Tumor Biology

, Volume 35, Issue 12, pp 12293–12298 | Cite as

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

  • Shaomei Cheng
  • Lin Han
  • Jingyan Guo
  • Qing Yang
  • Jianfang Zhou
  • Xiangshan Yang
Research Article


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.


CCR7 Epithelial ovarian carcinomas Hypoxia EMT 



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

Conflicts of interest



  1. 1.
    Wu X, Lee VC, Chevalier E, Hwang ST. Chemokine receptors as targets for cancer therapy. Curr Pharm Des. 2009;15:742–57.Google Scholar
  2. 2.
    Menon U, Gentry-Maharaj A, Jacobs I. Ovarian cancer screening and mortality. JAMA. 2011;306:1544.PubMedCrossRefGoogle Scholar
  3. 3.
    Bandera CA. Advances in the understanding of risk factors for ovarian cancer. J Reprod Med. 2005;50:399–406.PubMedGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Savagner P. The epithelial-mesenchymal transition (EMT) phenomenon. Ann Oncol. 2010;21:89–92.CrossRefGoogle Scholar
  15. 15.
    Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCentralPubMedGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 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.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Shaomei Cheng
    • 1
  • Lin Han
    • 2
  • Jingyan Guo
    • 3
  • Qing Yang
    • 2
  • Jianfang Zhou
    • 2
  • Xiangshan Yang
    • 4
  1. 1.Department of GynecologyAffiliated Hospital of Shandong Academy of Medical SciencesJinanChina
  2. 2.Department of MedicineAffiliated Hospital of Shandong Academy of Medical SciencesJinanChina
  3. 3.Department of PharmacyAffiliated Hospital of Shandong Academy of Medical SciencesJinanChina
  4. 4.Department of PathologyAffiliated Hospital of Shandong Academy of Medical SciencesJinanChina

Personalised recommendations