Expression of the LGI1 gene product in astrocytic gliomas: downregulation with malignant progression

Abstract

Loss of heterozygosity in the long arm of chromosome 10q is a frequent event in gliomas. It may involve the LGI1/epitempin gene, which is located in chromosomal region 10q23 approximately 24 and has been proposed to encode a tumor suppressor inactivated in the progression of brain tumors. Nevertheless, so far no data are available demonstrating that the reduced expression of the LGI1 transcript in high-grade astrocytic tumors indeed results in a decreased level of LGI1 protein in the tumor cells. Thus, the aim of the present study was to analyze the expression of the LGI1 protein in a series (ten of each) of pilocytic astrocytomas, astrocytomas [World Health Organization (WHO) grade II], anaplastic astrocytomas (WHO grade III), and glioblastoma multiforme (WHO grade IV). Immunohistochemistry demonstrated a strong expression of the LGI1 protein in normal brain tissue as well as in the majority of pilocytic astrocytomas and astrocytomas (WHO grade II). In anaplastic astrocytomas, the number of tumor cells expressing LGI1 decreased, while LGI1 expression was completely absent from the glioblastomas of this series. This highly significant reduction of LGI1 protein expression in the progression of astrocytic brain tumors lends further support to the hypothesized function of LGI1 as a type-II tumor suppressor gene in glioma pathogenesis.

Expression studies in gliomas and glial cells do not support a tumor suppressor role for LGI11

“…In 16 (45.7%) of 35 GBMs, LGI1 expression was very low or absent and was completely absent in all cell lines. In only two of 35 low-grade gliomas, LGI1 expression was decreased or absent, while in other cases, expression levels were comparable to normal brain (two samples examined), confirming previous data (Besleaga et al, 2003;Chernova et al, 1998). (See supplementary data, Fig.…”

Differential expression of the LGI and SLIT families of genes in human cancer cells

“…In this cell line there is no normal copy of chromosome 10, which suggested that the translocation breakpoint might affect expression of the remaining copy of gene(s) located at the 10q24 breakpoint. In support of this, it has now been demonstrated by two groups that LGI1 is expressed at detectable levels in low grade gliomas but not in high grade gliomas (Chernova et al, 1998;Besleaga et al, 2003). The final stage of glioma progression gives rise to the highly invasive glioblastoma multiforme (GBM).…”

The Tumor Suppressor Function of LGI1

“…The downregulation of LGI1 might result in the increase of MPP expression supporting tumor growth and metastasis formation. These findings raised the possibility that the tumor suppressor function of LGI1 might impede malignant development, thus it was proposed to function as a type-II tumor suppressor gene (Besleaga et al, 2003).…”

“…Immunohistochemistry and mRNA analysis showed that LGI1 levels are very low or completely absent in most tumor tissues and in several cancer cell lines including, www.intechopen.com glioblastoma, neuroblastoma, melanoma and breast, furthermore the decrease of LGI1 expression shows a significant correlation with the grade of malignancy of astrocytic gliomas (Rossi et al, 2005;Besleaga et al, 2003). DNA microarrays, SAGE and EST number suggest low or absent expression in the majority of tumor tissues (see Gabellini, 2007).…”

“…A gradual decline in the expression of LGI1 gene accompanies the malignant progression of gliomas (Besleaga et al, 2003). Northern blot, RT-PCR and immunohystochemistry of various brain tumor samples revealed that in the majority of lowgrade tumor such as pilocytic astrocytomas and astrocytomas, defined by the World Health Organization (WHO) grade II, the expression of LGI1 was similar to that of normal brain; in anaplastic astrocytomas (WHO grade III) the levels of LGI1 was consistently lower than in normal tissue, whereas LGI1 expression was absent in 80% of glioblastoma multiforme samples (WHO grade IV).…”