Neuregulin 1 Enhances Cell Adhesion Molecule L1 Expression in Human Glioma Cells and Promotes Their Migration as a Function of Malignancy

Similar functions of L1, a cell adhesion molecule, and the cytokine neuregulin 1 (Nrg1) have been suggested in tumorigenesis and the promotion of metastasis. We studied the relationships of Nrg1 and L1 expression in human gliomas. Using immunofluorescence staining on a human glioma tissue microarray, we found a positive correlation between levels of L1 and Nrg1α or Nrg1β expression; expression tended to increase with increasing WHO (World Health Organization) tumor grade. L1 was also found to colocalize with either Nrg1 isoform. In cultures of U87-MG human glioblastoma and human U251 and SHG-44 glioma cells, the base levels of full-length L1 expression were increased by the 2 Nrg1 molecules in the nanomolar range, and Nrg1 siRNA downregulated full-length L1 expression in these tumor cell lines. U87-MG cells treated with either Nrg1 isoform also showed enhanced migration when compared with that treated with vehicle control. In addition, administration of either lapatinib (a dual inhibitor of both the epidermal growth factor receptor and ErbB-2) or erlotinib (an inhibitor of the epidermal growth factor receptor) in combination with either Nrg1α or Nrg1β inhibited the L1 expression elicited by these cytokines in U87-MG cells. Together, our data suggest that Nrg1 regulates L1 expression in gliomas, and that Nrg1 may contribute to malignancy by upregulating the L1 expression in glioblastoma cells, thereby enhancing their migration.