Abstract
Glioblastoma multiforme (GBM) is one of the most malignant and aggressive brain tumors with great amount of hyaluronan (HA) secretion and CD44 overexpression (HA receptor). CD44 has been suggested as a cancer stem cells (CSCs) marker. However, several clinical studies have indicated that CD44low glioma cell exhibit CSCs traits. Additionally, our previous study indicated that more CD44 expression was associated with a better prognosis in GBM patients. To determine whether CD44 is an appropriate marker of glioma stem cells (GSCs), we manipulated CD44 expression using intrinsic (CD44 knockdown, CD44kd) and extrinsic (HA supplement, HA+) methods. Our results show that CD44kd suppressed cell proliferation by retarding cell cycle progression from G0/G1 to S phase. Furthermore, it caused GSCs traits, including lower expression of differentiation marker (glial fibrillary acidic protein, GFAP), a higher level of sphere formation and higher expression of stem cell markers (CD133, nestin and Oct4). The reduction of CD44 expression induced by HA+ was accompanied by an increase in GSCs properties. Interestingly, the presence of HA+ in glioma cells with GSC traits conversely facilitated differentiation. Our data indicated that the CD44 low-expressing cells exhibit more GSCs straits, suggesting that CD44 is not an appropriate marker for GSCs. Furthermore, the preferential expression of CD44 at the invasive rim in rat glioma specimen implies that CD44 may be more important for invasion and migration instead of GSCs marker in glioma.