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.

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…As an example, we can refer to EMMPRIN, a class of glycoprotein secreted by tumor cells, which stimulates MMP-2 expression by fibroblasts (Biswas et al, 2010). Nonetheless, factors accounting for the unbalanced regulation of the enzyme are continuously identified; this is the case of the L1CAM adhesion molecule in a model of lung metastasis and of an E3 uniquitin ligase (c-Cbl) (Hauser et al, 2011;Lee and Tsygankov, 2010;Song et al, 2010).…”

Molecular targets and pathways involved in liver metastasis of colorectal cancer

“…Exon 2 is involved in homophilic and heterophilic binding to neural ligands contactin and TAX-1 and the cytoplasmic sequence encoded by exon 27 is necessary for clathrin-dependent endocytosis in vitro [89,90]. Only FL-L1CAM was able to promote experimental metastasis of HT1080 fibrosarcoma, SKOV3ip, and L-CI.5 s to the lungs and to the liver, respectively [91]. Metastasis formation correlated with increased invasive potential, elevated MMP2 and MMP9 expression in vitro, and enhanced proteolytic activity of these MMPs in vivo.…”

Dual REST‐dependence of L1CAM: from gene expression to alternative splicing governed by Nova2 in neural cells

“…2001) and cytoplasmic (Herron et al. 2009) proteins, respectively, the two spliced exons appear functionally important in neural cells and also in some tumours where fl‐L1, and not sh‐L1, promotes liver and lung metastases (Hauser et al. 2011).…”