Overexpression of CD99 Increases the Migration and Invasiveness of Human Malignant Glioma Cells

Abstract

The malignant glioma is the most common primary human brain tumor, and its migration and invasiveness away from the primary tumor mass are considered a leading cause of tumor recurrence and treatment failure. Recently, gene expression profiling revealed that the transmembrane glycoprotein CD99 is more highly expressed in malignant glioma than in normal brain. Although its function is not completely understood, CD99 is implicated in cell adhesion and migration in a variety of different cell types. CD99 has wild-type and splice variant isoforms. Previous studies have shown that wild-type CD99 may be an oncosuppressor in some tumors, distinct from the role of the splice variant isoform. In this study, our data reveal that only wild-type CD99 is expressed in human glioma cells and tissues. Using a tissue microarray, we validated that gliomas demonstrate higher expression of CD99 compared with nonneoplastic brain. To assess the role of CD99 in glioma migration and invasion, we inhibited CD99 expression by siRNA and demonstrated decreased glioma migration and invasion. In contrast, when CD99 was overexpressed in glioma cells, we observed enhancement of cell migration and invasiveness. An orthotopic brain tumor model demonstrates that CD99 overexpression significantly increases invasiveness and decreases survival rate. Interestingly, Rac activity was decreased and Rho activity was increased in CD99 overexpressing glioma cells, and the proportion of amoeboid cells to mesenchymal cells was significantly increased. Taken together, our findings suggest that CD99 may play an important role in the migration and invasion of human gliomas independent of Akt, ERK, or JNK signaling pathways. Moreover, CD99 might be involved in amoeboid-mesenchymal transition in glioma migration. CD99 may be an important future target to inhibit migration and invasion, especially in CD99-expressing gliomas.

PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth

“…In human glioma cells over-expression of CD99 is implicated in MAT, resulting in rounded morphology, increased Rho activity, and enhanced migration [64]. These properties superficially resemble the phenotype of our DM cells ( Fig.…”

PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth

“…The DM and TM altered morphology is dependent upon activated ROCK, which leads to stiffening of cortical actomyosin (Sahai and Marshall, 2003). In human glioma cells over-expression of CD99 is implicated in MAT, resulting in rounded morphology, increased Rho activity, and enhanced migration (Seol et al, 2012). These properties superficially resemble the phenotype of our DM cells ( Figure 1E-F), however DM cell migration involved pseudopodia and cell adhesion as evidenced in cell migration videos (File S1).…”

Atypical teratoid/ rhabdoid tumor, an immunohistochemical study of potential diagnostic and prognostic markers

“…In CNS tumors, CD99 is well described in ependymoma, with a specific dot‐like cytoplasmic staining pattern . It has recently been linked to invasiveness of glioma . In our cohort, CD99 was positive in 13 (68.4%) cases, four of which showed strong and diffuse membranous staining (overall score 7).…”