CD146 is highly expressed in glioma stem cells and acts as a cell cycle regulator
CD146 is highly expressed in glioma stem cells and acts as a cell cycle regulator
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DOI：
10.1007/s11060-019-03200-4
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发表时间：
2019-05
影响因子：
3.9
通讯作者：
T. Yawata;Y. Higashi;Y. Kawanishi;T. Nakajo;Naoki Fukui;H. Fukuda;T. Ueba
中科院分区：
文献类型：
--
作者：
T. Yawata;Y. Higashi;Y. Kawanishi;T. Nakajo;Naoki Fukui;H. Fukuda;T. Ueba
CD146在多种恶性肿瘤中高表达，参与肿瘤的恶性表型，参与肿瘤的转移和致瘤活动。然而，对CD146在脑肿瘤中的表达和功能的研究还很有限。方法我们在常规培养的胶质瘤细胞和肿瘤球(TS)中过表达或下调了CD146。使用干细胞标记CD133和胶质前体标记A2B5，用流式细胞仪分析胶质瘤细胞及其干细胞在细胞周期不同时相的分布。结果大部分表达CD133的胶质瘤干细胞(GSCs)也呈CD146阳性。GSC中CD146基因的敲除显著影响了细胞的生长。细胞周期分析显示，CD146和CD133双阳性细胞大多处于G2/M期。CD146在亲本胶质瘤细胞中的异位表达导致大部分分化细胞停滞在G0/G1期。相反，CD146在GSCs中的异位表达导致G2/M期CD133阳性细胞数量增加。此外，CD146基因敲除减少了处于G2/M期的CD133阳性细胞的数量，这与抑制细胞生长的作用一致。免疫组织化学分析显示CD146在世界卫生组织III、IV级胶质瘤中的表达显著上调，并与CD133的表达呈正相关。结论CD146主要表达于胶质瘤干细胞的分裂中，可能成为治疗胶质瘤干细胞的潜在靶点。
IntroductionCD146 is highly expressed in various malignant tumors and contributes to their malignancy phenotype, which involves metastatic and tumorigenic activity. However, studies on the expression and function of CD146 in brain tumors are limited.MethodsWe over-expressed or knocked-down CD146 in both conventionally cultured glioma cells and tumor spheres (TS). The distribution of glioma cells and their stem cells in different cell cycle phases was analyzed by flow cytometry using the stem cell marker CD133 and the glial precursor marker A2B5. CD146 expression was immunohistochemically examined in glioma tissues.ResultsThe majority of glioma stem cells (GSCs) expressing CD133 were also CD146-positive. CD146 knockdown in GSCs significantly compromised cell growth. Cell cycle analysis revealed that most of the CD146 and CD133 double-positive cells were in the G2/M phase. Ectopic expression of CD146 in parental glioma cells resulted in cell cycle arrest of most differentiated cells in G0/G1 phase. In contrast, ectopic expression of CD146 in GSCs resulted in an increase in the number of CD133-positive cells in the G2/M phase. Furthermore, CD146 knockdown reduced the number of CD133-positive cells in the G2/M phase, which was consistent with effects of cell growth inhibition. Immunohistochemical analysis revealed that CD146 expression was significantly upregulated in World Health Organization (WHO) Grade III and IV glioma and positively correlated with CD133 expression.ConclusionsCD146 is mainly expressed in dividing GSCs and may be a potential target for eradicating glioma stem cells.