title: Full-length L1CAM and not its Δ2Δ27 splice variant promotes metastasis through induction of gelatinase expression.
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.
authors.affiliation: Institut für Experimentelle Onkologie und Therapieforschung Klinkum rechts der Isar der Technischen Universität München, München, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hauser
authors.forename: Laura
authors.initials: L
authors.lastname: Bickel
authors.forename: Dirk
authors.initials: D
authors.lastname: Weinspach
authors.forename: Michael
authors.initials: M
authors.lastname: Gerg
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schäfer
authors.forename: Marco
authors.initials: M
authors.lastname: Pfeifer
authors.forename: John
authors.initials: J
authors.lastname: Hazin
authors.forename: Florian
authors.initials: F
authors.lastname: Schelter
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: Weidle
authors.forename: Juliane
authors.initials: J
authors.lastname: Ramser
authors.forename: Juliane
authors.initials: J
authors.lastname: Volkmann
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmitt
authors.forename: Florian
authors.initials: F
authors.lastname: Schrötzlmair
authors.forename: Peter
authors.initials: P
authors.lastname: Altevogt
authors.forename: Achim
authors.initials: A
authors.lastname: Krüger
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D011992:Endosomes / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D005354:Fibrosarcoma / Q000235:genetics / Q000473:pathology; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics*; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D021381:Protein Transport
chemical_list: D039842:Neural Cell Adhesion Molecule L1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9