Gene expression profiling of the hedgehog signaling pathway in human meningiomas

Abstract

The Hedgehog (Hh) signaling pathway has an important role during embryogenesis and in adult life, regulating proliferation, angiogenesis, matrix remodeling and stem-cell renewal. Deregulation of the Hh pathway is involved in tumor development, since mutations in several components of this pathway were found in patients with basal cell carcinoma, medulloblastoma and other tumors; however, the role of Hh in meningiomas has not been studied yet. Meningiomas represent 30% of primary cranial tumors, are mostly benign and prevail in the second half of life. Novel therapies for meningiomas such as targeted molecular agents could use Hh pathway components. To provide information concerning molecular alterations, by use of real-time RT-PCR, we studied expression at the mRNA level of 32 Hh pathway and target genes in 36 meningioma specimens of different grades. mRNA levels of 16 genes, involved mainly in Hh pathway activation and cell proliferation, increased in meningiomas in comparison with normal tissue, whereas those of 7 genes, mainly related to Hh pathway repression, decreased. The most significant changes occurred in signal transduction (SMO) and GLI-transcription factor genes, and the target FOXM1 mRNA attained the highest values; their over-expression was found in aggressive and in benign tumors. Some proliferation-related genes (SPP1, IGF2) were overexpressed in higher meningioma grades. A correlation in expression between genes with a similar function was also found. Our results show a marked activation of the Hh pathway in meningiomas, which may be important for their biological and clinical characterization and would be useful for gene therapy.

Figure 1

mRNA levels of 32 Hedgehog pathway genes, target genes and the proliferation marker MKI67 in different meningioma grades (MGI, MGII and MGIII). Median standardized mRNA levels in meningiomas were determined relative to the median mRNA level in normal meninges, which has an assigned value of 1 and is indicated by a horizontal line. Statistically significant differences in mRNA levels between meningiomas and normal tissue are denoted by asterisk. The tests used and P values are as in Table 2.

Figure 2

mRNA levels of PTCH1, SMO, GLI2 and FOXM1. The figure shows standardized mRNA levels of each gene in six individual normal meninges (N), 23 grade I meningiomas (MGI), 9 grade II meningiomas (MGII) and 4 grade III meningiomas (MGIII). Median values are indicated for normal meninges and each tumor group by horizontal bars. P values for the three tumor grades versus normal tissue are as in Table 2.