Tumor Biology

, Volume 34, Issue 5, pp 2703–2708 | Cite as

CCL19/CCR7 upregulates heparanase via specificity protein-1 (Sp1) to promote invasion of cell in lung cancer

  • Qingfu Zhang
  • Limei Sun
  • Liying Yin
  • Jian Ming
  • Siyang Zhang
  • Wenting Luo
  • Xueshan Qiu
Research Article


CCL19/chemokine receptor 7 (CCR7) has been found to be associated with tumor growth, angiogenesis, invasion, and lymph node metastasis. Our previous study demonstrated that CCR7 overexpressed in non-small cell lung cancer (NSCLC) and had close relationship with tumor invasion and lymph node metastasis. However, the molecular mechanism of CCR7 promoting invasion of human NSCLC cells is still unclear. In this study, we demonstrated that human lung adenocarcinoma A549 cells treated with recombinant human CCL19 could obviously upregulate the expression of Sp1 and heparanase at both the mRNA and protein levels. After blockage of CCR7, Sp1 and heparanase expressions were inhibited. Following inhibition of Sp1, heparanase expression was downregulated. The analysis showed the promoter region of heparanase gene containing a number of potential sp1 binding sites (5′-GGGGC-3′). Chromatin immunoprecipitation analysis demonstrated that Sp1 could bind to the heparanase promoter. Cell invasion assays showed that the invasion ability of A549 cells was increased with CCL19 incubation compared to the control cells. These results suggested that CCL19/CCR7 may upregulate the expression of heparanase via Sp1 and contribute to the invasion of A549 cells.


Lung neoplasms Heparanase Chemokine receptor 7 (CCR7) Invasion Chemokines 



This study was supported by Natural Science Foundation of Liaoning Province of China (no. 200904387).

Conflicts of interest



  1. 1.
    Keeleya EC, Mehradb B, Strieter RM. Chemokines as mediators of tumor angiogenesis and neovascularization. Exp Cell Res. 2011;317(5):685–90.CrossRefGoogle Scholar
  2. 2.
    Iijima N, Yanagawa Y, Clingan JM, Onoé K. CCR7-mediated c-Jun N-terminal kinase activation regulates cell migration in mature dendritic cells. Int Immunol. 2005;17(9):1201–12.CrossRefPubMedGoogle Scholar
  3. 3.
    Nagira M, Imai T, Yoshida R, Takagi S, Iwasaki M, Baba M, et al. A lymphocyte-specific CC chemokine, secondary lymphoid tissue chemokine (SLC), is a highly efficient chemoattractant for B cells and activated T cells. Eur J Immunol. 1998;28(5):1516–23.CrossRefPubMedGoogle Scholar
  4. 4.
    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(9):3406–12.PubMedGoogle Scholar
  5. 5.
    Vlodavsky I, Goldshmidt O, Zcharia E, Atzmon R, Rangini-Guatta Z, Elkin M, et al. Mammalian heparanase: involvement in cancer metastasis, angiogenesis and normal development. Semin Cancer Biol. 2002;12(2):121–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Ilan N, Elkin M, Vlodavsky I. Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis. Int J Biochem Cell Biol. 2006;38(12):2018–39.CrossRefPubMedGoogle Scholar
  7. 7.
    Tang Z, Yu M, Miller F, Berk RS, Tromp G, Kosir MA. Increased invasion through basement membrane by CXCL7-transfected breast cells. Am J Surg. 2008;196(5):690–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Yadav BS, Sharma SC, Singh R, Singh G, Kumar V. Postmastectomy radiation and survival in patients with breast cancer. J Cancer Res Ther. 2007;3(4):218–24.CrossRefPubMedGoogle Scholar
  9. 9.
    Wang W, Goswami S, Lapidus K, Wells AL, Wyckoff JB, Sahai E, et al. Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors. Cancer Res. 2004;64(23):8585–94.CrossRefPubMedGoogle Scholar
  10. 10.
    Wang W, Wyckoff JB, Goswami S, Wang Y, Sidani M, Segall JE, et al. Coordinated regulation of pathways for enhanced cell motility and chemotaxis is conserved in rat and mouse mammary tumors. Cancer Res. 2007;67(8):3505–11.CrossRefPubMedGoogle Scholar
  11. 11.
    Fidler IJ. Critical determinants of metastasis. Semin Cancer Biol. 2002;12(2):89–96.CrossRefPubMedGoogle Scholar
  12. 12.
    Fidler IJ. The organ microenvironment and cancer metastasis. Differentiation. 2002;70(9–10):498–505.CrossRefPubMedGoogle Scholar
  13. 13.
    Liotta LA. An attractive force in metastasis. Nature. 2001;410(6824):24–5.CrossRefPubMedGoogle Scholar
  14. 14.
    Park CC, Bissell MJ, Barcellos-Hoff MH. The influence of the microenvironment on the malignant phenotype. Mol Med Today. 2000;6(8):324–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Kodama J, Hasengaowa, Kusumoto T, Seki N, Matsuo T, Ojima Y, et al. Association of CXCR4 and CCR7 chemokine receptor expression and lymph node metastasis in human cervical cancer. Ann Oncol. 2007;18(1):70–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Takeuchi H, Fujimoto A, Tanaka M, Yamano T, Hsueh E, Hoon DS. CCL21 chemokine regulates chemokine receptor CCR7 bearing malignant melanoma cells. Clin Cancer Res. 2004;10(7):2351–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Günther K, Leier J, Henning G, Dimmler A, Weissbach R, Hohenberger W, et al. Prediction of lymph node metastasis in colorectal carcinoma by expression of chemokine receptor CCR7. Int J Cancer. 2005;116(5):726–33.CrossRefPubMedGoogle Scholar
  18. 18.
    Yan C, Zhu ZG, Yu YY, Ji J, Zhang Y, Ji YB, et al. Expression of vascular endothelial growth factor C and chemokine receptor CCR7 in gastric carcinoma and their values in predicting lymph node metastasis. World J Gastroenterol. 2004;10(6):783–90.PubMedGoogle Scholar
  19. 19.
    Mashino K, Sadanaga N, Yamaguchi H, Tanaka F, Ohta M, Shibuta K, et al. Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma. Cancer Res. 2002;62(10):2937–41.PubMedGoogle Scholar
  20. 20.
    Tsuzuki H, Takahashi N, Kojima A, Narita N, Sunaga H, Takabayashi T, et al. Oral and oropharyngeal squamous cell carcinomas expressing CCR7 have poor prognoses. Auris Nasus Larynx. 2006;33(1):37–42.CrossRefPubMedGoogle Scholar
  21. 21.
    Takanami I. Overexpression of CCR7 mRNA in nonsmall cell lung cancer: correlation with lymph node metastasis. Int J Cancer. 2003;105(2):186–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Li Y, Qiu X, Zhang S, Zhang Q, Wang E. Hypoxia induced CCR7 expression via HIF-1α and HIF-2α correlates with migration and invasion in BE1 cells. Cancer Biol Ther. 2009;8(4):322–30.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Qingfu Zhang
    • 1
  • Limei Sun
    • 1
  • Liying Yin
    • 2
  • Jian Ming
    • 3
  • Siyang Zhang
    • 4
  • Wenting Luo
    • 1
  • Xueshan Qiu
    • 1
  1. 1.Department of Pathologythe First Affiliated Hospital and College of Basic Medical Sciences of China Medical UniversityShenyangPeople’s Republic of China
  2. 2.Department of PathologyNo 5 People’s HospitalDalianPeople’s Republic of China
  3. 3.No. 202 Hospital of People Liberation Army of ChinaShenyangPeople’s Republic of China
  4. 4.Center of Laboratory Technology and Experimental MedicineChina Medical UniversityShenyangPeople’s Republic of China

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