Functional Role of Matrix gla Protein in Glioma Cell Migration

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor subtype. Despite that metastasis of GBM beyond the central nervous system (CNS) is rare, its malignancy is attributed to the highly infiltration trait, leading to the difficulty of complete surgical excision. Matrix gla protein (MGP) is a vitamin K-dependent small secretory protein, and functions as a calcification inhibitor. The involvement of MGP function in glioma cell dynamics remains to be clarified. The study showed that a low proliferative rat C6 glioma cell line named as C6-2 exhibited faster migratory and invasive capability compared to that observed in a high tumorigenic rat C6 glioma cell line (called as C6-1). Interestingly, C6-2 cells expressed higher levels of MGP molecules than C6-1 cells did. Lentivirus-mediated short hairpin RNA (shRNA) against MGP gene expression (MGP-KD) in C6-2 cells or lentivirus-mediated overexpression of MGP transcripts in C6-1 cells resulted in the morphological alteration of the two cell lines. Moreover, MGP-KD caused a decline in cell migration and invasion ability of C6-2 cells. In contrast, increased expression of MGP in C6-1 cells promoted their cell migration and invasion. The observations were further verified by the results from the implantation of C6-1 and C6-2 cells into ex vivo brain slice and in vivo rat brain. Thus, our results demonstrate that the manipulation of MGP expression in C6 glioma cells can mediate glioma cell migratory activity. Moreover, our findings indicate the possibility that high proliferative glioma cells expressing a high level of MGP may exist and contribute to tumor infiltration and recurrence.