Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Neuropilin-1 contributes to esophageal squamous cancer progression via promoting P65-dependent cell proliferation

Oncogene volume 37, pages 935–943 (2018)Cite this article

Subjects

Abstract

Neuropilin-1 (NRP1) is a non-kinase receptor recently implicated in tumor progression. Here we revealed that over-expression of NRP1 correlates with poor prognosis in esophageal squamous cell carcinoma (ESCC). NRP1-knockdown suppressed ESCC cell proliferation and xenograft tumor growth. Reduced NRP1 expression downregulated P65 mRNA and protein expression, and ectopic expression of P65-restored cell proliferation in NRP1-silenced cells. NRP1 regulates P65 transcription by activating cAMP responsive element binding protein (CREB). NRP1 interacted with and activated epidermal growth factor receptor (EGFR), and b1/b2 domain of NRP1 is responsible for the activation of EGFR. We also found that EGFR regulated CREB transcriptional activity via AKT. These data suggest that NRP1 is an upstream regulator in the P65-dependent proliferation signaling pathway and a candidate therapeutic target for ESCC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Shang L, Wang M . Molecular alterations and clinical relevance in esophageal squamous cell carcinoma. Front Med 2013; 7: 401–410.

    Article  Google Scholar 

  2. Wang XM, Shang L, Zhang Y, Hao JJ, Shi F, Luo W et al. PTP1B contributes to calreticulin-induced metastatic phenotypes in esophageal squamous cell carcinoma. Mol Cancer Res 2013; 11: 986–994.

    Article  CAS  Google Scholar 

  3. Shi F, Shang L, Pan BQ, Wang XM, Jiang YY, Hao JJ et al. Calreticulin promotes migration and invasion of esophageal cancer cells by upregulating neuropilin-1 expression via STAT5A. Clin Cancer Res 2014; 20: 6153–6162.

    Article  CAS  Google Scholar 

  4. Nakamura F, Goshima Y . Structural and functional relation of neuropilins. Adv Exp Med Biol 2002; 515: 55–69.

    Article  CAS  Google Scholar 

  5. Guttmann-Raviv N, Kessler O, Shraga-Heled N, Lange T, Herzog Y, Neufeld G . The neuropilins and their role in tumorigenesis and tumor progression. Cancer Lett 2006; 231: 1–11.

    Article  CAS  Google Scholar 

  6. Gu C, Limberg BJ, Whitaker GB, Perman B, Leahy DJ, Rosenbaum JS et al. Characterization of neuropilin-1 structural features that confer binding to semaphorin 3A and vascular endothelial growth factor 165. J Biol Chem 2002; 277: 18069–18076.

    Article  CAS  Google Scholar 

  7. Rizzolio S, Tamagnone L . Multifaceted role of neuropilins in cancer. Curr Med Chem 2011; 18: 3563–3575.

    Article  CAS  Google Scholar 

  8. Ohsaka A, Hirota-Komatsu S, Araki M, Komatsu N . Platelet-derived growth factor receptors form complexes with neuropilin-1 during megakaryocytic differentiation of thrombopoietin-dependent UT-7/TPO cells. Biochem Biophys Res Commun 2015; 459: 443–449.

    Article  CAS  Google Scholar 

  9. Hu C, Jiang X . Role of NRP-1 in VEGF-VEGFR2-independent tumorigenesis. Target Oncol 2016; 11: 501–505.

    Article  Google Scholar 

  10. Perkins ND . The diverse and complex roles of NF-kappaB subunits in cancer. Nat Rev Cancer 2012; 12: 121–132.

    Article  CAS  Google Scholar 

  11. Shaywitz AJ, Greenberg ME . CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 1999; 68: 821–861.

    Article  CAS  Google Scholar 

  12. Chaudhary B, Khaled YS, Ammori BJ, Elkord E . Neuropilin 1: function and therapeutic potential in cancer. Cancer Immunol Immunother 2014; 63: 81–99.

    Article  CAS  Google Scholar 

  13. Brand TM, Iida M, Li C, Wheeler DL . The nuclear epidermal growth factor receptor signaling network and its role in cancer. Discov Med 2011; 12: 419–432.

    PubMed  PubMed Central  Google Scholar 

  14. Du K, Montminy M . CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem 1998; 273: 32377–32379.

    Article  CAS  Google Scholar 

  15. Wild JR, Staton CA, Chapple K, Corfe BM . Neuropilins: expression and roles in the epithelium. Int J Exp Pathol 2012; 93: 81–103.

    Article  CAS  Google Scholar 

  16. Ghosh S, Sullivan CA, Zerkowski MP, Molinaro AM, Rimm DL, Camp RL et al. High levels of vascular endothelial growth factor and its receptors (VEGFR-1, VEGFR-2, neuropilin-1) are associated with worse outcome in breast cancer. Hum Pathol 2008; 39: 1835–1843.

    Article  CAS  Google Scholar 

  17. Naik A, Al-Zeheimi N, Bakheit CS, Al Riyami M, Al Jarrah A, Al Moundhri MS et al. Neuropilin-1 associated molecules in the blood distinguish poor prognosis breast cancer: a cross-sectional study. Sci Rep 2017; 7: 3301.

    Article  Google Scholar 

  18. Berge M, Allanic D, Bonnin P, de Montrion C, Richard J, Suc M et al. Neuropilin-1 is upregulated in hepatocellular carcinoma and contributes to tumour growth and vascular remodelling. J Hepatol 2011; 55: 866–875.

    Article  CAS  Google Scholar 

  19. Zhang Y, Liu P, Jiang Y, Dou X, Yan J, Ma C et al. High expression of neuropilin-1 associates with unfavorable clinicopathological features in hepatocellular carcinoma. Pathol Oncol Res 2016; 22: 367–375.

    Article  CAS  Google Scholar 

  20. Hong TM, Chen YL, Wu YY, Yuan A, Chao YC, Chung YC et al. Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clin Cancer Res 2007; 13: 4759–4768.

    Article  CAS  Google Scholar 

  21. Xu Y, Li P, Zhang X, Wang J, Gu D, Wang Y . Prognostic implication of neuropilin-1 upregulation in human nasopharyngeal carcinoma. Diagn Pathol 2013; 8: 155.

    Article  Google Scholar 

  22. Lu J, Cheng Y, Zhang G, Tang Y, Dong Z, McElwee KJ et al. Increased expression of neuropilin 1 in melanoma progression and its prognostic significance in patients with melanoma. Mol Med Rep 2015; 12: 2668–2676.

    Article  CAS  Google Scholar 

  23. Jiang H, Xi Q, Wang F, Sun Z, Huang Z, Qi L . Increased expression of neuropilin 1 is associated with epithelial ovarian carcinoma. Mol Med Rep 2015; 12: 2114–2120.

    Article  CAS  Google Scholar 

  24. Song X, Zhang W, Zhang Y, Zhang H, Fu Z, Ye J et al. Expression of semaphorin 3A and neuropilin 1 with clinicopathological features and survival in human tongue cancer. Med Oral Patol Oral Cir Bucal 2012; 17: e962–e968.

    Article  Google Scholar 

  25. Shahrabi-Farahani S, Gallottini M, Martins F, Li E, Mudge DR, Nakayama H et al. Neuropilin 1 receptor is up-regulated in dysplastic epithelium and oral squamous cell carcinoma. Am J Pathol 2016; 186: 1055–1064.

    Article  CAS  Google Scholar 

  26. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  Google Scholar 

  27. Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar C, Riedemann L, Walsh EC et al. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 2013; 152: 1065–1076.

    Article  CAS  Google Scholar 

  28. Han Z, Jiang G, Zhang Y, Xu J, Chen C, Zhang L et al. Effects of RNA interference-mediated NRP-1 silencing on the proliferation and apoptosis of breast cancer cells. Mol Med Rep 2015; 12: 513–519.

    Article  CAS  Google Scholar 

  29. Li L, Jiang X, Zhang Q, Dong X, Gao Y, He Y et al. Neuropilin-1 is associated with clinicopathology of gastric cancer and contributes to cell proliferation and migration as multifunctional co-receptors. J Exp Clin Cancer Res 2016; 35: 16.

    Article  Google Scholar 

  30. Matkar PN, Singh KK, Rudenko D, Kim YJ, Kuliszewski MA, Prud'homme GJ et al. Novel regulatory role of neuropilin-1 in endothelial-to-mesenchymal transition and fibrosis in pancreatic ductal adenocarcinoma. Oncotarget 2016; 7: 69489–69506.

    Article  Google Scholar 

  31. Chu W, Song X, Yang X, Ma L, Zhu J, He M et al. Neuropilin-1 promotes epithelial-to-mesenchymal transition by stimulating nuclear factor-kappa B and is associated with poor prognosis in human oral squamous cell carcinoma. PLoS One 2014; 9: e101931.

    Article  Google Scholar 

  32. Glinka Y, Mohammed N, Subramaniam V, Jothy S, Prud'homme GJ . Neuropilin-1 is expressed by breast cancer stem-like cells and is linked to NF-kappaB activation and tumor sphere formation. Biochem Biophys Res Commun 2012; 425: 775–780.

    Article  CAS  Google Scholar 

  33. Hoesel B, Schmid JA . The complexity of NF-kappaB signaling in inflammation and cancer. Mol Cancer 2013; 12: 86.

    Article  CAS  Google Scholar 

  34. Li ZW, Chen H, Campbell RA, Bonavida B, Berenson JR . NF-kappaB in the pathogenesis and treatment of multiple myeloma. Curr Opin Hematol 2008; 15: 391–399.

    Article  CAS  Google Scholar 

  35. Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S, Nakshatri H . NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 2007; 26: 711–724.

    Article  CAS  Google Scholar 

  36. Qiao L, Zhang H, Yu J, Francisco R, Dent P, Ebert MP et al. Constitutive activation of NF-kappaB in human hepatocellular carcinoma: evidence of a cytoprotective role. Hum Gene Ther 2006; 17: 280–290.

    Article  CAS  Google Scholar 

  37. Weichert W, Boehm M, Gekeler V, Bahra M, Langrehr J, Neuhaus P et al. High expression of RelA/p65 is associated with activation of nuclear factor-kappaB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis. Br J Cancer 2007; 97: 523–530.

    Article  CAS  Google Scholar 

  38. Scartozzi M, Bearzi I, Pierantoni C, Mandolesi A, Loupakis F, Zaniboni A et al. Nuclear factor-kB tumor expression predicts response and survival in irinotecan-refractory metastatic colorectal cancer treated with cetuximab-irinotecan therapy. J Clin Oncol 2007; 25: 3930–3935.

    Article  CAS  Google Scholar 

  39. Al-Saad S, Al-Shibli K, Donnem T, Persson M, Bremnes RM, Busund LT . The prognostic impact of NF-kappaB p105, vimentin, E-cadherin and Par6 expression in epithelial and stromal compartment in non-small-cell lung cancer. Br J Cancer 2008; 99: 1476–1483.

    Article  CAS  Google Scholar 

  40. Izzo JG, Malhotra U, Wu TT, Luthra R, Correa AM, Swisher SG et al. Clinical biology of esophageal adenocarcinoma after surgery is influenced by nuclear factor-kappaB expression. Cancer Epidemiol Biomarkers Prev 2007; 16: 1200–1205.

    Article  CAS  Google Scholar 

  41. Lin DC, Zhang Y, Pan QJ, Yang H, Shi ZZ, Xie ZH et al. PLK1 Is transcriptionally activated by NF-kappaB during cell detachment and enhances anoikis resistance through inhibiting beta-catenin degradation in esophageal squamous cell carcinoma. Clin Cancer Res 2011; 17: 4285–4295.

    Article  CAS  Google Scholar 

  42. Sakamoto KM, Grant S, Saleiro D, Crispino JD, Hijiya N, Giles F et al. Targeting novel signaling pathways for resistant acute myeloid leukemia. Mol Genet Metab 2015; 114: 397–402.

    Article  CAS  Google Scholar 

  43. Sakamoto KM, Frank DA . CREB in the pathophysiology of cancer: implications for targeting transcription factors for cancer therapy. Clin Cancer Res 2009; 15: 2583–2587.

    Article  CAS  Google Scholar 

  44. Wang YN, Yamaguchi H, Hsu JM, Hung MC . Nuclear trafficking of the epidermal growth factor receptor family membrane proteins. Oncogene 2010; 29: 3997–4006.

    Article  CAS  Google Scholar 

  45. Rizzolio S, Rabinowicz N, Rainero E, Lanzetti L, Serini G, Norman J et al. Neuropilin-1-dependent regulation of EGF-receptor signaling. Cancer Res 2012; 72: 5801–5811.

    Article  CAS  Google Scholar 

  46. Shang L, Liu HJ, Hao JJ, Jiang YY, Shi F, Zhang Y et al. A panel of overexpressed proteins for prognosis in esophageal squamous cell carcinoma. PLoS One 2014; 9: e111045.

    Article  Google Scholar 

  47. Muhl L, Folestad EB, Gladh H, Wang Y, Moessinger C, Jakobsson L et al. Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-D-PDGFRbeta signaling. J Cell Sci 2017; 130: 1365–1378.

    Article  CAS  Google Scholar 

  48. Jia H, Cheng L, Tickner M, Bagherzadeh A, Selwood D, Zachary I . Neuropilin-1 antagonism in human carcinoma cells inhibits migration and enhances chemosensitivity. Br J Cancer 2010; 102: 541–552.

    Article  CAS  Google Scholar 

  49. Dong JC, Gao H, Zuo SY, Zhang HQ, Zhao G, Sun SL et al. Neuropilin 1 expression correlates with the Radio-resistance of human non-small-cell lung cancer cells. J Cell Mol Med 2015; 19: 2286–2295.

    Article  CAS  Google Scholar 

  50. Wey JS, Gray MJ, Fan F, Belcheva A, McCarty MF, Stoeltzing O et al. Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells. Br J Cancer 2005; 93: 233–241.

    Article  CAS  Google Scholar 

  51. Lee E, Koskimaki JE, Pandey NB, Popel AS . Inhibition of lymphangiogenesis and angiogenesis in breast tumor xenografts and lymph nodes by a peptide derived from transmembrane protein 45A. Neoplasia 2013; 15: 112–124.

    Article  CAS  Google Scholar 

  52. Li X, Fan S, Pan X, Xiaokaiti Y, Duan J, Shi Y et al. Nordihydroguaiaretic acid impairs prostate cancer cell migration and tumor metastasis by suppressing neuropilin 1. Oncotarget 2016; 7: 86225–86238.

    PubMed  PubMed Central  Google Scholar 

  53. Xin Y, Li J, Wu J, Kinard R, Weekes CD, Patnaik A et al. Pharmacokinetic and pharmacodynamic analysis of circulating biomarkers of anti-NRP1, a novel antiangiogenesis agent, in two phase I trials in patients with advanced solid tumors. Clin Cancer Res 2012; 18: 6040–6048.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by National Natural Science Foundation of China (31471327, 81330052, 81520108023) and CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001).

Author information

Authors and Affiliations

  1. State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China

    F Shi, L Shang, L-Y Yang, Y-Y Jiang, X-M Wang, J-J Hao, Y Zhang, Y Cai, X Xu, Q-M Zhan & M-R Wang

  2. Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Science/Xiangya Hospital, Central South University, Changsha, China

    F Shi, L Shang & Y Cao

  3. Department of Histology and Embryology, Anhui Medical University, Hefei, China

    D-K Huang & X-M Jia

Authors
  1. F Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Shang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L-Y Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y-Y Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. X-M Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J-J Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D-K Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Y Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. X Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Q-M Zhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. X-M Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Y Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M-R Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to X-M Jia, Y Cao or M-R Wang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, F., Shang, L., Yang, LY. et al. Neuropilin-1 contributes to esophageal squamous cancer progression via promoting P65-dependent cell proliferation. Oncogene 37, 935–943 (2018). https://doi.org/10.1038/onc.2017.399

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.399

Search

Advanced search

Quick links