组蛋白去乙酰化酶3在星形细胞瘤中的表达及其临床意义

Expression of Histone Deacetylase 3 in Astrocytic Gliomas and Its Clinical Significance

目的探讨组蛋白去乙酰化酶3(HDAC3)在星形细胞瘤中的表达及其临床意义。方法选择华中科技大学同济医学院附属同济医院1996年1月—2008年1月收治的283例原发性星形细胞瘤患者和52例复发患者,其中WHO分级Ⅱ级59例,Ⅲ级26例,Ⅳ级250例;收集其手术切除标本,提取典型病变区域制作成组织芯片(TMA)。采用荧光定量PCR检测HDAC3在肿瘤干细胞、胶质瘤贴壁细胞和星形细胞瘤组织中的表达,对TMA进行免疫组化染色。结果 HDAC3在肿瘤干细胞NCH421k和NCH441中的平均相对表达量为1.14和0.95,在胶质瘤贴壁细胞中为2.04,在星形细胞瘤中为1.06。HDAC3在瘤细胞胞核和胞质中呈阳性表达。HDAC3胞核总阳性表达率为16.7%(56/335),其中WHO分级Ⅳ级者为13.6%(34/250),WHO分级Ⅲ级者为0,WHO分级Ⅱ级者为37.3%(22/59);HDAC3胞质总阳性表达率为49.3%(165/335),其中WHO分级Ⅳ级者为42.0%(105/250),WHO分级Ⅲ级者为65.4%(17/26),WHO分级Ⅱ级者为72.9%(43/59)。23例复发患者两次TMA保存完整,其中5例WHO分级恶化,18例WHO分级无恶化。5例WHO分级恶化患者中,HDAC3胞核染色强度减弱2例,稳定2例,增强1例;胞质染色强度稳定4例,增强1例。18例WHO分级无恶化患者中,HDAC3胞核染色强度减弱2例,稳定13例,增强3例;胞质染色强度减弱4例,稳定9例,增强5例。HDAC3胞核阳性表达率与患者整体生存率呈正相关(r=0.148,P=0.007),阳性表达强度与WHO分级Ⅳ级患者生存率呈负相关(r=-0.503,P=0.037);HDAC3胞质阳性表达强度与患者整体生存率呈负相关(r=-0.140,P=0.014),阳性表达率与WHO分级Ⅳ级患者生存率呈负相关(r=-0.544,P=0.013)。结论胞核HDAC3的高表达预示较好的预后。HDAC3在胞核及胞质内的表达移位对胶质瘤的生物学特性起着重要调控作用。

Objective To investigate the expression of histone deacetylase 3 （HDAC3） in astrocytic gliomas and its clinical significance. Methods A total of 283 patients with primary astrocytic gliomas and 52 recurrent patients （including 59 cases of WHO grade II , 26 WHO grade III, 250 WHO grade IV ） admitted to Tongji Hospital Affiliated to Tongji Medical College from January 1996 to January 2008 were enrolled in this study. Surgical specimens were collected, typical lesion area extracted to make tissue microarray （TMA）. Fluorogenic quantitative PCR was used to determine the expression of HDAC3 in tumor stem ceils, glioma adherent ceils, astrocytic gliomas and immunohistochemical staining performed on TMA. Results The mean relative expression of HDAC3 was 1.14 in NCH421k, 0. 95 in MCH441 of tumor stem cells, 2. 04 in glioma adherent cells, 1.06 in astrocytic gliomas. HDAC3 expressed positively in oncocyte nucleus and kytoplasm. The nucleus total positive expression rate was 16. 7% （56/335）, thereinto patients graded WHO IV accounting for 13. 6% （34/250）, those graded WHOIII for 0, those graded WHO II for 37. 3% （22/59）. The kytoplasm total positive expression rate was 49. 3% （ 165/335）, thereinto patients graded WHO IV accounting for 42.0% （ 105/250）, those graded WHO III for 65.4% （ 17/26）, those graded WHO II for 72. 9% （43/59）. In 23 recurrent patients, 5 had deteriorated WHO grading, 18 had no. In the 5 patients with deteriorated WHO grading, 2 had decreased HADC3 nucelus staining intensity, 2 had stable, 1 had enhanced; 4 had stable kytoplasm staining intensity, 1 had enhanced. In the 18 patients without deteriorated WHO grading, 2 had decreased HADC3 nu- eelus staining intensity, 13 had stable, 3 had enhanced; 4 had decreased kytoplasm staining intensity, 9 had stable, 5 had enhanced. The nucleus positive expression rate was positively correlated with patients＇overall survival （r = 0. 148, P = 0. 007 ）, positive expression intensity negatively with survival of patients graded WHO 1V （ r = - 0. 503, P = 0. 037 ） ; HDAC3 kytoplasm positive expression intensity was negatively correlated with patients＇ overall survival （ r = - 0. 140, P = 0. 014）, positive expression negatively with survival of patients graded WHO IV （ r = - 0. 544, P = 0. 013 ）. Conclusion Overexpression of nucleus HDAC3 may indicate a better prognosis of patients with primary astroeytic gliomas. The expression shift of HDAC3 in nucleus and cytoplasm plays an important role in regulating biological characteristics of astroeytic gliomas.