Skip to main content
SpringerLink
Log in

Contribution of EVX1 in Aggressiveness of Esophageal Squamous Cell Carcinoma

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

Homeobox genes play an overruling role in the regional cell fate determination during development. EVX1 is known as a new target gene of BMP signaling pathway, a group of morphogens which are making the largest subset within the transformation growth factor beta (TGF-β) superfamily. In this study, we aimed to enlighten the expression level of EVX1 in esophageal squamous cell carcinoma (ESCC) and to disclose its apparent roles in maintenance and progression of the disease. The expression level of EVX1 was analyzed in fresh tumoral tissues in comparison with distant tumor-free tissues of 50 ESCC patients using relative comparative real-time PCR. The importance of EVX1 in development and cancer was also reviewed. EVX1 was underexpressed in 70 % of tumor samples. There was a significant correlation between down-regulation of EVX1 and lymph node metastasis of tumor cells (p = 0.027). Furthermore, EVX1 underexpression was significantly correlated with depth of tumor cell invasion (P = 0.037). To the best of our knowledge, this is the first report highlighting EVX1 expression in ESCC to date. The clinicopathological relevance of EVX1 mRNA expression in ESCC targeted this gene as a new independent molecular marker for advanced tumor, which determine the characteristics and behavior of aggressive ESCC.

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

Similar content being viewed by others

References

  1. Ruiz i Altaba A, Choi T, Melton DA (1991) Expression of the Xhox3 homeobox protein in xenopus embryos: blocking its early function suggests the requirement of Xhox3 for normal posterior development. Develop Growth Differ 33:651–669

    Article  CAS  Google Scholar 

  2. Ruiz i Altaba A, Melton DA (1989a) Bimodal and graded expression of the xenopus homeobox gene Xhox3 during embryonic development. Development 106:173–183

    CAS  PubMed  Google Scholar 

  3. Ruiz i Altaba A, Melton DA (1989b) Involvement of the xenopus homeobox gene Xhox3 in pattern formation along the anterior–posterior axis. Cell 57:317–326

    Article  CAS  PubMed  Google Scholar 

  4. Briata P, Van De Werken R, Airoldi I, Ilengo C, Di Blas E, Boncinelli E, Corte G (1995) Transcriptional repression by the human homeobox protein EVX1 in transfected mammalian cells. J Biophys Chem 270:27695–27701. doi:10.1074/jbc.270.46.27695

    CAS  Google Scholar 

  5. Hui X, Long-jiang L, Fang X, Bo H, Zhuang Z, Jiang W (2012) Differentially expressed homeobox genes in salivary adenoid cystic carcinoma versus normal salivary gland tissue. Life Sci J 9(2):292–296

    Google Scholar 

  6. Guo X, Wang XF (2009) Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res 19(1):71–88. doi:10.1038/cr.2008.302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Blanco Calvo M, Bolós Fernández V, Medina Villaamil V, Aparicio Gallego G, Díaz Prado S, Grande Pulido E (2009) Biology of BMP signalling and cancer. Clin Transl Oncol 11(3):126–137. doi:10.1007/S12094-009-0328-8

    Article  CAS  PubMed  Google Scholar 

  8. Zhang G, Mai R, Huang B (2010) ADH1B Arg47His polymorphism is associated with esophageal cancer risk in high-incidence Asian population: evidence from a meta-analysis. PLoS One 5(10):e13679. doi:10.1371/journal.pone.0013679

    Article  PubMed  PubMed Central  Google Scholar 

  9. Baldwin, K. (2015). Esophageal Cancer. Retrieved from http://emedicine.medscape.com/article/277930-overview

  10. Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434(7035):843–850. doi:10.1038/nature03319

    Article  CAS  PubMed  Google Scholar 

  11. Taipale J, Beachy PA (2001) The hedgehog and Wnt signalling pathways in cancer. Nature 411(6835):349–354. doi:10.1038/35077219

    Article  CAS  PubMed  Google Scholar 

  12. Grier DG, Thompson A, Kwasniewska A, McGonigle GJ, Halliday HL, Lappin TR (2005) The pathophysiology of HOX genes and their role in cancer. J Pathol 205(2):154–171. doi:10.1002/path.1710

    Article  CAS  PubMed  Google Scholar 

  13. Zhai Y, Kuick R, Nan B, Ota I, Weiss SJ, Trimble CL, Fearon ER, Cho KR (2007) Gene expression analysis of preinvasive and invasive cervical squamous cell carcinomas identifies HOXC10 as a key mediator of invasion. Cancer Res 67(21):10163–10172. doi:10.1158/0008-5472.CAN-07-2056

    Article  CAS  PubMed  Google Scholar 

  14. Sobin LH, Gospodarowicz MK, Wittekind C (2011) TNM classification of malignant tumours. Wiley, London

    Google Scholar 

  15. Garcia-Fernandez J (2005) The genesis and evolution of homeobox gene clusters. Nat Rev Genet 6(12):881–892. doi:10.1038/nrg1723

    Article  CAS  PubMed  Google Scholar 

  16. Rauch T, Wang Z, Zhang X, Zhong X, Wu X, Lau SK, Kernstine KH, Riggs AD, Pfeifer GP (2007) Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay. Proc Natl Acad Sci U S A 104(13):5527–5532. doi:10.1073/pnas.0701059104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Osada S, Ohmori SY, Taira M (2003) XMAN1, an inner nuclear membrane protein, antagonizes BMP signaling by interacting with Smad1 in xenopus embryos. Development 130(9):1783–1794. doi:10.1242/dev.00401

    Article  CAS  PubMed  Google Scholar 

  18. Takebayashi-Suzuki K, Funami J, Tokumori D, Saito A, Watabe T, Miyazono K, Kanda A, Suzuki A (2003) Interplay between the tumor suppressor p53 and TGF beta signaling shapes embryonic body axes in xenopus. Development 130(17):3929–3939. doi:10.1242/dev.00615

    Article  CAS  PubMed  Google Scholar 

  19. Spyropoulos DD, Capecchi MR (1994) Targeted disruption of the even-skipped gene, evx1, causes early postimplantation lethality of the mouse conceptus. Genes Dev 8(16):1949–1961. doi:10.1101/gad.8.16.1949

    Article  CAS  PubMed  Google Scholar 

  20. Alev C, Wu Y, Kasukawa T, Jakt LM, Ueda HR, Sheng G (2010) Transcriptomic landscape of the primitive streak. Development 137(17):2863–2874. doi:10.1242/dev.053462

    Article  CAS  PubMed  Google Scholar 

  21. Bastian H, Gruss P (1990) A murine even-skipped homologue, Evx 1, is expressed during early embryogenesis and neurogenesis in a biphasic manner. EMBO J 9(6):1839–1852

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Dush MK, Martin GR (1992) Analysis of mouse Evx genes: Evx-1 displays graded expression in the primitive streak. Dev Biol 151(1):273–287. doi:10.1016/0168-9525(92)90245-Y

    Article  CAS  PubMed  Google Scholar 

  23. Fuchtbauer EM (1995) Expression of M-twist during postimplantation development of the mouse. Dev Dyn 204(3):316–322. doi:10.1002/aja.1002040309

    Article  CAS  PubMed  Google Scholar 

  24. Wolf C, Thisse C, Stoetzel C, Thisse B, Gerlinger P, Perrin-Schmitt F (1991) The M-twist gene of Mus is expressed in subsets of mesodermal cells and is closely related to the xenopus X-twi and the drosophila twist genes. Dev Biol 143(2):363–373. doi:10.1016/0012-1606(91)90086-I

    Article  CAS  PubMed  Google Scholar 

  25. Kanai-Azuma M, Kanai Y, Gad JM, Tajima Y, Taya C, Kurohmaru M, Sanai Y, Yonekawa H, Yazaki K, Tam PP, Hayashi Y (2002) Depletion of definitive gut endoderm in Sox17-null mutant mice. Development 129(10):2367–2379

    CAS  PubMed  Google Scholar 

  26. Yasunaga M, Tada S, Torikai-Nishikawa S, Nakano Y, Okada M, Jakt LM, Nishikawa S, Chiba T, Era T, Nishikawa S (2005) Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nat Biotechnol 23(12):1542–1550. doi:10.1038/nbt1167

    Article  CAS  PubMed  Google Scholar 

  27. Jones CM, Dale L, Hogan BL, Wright CV, Smith JC (1996) Bone morphogenetic protein-4 (BMP-4) acts during gastrula stages to cause ventralization of xenopus embryos. Development 122(5):1545–1554

    CAS  PubMed  Google Scholar 

  28. Nostro MC, Cheng X, Keller GM, Gadue P (2008) Wnt, activin, and BMP signaling regulate distinct stages in the developmental pathway from embryonic stem cells to blood. Cell Stem Cell 2(1):60–71. doi:10.1016/j.stem.2007.10.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kalisz M, Winzi M, Bisgaard HC, Serup P (2012) Even-skipped homeobox 1 controls human ES cell differentiation by directly repressing goosecoid expression. Dev Biol 362:94–103. doi:10.1016/j.ydbio.2011.11.017

    Article  CAS  PubMed  Google Scholar 

  30. Yasuo H, Lemaire P (2001) Role of goosecoid, xnot and Wnt antagonists in the maintenance of the notochord genetic programme in xenopus gastrulae. Development 128(19):3783–3793

    CAS  PubMed  Google Scholar 

  31. Luu O, Nagel M, Wacker S, Lemaire P, Winklbauer R (2008) Control of gastrula cell motility by the goosecoid/mix.1/siamois network: basic patterns and paradoxical effects. Dev Dyn 237(5):1307–1320. doi:10.1002/dvdy.21522

    Article  PubMed  Google Scholar 

  32. Hartwell KA, Muir B, Reinhardt F, Carpenter AE, Sgroi DC, Weinberg RA (2006) The Spemann organizer gene, goosecoid, promotes tumor metastasis. Proc Natl Acad Sci U S A 103(50):18969–18974. doi:10.1073/pnas.0608636103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Forghanifard MM, Moaven O, Farshchian M, Montazer M, Raeisossadati R, Abdollahi A, Moghbeli M, Nejadsattari T, Parivar K, Abbaszadegan MR (2012) Expression analysis elucidates the roles of MAML1 and Twist1 in esophageal squamous cell carcinoma aggressiveness and metastasis. Ann Surg Oncol 19(3):743–749. doi:10.1245/s10434-011-2074-8

    Article  PubMed  Google Scholar 

  34. Ansieau S, Morel AP, Hinkal G, Bastid J, Puisieux A (2010) TWISTing an embryonic transcription factor into an oncoprotein. Oncogene 29(22):3173–3184. doi:10.1038/onc.2010.92

    Article  CAS  PubMed  Google Scholar 

  35. Christiansen JJ, Rajasekaran AK (2006) Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 66(17):8319–8326. doi:10.1158/0008-5472.CAN-06-0410

    Article  CAS  PubMed  Google Scholar 

  36. Klymkowsky MW, Savagner P (2009) Epithelial-mesenchymal transition: a cancer researcher’s conceptual friend and foe. Am J Pathol 174(5):1588–1593. doi:10.2353/ajpath.2009.080545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927–939. doi:10.1016/j.cell.2004.06.006

    Article  CAS  PubMed  Google Scholar 

  38. Sasaki K, Natsugoe S, Ishigami S, Matsumoto M, Okumura H, Setoyama T, Uchikado Y, Kita Y, Tamotsu K, Sakamoto A, Owaki T, Aikou T (2009) Significance of twist expression and its association with E-cadherin in esophageal squamous cell carcinoma. J Exp Clin Cancer Res 28:158. doi:10.1186/1756-9966-28-158

    Article  PubMed  PubMed Central  Google Scholar 

  39. Yuen HF, Chan YP, Wong ML, Kwok WK, Chan KK, Lee PY, Srivastava G, Law SY, Wong YC, Wang X, Chan KW (2007) Upregulation of twist in oesophageal squamous cell carcinoma is associated with neoplastic transformation and distant metastasis. J Clin Pathol 60(5):510–514. doi:10.1136/jcp.2006.039099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Du YC, Oshima H, Oguma K, Kitamura T, Itadani H, Fujimura T, Piao YS, Yoshimoto T, Minamoto T, Kotani H, Taketo MM, Oshima M (2009) Induction and down-regulation of Sox17 and its possible roles during the course of gastrointestinal tumorigenesis. Gastroenterology 137(4):1346–1357. doi:10.1053/j.gastro.2009.06.041

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge the colleagues at Division of Human Genetics for their kindly technical assistances.

Author information

Authors and Affiliations

  1. Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Afsaneh Javdani Mallak, Mohammad Reza Abbaszadegan & Pegah Naeemi Khorasanizadeh

  2. Department of Biology, Damghan Branch, Islamic Azad University, Cheshmeh-Ali Boulevard, Sa’dei Square, P.O. Box: 3671639998, Damghan, Iran

    Mohammad Mahdi Forghanifard

Authors
  1. Afsaneh Javdani Mallak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Reza Abbaszadegan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pegah Naeemi Khorasanizadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammad Mahdi Forghanifard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammad Mahdi Forghanifard.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mallak, A.J., Abbaszadegan, M.R., Khorasanizadeh, P.N. et al. Contribution of EVX1 in Aggressiveness of Esophageal Squamous Cell Carcinoma. Pathol. Oncol. Res. 22, 341–347 (2016). https://doi.org/10.1007/s12253-015-0005-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-015-0005-x

Keywords

Search

Navigation