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CXCR7 signaling induced epithelial–mesenchymal transition by AKT and ERK pathways in epithelial ovarian carcinomas

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Tumor Biology

Abstract

Epithelial–mesenchymal transition (EMT) plays an important role in oncogenesis, through which cancer cells acquire an invasion and metastasis capacity. Notably, the chemokine receptor CXCR7 and its ligands CCL19 can also facilitate lymph node metastasis in epithelial ovarian carcinomas. Here, we assumed that CXCR7 might be involved in the EMT process of epithelial ovarian carcinomas. In our study, CXCR7 activation and inhibition in SKOV3 were induced with exogenous CCL19 and CXCR7 small interfering RNA (CXCR7 siRNA), respectively. AKT and ERK protein of CXCR7 pathways as well as biomarkers (vimentin, snail, N-cadherin, and E-cadherin) of EMT were detected using the Western blot. Our results showed that CCL19 can induce AKT and ERK phosphorylation in a dose-dependent fashion; however, CXCR7 siRNA efficaciously suppressed CCL19-induced AKT and ERK phosphorylation in comparison with control siRNA. Importantly, CCL19 alone treatment can upregulate the expression of vimentin, snail, and N-cadherin of SKOV3 and downregulate the expression of E-cadherin. Conversely, knockdown of CXCR7 did not reveal any changes compared with CCL19 and the control. In conclusion, these findings demonstrate that EMT can be regulated by the CCL19/CXCR7 axis in epithelial ovarian carcinomas and then involved in the tumor cell invasion and metastasis process via activation of AKT and ERK pathways. Our study lays a new foundation for the treatment of epithelial ovarian carcinomas through antagonizing CXCR7.

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References

  1. Jayson GC, Kohn EC, Kitchener HC, Ledermann JA. Ovarian cancer. Lancet. 2014;S0140–6736:62146–7.

  2. Harter P, Hilpert F, Mahner S, Heitz F, Pfisterer J, du Bois A. Systemic therapy in recurrent ovarian cancer: current treatment options and new drugs. Expert Rev Anticancer Ther. 2010;10:81–8.

    Article  CAS  PubMed  Google Scholar 

  3. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Gynecologic Oncology Group Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365:2473–83.

    Article  CAS  PubMed  Google Scholar 

  4. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484–96.

    Article  CAS  PubMed  Google Scholar 

  5. Moustakas A, Heldin P. TGFβ and matrix-regulated epithelial to mesenchymal transition. Biochim Biophys Acta. 1840;2014:2621–34.

    Google Scholar 

  6. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nieto MA. Epithelial plasticity: a common theme in embryonic and cancer cells. Science. 2013;342:1234850.

    Article  PubMed  Google Scholar 

  8. Li Y, Ma J, Qian X, Wu Q, Xia J, Miele L, et al. Regulation of EMT by Notch signaling pathway in tumor progression. Curr Cancer Drug Targets. 2013;13:957–62.

    Article  CAS  PubMed  Google Scholar 

  9. Balogh P, Katz S, Kiss AL. The role of endocytic pathways in TGF-β signaling. Pathol Oncol Res. 2013;19:141–8.

    Article  CAS  PubMed  Google Scholar 

  10. Fuxe J, Karlsson MC. TGF-β-induced epithelial-mesenchymal transition: a link between cancer and inflammation. Semin Cancer Biol. 2012;22:455–61.

    Article  CAS  PubMed  Google Scholar 

  11. Gao D, Vahdat LT, Wong S, Chang JC, Mittal V. Microenvironmental regulation of epithelial-mesenchymal transitions in cancer. Cancer Res. 2012;72:4883–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dave B, Mittal V, Tan NM, Chang JC. Epithelial-mesenchymal transition, cancer stem cells and treatment resistance. Breast Cancer Res. 2012;14:202.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Roy I, Evans DB, Dwinell MB. Chemokines and chemokine receptors: update on utility and challenges for the clinician. Surgery. 2014;155:961–73.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Yoshie O. Chemokine receptors as therapeutic targets. Nihon Rinsho Meneki Gakkai Kaishi. 2013;36:189–96.

    Article  CAS  PubMed  Google Scholar 

  15. Ding Y, Shimada Y, Maeda M, Kawabe A, Kaganoi J, Komoto I, et al. Association of CC chemokine receptor 7 with lymph node metastasis of esophageal squamous cell carcinoma. Clin Cancer Res. 2003;9:3406–12.

    CAS  PubMed  Google Scholar 

  16. Takanami I. Overexpression of CCR7 mRNA in nonsmall cell lung cancer: correlation with lymph node metastasis. Int J Cancer. 2003;105:186–9.

    Article  CAS  PubMed  Google Scholar 

  17. Wang J, Xi L, Hunt JL, Gooding W, Whiteside TL, Chen Z, et al. Expression pattern of chemokine receptor 6 (CCR6) and CCR7 in squamous cell carcinoma of the head and neck identifies a novel metastatic phenotype. Cancer Res. 2004;64:1861–6.

    Article  CAS  PubMed  Google Scholar 

  18. Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50–6.

    Article  PubMed  Google Scholar 

  19. Aliaga JC, Deschênes C, Beaulieu JF, Calvo EL, Rivard N. Requirement of the MAP kinase cascade for cell cycle progression and differentiation of human intestinal cells. Am J Physiol. 1999;277:631–41.

    Google Scholar 

  20. Widmann C, Gibson S, Jarpe MB, Johnson GL. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev. 1999;79:143–80.

    CAS  PubMed  Google Scholar 

  21. Puddicombe SM, Davies DE. The role of MAP kinases in intracellular signal transduction in bronchial epithelium. Clin Exp Allergy. 2000;30:7–11.

    Article  CAS  PubMed  Google Scholar 

  22. Saxena M, Mustelin T. Extracellular signals and scores of phosphatases: all roads lead to MAP kinase. Semin Immunol. 2000;12:387–96.

    Article  CAS  PubMed  Google Scholar 

  23. Liu FY, Safdar J, Li ZN, Fang QG, Zhang X, Xu ZF, et al. CCR7 regulates cell migration and invasion through MAPKs in metastatic squamous cell carcinoma of head and neck. Int J Oncol. 2014. doi:10.3892/ijo.2014.2674.

  24. Zhang W, Tu G, Lv C, Long J, Cong L, Han Y. Matrix metalloproteinase-9 is up-regulated by CCL19/CCR7 interaction via PI3K/Akt pathway and is involved in CCL19-driven BMSCs migration. Biochem Biophys Res Commun. 2014;451:222–8.

    Article  CAS  PubMed  Google Scholar 

  25. Imai T, Horiuchi A, Wang C, Oka K, Ohira S, Nikaido T, et al. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am J Pathol. 2003;3:1437–47.

    Article  Google Scholar 

  26. Wang H, Fang R, Wang XF, Zhang F, Chen DY, Zhou B, et al. Stabilization of Snail through AKT/GASK-3β signaling pathway is required for TNF-a-induced epithelial-mesenchymal transition in prostate cancer PC3 cells. Eur J Pharmacol. 2013;714:48–55.

    Article  CAS  PubMed  Google Scholar 

  27. Nagarajan D, Melo T, Deng Z, Almeida C, Zhao W. ERK/GSK3β/Snail signaling mediates radiation-induced alveolar epithelial-to-mesenchymal transition. Free Radic Biol Med. 2012;52:983–92.

    Article  CAS  PubMed  Google Scholar 

  28. Li Y, Qiu X, Zhang S, Zhang Q, Wang E. Hypoxia induced CCR7 expression via HIF-1alpha and HIF-2alpha correlates with migration and invasion in lung cancer cells. Cancer Biol Ther. 2009;8:322–30.

    Article  CAS  PubMed  Google Scholar 

  29. 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;3:3810–20.

    Google Scholar 

  30. Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci U S A. 2008;3:6392–7.

    Article  Google Scholar 

  31. Kaidi A, Williams AC, Paraskeva C. Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol. 2007;3:210–7.

    Article  Google Scholar 

  32. Yang F, Sun L, Li Q, Han X, Lei L, Zhang H, et al. SET8 promotes epithelial–mesenchymal transition and confers TWIST dual transcriptional activities. EMBO J. 2012;3:110–23.

    Article  Google Scholar 

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Acknowledgments

We greatly thank other members in the lab for valuable suggestions and writing.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, No. 107 West Wenhua Road, Jinan, 250012, Shandong, China

    Hao Yu & Peishu Liu

  2. Department of Gynecologic Oncology, Shandong Cancer Hospital, Jinan, 250117, Shandong, China

    Hao Yu

  3. Department of Obstetrics and Gynecology, Jinan Fourth People’s Hospital, Jinan, Shandong, China

    Linlin Zhang

Authors
  1. Hao Yu
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  2. Linlin Zhang
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  3. Peishu Liu
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Correspondence to Peishu Liu.

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Hao Yu and Linlin Zhang contributed equally to this work.

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Yu, H., Zhang, L. & Liu, P. CXCR7 signaling induced epithelial–mesenchymal transition by AKT and ERK pathways in epithelial ovarian carcinomas. Tumor Biol. 36, 1679–1683 (2015). https://doi.org/10.1007/s13277-014-2768-1

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  • DOI: https://doi.org/10.1007/s13277-014-2768-1

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