Skip to main content

Advertisement

SpringerLink
Log in

PRRX1 promotes epithelial–mesenchymal transition through the Wnt/β-catenin pathway in gastric cancer

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Carcinoma cells hijack the epithelial–mesenchymal transition (EMT) for tumor dissemination. Paired-related homeobox 1 (PRRX1) has been identified as a new EMT inducer. However, the function of PRRX1 in gastric cancer has not been elucidated. In this study, we observed that PRRX1 expression levels were upregulated and positively correlated with metastasis and EMT markers in human gastric cancer specimens. PRRX1 overexpression had distinct effects on the cell morphology, proliferation, migration and invasion of BGC823 and SGC7901 gastric cancer cells both in vitro and in xenografts. PRRX1 overexpression resulted in the regulation of the EMT molecular markers N-cadherin, E-cadherin and vimentin as well as the levels of intranuclear β-catenin and the Wnt/β-catenin target c-Myc. Furthermore, the inhibition of the Wnt/β-catenin pathway by XAV939 offset the effects of PRRX1 overexpression. These findings demonstrate that PRRX1 promotes EMT in gastric cancer cells through the activation of Wnt/β-catenin signaling and that PRRX1 upregulation is closely correlated with gastric cancer metastasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331(6024):1559–64. doi:10.1126/science.1203543.

    Article  CAS  PubMed  Google Scholar 

  2. Kalluri R, Weinberg RA. The basics of epithelial–mesenchymal transition. J Clin Investig. 2009;119(6):1420.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. Spatiotemporal regulation of epithelial–mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell. 2012;22(6):725–36. doi:10.1016/j.ccr.2012.09.022.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Tsai JH, Yang J. Epithelial–mesenchymal plasticity in carcinoma metastasis. Genes Dev. 2013;27(20):2192–206. doi:10.1101/gad.225334.113.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW, Williams ED. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res. 2006;66(23):11271–8.

    Article  CAS  PubMed  Google Scholar 

  6. Busch EL, McGraw KA, Sandler RS. The potential for markers of epithelial–mesenchymal transition to improve colorectal cancer outcomes: a systematic review. Cancer Epidemiol Biomarkers Prev. 2014;23(7):1164–75.

    Article  CAS  PubMed  Google Scholar 

  7. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Eckert MA, Lwin TM, Chang AT, Kim J, Danis E, Ohno-Machado L, et al. Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell. 2011;19(3):372–86. doi:10.1016/j.ccr.2011.01.036.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Fan XJ, Wan XB, Yang ZL, Fu XH, Huang Y, Chen DK, et al. Snail promotes lymph node metastasis and Twist enhances tumor deposit formation through epithelial–mesenchymal transition in colorectal cancer. Hum Pathol. 2013;44(2):173–80. doi:10.1016/j.humpath.2012.03.029.

    Article  CAS  PubMed  Google Scholar 

  10. Sanchez-Tillo E, Lazaro A, Torrent R, Cuatrecasas M, Vaquero E, Castells A, et al. ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene. 2010;29(24):3490–500.

    Article  CAS  PubMed  Google Scholar 

  11. Wiles ET, Bell R, Thomas D, Beckerle M, Lessnick SL. ZEB2 represses the epithelial phenotype and facilitates metastasis in Ewing sarcoma. Genes Cancer. 2013;4(11–12):486–500.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Chaudhury A, Hussey GS, Ray PS, Jin G, Fox PL, Howe PH. TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nat Cell Biol. 2010;12(3):286–93. doi:10.1038/ncb2029.

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Cai X, Brophy M, Hahn S, McManus J, Chang B, Pasula S, et al. The role of epsin in promoting epithelial–mesenchymal transition and metastasis by activating NF-κB signaling in breast cancer. Cancer Res. 2012;72(24 supplement 3):3292.

  14. Timmerman LA, Grego-Bessa J, Raya A, Bertrán E, Pérez-Pomares JM, Díez J, et al. Notch promotes epithelial–mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 2004;18(1):99–115.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96. doi:10.1038/nrm3758.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Howard S, Deroo T, Fujita Y, Itasaki N. A positive role of cadherin in Wnt/beta-catenin signalling during epithelial–mesenchymal transition. PLoS ONE. 2011;6(8):e23899. doi:10.1371/journal.pone.0023899.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Ocana OH, Corcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S, et al. Metastatic colonization requires the repression of the epithelial–mesenchymal transition inducer Prrx1. Cancer Cell. 2012;22(6):709–24. doi:10.1016/j.ccr.2012.10.012.

    Article  CAS  PubMed  Google Scholar 

  18. Takahashi Y, Sawada G, Kurashige J, Uchi R, Matsumura T, Ueo H, et al. Paired related homoeobox 1, a new EMT inducer, is involved in metastasis and poor prognosis in colorectal cancer. Br J Cancer. 2013;109(2):307–11. doi:10.1038/bjc.2013.339.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA. Epithelial–mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Investig. 2009;119(6):1438.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Saitoh M, Miyazawa K. Transcriptional and post-transcriptional regulation in TGF-β-mediated epithelial–mesenchymal transition. J Biochem. 2012;151(6):563–71.

    Article  CAS  PubMed  Google Scholar 

  21. Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–54.

    Article  CAS  PubMed  Google Scholar 

  22. Grueneberg DA, Natesan S, Alexandre C, Gilman MZ. Human and Drosophila homeodomain proteins that enhance the DNA-binding activity of serum response factor. Science. 1992;257(5073):1089–95.

    Article  CAS  PubMed  Google Scholar 

  23. Lu M-F, Cheng H-T, Kern MJ, Potter SS, Tran B, Diekwisch T, et al. prx-1 functions cooperatively with another paired-related homeobox gene, prx-2, to maintain cell fates within the craniofacial mesenchyme. Development. 1999;126(3):495–504.

    CAS  PubMed  Google Scholar 

  24. Reichert M, Takano S, von Burstin J, Kim S-B, Lee J-S, Ihida-Stansbury K, et al. The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis. Genes Dev. 2013;27(3):288–300.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Takano S, Reichert M, Heeg S, Bakir B, Rhim AD, Stanger B, et al. 339 The Prrx1 homeobox transcription factor regulates invasion and EMT in pancreatic cancer. Gastroenterology. 2013;144(5):S-71.

    Google Scholar 

  26. Micalizzi DS, Farabaugh SM, Ford HL. Epithelial–mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia. 2010;15(2):117–34.

    Article  PubMed Central  PubMed  Google Scholar 

  27. De Wever O, Pauwels P, De Craene B, Sabbah M, Emami S, Redeuilh G, et al. Molecular and pathological signatures of epithelial–mesenchymal transitions at the cancer invasion front. Histochem Cell Biol. 2008;130(3):481–94.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Clements WM, Wang J, Sarnaik A, Kim OJ, MacDonald J, Fenoglio-Preiser C, et al. β-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res. 2002;62(12):3503–6.

    CAS  PubMed  Google Scholar 

  29. Huang J, Xiao D, Li G, Ma J, Chen P, Yuan W, et al. EphA2 promotes epithelial–mesenchymal transition through the Wnt/beta-catenin pathway in gastric cancer cells. Oncogene. 2014;33(21):2737–47. doi:10.1038/onc.2013.238.

    Article  CAS  PubMed  Google Scholar 

  30. Jing Y, Han Z, Zhang S, Liu Y, Wei L. Epithelial–mesenchymal transition in tumor microenvironment. Cell Biosci. 2011;1:29.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Malanchi I, Peinado H, Kassen D, Hussenet T, Metzger D, Chambon P, et al. Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature. 2008;452(7187):650–3. doi:10.1038/nature06835.

    Article  CAS  PubMed  Google Scholar 

  32. Mao J, Fan S, Ma W, Fan P, Wang B, Zhang J, et al. Roles of Wnt/beta-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment. Cell Death Dis. 2014;5:e1039. doi:10.1038/cddis.2013.515.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010;327(5973):1650–3. doi:10.1126/science.1186624.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Shimozaki K, Clemenson GD Jr, Gage FH. Paired related homeobox protein 1 is a regulator of stemness in adult neural stem/progenitor cells. J Neurosci. 2013;33(9):4066–75. doi:10.1523/JNEUROSCI.4586-12.2013.

    Article  CAS  PubMed  Google Scholar 

  35. Otsuki S, Inokuchi M, Enjoji M, Ishikawa T, Takagi Y, Kato K, et al. Vimentin expression is associated with decreased survival in gastric cancer. Oncol Rep. 2011;25(5):1235–42.

    PubMed  Google Scholar 

  36. Dicken BJ, Graham K, Hamilton SM, Andrews S, Lai R, Listgarten J, et al. Lymphovascular invasion is associated with poor survival in gastric cancer: an application of gene-expression and tissue array techniques. Ann Surg. 2006;243(1):64.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Yang D, Sun Y, Hu L, Zheng H, Ji P, Pecot CV, et al. Integrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer. Cancer Cell. 2013;23(2):186–99.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Zhang Y, Zheng L, Huang J, Gao F, Lin X, He L, et al. MiR-124 radiosensitizes human colorectal cancer cells by targeting PRRX1. PLoS ONE. 2014;9(4):e93917.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from the National Natural Science Foundation of China (No. 81172295).

Conflict of interest

The authors declare no financial or other conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, the First Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China

    Jinbao Guo, Zhongxue Fu, Jinlai Wei, Weidong Lu, Jihong Feng & Shouru Zhang

Authors
  1. Jinbao Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhongxue Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jinlai Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weidong Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jihong Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shouru Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhongxue Fu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, J., Fu, Z., Wei, J. et al. PRRX1 promotes epithelial–mesenchymal transition through the Wnt/β-catenin pathway in gastric cancer. Med Oncol 32, 393 (2015). https://doi.org/10.1007/s12032-014-0393-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-014-0393-x

Keywords

Search

Navigation