Enhancer of Zeste Homologue 2 (EZH2) Expression Is Associated with Cell Proliferation in Medulloblastoma
Min Shi, Jingxin Qiu, Thomas W Smith, Daniel L Kilpatrick, Wei Wang. UMass Memorial Medical Center, Worcester, MA; Roswell Park Cancer Institute, Buffalo, NY; UMass Medical School, Worcester, MA
Background: A failure in control of proliferation of cerebellar granule neural progenitors (CGNPs) is thought to lead to medulloblastoma (MB), the most common malignant brain tumor in children. The molecular events associated with the development of MB are not fully understood. EZH2 is a member of the polycomb group family of proteins important for transcriptional regulation. EZH2 expression is associated with high proliferation and aggressive behavior in cancers. In this study, we investigated the expression of EZH2 and its relationship with cell proliferation in human MB and during CGNP development in mice.
Design: Eighteen MB cases were examined by immunohistochemistry for EZH2 and Ki-67 proliferative index. Since normal mouse CGN development has been shown to recapitulate MB, EZH2 expression and functional assay were investigated in early postnatal cerebellum of CD1 mice. EZH2 expression was examined by immunohistochemistry. After knockdown of EZH2 expression using a lentiviral vector shRNA approach, we performed BrdU incorporation assay to determine whether EZH2 knockdown impaired CGNP proliferation.
Results: EZH2 nuclear staining was identified in all 18 MB cases whereas normal cerebellar tissue surrounding the tumor or normal mature cerebellum had no EZH2 expression (Fig1A). Fifteen cases (83%) showed moderate to strong EZH2 expression and 3 cases (17%) exhibited weak expression. Ki-67 proliferative indices were significantly higher in cases with moderate to strong EZH2 expression (mean=42%) compared to those with weak EZH2 expression (mean=8%) (P < 0.05), suggesting that EZH2 expression in MB is closely associated with tumor cell proliferation. EZH2 was highly expressed in the CGNPs in postnatal day 6 mice. When stable EZH2 knockdown was achieved in this model, the BrdU incorporation assay showed significant suppression of the proliferation of CGNPs in comparison to non-siliencing control (NS) (Fig1B).
Conclusions: EZH2 is highly expressed in MB and appears to play a major role in controlling tumor cell proliferation. These findings suggest that EZH2 could potentially be an important therapeutic target for MB.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 266, Monday Morning