Limits...
A transcriptomic signature mediated by HOXA9 promotes human glioblastoma initiation, aggressiveness and resistance to temozolomide.

Pojo M, Gonçalves CS, Xavier-Magalhães A, Oliveira AI, Gonçalves T, Correia S, Rodrigues AJ, Costa S, Pinto L, Pinto AA, Lopes JM, Reis RM, Rocha M, Sousa N, Costa BM - Oncotarget (2015)

Bottom Line: Additionally, HOXA9 promoted the malignant transformation of human immortalized astrocytes in an orthotopic in vivo model, and caused tumor-associated death.Importantly, the pharmacological inhibition of BCL2 with the BH3 mimetic ABT-737 reverted temozolomide resistance in HOXA9-positive cells.These data establish HOXA9 as a driver of glioma initiation, aggressiveness and resistance to therapy.

View Article: PubMed Central - PubMed

Affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar 4710-057 Braga, Portugal.

ABSTRACT
Glioblastoma is the most malignant brain tumor, exhibiting remarkable resistance to treatment. Here we investigated the oncogenic potential of HOXA9 in gliomagenesis, the molecular and cellular mechanisms by which HOXA9 renders glioblastoma more aggressive, and how HOXA9 affects response to chemotherapy and survival. The prognostic value of HOXA9 in glioblastoma patients was validated in two large datasets from TCGA and Rembrandt, where high HOXA9 levels were associated with shorter survival. Transcriptomic analyses identified novel HOXA9-target genes with key roles in cancer-related processes, including cell proliferation, DNA repair, and stem cell maintenance. Functional studies with HOXA9-overexpressing and HOXA9-silenced glioblastoma cell models revealed that HOXA9 promotes cell viability, stemness and invasion, and inhibits apoptosis. Additionally, HOXA9 promoted the malignant transformation of human immortalized astrocytes in an orthotopic in vivo model, and caused tumor-associated death. HOXA9 also mediated resistance to temozolomide treatment in vitro and in vivo via upregulation of BCL2. Importantly, the pharmacological inhibition of BCL2 with the BH3 mimetic ABT-737 reverted temozolomide resistance in HOXA9-positive cells. These data establish HOXA9 as a driver of glioma initiation, aggressiveness and resistance to therapy. In the future, the combination of BH3 mimetics with temozolomide should be further explored as an alternative treatment for glioblastoma.

No MeSH data available.


Related in: MedlinePlus

HOXA9 expression is associated with WHO glioma grade and is an independent prognostic factor in glioblastoma patients(A) Expression levels of HOXA9 in 10 unmatched normal controls, 27 lower-grade gliomas (LGG) and 572 glioblastoma (GBM) patients from TCGA. HOXA9 is significantly overexpressed in GBM patients compared to LGG or normal samples (*** = p < 0.0001). (B)HOXA9 high expression (TCGA level 3 ≥ 3) is more frequent in the mesenchymal (10.34%) and in the proneural subtypes (7.02%). (C)HOXA9 gene copy number status in 372 GBM specimens from TCGA. HOXA9 is amplified (Log2 Copy Number Tumor/Normal ≥ 0.5) in 31% (n = 114) of GBM samples. The normal copy number interval is between the red dashed lines. (D) Heatmap representation of DNA methylation levels (TCGA β-values) of the chromosomal region encompassing HOXA9 in 74 GBM samples from TCGA. A total of 25 methylation probes (blue squares) were assessed, encompassing the CpG island (> 300 bp, represented in green). The color code (grades of red color corresponding to different methylation indexes) is shown below the heatmap. Each line corresponds to a patient and each column to a probe. The lines within HOXA9 correspond to introns. (E) Kaplan-Meier survival curves of 554 GBM patients from TCGA indicate that patients whose tumors present high levels of HOXA9 expression show a statistically significant shorter overall survival when compared to those whose tumors present lower levels of HOXA9 (Log-rank test, p-value = 0.017). (F) Univariate and multivariate analyses of associations between HOXA9 expression levels and survival of patients with glioblastoma (adjusted for patient age, KPS, gender, treatment with chemotherapy, and MGMT methylation status). (G) Kaplan-Meier survival curves of 181 GBM patients from REMBRANDT dataset confirms that patients whose tumors present high levels of HOXA9 expression (78/181) present a statistically significant shorter overall survival when compared to those whose tumors present lower levels (Log-rank test, p-value = 0.014).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4480707&req=5

Figure 1: HOXA9 expression is associated with WHO glioma grade and is an independent prognostic factor in glioblastoma patients(A) Expression levels of HOXA9 in 10 unmatched normal controls, 27 lower-grade gliomas (LGG) and 572 glioblastoma (GBM) patients from TCGA. HOXA9 is significantly overexpressed in GBM patients compared to LGG or normal samples (*** = p < 0.0001). (B)HOXA9 high expression (TCGA level 3 ≥ 3) is more frequent in the mesenchymal (10.34%) and in the proneural subtypes (7.02%). (C)HOXA9 gene copy number status in 372 GBM specimens from TCGA. HOXA9 is amplified (Log2 Copy Number Tumor/Normal ≥ 0.5) in 31% (n = 114) of GBM samples. The normal copy number interval is between the red dashed lines. (D) Heatmap representation of DNA methylation levels (TCGA β-values) of the chromosomal region encompassing HOXA9 in 74 GBM samples from TCGA. A total of 25 methylation probes (blue squares) were assessed, encompassing the CpG island (> 300 bp, represented in green). The color code (grades of red color corresponding to different methylation indexes) is shown below the heatmap. Each line corresponds to a patient and each column to a probe. The lines within HOXA9 correspond to introns. (E) Kaplan-Meier survival curves of 554 GBM patients from TCGA indicate that patients whose tumors present high levels of HOXA9 expression show a statistically significant shorter overall survival when compared to those whose tumors present lower levels of HOXA9 (Log-rank test, p-value = 0.017). (F) Univariate and multivariate analyses of associations between HOXA9 expression levels and survival of patients with glioblastoma (adjusted for patient age, KPS, gender, treatment with chemotherapy, and MGMT methylation status). (G) Kaplan-Meier survival curves of 181 GBM patients from REMBRANDT dataset confirms that patients whose tumors present high levels of HOXA9 expression (78/181) present a statistically significant shorter overall survival when compared to those whose tumors present lower levels (Log-rank test, p-value = 0.014).

Mentions: HOXA9 expression was analyzed in WHO grades II/III glioma patients (27) and grade IV GBM patients (572) deposited in TCGA [17]. HOXA9 was found to be highly overexpressed in a subset of GBM patients comparing to lower grades glioma (LGG, WHO grades II/III) patients and normal controls (Figure 1A), confirming that HOXA9 is associated with glioma grade and may be important in tumor progression. According to the four GBM molecular subgroups [18], HOXA9 overexpression was more frequent in the mesenchymal (10.34%) and in the proneural subtypes (7.02%; Figure 1B).


A transcriptomic signature mediated by HOXA9 promotes human glioblastoma initiation, aggressiveness and resistance to temozolomide.

Pojo M, Gonçalves CS, Xavier-Magalhães A, Oliveira AI, Gonçalves T, Correia S, Rodrigues AJ, Costa S, Pinto L, Pinto AA, Lopes JM, Reis RM, Rocha M, Sousa N, Costa BM - Oncotarget (2015)

HOXA9 expression is associated with WHO glioma grade and is an independent prognostic factor in glioblastoma patients(A) Expression levels of HOXA9 in 10 unmatched normal controls, 27 lower-grade gliomas (LGG) and 572 glioblastoma (GBM) patients from TCGA. HOXA9 is significantly overexpressed in GBM patients compared to LGG or normal samples (*** = p < 0.0001). (B)HOXA9 high expression (TCGA level 3 ≥ 3) is more frequent in the mesenchymal (10.34%) and in the proneural subtypes (7.02%). (C)HOXA9 gene copy number status in 372 GBM specimens from TCGA. HOXA9 is amplified (Log2 Copy Number Tumor/Normal ≥ 0.5) in 31% (n = 114) of GBM samples. The normal copy number interval is between the red dashed lines. (D) Heatmap representation of DNA methylation levels (TCGA β-values) of the chromosomal region encompassing HOXA9 in 74 GBM samples from TCGA. A total of 25 methylation probes (blue squares) were assessed, encompassing the CpG island (> 300 bp, represented in green). The color code (grades of red color corresponding to different methylation indexes) is shown below the heatmap. Each line corresponds to a patient and each column to a probe. The lines within HOXA9 correspond to introns. (E) Kaplan-Meier survival curves of 554 GBM patients from TCGA indicate that patients whose tumors present high levels of HOXA9 expression show a statistically significant shorter overall survival when compared to those whose tumors present lower levels of HOXA9 (Log-rank test, p-value = 0.017). (F) Univariate and multivariate analyses of associations between HOXA9 expression levels and survival of patients with glioblastoma (adjusted for patient age, KPS, gender, treatment with chemotherapy, and MGMT methylation status). (G) Kaplan-Meier survival curves of 181 GBM patients from REMBRANDT dataset confirms that patients whose tumors present high levels of HOXA9 expression (78/181) present a statistically significant shorter overall survival when compared to those whose tumors present lower levels (Log-rank test, p-value = 0.014).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480707&req=5

Figure 1: HOXA9 expression is associated with WHO glioma grade and is an independent prognostic factor in glioblastoma patients(A) Expression levels of HOXA9 in 10 unmatched normal controls, 27 lower-grade gliomas (LGG) and 572 glioblastoma (GBM) patients from TCGA. HOXA9 is significantly overexpressed in GBM patients compared to LGG or normal samples (*** = p < 0.0001). (B)HOXA9 high expression (TCGA level 3 ≥ 3) is more frequent in the mesenchymal (10.34%) and in the proneural subtypes (7.02%). (C)HOXA9 gene copy number status in 372 GBM specimens from TCGA. HOXA9 is amplified (Log2 Copy Number Tumor/Normal ≥ 0.5) in 31% (n = 114) of GBM samples. The normal copy number interval is between the red dashed lines. (D) Heatmap representation of DNA methylation levels (TCGA β-values) of the chromosomal region encompassing HOXA9 in 74 GBM samples from TCGA. A total of 25 methylation probes (blue squares) were assessed, encompassing the CpG island (> 300 bp, represented in green). The color code (grades of red color corresponding to different methylation indexes) is shown below the heatmap. Each line corresponds to a patient and each column to a probe. The lines within HOXA9 correspond to introns. (E) Kaplan-Meier survival curves of 554 GBM patients from TCGA indicate that patients whose tumors present high levels of HOXA9 expression show a statistically significant shorter overall survival when compared to those whose tumors present lower levels of HOXA9 (Log-rank test, p-value = 0.017). (F) Univariate and multivariate analyses of associations between HOXA9 expression levels and survival of patients with glioblastoma (adjusted for patient age, KPS, gender, treatment with chemotherapy, and MGMT methylation status). (G) Kaplan-Meier survival curves of 181 GBM patients from REMBRANDT dataset confirms that patients whose tumors present high levels of HOXA9 expression (78/181) present a statistically significant shorter overall survival when compared to those whose tumors present lower levels (Log-rank test, p-value = 0.014).
Mentions: HOXA9 expression was analyzed in WHO grades II/III glioma patients (27) and grade IV GBM patients (572) deposited in TCGA [17]. HOXA9 was found to be highly overexpressed in a subset of GBM patients comparing to lower grades glioma (LGG, WHO grades II/III) patients and normal controls (Figure 1A), confirming that HOXA9 is associated with glioma grade and may be important in tumor progression. According to the four GBM molecular subgroups [18], HOXA9 overexpression was more frequent in the mesenchymal (10.34%) and in the proneural subtypes (7.02%; Figure 1B).

Bottom Line: Additionally, HOXA9 promoted the malignant transformation of human immortalized astrocytes in an orthotopic in vivo model, and caused tumor-associated death.Importantly, the pharmacological inhibition of BCL2 with the BH3 mimetic ABT-737 reverted temozolomide resistance in HOXA9-positive cells.These data establish HOXA9 as a driver of glioma initiation, aggressiveness and resistance to therapy.

View Article: PubMed Central - PubMed

Affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar 4710-057 Braga, Portugal.

ABSTRACT
Glioblastoma is the most malignant brain tumor, exhibiting remarkable resistance to treatment. Here we investigated the oncogenic potential of HOXA9 in gliomagenesis, the molecular and cellular mechanisms by which HOXA9 renders glioblastoma more aggressive, and how HOXA9 affects response to chemotherapy and survival. The prognostic value of HOXA9 in glioblastoma patients was validated in two large datasets from TCGA and Rembrandt, where high HOXA9 levels were associated with shorter survival. Transcriptomic analyses identified novel HOXA9-target genes with key roles in cancer-related processes, including cell proliferation, DNA repair, and stem cell maintenance. Functional studies with HOXA9-overexpressing and HOXA9-silenced glioblastoma cell models revealed that HOXA9 promotes cell viability, stemness and invasion, and inhibits apoptosis. Additionally, HOXA9 promoted the malignant transformation of human immortalized astrocytes in an orthotopic in vivo model, and caused tumor-associated death. HOXA9 also mediated resistance to temozolomide treatment in vitro and in vivo via upregulation of BCL2. Importantly, the pharmacological inhibition of BCL2 with the BH3 mimetic ABT-737 reverted temozolomide resistance in HOXA9-positive cells. These data establish HOXA9 as a driver of glioma initiation, aggressiveness and resistance to therapy. In the future, the combination of BH3 mimetics with temozolomide should be further explored as an alternative treatment for glioblastoma.

No MeSH data available.


Related in: MedlinePlus