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

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Tumor Biology

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Abstract

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.

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References

  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.

    Article  PubMed  Google Scholar 

  2. Finley DS, Pantuck AJ, Belldegrun AS. Tumor biology and prognostic factors in renal cell carcinoma. Oncologist. 2011;16 Suppl 2:4–13.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  7. Vogel WF, Abdulhussein R, Ford CE. Sensing extracellular matrix: an update on discoidin domain receptor function. Cell Signal. 2006;18:1108–16.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  13. Edwards DR, Murphy G. Cancer. Proteases—invasion and more. Nature. 1998;394:527–8.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  20. Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15:740–6.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Borza CM, Pozzi A. Discoidin domain receptors in disease. Matrix Biol J Int Soc Matrix Biol. 2014;34:185–92.

    Article  CAS  Google Scholar 

  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. 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.

    CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  38. Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004;118:277–9.

    Article  CAS  PubMed  Google Scholar 

  39. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  42. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–57.

    Article  CAS  PubMed  Google Scholar 

  43. Ferrara N, Alitalo K. Clinical applications of angiogenic growth factors and their inhibitors. Nat Med. 1999;5:1359–64.

    Article  CAS  PubMed  Google Scholar 

  44. Weis SM, Cheresh DA. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med. 2011;17:1359–70.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

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.

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    Authors and Affiliations

    1. Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, Jiangsu, 221002, China

      Jingyuan Song, Xiao Chen, Jin Bai, Qinghua Liu, Hui Li, Jianwan Xie, Hui Jing & Junnian Zheng

    2. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou, Jiangsu, 221002, China

      Junnian Zheng

    3. Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, 221002, China

      Junnian Zheng

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    1. Jingyuan Song
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    Jingyuan Song and Xiao Chen contributed equally to this work.

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    Song, J., Chen, X., Bai, J. et al. Discoidin domain receptor 1 (DDR1), a promising biomarker, induces epithelial to mesenchymal transition in renal cancer cells. Tumor Biol. 37, 11509–11521 (2016). https://doi.org/10.1007/s13277-016-5021-2

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