Tumor Biology

, Volume 37, Issue 8, pp 11509–11521 | Cite as

Discoidin domain receptor 1 (DDR1), a promising biomarker, induces epithelial to mesenchymal transition in renal cancer cells

  • Jingyuan Song
  • Xiao Chen
  • Jin Bai
  • Qinghua Liu
  • Hui Li
  • Jianwan Xie
  • Hui Jing
  • Junnian Zheng
Original Article


Discoidin domain receptor I (DDR1) is confirmed as a receptor tyrosine kinase (RTK), which plays a consequential role in a variety of cancers. Nevertheless, the influence of DDR1 expression and development in renal clear cell carcinoma (RCCC) are still not well corroborated. In our research, we firstly discovered that the expression level of DDR1 was remarkable related to TNM stage (p = 0.032), depth of tumor invasion (p = 0.047), and lymph node metastasis (p = 0.034) in 119 RCCC tissue samples using tissue microarray. The function of DDR1 was then evaluated in vitro using collagen I and DDR1 small interfering RNA (siRNA) to regulate the expression of DDR1 in OS-RC-2 and ACHN renal cancer cells (RCC). DDR1 expression correlated with increased RCC cell migration, invasion, and angiogenesis. Further study revealed that high expression of DDR1 can result in epithelial to mesenchymal transition (EMT) activation. Western blot assay showed that the N-cadherin protein and vimentin were induced while E-cadherin was reduced after DDR1 over expression. Our results suggest that DDR1 is both a prognostic marker for RCCC and a potential functional target for therapy.


DDR1 EMT Biomarker Renal cancer cells 



This study is supported by National Natural Science Foundation of China (NSFC), No.81301806; Jiangsu Planned Projects for Postdoctoral Research Funds, No.1501060A; six talent peaks project in Jiangsu Province, No.WSW-056.

Compliance with ethical standards

Conflicts of interest



  1. 1.
    Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62:220–41.CrossRefPubMedGoogle Scholar
  2. 2.
    Finley DS, Pantuck AJ, Belldegrun AS. Tumor biology and prognostic factors in renal cell carcinoma. Oncologist. 2011;16 Suppl 2:4–13.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Coppin C, Kollmannsberger C, Le L, Porzsolt F, Wilt TJ. Targeted therapy for advanced renal cell cancer (rcc): a cochrane systematic review of published randomised trials. BJU Int. 2011;108:1556–63.CrossRefPubMedGoogle Scholar
  4. 4.
    Valiathan RR, Marco M, Leitinger B, Kleer CG, Fridman R. Discoidin domain receptor tyrosine kinases: new players in cancer progression. Cancer Metastasis Rev. 2012;31:295–321.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell. 1997;1:13–23.CrossRefPubMedGoogle Scholar
  6. 6.
    Shrivastava A, Radziejewski C, Campbell E, Kovac L, McGlynn M, Ryan TE, et al. An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol Cell. 1997;1:25–34.CrossRefPubMedGoogle Scholar
  7. 7.
    Vogel WF, Abdulhussein R, Ford CE. Sensing extracellular matrix: an update on discoidin domain receptor function. Cell Signal. 2006;18:1108–16.CrossRefPubMedGoogle Scholar
  8. 8.
    Yamanaka R, Arao T, Yajima N, Tsuchiya N, Homma J, Tanaka R, et al. Identification of expressed genes characterizing long-term survival in malignant glioma patients. Oncogene. 2006;25:5994–6002.CrossRefPubMedGoogle Scholar
  9. 9.
    Johansson FK, Goransson H, Westermark B. Expression analysis of genes involved in brain tumor progression driven by retroviral insertional mutagenesis in mice. Oncogene. 2005;24:3896–905.CrossRefPubMedGoogle Scholar
  10. 10.
    Heinzelmann-Schwarz VA, Gardiner-Garden M, Henshall SM, Scurry J, Scolyer RA, Davies MJ, et al. Overexpression of the cell adhesion molecules ddr1, claudin 3, and ep-cam in metaplastic ovarian epithelium and ovarian cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2004;10:4427–36.CrossRefGoogle Scholar
  11. 11.
    Weiner HL, Huang H, Zagzag D, Boyce H, Lichtenbaum R, Ziff EB. Consistent and selective expression of the discoidin domain receptor-1 tyrosine kinase in human brain tumors. Neurosurgery. 2000;47:1400–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Park HS, Kim KR, Lee HJ, Choi HN, Kim DK, Kim BT, et al. Overexpression of discoidin domain receptor 1 increases the migration and invasion of hepatocellular carcinoma cells in association with matrix metalloproteinase. Oncol Rep. 2007;18:1435–41.PubMedGoogle Scholar
  13. 13.
    Edwards DR, Murphy G. Cancer. Proteases—invasion and more. Nature. 1998;394:527–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Yoshimoto M, Itoh F, Yamamoto H, Hinoda Y, Imai K, Yachi A. Expression of mmp-7(pump-1) mrna in human colorectal cancers. Int J Cancer J Int Cancer. 1993;54:614–8.CrossRefGoogle Scholar
  15. 15.
    Senota A, Itoh F, Yamamoto H, Adachi Y, Hinoda Y, Imai K. Relation of matrilysin messenger rna expression with invasive activity in human gastric cancer. Clin Exp Metastasis. 1998;16:313–21.CrossRefPubMedGoogle Scholar
  16. 16.
    Uhm JH, Dooley NP, Villemure JG, Yong VW. Glioma invasion in vitro: regulation by matrix metalloprotease-2 and protein kinase c. Clin Exp Metastasis. 1996;14:421–33.CrossRefPubMedGoogle Scholar
  17. 17.
    Mikami S, Oya M, Mizuno R, Kosaka T, Katsube K, Okada Y. Invasion and metastasis of renal cell carcinoma. Med Mol Morphol. 2014;47:63–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Sato A, Nagase H, Obinata D, Fujiwara K, Fukuda N, Soma M, et al. Inhibition of mmp-9 using a pyrrole-imidazole polyamide reduces cell invasion in renal cell carcinoma. Int J Oncol. 2013;43:1441–6.PubMedGoogle Scholar
  19. 19.
    Lu H, Yang Z, Zhang H, Gan M, Zhou T, Wang S. The expression and clinical significance of matrix metalloproteinase 7 and tissue inhibitor of matrix metalloproteinases 2 in clear cell renal cell carcinoma. Exp Ther Med. 2013;5:890–6.PubMedGoogle Scholar
  20. 20.
    Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15:740–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172:973–81.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Shintani Y, Fukumoto Y, Chaika N, Svoboda R, Wheelock MJ, Johnson KR. Collagen i-mediated up-regulation of n-cadherin requires cooperative signals from integrins and discoidin domain receptor 1. J Cell Biol. 2008;180:1277–89.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Borza CM, Pozzi A. Discoidin domain receptors in disease. Matrix Biol J Int Soc Matrix Biol. 2014;34:185–92.CrossRefGoogle Scholar
  24. 24.
    L’Hote CG, Thomas PH, Ganesan TS. Functional analysis of discoidin domain receptor 1: effect of adhesion on ddr1 phosphorylation. FASEB J Off Publ Fed Am Soc Exp Biol. 2002;16:234–6.Google Scholar
  25. 25.
    Alves F, Saupe S, Ledwon M, Schaub F, Hiddemann W, Vogel WF. Identification of two novel, kinase-deficient variants of discoidin domain receptor 1: differential expression in human colon cancer cell lines. FASEB J Off Publ Fed Am Soc Exp Biol. 2001;15:1321–3.Google Scholar
  26. 26.
    Sanchez MP, Tapley P, Saini SS, He B, Pulido D, Barbacid M. Multiple tyrosine protein kinases in rat hippocampal neurons: Isolation of ptk-3, a receptor expressed in proliferative zones of the developing brain. Proc Natl Acad Sci U S A. 1994;91:1819–23.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Johnson JD, Edman JC, Rutter WJ. A receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin i-like domain. Proc Natl Acad Sci U S A. 1993;90:5677–81.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Laval S, Butler R, Shelling AN, Hanby AM, Poulsom R, Ganesan TS. Isolation and characterization of an epithelial-specific receptor tyrosine kinase from an ovarian cancer cell line. Cell Growth Differ Mol Biol J Am Assoc Cancer Res. 1994;5:1173–83.Google Scholar
  29. 29.
    Vogel WF, Aszodi A, Alves F, Pawson T. Discoidin domain receptor 1 tyrosine kinase has an essential role in mammary gland development. Mol Cell Biol. 2001;21:2906–17.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Alves F, Vogel W, Mossie K, Millauer B, Hofler H, Ullrich A. Distinct structural characteristics of discoidin i subfamily receptor tyrosine kinases and complementary expression in human cancer. Oncogene. 1995;10:609–18.PubMedGoogle Scholar
  31. 31.
    Miao L, Zhu S, Wang Y, Li Y, Ding J, Dai J, et al. Discoidin domain receptor 1 is associated with poor prognosis of non-small cell lung cancer and promotes cell invasion via epithelial-to-mesenchymal transition. Med Oncol. 2013;30:626.CrossRefPubMedGoogle Scholar
  32. 32.
    Toy KA, Valiathan RR, Nunez F, Kidwell KM, Gonzalez ME, Fridman R, et al. Tyrosine kinase discoidin domain receptors ddr1 and ddr2 are coordinately deregulated in triple-negative breast cancer. Breast Cancer Res Treat. 2015;150:9–18.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Huo Y, Yang M, Liu W, Yang J, Fu X, Liu D, et al. High expression of ddr1 is associated with the poor prognosis in Chinese patients with pancreatic ductal adenocarcinoma. J Exp Clin Cancer Res CR. 2015;34:88.CrossRefPubMedGoogle Scholar
  34. 34.
    Rudra-Ganguly N, Lowe C, Mattie M, Chang MS, Satpayev D, Verlinsky A, et al. Discoidin domain receptor 1 contributes to tumorigenesis through modulation of tgfbi expression. PLoS One. 2014;9, e111515.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Hou G, Vogel W, Bendeck MP. The discoidin domain receptor tyrosine kinase ddr1 in arterial wound repair. J Clin Invest. 2001;107:727–35.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ruiz PA, Jarai G. Collagen i induces discoidin domain receptor (ddr) 1 expression through ddr2 and a jak2-erk1/2-mediated mechanism in primary human lung fibroblasts. J Biol Chem. 2011;286:12912–23.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Maeda M, Johnson KR, Wheelock MJ. Cadherin switching: essential for behavioral but not morphological changes during an epithelium-to-mesenchyme transition. J Cell Sci. 2005;118:873–87.CrossRefPubMedGoogle Scholar
  38. 38.
    Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004;118:277–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.CrossRefPubMedGoogle Scholar
  40. 40.
    Sarkar FH, Li Y, Wang Z, Kong D. Pancreatic cancer stem cells and emt in drug resistance and metastasis. Minerva Chir. 2009;64:489–500.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Battaglia S, Benzoubir N, Ghigna MR, Guettier C, Brechot C, Bourgeade MF. Epithelial-mesenchymal transition and hepatocellular carcinoma. Ann Pathol. 2009;29(Spec No 1):S65–6.CrossRefPubMedGoogle Scholar
  42. 42.
    Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–57.CrossRefPubMedGoogle Scholar
  43. 43.
    Ferrara N, Alitalo K. Clinical applications of angiogenic growth factors and their inhibitors. Nat Med. 1999;5:1359–64.CrossRefPubMedGoogle Scholar
  44. 44.
    Weis SM, Cheresh DA. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med. 2011;17:1359–70.CrossRefPubMedGoogle Scholar
  45. 45.
    Cao YEG, Wang E, Pal K, Dutta SK, Bar-Sagi D, Mukhopadhyay D. Vegf exerts an angiogenesis-independent function in cancer cells to promote their malignant progression. Cancer Res. 2012;72:3912–8.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Reel B, Korkmaz CG, Arun MZ, Yildirim G, Ogut D, Kaymak A, et al. The regulation of matrix metalloproteinase expression and the role of discoidin domain receptor 1/2 signalling in zoledronate-treated pc3 cells. J Cancer. 2015;6:1020–9.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Fu HL, Sohail A, Valiathan RR, Wasinski BD, Kumarasiri M, Mahasenan KV, et al. Shedding of discoidin domain receptor 1 by membrane-type matrix metalloproteinases. J Biol Chem. 2013;288:12114–29.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Castro-Sanchez L, Soto-Guzman A, Guaderrama-Diaz M, Cortes-Reynosa P, Salazar EP. Role of ddr1 in the gelatinases secretion induced by native type iv collagen in mda-mb-231 breast cancer cells. Clin Exp Metastasis. 2011;28:463–77.CrossRefPubMedGoogle Scholar
  49. 49.
    Kim HG, Tan L, Weisberg EL, Liu F, Canning P, Choi HG, et al. Discovery of a potent and selective ddr1 receptor tyrosine kinase inhibitor. ACS Chem Biol. 2013;8:2145–50.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Carafoli F, Mayer MC, Shiraishi K, Pecheva MA, Chan LY, Nan R, et al. Structure of the discoidin domain receptor 1 extracellular region bound to an inhibitory fab fragment reveals features important for signaling. Structure. 2012;20:688–97.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Jingyuan Song
    • 1
  • Xiao Chen
    • 1
  • Jin Bai
    • 1
  • Qinghua Liu
    • 1
  • Hui Li
    • 1
  • Jianwan Xie
    • 1
  • Hui Jing
    • 1
  • Junnian Zheng
    • 1
    • 2
    • 3
  1. 1.Jiangsu Key Laboratory of Biological Cancer TherapyXuzhou Medical CollegeXuzhouChina
  2. 2.Jiangsu Center for the Collaboration and Innovation of Cancer BiotherapyXuzhouChina
  3. 3.Affiliated Hospital of Xuzhou Medical CollegeXuzhouChina

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