**Part 7**

**LGI1 in Treatment of Glioma** 

216 Novel Therapeutic Concepts in Targeting Glioma

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**11** 

*Italy* 

Nadia Gabellini *University of Padova* 

**The Tumor Suppressor Function of LGI1** 

The Leucine rich Glioma Inactivated 1 (LGI1) gene has been related to different pathologies such as epilepsy and cancer. The aim of this chapter is to present the evidences on the tumor suppressor function of LGI1. Initially LGI1 gene was identified at the brake point of a balanced chromosome translocation in a glioblastoma cell line (Chernova et al., 1998). The observation that this rearrangement abolished expression of LGI1 and that expression of LGI1 is absent in most high-grade gliomas lead to the hypothesis that it may function as

The tumor suppressor function was sustained by the re-expression of LGI1 in glioblastoma cells, lacking endogenous expression, LGI1 inhibited cell proliferation and migration (Kunapuli et al., 2003). The role of tumor suppressor was further supported by the identification of several mutations in LGI1 gene associated with gliomas (Barnholtz-Sloan et al., 2008). The tumor suppressor function of LGI1 was supported also by the results of LGI1 expression in neuroblastoma and adenocarcinoma cells, in which endogenous expression is very low or absent. The expression of LGI1 in these cancer cells not only produced a potent inhibition of cell proliferation, as in the case of glioblastoma cells, but also impaired cell survival (Gabellini et al., 2006; Gabellini & Masola, 2009). Moreover a study on malignant

esophageal tumors showed a significant downregulation of LGI1 (Peng et al. 2008).

Investigations on the mechanism of spontaneous cell death caused by the expression of LGI1 in neuroblastoma cells showed the induction of intrinsic apoptosis, produced by an unbalance of important regulator of mitochondrial membrane permeability, namely of the anti-apoptotic B-cell lymphoma 2 gene (BCL2) and of the pro-apoptotic B-cell lymphoma 2-associated X protein gene (BAX). These studies also pointed out a possible involvement of LGI1 in the negative regulation of essential signaling pathways supporting cell proliferation and survival.

Consistently with the evidence that LGI1 triggered a mitochondrial pathway of apoptosis, the phosphoinositide 3-kinase (PI3K/AKT) pathway, important regulator of BCL proteins,

**1. Introduction** 

tumor suppressor.

**1.2 Induction of apoptosis**

**1.3 Regulation of signaling pathways**

**1.1 Evidences for the tumor suppressor function**
