Skip to main content

Advertisement

SpringerLink
Log in

Overexpression of L1CAM is Associated with Tumor Progression and Prognosis via ERK Signaling in Gastric Cancer

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

L1 cell adhesion molecule (L1CAM), which belongs to the immunoglobulin superfamily, has recently been observed in a variety of human malignancies. However, its clinical implication in gastric cancer remains unclear. The aim of this study was to explore the role of L1CAM in gastric cancer and to analyze its correlation with tumor progression and prognosis.

Methods

L1CAM expression was measured in human gastric cancer cell lines and knockdown was conducted using siRNA. Cell proliferation, invasion and migration ability was assessed in vitro. The downstream pathway of L1CAM was explored by western blot analysis. L1CAM expression was measured in 112 pairs of human gastric cancer and adjacent noncancerous tissues using real-time quantitative RT-PCR, and the correlation with clinicopathological features and prognosis was analyzed.

Results

L1CAM downregulation by siRNA significantly decreased cell proliferation, migration, and invasion in gastric cancer cell lines. Phosphorylated ERK levels began to decline more rapidly in L1CAM knockdown cells compared with parental cells. L1CAM overexpression was significantly correlated with local tumor cell growth (P = 0.041), distant metastasis (P = 0.047), and tumor stage (P = 0.031). The overall survival in patients with high L1CAM expression was significantly shorter than that of patients with low L1CAM expression (P = 0.02).

Conclusions

L1CAM overexpression may be a critical prognostic factor in patients with gastric cancer, and was strongly associated with tumor proliferation, migration, and invasion through the ERK pathway. L1CAM might be an attractive therapeutic molecular target for the treatment of gastric cancer patients.

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

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007;357:1810–20.

    Article  CAS  PubMed  Google Scholar 

  3. Koizumi W, Narahara H, Hara T, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008;9:215–21.

    Article  CAS  PubMed  Google Scholar 

  4. Moos M, Tacke R, Scherer H, et al. Neural adhesion molecule L1 as a member of the immunoglobulin superfamily with binding domains similar to fibronectin. Nature. 1988;334:701–3.

    Article  CAS  PubMed  Google Scholar 

  5. Thies A, Schachner M, Moll I, et al. Overexpression of the cell adhesion molecule L1 is associated with metastasis in cutaneous malignant melanoma. Eur J Cancer. 2002;38:1708–16.

    Article  CAS  PubMed  Google Scholar 

  6. Fogel M, Gutwein P, Mechtersheimer S, et al. L1 expression as a predictor of progression and survival in patients with uterine and ovarian carcinomas. Lancet. 2003;362:869–75.

    Article  CAS  PubMed  Google Scholar 

  7. Bondong S, Kiefel H, Hielscher T, et al. Prognostic significance of L1CAM in ovarian cancer and its role in constitutive NF-kappaB activation. Ann Oncol. 2012;23:1795–802.

    Article  CAS  PubMed  Google Scholar 

  8. Boo Y-J, Park J-M, Kim J, et al. L1 expression as a marker for poor prognosis, tumor progression, and short survival in patients with colorectal cancer. Ann Surg Oncol. 2007;14:1703–11.

    Article  PubMed  Google Scholar 

  9. Tischler V, Pfeifer M, Hausladen S, et al. L1CAM protein expression is associated with poor prognosis in non-small cell lung cancer. Mol Cancer. 2011;10:127.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Gavert N, Conacci-Sorrell M, Gast D, et al. L1, a novel target of beta-catenin signaling, transforms cells and is expressed at the invasive front of colon cancers. J Cell Biol. 2005;168:633–42.

    Article  CAS  PubMed  Google Scholar 

  11. Shtutman M, Levina E, Ohouo P, et al. Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases scattering and motility of MCF7 breast carcinoma cells. Cancer Res. 2006;66:11370–80.

    Article  CAS  PubMed  Google Scholar 

  12. Schaefer AW, Kamiguchi H, Wong EV, et al. Activation of the MAPK signal cascade by the neural cell adhesion molecule L1 requires L1 internalization. J Biol Chem. 1999;274:37965–73.

    Article  CAS  PubMed  Google Scholar 

  13. Silletti S, Yebra M, Perez B, et al. Extracellular signal-regulated kinase (ERK)-dependent gene expression contributes to L1 cell adhesion molecule-dependent motility and invasion. J Biol Chem. 2004;279:28880–8.

    Article  CAS  PubMed  Google Scholar 

  14. Cheng L, Lemmon S, Lemmon V. RanBPM is an L1-interacting protein that regulates L1-mediated mitogen-activated protein kinase activation. J Neurochem. 2005;94:1102–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Izumoto S, Ohnishi T, Arita N, et al. Gene expression of neural cell adhesion molecule L1 in malignant gliomas and biological significance of L1 in glioma invasion. Cancer Res. 1996;56:1440–4.

    CAS  PubMed  Google Scholar 

  16. Suzuki T, Izumoto S, Fujimoto Y, et al. Clinicopathological study of cellular proliferation and invasion in gliomatosis cerebri: important role of neural cell adhesion molecule L1 in tumour invasion. J Clin Pathol. 2005;58:166–71.

    Article  CAS  PubMed  Google Scholar 

  17. Stoeck A, Gast D, Sanderson MP, et al. L1-CAM in a membrane-bound or soluble form augments protection from apoptosis in ovarian carcinoma cells. Gynecologic Oncol. 2007; 104:461–9.

    Article  CAS  Google Scholar 

  18. Wolterink S, Moldenhauer G, Fogel M, et al. Therapeutic antibodies to human L1CAM: functional characterization and application in a mouse model for ovarian carcinoma. Cancer Res. 2010; 70:2504–15.

    Article  CAS  PubMed  Google Scholar 

  19. Gavert N. Expression of L1-CAM and ADAM10 in human colon cancer cells induces metastasis. Cancer Res. 2007;67:7703–12.

    Article  CAS  PubMed  Google Scholar 

  20. Meier F, Busch S, Gast D, et al. The adhesion molecule L1 (CD171) promotes melanoma progression. Int J Cancer. 2006;119:549–55.

    Article  CAS  PubMed  Google Scholar 

  21. Geismann C, Morscheck M, Koch D, et al. Up-regulation of L1CAM in pancreatic duct cells is transforming growth factor beta1- and slug-dependent: role in malignant transformation of pancreatic cancer. Cancer Res. 2009;69:4517–26.

    Article  CAS  PubMed  Google Scholar 

  22. Sebens Muerkoster S, Werbing V, Sipos B, et al. Drug-induced expression of the cellular adhesion molecule L1CAM confers anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells. Oncogene. 2007;26:2759–68.

    Google Scholar 

  23. Kodera Y, Nakanishi H, Ito S, et al. Expression of L1 cell adhesion molecule is a significant prognostic factor in pT3-stage gastric cancer. Anticancer Res. 2009;29:4033–9.

    PubMed  Google Scholar 

  24. Raveh S, Gavert N, Ben-Ze’ev A. L1 cell adhesion molecule (L1CAM) in invasive tumors. Cancer Lett. 2009;282:137–45.

    Article  CAS  PubMed  Google Scholar 

  25. Siesser PF, Maness PF. L1 cell adhesion molecules as regulators of tumor cell invasiveness. Cell Adh Migr. 2009;3:275–7.

    Article  PubMed  Google Scholar 

  26. Hai J, Zhu C-Q, Bandarchi B, et al. L1 cell adhesion molecule promotes tumorigenicity and metastatic potential in non-small cell lung cancer. Clin Cancer Res. 2012;18:1914–24.

    Article  CAS  PubMed  Google Scholar 

  27. Gavert N, Ben-Shmuel A, Raveh S, Ben-Ze’ev A. L1-CAM in cancerous tissues. Expert Opin Biol Ther. 2008;8:1749–57.

    Article  CAS  PubMed  Google Scholar 

  28. Kohno M, Pouyssegur J. Targeting the ERK signaling pathway in cancer therapy. Ann Med. 2006;38:200–11.

    Article  CAS  PubMed  Google Scholar 

  29. Gavert N, Ben-Shmuel A, Lemmon V, et al. Nuclear factor-kappa B signaling and ezrin are essential for L1-mediated metastasis of colon cancer cells. J Cell Sci. 2010;123:2134–42.

    Article  Google Scholar 

  30. Ebeling O, Duczmal A, Aigner S, et al. L1 adhesion molecule on human lymphocytes and monocytes: expression and involvement in binding to alpha v beta 3 integrin. Eur J Immunol. 1996;26:2508–16.

    Article  CAS  PubMed  Google Scholar 

  31. Arlt MJE, Novak-Hofer I, Gast D, et al. Efficient inhibition of intra-peritoneal tumor growth and dissemination of human ovarian carcinoma cells in nude mice by anti-L1-cell adhesion molecule monoclonal antibody treatment. Cancer Res. 2006;66:936–43.

    Article  CAS  PubMed  Google Scholar 

  32. Gast D, Riedle S, Issa Y, et al. The cytoplasmic part of L1-CAM controls growth and gene expression in human tumors that is reversed by therapeutic antibodies. Oncogene. 2008;27:1281–9.

    Article  CAS  PubMed  Google Scholar 

  33. Schafer H, Dieckmann C, Korniienko O, et al. Combined treatment of L1CAM antibodies and cytostatic drugs improve the therapeutic response of pancreatic and ovarian carcinoma. Cancer Lett. 2012;319:66–82.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan

    Takeshi Ito MD, Suguru Yamada MD, PhD, FACS, Chie Tanaka MD, PhD, Toshifumi Murai MD, Daisuke Kobayashi MD, PhD, Tsutomu Fujii MD, PhD, FACS, Goro Nakayama MD, PhD, Hiroyuki Sugimoto MD, PhD, Masahiko Koike MD, PhD, Shuji Nomoto MD, PhD, Michitaka Fujiwara MD, PhD & Yasuhiro Kodera MD, PhD, FACS

  2. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Sachiko Ito PhD

Authors
  1. Takeshi Ito MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Suguru Yamada MD, PhD, FACS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chie Tanaka MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sachiko Ito PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toshifumi Murai MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daisuke Kobayashi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tsutomu Fujii MD, PhD, FACS
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Goro Nakayama MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiroyuki Sugimoto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masahiko Koike MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shuji Nomoto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michitaka Fujiwara MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yasuhiro Kodera MD, PhD, FACS
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suguru Yamada MD, PhD, FACS.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Fig. S1

Silencing of L1CAM by siRNA knockdown in representative cell lines. The mRNA levels of L1CAM in L1CAM and parental KATOIII, MKN1, MKN74, SC-6-JCK and MKN28 cells were confirmed by real-time PCR with GAPDH serving as a loading control (a). The protein levels of L1CAM in these cells were confirmed by western blot analysis with β-actin as a loading control (b, c). Cont: Control (PPT 388 kb)

Supplementary material 2 (PPT 170 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ito, T., Yamada, S., Tanaka, C. et al. Overexpression of L1CAM is Associated with Tumor Progression and Prognosis via ERK Signaling in Gastric Cancer. Ann Surg Oncol 21, 560–568 (2014). https://doi.org/10.1245/s10434-013-3246-5

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-013-3246-5

Keywords

Search

Navigation