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Full-Length L1CAM and Not Its Δ2Δ27 Splice Variant Promotes Metastasis through Induction of Gelatinase Expression

By Stephanie Hauser, Laura Bickel, Dirk Weinspach, Michael Gerg, Michael K. Schäfer, Marco Pfeifer, John Hazin, Florian Schelter, Ulrich H. Weidle, Juliane Ramser, Juliane Volkmann, Alfons Meindl, Manfred Schmitt, Florian Schrötzlmair, Peter Altevogt and Achim Krüger

Abstract

Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3081839
Provided by: PubMed Central

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Citations

  1. (1994). A general method for the generation of high-titer, pantropic retroviral vectors: highly efficient infection of primary hepatocytes.
  2. (1996). A nonneuronal isoform of cell adhesion molecule L1: tissue-specific expression and functional analysis.
  3. (1995). A transient three-plasmid expression system for the production of high titer retroviral vectors.
  4. (2004). Activation of EGF receptor kinase by L1-mediated homophilic cell interactions.
  5. (1999). Activation of the MAPK signal cascade by the neural cell adhesion molecule L1 requires L1 internalization.
  6. (2009). Alternative splicing and disease.
  7. (2008). Alternative splicing and tumor progression.
  8. (2007). Alternative splicing in cancer: noise, functional, or systematic?
  9. (1987). Alternative splicing: a ubiquitous mechanism for the generation of multiple protein isoforms from single genes.
  10. (2007). Alternative splicing: an emerging topic in molecular and clinical oncology.
  11. (2001). Alternative use of a mini exon of the L1 gene affects L1 binding to neural ligands.
  12. (1998). An endocytosed TGN38 chimeric protein is delivered to the TGN after trafficking through the endocytic recycling compartment in CHO cells.
  13. (2008). Antibodies directed against L1-CAM synergize with Genistein in inhibiting growth and survival pathways in SKOV3ip human ovarian cancer cells.
  14. (2005). Antimetastatic activity of a novel mechanism-based gelatinase inhibitor.
  15. (2010). Ben-Ze’ev A
  16. Ben-Ze’ev A (2008) L1-CAM in cancerous tissues.
  17. Ben-Ze’ev A (2009) L1 cell adhesion molecule (L1CAM) in invasive tumors.
  18. (2006). Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases scattering and motility of MCF7 breast carcinoma cells.
  19. (1996). Characterization of gelatinases linked to extracellular matrix invasion in ovarian adenocarcinoma: purification of matrix metalloproteinase 2.
  20. (2008). Characterization of the neuron-specific L1-CAM cytoplasmic tail: naturally disordered in solution it exercises different binding modes for different adaptor proteins.
  21. (2000). Differential expression of alternatively spliced neural cell adhesion molecule L1 isoforms during oligodendrocyte maturation.
  22. (2008). Distinct Functionality of Tumor Cell-Derived Gelatinases during Formation of Liver Metastases.
  23. (2005). Distribution and dynamics of Lamp1-containing endocytic organelles in fibroblasts deficient in BLOC-3.
  24. (2001). Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins.
  25. (2006). 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.
  26. (2009). Expression and prognostic value of L1-CAM in breast cancer.
  27. (1994). Expression of 72 kDa type IV collagenase and invasion activity of human glioma cells.
  28. (2004). Extracellular signal-regulated kinase (ERK)-dependent gene expression contributes to L1 cell adhesion molecule-dependent motility and invasion.
  29. (2005). Gelatinase-mediated migration and invasion of cancer cells.
  30. (1981). Heterogeneity of malignant cells from a human colonic carcinoma.
  31. (1999). Highly activated matrix metalloproteinase-2 secreted from clones of metastatic lung nodules of nude mice injected with human fibrosarcoma HT1080.
  32. (2005). Identification of L1CAM, Jagged2 and Neuromedin U as ovarian cancer-associated antigens.
  33. (2002). Increase in Gelatinase-specificity of Matrix Metalloproteinase Inhibitors Correlates with Antimetastatic Efficacy in a T-Cell Lymphoma Model.
  34. (2008). Kinetic analysis of L1 homophilic interaction: role of the first four immunoglobulin domains and implications on binding mechanism.
  35. (2005). Kru ¨ger A
  36. (2008). L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth.
  37. (2005). L1 augments cell migration and tumor growth but not beta3 integrin expression in ovarian carcinomas.
  38. (2009). L1 cell adhesion molecules as regulators of tumor cell invasiveness.
  39. (2002). L1 endocytosis is controlled by a phosphorylation-dephosphorylation cycle stimulated by outside-in signaling by L1.
  40. (2007). L1 expression as a marker for poor prognosis, tumor progression, and short survival in patients with colorectal cancer.
  41. (2003). L1 expression as a predictor of progression and survival in patients with uterine and ovarian carcinomas.
  42. (2007). L1 is associated with micrometastatic spread and poor outcome in colorectal cancer.
  43. (2002). L1 mediated homophilic binding and neurite outgrowth are modulated by alternative splicing of exon 2.
  44. (2010). L1 syndrome mutations impair neuronal L1 function at different levels by divergent mechanisms.
  45. (2010). L1CAM malfunction in the nervous system and human carcinomas.
  46. (1993). Levels of matrix metalloproteases in bladder cancer correlate with tumor grade and invasion.
  47. (2005). Mechanical properties, proteolytic degradability and biological modifications affect angiogenic process extension into native and modified fibrin matrices in vitro.
  48. (2009). Metastasis mechanisms.
  49. (2005). Modulation of receptor recycling and degradation by the endosomal kinesin KIF16B.
  50. (2003). Molecular mechanisms of tumor invasion and metastasis: an integrated view.
  51. (2001). Multicolour imaging of post-Golgi sorting and trafficking in live cells.
  52. (1988). Neural adhesion molecule L1 as a member of the immunoglobulin superfamily with binding domains similar to fibronectin.
  53. (1995). of the gene for neural cell adhesion molecule L1 is alternatively spliced in B cells.
  54. (1989). Revised FIGO staging for gynaecological cancer.
  55. (1994). Scattered micrometastases visualized at the single-cell level: detection and re-isolation of lacZ-labeled metastasized lymphoma cells.
  56. (2007). Spatial regulation of EGFR signaling by Sprouty2.
  57. (2000). Stamenkovic I
  58. (2008). The biological role of HGF-MET axis in tumor growth and development of metastasis.
  59. (2006). The complexity of targeting EGFR signalling in cancer: from expression to turnover.
  60. (2006). The connection between splicing and cancer. J Cell Sci 119: 2635–2641. 8 . S c o t l a n d iK ,Z u n t i n iM ,M a n a r aM C ,S c i a n d r aM ,R o c c h iA ,e ta l
  61. (2008). The cytoplasmic part of L1-CAM controls growth and gene expression in human tumors that is reversed by therapeutic antibodies.
  62. (1998). The neural cell adhesion molecule L1 interacts with the AP-2 adaptor and is endocytosed via the clathrin-mediated pathway.
  63. (1998). The neural cell adhesion molecule L1: genomic organisation and differential splicing is conserved between man and the pufferfish Fugu.
  64. (2008). The RGD integrin binding site in human L1-CAM is important for nuclear signaling.
  65. (2010). Therapeutic antibodies to human L1CAM: functional characterization and application in a mouse model for ovarian carcinoma.
  66. (2006). Transforming growth factor-beta in cancer and metastasis.
  67. (2009). Up-regulation of L1CAM in pancreatic duct cells is transforming growth factor beta1- and slug-dependent: role in malignant transformation of pancreatic cancer.
  68. (2010). Upregulation of L1CAM is linked to loss of hormone receptors and E-cadherin in aggressive subtypes of endometrial carcinomas.
  69. (1992). Variants of human L1 cell adhesion molecule arise through alternate splicing of RNA.