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Inflammatory CXCL12-CXCR4/CXCR7 axis mediates G-protein signaling pathway to influence the invasion and migration of nasopharyngeal carcinoma cells

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Tumor Biology

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This study explored whether the migration, invasion, and apoptosis of nasopharyngeal carcinoma (NPC) cells were affected by the CXCR4/CXCR7-CXCL12 axis and if this mechanism was related to G-protein signaling pathway. A total of 72 NPC patients admitted in our hospital between April 2013 and February 2015 were incorporated in this study. Immunohistochemistry was performed to compare the expression levels of CXCR4, CXCR7, and CXCL12 between NPC tissues and adjacent normal tissues. Then, the correlation analysis was implemented to assess the association among CXCR4, CXCR7, and CXCL12 expressions. Jellyfish glow protein experiment was carried out after the cultivation of CNE-2Z cell lines in order to observe the intracellular calcium mobilization resulted from G-protein activation contributed by CXCR4/CXCR7-CXCL12 axis. The impact of CXCR4/CXCR7-CXCL12 axis on the migration and invasion of NPC cells was explored using transwell experiments. Finally, the anti-apoptosis effects of CXCR4/CXCR7-CXCL12 axis on NPC cells were investigated by the splicing of poly ADP-ribose polymerase (PARP). Compared to NPC patients with low-grade (stage I–II) tumor node metastasis (TNM) and those without lymph node metastasis, the expression of CXCR4, CXCR7, and CXCL12 were significantly higher in NPC patients with high-grade (stage III–IV) TNM and those with lymph node metastasis (P < 0.05). Moreover, there was significant positive correlation between the expression level of CXCL12 and CXCR7 (r s = 0.484, P < 0.001) as well as the expression level of CXCL12 and CXCR4 (r s = 0.414, P < 0.001). As suggested by cellular experiments using CNE-2Z, the calcium mobilization degree induced by CXCR4-CXCL12 axis in activating G proteins seemed to be slightly more effective than that induced by CXCR4/CXCR7-CXCL12 axis, while the CXCR7-CXCL12 axis could hardly activate calcium mobilization. Furthermore, the transwell experiment showed that CXCR4/CXCR7-CXCL12 axis could exacerbate the migration and invasion of NPC cells (P < 0.05). The transwell experiment also suggested that the CXCR4/CXCR7-CXCL12 axis was associated with the expression of matrix metallo proteinase 9 (MMP9) which is a substance in the downstream of G-protein pathways (P < 0.05). Results from PARP shear zone also indicated that the CXCR4/CXCR7-CXCL12 axis could suppress NPC cell apoptosis (P < 0.05). The expressional levels of CXCR4, CXCR7, and CXCL12 significantly varied with clinical stages and status of lymph node metastasis of NPC patients. This revealed potential indicators which can be used for NPC prognosis. Additionally, the CXCR4/CXCR7-CXCL12 axis may regulate the expression of downstream proteins (e.g., MMP-9) through the activation of G-protein signaling pathways. These conclusions may provide key evidence for NPC aetiology which can be further investigated to develop novel molecular targets for NPC treatments.

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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. Lee AW, Ma BB, Ng WT, Chan AT. Management of nasopharyngeal carcinoma: current practice and future perspective. J Clin Oncol. 2015;33:3356–64.

    Article  CAS  PubMed  Google Scholar 

  3. Yan M, Kumachev A, Siu LL, Chan KK. Chemoradiotherapy regimens for locoregionally advanced nasopharyngeal carcinoma: a Bayesian network meta-analysis. Eur J Cancer. 2015;51:1570–9.

    Article  PubMed  Google Scholar 

  4. Wei P, Niu M, Pan S, Zhou Y, Shuai C, Wang J, et al. Cancer stem-like cell: a novel target for nasopharyngeal carcinoma therapy. Stem Cell Res Ther. 2014;5:44.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Luo DH, Chen QY, Liu H, Xu LH, Zhang HZ, Zhang L, et al. The independent, unfavorable prognostic factors endothelin a receptor and chemokine receptor 4 have a close relationship in promoting the motility of nasopharyngeal carcinoma cells via the activation of AKT and MAPK pathways. J Transl Med. 2013;11:203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Peng H, Huang Y, Rose J, Erichsen D, Herek S, Fujii N, et al. Stromal cell-derived factor 1-mediated CXCR4 signaling in rat and human cortical neural progenitor cells. J Neurosci Res. 2004;76:35–50.

    Article  CAS  PubMed  Google Scholar 

  7. Wang N, Wu QL, Fang Y, Mai HQ, Zeng MS, Shen GP, et al. Expression of chemokine receptor CXCR4 in nasopharyngeal carcinoma: pattern of expression and correlation with clinical outcome. J Transl Med. 2005;3:26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li J, Mo HY, Xiong G, Zhang L, He J, Huang ZF, et al. Tumor microenvironment macrophage inhibitory factor directs the accumulation of interleukin-17-producing tumor-infiltrating lymphocytes and predicts favorable survival in nasopharyngeal carcinoma patients. J Biol Chem. 2012;287:35484–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang Y, Huang J, Li Y, Yang GY. Roles of chemokine CXCL12 and its receptors in ischemic stroke. Curr Drug Targets. 2012;13:166–72.

    Article  CAS  PubMed  Google Scholar 

  10. Xu J, Deng X, Tang M, Li L, Xiao L, Yang L, et al. Tyrosylprotein sulfotransferase-1 and tyrosine sulfation of chemokine receptor 4 are induced by Epstein-Barr virus encoded latent membrane protein 1 and associated with the metastatic potential of human nasopharyngeal carcinoma. PLoS One. 2013;8, e56114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shinjyo N, Stahlberg A, Dragunow M, Pekny M, Pekna M. Complement-derived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells. Stem Cells. 2009;27:2824–32.

    Article  CAS  PubMed  Google Scholar 

  12. Slinger E, Langemeijer E, Siderius M, Vischer HF, Smit MJ. Herpesvirus-encoded GPCRs rewire cellular signaling. Mol Cell Endocrinol. 2011;331:179–84.

    Article  CAS  PubMed  Google Scholar 

  13. Lu J, Luo H, Liu X, Peng Y, Zhang B, Wang L, et al. miR-9 targets CXCR4 and functions as a potential tumor suppressor in nasopharyngeal carcinoma. Carcinogenesis. 2014;35:554–63.

    Article  CAS  PubMed  Google Scholar 

  14. Ou DL, Chen CL, Lin SB, Hsu CH, Lin LI. Chemokine receptor expression profiles in nasopharyngeal carcinoma and their association with metastasis and radiotherapy. J Pathol. 2006;210:363–73.

    Article  CAS  PubMed  Google Scholar 

  15. Domanska UM, Kruizinga RC, Nagengast WB, Timmer-Bosscha H, Huls G, de Vries EG, et al. A review on CXCR4/CXCL12 axis in oncology: no place to hide. Eur J Cancer. 2013;49:219–30.

    Article  CAS  PubMed  Google Scholar 

  16. Levoye A, Balabanian K, Baleux F, Bachelerie F, Lagane B. CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood. 2009;113:6085–93.

    Article  CAS  PubMed  Google Scholar 

  17. Heinrich EL, Lee W, Lu J, Lowy AM, Kim J. Chemokine CXCL12 activates dual CXCR4 and CXCR7-mediated signaling pathways in pancreatic cancer cells. J Transl Med. 2012;10:68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Luker KE, Lewin SA, Mihalko LA, Schmidt BT, Winkler JS, Coggins NL, et al. Scavenging of CXCL12 by CXCR7 promotes tumor growth and metastasis of CXCR4-positive breast cancer cells. Oncogene. 2012;31:4750–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Luo HN, Li XP, Liu X, Zhang GH, Liu YL. Association of CXCR4 and SDF-1alpha with organ-specific metastasis of nasopharyngeal carcinoma. Zhonghua Zhong Liu Za Zhi. 2009;31:260–4.

    CAS  PubMed  Google Scholar 

  20. Xu Y, Zhang SZ, Huang PC, Chen J, Cai KR. Expression of chemokine receptor CXCR4 in nasopharyngeal carcinoma cells. Ai Zheng. 2004;23:136–40.

    CAS  PubMed  Google Scholar 

  21. Xu D, Li R, Wu J, Jiang L, Zhong HA. Drug Design targeting the CXCR4/CXCR7/CXCL12 pathway. Curr Top Med Chem. 2015.

  22. Filippo TR, Galindo LT, Barnabe GF, Ariza CB, Mello LE, Juliano MA, et al. CXCL12 N-terminal end is sufficient to induce chemotaxis and proliferation of neural stem/progenitor cells. Stem Cell Res. 2013;11:913–25.

    Article  CAS  PubMed  Google Scholar 

  23. da Guo D, Li QN, Li CM, Bi HS. Zinc oxide nanoparticles inhibit murine photoreceptor-derived cell proliferation and migration via reducing TGF-beta and MMP-9 expression in vitro. Cell Prolif. 2015;48:198–208.

    Article  CAS  PubMed  Google Scholar 

  24. Liu Z, Li L, Yang Z, Luo W, Li X, Yang H, et al. Increased expression of MMP9 is correlated with poor prognosis of nasopharyngeal carcinoma. BMC Cancer. 2010;10:270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gallo J, Kamaly N, Lavdas I, Stevens E, Nguyen QD, Wylezinska-Arridge M, et al. CXCR4-targeted and MMP-responsive iron oxide nanoparticles for enhanced magnetic resonance imaging. Angew Chem Int Ed Engl. 2014;53:9550–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yu Y, Li H, Xue B, Jiang X, Huang K, Ge J, et al. SDF-1/CXCR7 axis enhances ovarian cancer cell invasion by MMP-9 expression through p38 MAPK pathway. DNA Cell Biol. 2014;33:543–9.

    Article  CAS  PubMed  Google Scholar 

  27. Sun W, Liu J, Huan Y, Zhang C. Intracranial injection of recombinant stromal-derived factor-1 alpha (SDF-1alpha) attenuates traumatic brain injury in rats. Inflamm Res. 2014;63:287–97.

    Article  CAS  PubMed  Google Scholar 

  28. Shanmugaratnam K, Sobin LH. The World Health Organization histological classification of tumours of the upper respiratory tract and ear. A commentary on the second edition. Cancer. 1993;71:2689–97.

    Article  CAS  PubMed  Google Scholar 

  29. Vindrieux D, Escobar P, Lazennec G. Emerging roles of chemokines in prostate cancer. Endocr Relat Cancer. 2009;16:663–73.

    Article  CAS  PubMed  Google Scholar 

  30. Sun X, Cheng G, Hao M, Zheng J, Zhou X, Zhang J, et al. CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev. 2010;29:709–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006;107:1761–7.

    Article  CAS  PubMed  Google Scholar 

  32. Wojcechowskyj JA, Lee JY, Seeholzer SH, Doms RW. Quantitative phosphoproteomics of CXCL12 (SDF-1) signaling. PLoS One. 2011;6, e24918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Samara GJ, Lawrence DM, Chiarelli CJ, Valentino MD, Lyubsky S, Zucker S, et al. CXCR4-mediated adhesion and MMP-9 secretion in head and neck squamous cell carcinoma. Cancer Lett. 2004;214:231–41.

    Article  CAS  PubMed  Google Scholar 

  34. Muller 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  CAS  PubMed  Google Scholar 

  35. Wang J, Shiozawa Y, Wang Y, Jung Y, Pienta KJ, Mehra R, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem. 2008;283:4283–94.

    Article  CAS  PubMed  Google Scholar 

  36. Halder K, Banerjee S, Ghosh S, Bose A, Das S, Chowdhury BP, et al. Mycobacterium indicus pranii (Mw) inhibits invasion by reducing matrix metalloproteinase (MMP-9) via AKT/ERK-1/2 and PKCalpha signalling: a potential candidate in melanoma cancer therapy. Cancer Biol Ther. 2015.

  37. Chen WL, Sheu JR, Chen RJ, Hsiao SH, Hsiao CJ, Chou YC, et al. Mycobacterium tuberculosis upregulates TNF-alpha expression via TLR2/ERK signaling and induces MMP-1 and MMP-9 production in human pleural mesothelial cells. PLoS One. 2015;10, e0137979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gao J, Liu X, Yang F, Liu T, Yan Q, Yang X. By inhibiting Ras/Raf/ERK and MMP-9, knockdown of EpCAM inhibits breast cancer cell growth and metastasis. Oncotarget. 2015;6:27187–98.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 2006;203:2201–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang Y, Tsai ML, Chiou LY, Ho CT, Pan MH. Antitumor activity of garcinol in human prostate cancer cells and xenograft mice. J Agric Food Chem. 2015.

  41. Hattermann K, Held-Feindt J, Lucius R, Muerkoster SS, Penfold ME, Schall TJ, et al. The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Cancer Res. 2010;70:3299–308.

    Article  CAS  PubMed  Google Scholar 

  42. Hattermann K, Holzenburg E, Hans F, Lucius R, Held-Feindt J, Mentlein R. Effects of the chemokine CXCL12 and combined internalization of its receptors CXCR4 and CXCR7 in human MCF-7 breast cancer cells. Cell Tissue Res. 2014;357:253–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhu B, Xu D, Deng X, Chen Q, Huang Y, Peng H, et al. CXCL12 enhances human neural progenitor cell survival through a CXCR7- and CXCR4-mediated endocytotic signaling pathway. Stem Cells. 2012;30:2571–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by Shangdong Province Natural Science Foundation (ZR2011HM058).

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Authors and Affiliations

  1. Department of Radiation Oncology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong Province, China

    Naian Qiao, Lin Wang & Tao Wang

  2. Department of Ultrasonography, Qilu Hospital, Shandong University, No. 107 West Wenhua Road, Lixia District, Jinan, 250012, Shandong Province, China

    Haiying Li

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  1. Naian Qiao
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Correspondence to Haiying Li.

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Qiao, N., Wang, L., Wang, T. et al. Inflammatory CXCL12-CXCR4/CXCR7 axis mediates G-protein signaling pathway to influence the invasion and migration of nasopharyngeal carcinoma cells. Tumor Biol. 37, 8169–8179 (2016). https://doi.org/10.1007/s13277-015-4686-2

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