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:

Fas signaling promotes motility and metastasis through epithelial–mesenchymal transition in gastrointestinal cancer

Oncogene volume 32, pages 1183–1192 (2013)Cite this article

Subjects

Abstract

Fas signaling was reported to participate in cell apoptosis. However, this pathway has also been shown to promote tumor cell motility, leading to the hypothesis that Fas signaling may induce epithelial–mesenchymal transition (EMT) to promote metastasis. The effects of Fas-ligand (FasL) treatment and inhibition of Fas signaling on colorectal and gastric cancer cells were tested using motility assay, immunofluorescence, RT–PCR and immunoblot analyses. Fas signaling downregulated epithelial markers, upregulated mesenchymal markers and promoted motility in gastrointestinal (GI) cancer cells. FasL treatment also increased the expression of EMT transcriptional factors in the nucleus and induced a spindle shape cell morphology in these cells. Knockdown of Snail or Twist expression significantly decreased FasL-induced motility. The ERK1/2 pathway was activated by Fas signaling and is required for FasL-induced EMT and motility. Moreover, oxaliplatin, a chemotherapeutic agent, induced EMT partly through Fas signaling. Evaluation of human GI clinical specimens showed that FasL expression increased whereas E-cadherin expression decreased during GI cancer progression. Both markers were significantly inversely correlated. Tissue samples with a non-EMT phenotype were mainly distributed in patients with early cancer stages, whereas samples with an EMT phenotype were mostly distributed in patients with advanced cancer stages. A non-EMT phenotype significantly correlated with better prognosis. Altogether, these data indicate that Fas signaling may induce EMT to promote tumor motility and metastasis in GI cancer in vivo and in vitro.

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
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Abbreviations

CRC:

colorectal cancer

EMT:

epithelial–mesenchymal transition

GC:

gastric cancer

GI:

gastrointestinal

IHC:

immunohistochemistry

References

  1. Curtin JF, Cotter TG . Live and let die: regulatory mechanisms in Fas-mediated apoptosis. Cell Signal, 2003; 15: 983–992.

    Article  CAS  PubMed  Google Scholar 

  2. Shinohara H, Yagita H, Ikawa Y, Oyaizu N . Fas drives cell cycle progression in glioma cells via extracellular signalregulated kinase activation. Cancer Res, 2000; 60: 1766–1772.

    CAS  PubMed  Google Scholar 

  3. Park DR, Thomsen AR, Frevert CW, Pham U, Skerrett SJ, Kiener PA et al. Fas (CD95) induces proinflammatory cytokine responses by human monocytes and monocyte-derived macrophagesJ Immunol, 2003; 170: 6209–6216.

    Article  CAS  PubMed  Google Scholar 

  4. Choi C, Xu X, Oh JW, Lee SJ, Gillespie GY, Park H et al. Fas-induced expression of chemokines in human glioma cells: involvement of extracellular signal-regulated Kinase1/2 and p38 mitogen-activated protein kinase. Cancer Res, 2001; 61: 3084–3091.

    CAS  PubMed  Google Scholar 

  5. Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C et al. CD95 promotes tumor growth. Nature, 2010; 465: 492–496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Barnhart BC, Legembre P, Pietras E, Bubici C, Franzoso G, Peter ME . CD95 ligand induces motility and invasiveness of apoptosis-resistant tumor cells. EMBO J, 2004; 23: 3175–3185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Desbarats J, Newell MK . Fas engagement accelerates liver regeneration after partial hepatectomy. Nat Med, 2000; 6: 920–923.

    Article  CAS  PubMed  Google Scholar 

  8. Lavrik IN, Golks A, Riess D, Bentele M, Eils R, Krammer PH . Analysis of CD95 threshold signaling. J Biol Chem, 2007; 282: 13664–13671.

    Article  CAS  PubMed  Google Scholar 

  9. Kleber S, Sancho-Martinez I, Wiestler B, Beisel A, Gieffers C, Hill O et al. Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell, 2008; 13: 235–248.

    Article  CAS  PubMed  Google Scholar 

  10. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D et al. Global cancer statistics. CA: Cancer J Clin, 2011; 61: 69–90.

    Google Scholar 

  11. Griffin MR, Bergstralh EJ, Coffey RJ, Beart RW, Melton LJ . Predictors of survival after curative resection of carcinoma of the colon and rectum. Cancer, 1987; 60: 2318–2324.

    Article  CAS  PubMed  Google Scholar 

  12. O'Brien DI, Nally K, Kelly RG, O’Connor TM, Shanahan F, O’Connell J . Targeting the Fas/Fas ligand pathway in cancer. Expert Opin Ther Targets, 2005; 9: 1031–1044.

    Article  CAS  PubMed  Google Scholar 

  13. Adam R, Pascal G, Castaing D, Azoulay D, Delvart V, Paule B et al. Tumor progression while on chemotherapy. Ann Surg, 2004; 240: 1052–1064.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kalluri R . EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest, 2009; 119: 1417–1419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Przybylo JA, Radisky DC . Matrix metalloproteinase-induced epithelial mesenchymal transition: tumor progression at Snail’s pace. Int J Biochem Cell Biol, 2007; 39: 1082–1088.

    Article  CAS  PubMed  Google Scholar 

  16. Turley EA, Veiseh M, Radisky DC, Bissell MJ . Mechanisms of disease: epithelial-mesenchymal transition—does cellular plasticity fuel neoplastic progression? Nat Clin Pract Oncol, 2008; 5: 280–290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Huber MA, Kraut N, Beug H . Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol, 2005; 17: 548–558.

    Article  CAS  PubMed  Google Scholar 

  18. Li H, Zheng H, Liu J, Houghton J . CD95 signaling induces EMT in colon cancer cells. Gastroenterology, 2011; 140: S–162.

    Google Scholar 

  19. Li H, Cai X, Fan X, Moquin B, Stoicov C, Houghton J . Fas Ag-FasL coupling leads to ERK1/2-mediated proliferation of gastric mucosal cells. Am J Physiol Gastrointest Liver Physiol, 2008; 294: G263–G275.

    Article  CAS  PubMed  Google Scholar 

  20. Mitsiades N, Yu WH, Poulaki V, Tsokos M, Stamenkovic I . Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity. Cancer Res, 2001; 61: 577–581.

    CAS  PubMed  Google Scholar 

  21. Ametller E, Garcia-Recio S, Costamagna D, Mayordomo C, Fernández-Nogueira P, Carbó N et al. Tumor promoting effects of CD95 signaling inchemoresistant cells. Mol Cancer, 2010; 9: 161.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Medici D, Hay ED, Goodenough DA . Cooperation between Snail and LEF-1 transcription factors is essential for TGF-1-induced epithelial-mesenchymal transition. Mol biol cell, 2006; 17: 1871–1879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Higgs HN, Peterson KJ . Phylogenetic analysis of the formin homology 2 domain. Mol Biol Cell, 2005; 16: 1–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kalluri R, Neilson EG . Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest, 2003; 112: 1776–1784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yan W, Fu Y, Tian D, Liao J, Liu M, Wang B et al. PI3 kinase/Akt signaling mediates epithelial-mesenchymal transition in hypoxic hepatocellular carcinoma cells. Biochem Biophys Res Commun, 2009; 382: 631–636.

    Article  CAS  PubMed  Google Scholar 

  26. Desbarats J, Birge RB, Mimouni-Rongy M, Weinstein DE, Palerme JS, Newell MK . Fas engagement induces neurite growth through ERK activation and p35 upregulation. Nat Cell Biol, 2003; 5: 118–125.

    Article  CAS  PubMed  Google Scholar 

  27. Zhu Q, Liu JY, Yang CM, Xu HW, Zhang AZ, Cui Y et al. Influence of antitumor drugs on the expression of Fas system in SW480 colon cancer cells. Eur J Gastroen Hepat, 2006; 18: 1071–1077.

    Article  CAS  Google Scholar 

  28. Yang AD, Fan F, Camp ER, van Buren G, Liu W, Somcio R et al. Chronic oxaliplatin resistance induces epithelial-to -mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res, 2006; 12: 4147–4153.

    Article  CAS  PubMed  Google Scholar 

  29. Pryczynicz A, Guziñska-Ustymowicz K, Kemona A . Fas/FasL expression in colorectal cancer. An immunohistochemical study. Folia Histochem Cytobiol, 2010; 48: 425–429.

    PubMed  Google Scholar 

  30. Tsanou E, Peschos D, Batistatou A, Charalabopoulos A, Charalabopoulos K . The E-cadherin adhesion molecule and colorectal cancer. Anticancer Res, 2008; 28: 3815–3826.

    PubMed  Google Scholar 

  31. Li H, Fan X, Stoicov C, Liu JH, Zubair S, Tsai E et al. Human and mouse colon cancer utilizes CD95 signaling for localgrowth and metastatic spread to liver. Gastroenterology, 2009; 137: 934–944.

    Article  CAS  PubMed  Google Scholar 

  32. Wang J, Wang XY, Gong W, Mi B, Liu S, Jiang B . Increased expression of b-Catenin, phosphorylated glycogen synthase kinase 3b, cyclin D1, and c-myc in laterally spreading colorectal tumors. J Histochem Cytochem, 2009; 57: 363–371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Soumaoro LT, Uetake H, Higuchi T, Takagi Y, Enomoto M, Sugihara K . Cyclooxygenase-2 expression: a significant prognostic indicator for patients with colorectal cancer. Clin Cancer Res, 2004; 10: 8465–8471.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by Science and Technology Project of Guangzhou (2009Z1-E051) and Nanfang Hospital President Foundation(2011C015).

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    H X Zheng, Y D Cai, Y D Wang, X B Cui, T T Xie, W J Li, L Peng, Y Zhang, Z Q Wang, J Wang & B Jiang

  2. Department of Gastroenterology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China

    Y D Cai

  3. Department of Medicine, Immunology Institute, Mount Sinai School of Medicine, NY, USA

    L Peng

  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Y Zhang

  5. Department of pathology, Mount Sinai School of Medicine, NY, USA

    Z Q Wang

Authors
  1. H X Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y D Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y D Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X B Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T T Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W J Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Z Q Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. B Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B Jiang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zheng, H., Cai, Y., Wang, Y. et al. Fas signaling promotes motility and metastasis through epithelial–mesenchymal transition in gastrointestinal cancer. Oncogene 32, 1183–1192 (2013). https://doi.org/10.1038/onc.2012.126

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.126

Keywords

This article is cited by

Search

Advanced search

Quick links