

  10. Suyama K, Shapiro I, Guttman M, Hazan RB. A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer Cell. 2002;2:301–14.

    Article  CAS  Google Scholar 

  11. Gomez-Nicola D, Pallas-Bazarra N, Valle-Argos B, Nieto-Sampedro M. CCR7 is expressed in astrocytes and upregulated after an inflammatory injury. J Neuroimmunol. 2010;227:87–92.

    Article  CAS  Google Scholar 

  12. Du J, Sun B, Zhao X, Gu Q, Dong X, Mo J, et al. Hypoxia promotes vasculogenic mimicry formation by inducing epithelial-mesenchymal transition in ovarian carcinoma. Gynecol Oncol. 2014;133:575–83.

    Article  CAS  Google Scholar 

  13. Copple BL. Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-beta-dependent mechanisms. Liver Int. 2010;30:669–82.

    Article  CAS  Google Scholar 

  14. Savagner P. The epithelial-mesenchymal transition (EMT) phenomenon. Ann Oncol. 2010;21:89–92.

    Article  Google Scholar 

  15. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.

    Article  CAS  Google Scholar 

  16. Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest. 2007;117:3810–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Wilson JL, Burchell J, Grimshaw MJ. Endothelins induce CCR7 expression by breast tumor cells via endothelin receptor A and hypoxia-inducible factor-1. Cancer Res. 2006;66:11802–7.

    Article  CAS  Google Scholar 

  18. Li X, Li P, Chang Y, Xu Q, Wu Z, Ma Q, et al. The SDF-1/CXCR4 axis induces epithelial–mesenchymal transition in hepatocellular carcinoma. Mol Cell Biochem. 2014;392:77–84.

    Article  CAS  Google Scholar 

  19. Fanelli MF, Chinen LT, Begnami MD, Costa Jr WL, Fregnami JH, Soares FA, et al. The influence of transforming growth factor-α, cyclooxygenase-2, matrix metalloproteinase (MMP)-7, MMP-9 and CXCR4 proteins involved in epithelial-mesenchymal transition on overall survival of patients with gastric cancer. Histopathology. 2012;61:153–61.

    Article  Google Scholar 

  20. Li X, Ma Q, Xu Q, Liu H, Lei J, Duan W, et al. SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial-mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway. Cancer Lett. 2012;322:169–76.

    Article  CAS  Google Scholar 

  21. Onoue T, Uchida D, Begum NM, Tomizuka Y, Yoshida H, Sato M. Epithelial-mesenchymal transition induced by the stromal cell-derived factor-1/CXCR4 system in oral squamous cell carcinoma cells. Int J Oncol. 2006;29:1133–8.

    CAS  PubMed  Google Scholar 

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Acknowledgments

We greatly thank other members in Yang Lab for valuable suggestions and writing.

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Correspondence to Shaomei Cheng.

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Cheng, S., Han, L., Guo, J. et al. The essential roles of CCR7 in epithelial-to-mesenchymal transition induced by hypoxia in epithelial ovarian carcinomas. Tumor Biol. 35, 12293–12298 (2014). https://doi.org/10.1007/s13277-014-2540-6

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  • DOI: https://doi.org/10.1007/s13277-014-2540-6

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