Li Bin, McCrudden Cian M, Yuen Hiu Fung, Xi Xinping, Lyu Peng, Chan Kwok Wah, Zhang Shu Dong, Kwok Hang Fai
Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR.
School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom.
Oncotarget. 2017 Feb 14;8(7):11144-11159. doi: 10.18632/oncotarget.14406.
CD133 has been shown to be an important stem cell factor that promotes glioma progression. However, the mechanism for CD133-mediated glioma progression has yet to be fully elucidated. In this study, we found that CD133 mRNA expression was a prognostic marker in three independent glioma patient cohorts, corroborating a putative role for CD133 in glioma progression. Importantly, we found that CD133 expression in glioma was highly correlated with the expression of HOX gene stem cell factors (HOXA5, HOXA7, HOXA10, HOXC4 and HOXC6). The expression of these HOX genes individually was significantly associated with survival. Interestingly, the prognostic significance of CD133 was dependent on the expression level of HOX genes, and vice versa. CD133 (p = 0.021) and HOXA7 (p = 0.001) were independent prognostic markers when the three glioma patient cohorts were combined (n = 231). Our results suggest that HOX genes may play a more important role in progression of glioma when CD133 expression is low. Furthermore, we showed that low-level expression of LIM2 in CD133-high glioma was associated with poorer survival, suggesting that LIM2 could be a therapeutic target for glioma expressing a high level of CD133. Connectivity mapping identified vinblastine and vincristine as agents that could reverse the CD133/HOX genes/LIM2-signature, and we confirmed this by in vitro analysis in glioma cell lines, demonstrating that CD133 and HOX genes were co-expressed and could be downregulated by vincristine. In conclusion, our data show that CD133 and HOX genes are important prognostic markers in glioma and shed light on possible treatment strategies for glioma expressing a high level of CD133.
CD133已被证明是促进胶质瘤进展的重要干细胞因子。然而，CD133介导胶质瘤进展的机制尚未完全阐明。在本研究中，我们发现CD133 mRNA表达是三个独立胶质瘤患者队列中的一个预后标志物，证实了CD133在胶质瘤进展中的假定作用。重要的是，我们发现胶质瘤中CD133的表达与HOX基因干细胞因子（HOXA5、HOXA7、HOXA10、HOXC4和HOXC6）的表达高度相关。这些HOX基因各自的表达与生存显著相关。有趣的是，CD133的预后意义取决于HOX基因的表达水平，反之亦然。当三个胶质瘤患者队列合并（n = 231）时，CD133（p = 0.021）和HOXA7（p = 0.001）是独立的预后标志物。我们的结果表明，当CD133表达低时，HOX基因可能在胶质瘤进展中起更重要的作用。此外，我们表明在CD133高表达的胶质瘤中LIM2的低水平表达与较差的生存相关，表明LIM2可能是高表达CD133的胶质瘤的治疗靶点。连接图谱确定长春碱和长春新碱为可逆转CD133/HOX基因/LIM2特征的药物，我们通过胶质瘤细胞系的体外分析证实了这一点，表明CD133和HOX基因共表达且可被长春新碱下调。总之，我们的数据表明CD133和HOX基因是胶质瘤重要的预后标志物，并为高表达CD133的胶质瘤的可能治疗策略提供了线索。
