CD133 in brain tumor: the prognostic factor - PubMed (original) (raw)
CD133 in brain tumor: the prognostic factor
Bin Li et al. Oncotarget. 2017.
Abstract
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.
Keywords: CD133; HOX; LIM2; brain tumor; stem cell.
Conflict of interest statement
CONFLICTS OF INTEREST
The authors declare no competing financial interests.
Figures
Figure 1. The association between CD133 and patient survival
Kaplan-Meier analyses for CD133 mRNA expression in (A) GSE4271, (B) GSE4412, (C) GSE7696, and (D) the combined cohort.
Figure 2. The association between CD133 mRNA expression and tumor grade
A histogram displaying the association between CD133 mRNA expression profile and tumor grading in the combined cohort.
Figure 3. The association between mRNA expression of HOX genes and survival
Kaplan-Meier analyses for (A) HOXA5, (B) HOXA7, (C) HOXA10, (D) HOXC4 and (E) HOXC6 mRNA expression in the combined cohort.
Figure 4. The association between CD133 mRNA expression and survival in glioma patients with different level of expression of HOX genes
Kaplan-Meier analyses for CD133 mRNA expression in the combined cohort of glioma patients expressing (A) a low level of HOXA5, (B) a high level of HOXA5, (C) a low level of HOXA7, (D) a high level of HOXA7, (E) a low level of HOXA10, (F) a high level of HOXA10, (G) a low level of HOXC4, (H) a high level of HOXC4, (I) a low level of HOXC6, and (J) a high level of HOXC6.
Figure 5. The association between mRNA expression of HOX genes and survival in glioma patients with different level of expression of CD133
Kaplan-Meier analyses for HOXA5 expression in (A) CD133-low and (B) CD133-high glioma, for HOXA7 expression in (C) CD133-low and (D) CD133-high glioma, for HOXA10 expression in (E) CD133-low and (F) CD133-high glioma, for HOXC4 expression in (G) CD133-low and (H) CD133-high glioma, and for HOXC6 expression in (I) CD133-low and (J) CD133-high glioma in the combined cohort.
Figure 6. The association between LIM2 mRNA expression and survival
(A) Kaplan-Meier analysis for LIM2 mRNA expression in the combined glioma patient cohort. Kaplan-Meier analyses for CD133 mRNA expression in patients with (B) a low level expression of LIM2 and (C) a high level expression of LIM2. Kaplan-Meier analyses for LIM2 mRNA expression in patients with (D) a low level expression of CD133 and (E) a high level expression of CD133.
Figure 7. The association between VEGFa mRNA expression, CD133 mRNA expression and survival
(A) A histogram showing the association between the expression levels of VEGFa and CD133. Kaplan-Meier analyses for CD133 mRNA expression in patients with (B) a low level expression of VEGFa and (C) a high level expression of VEGFa. Kaplan-Meier analyses for VEGFa mRNA expression in patients with (D) a low level expression of CD133 and (E) a high level expression of CD133.
Figure 8. Expression of CD133 and HOX genes in human glioblastoma cell lines treated with vincristine
(A) A histogram showing the relative expression of CD133 in control and vincristine treated U87 and U251 cells. (B) A histogram showing the relative expression of HOXA5 in control and vincristine treated U87 and U251 cells. (C) A histogram showing the relative expression of HOXA7 in control and vincristine treated U87 and U251 cells. (D) A histogram showing the relative expression of HOXC4 in control and vincristine treated U87 and U251 cells. (E) A histogram showing the relative expression of HOXC6 in control and vincristine treated U87 and U251 cells. (F) The percentage of cell viability of U87 and U251 cells treated with different concentration of vincristine determined by MTT assay. (G) The percentage of apoptotic cells in control and vincristine treated U87 and U251 cells as determined by Annexin V and PI staining through flow cytometry. Each data point with standard deviation represents three biological replicates.
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