A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing.

The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-ΔTM. The splicing factor NOVA2, which binds directly to L1CAM pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in ECs, leading to the release of soluble L1-ΔTM. The latter exerts high angiogenic function through both autocrine and paracrine activities. Mechanistically, L1-ΔTM-induced angiogenesis requires fibroblast growth factor receptor-1 signaling, implying a crosstalk between the two molecules. NOVA2 and L1-ΔTM are overexpressed in the vasculature of ovarian cancer, where L1-ΔTM levels correlate with tumor vascularization, supporting the involvement of NOVA2-mediated L1-ΔTM production in tumor angiogenesis. Finally, high NOVA2 expression is associated with poor outcome in ovarian cancer patients. Our results point to L1-ΔTM as a novel, EC-derived angiogenic factor which may represent a target for innovative antiangiogenic therapies.

HMGA1 protein expression in familial breast carcinoma patients.

HMGA protein overexpression is associated with a highly malignant phenotype and it is also causally related to neoplastic cell transformation. Our previous results have shown that HMGA1 was not expressed in normal breast tissue whereas HMGA1 staining was intense in 25% of hyperplastic lesions with cellular atypia and in 60% of sporadic ductal carcinomas. Moreover, HMGA1 protein levels were significantly correlated with c-Erb-B2 expression. These results suggested HMGA1 expression as a novel prognostic factor in breast ductal carcinomas. In order to investigate whether the HMGA1 detection might have a prognostic role also for inherited breast carcinomas we have analysed the expression of the HMGA1 proteins in 116 breast familial carcinomas associated with BRCA1 or BRCA2 or negative for mutations in both genes (BRCAX). HMGA1 expression was weakly positive in 23 (20%), moderately positive in 34 (29%) and strongly positive in 20 (17%) breast carcinomas, and was not detected in 39 of them (34%). Statistical analysis of the immunostaining data showed that HMGA1 was significantly overexpressed, with a more intense staining, in BRCA2 (p=0.0009) and BRCAX (p=0.0134) patients compared to BRCA1 ones. Furthermore, in BRCA2 positive patients, the expression of HMGA1 seems to correlate with a favourable prognosis with a median overall survival of 65 months and a 5-year survival rate of 80% for HMGA1-negative patients, while median overall survival in the HMGA1-positive subsets was not reached with 5-year survival rates ranging from 84% to 100% of patients (p=0.0198). Conversely, no correlation was found between HMGA1 expression and overall survival in patients carrying inherited mutations in the BRCA1 and in BRCAX patients.