Identifying RNA and Protein Expression Profile of Bone Invading and Non-Invading Meningiomas

Introduction: Although meningiomas are considered as benign primary brain tumors, a subset invades bone and adjacent neural and soft tissues and causes hyperostosis. Skull base bone-invading meningiomas represent a significant clinical challenge because complete surgical resection is often impossible, resulting in higher recurrence rates and repeat surgery. This study aims to identify differential gene and protein expression profile and altered signaling pathways of bone-invading and non-invading meningiomas, with the ultimate goal to establish potential novel therapeutic targets.

Methods: Archived tumor specimens of 75 patients with either bone invading or non-invading meningiomas were selected. RNA and tissue microarray were performed on the samples. The results of the array data were verified using real-time PCR analysis. Meningioma cell lines (IOMM-Lee, CH157-MN and F5) were used for in vitro and in vivo functional studies. Matrigel invasion assay, immunostaining, and western blotting were used to characterize the behavior of these cells in vitro. Xenograft intracranial meningioma tumors were generated in mice. Small-animal MRI was used to study tumor growth pattern and behavior. Meningioma tumor samples were also used for immunohistochemical analysis.

Results: RNA microarray data identified 222 differentially expressed genes, of which MMP16 and 19 were selected as novel matrix remodeling metalloproteinases involved in bone invasion. Real-time PCR analysis confirmed the overexpression of these genes in bone-invading meningiomas. In vitro studies identified a direct correlation between the invasive capacity of the meningioma cell lines and expression level of MMP16 and MMP19. siRNA inhibition of MMP16 demonstrated diminished proliferation and invasion in vitro and in vivo. The downstream signaling pathways regulated by MMP16 were identified as MAPK and AKT. In vivo studies using xenograft meningioma tumor models showed the tumor growth and invasion to the underlying bone tissue and confirmed our in vitro data.

Conclusion: We identify novel pathways that play an important contributory role to bone invasion in meningiomas. These results provide the basis of future studies to explore potential for targeting MMP16 and 19 in bone-invading meningiomas.