The tumor suppressor function of LGI1

Several evidences supporting the tumor suppressor role of LGI1 have been presented here. The discovery of chromosomal rearrangements leading to loss of LGI1 expression in glioblastoma cells, mutations in LGI1 gene specifically associated with gliobastoma and the downregulation of LGI1 expression in several tumors all point out a role of LGI1 in tumor suppression. Furthermore the findings that re-expression of LGI1 in glioblastoma cells impaired cell growth and migration ability through inhibition of the ERK1/2 pathway, with consequent downregulation of MMPs expression, support a role in the suppression of metastasis formation and tumor vascularization. This is in line with the downregulation of LGI1 expression observed in the malignant progression of gliomas. The findings that increased expression of LGI1 impaired growth and survival of neuroblastoma cells further strengthen the tumor suppressor role of LGI1. The involvement of LGI1 in the negative regulation of the PI3K/AKT pathway supporting cell proliferation and survival explains the mechanism of spontaneous cell death triggered by the elevation of LGI1 levels in neuroblatoma cells. The activation of intrinsic apoptosis triggered by LGI1 is consistent with a blockage of AKT activity, which regulates Bcl-2 family members involved in the control of mitochondrial membrane permeability. Furthermore, the interaction of LGI1 protein with voltage gated potassium channels (Kv1.1) shown to prevent channel inactivation by Kv1b subunit, provides an additional link with apoptosis since these channels are important regulators of cell survival. Because suppression of apoptosis in cancer cells is one of the main strategies to achieve the survival advantage required for malignant progression, it is feasible that alterations of LGI1 gene or downregulation of expression often observed in cancer cells might be required to suppress apoptosis through the inhibition of survival pathways linked to growth factor receptors and of Kv channels activity.