Institut für Experimentelle Onkologie und Therapieforschung Klinkum rechts der Isar der Technischen Universität München, München, Germany.
PLoS One. 2011 Apr 25;6(4):e18989. doi: 10.1371/journal.pone.0018989.
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.
肿瘤特异性剪接被认为有助于癌症的进展。在 L1 细胞黏附分子（L1CAM）的情况下，它在许多人类肿瘤中表达，并且常常与不良预后相关，选择性剪接导致全长形式（FL-L1CAM）和缺乏外显子 2 和 27 的剪接变体（SV-L1CAM）。到目前为止，还不清楚 SV-L1CAM，经典地被认为是肿瘤相关的，还是 FL-L1CAM 是促进转移的同工型。在这里，我们表明这两种变体都在人卵巢癌中表达，并且肿瘤细胞暴露于促转移因子会导致 FL-L1CAM 表达的特异性增加。在不同的肿瘤细胞中选择性过表达一种同工型表明，只有 FL-L1CAM 促进了小鼠的实验性肺和/或肝转移。此外，FL-L1CAM 的上调与体外侵袭潜能的增加以及基质金属蛋白酶（MMP）-2 和 -9 的表达和活性的升高以及体内明胶酶活性的增强相关联。总之，我们确定 FL-L1CAM 是促进转移的同工型，从而证明了所谓的肿瘤相关变体（这里是 SV-L1CAM）的高表达本身并不等同于该同工型在肿瘤进展中的决定性作用。
