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Expression of the Aldo-Ketoreductases AKR1B1 and AKR1B10 in Human Cancers.

Laffin B, Petrash JM - Front Pharmacol (2012)

Bottom Line: Using this database, we found that expression of AKR1B1 and AKR1B10 varies greatly by cancer type and tissue of origin, including agreement with previous reports that AKR1B10 is significantly over-expressed in cancers of the lungs and liver.AKR1B1 over-expression was found to be associated with shortened patient survival in acute myelogenous leukemias and multiple myelomas.High AKR1B10 expression tends to predict less aggressive clinical course generally, notably within lung cancers, where it tends to be highly over-expressed compared to normal tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, The School of Medicine, University of Colorado Aurora, CO, USA.

ABSTRACT
The American Cancer Society estimates that there will be more than 1.5 million new cases of cancer in 2011, underscoring the need for identification of new therapeutic targets and development of novel cancer therapies. Previous studies have implicated the human aldo-ketoreductases AKR1B1 and AKR1B10 in cancer, and therefore we examined AKR1B1 and AKR1B10 expression across all major human cancer types using the Oncomine cancer gene expression database (Compendia Biosciences, www.oncomine.com). Using this database, we found that expression of AKR1B1 and AKR1B10 varies greatly by cancer type and tissue of origin, including agreement with previous reports that AKR1B10 is significantly over-expressed in cancers of the lungs and liver. AKR1B1 is more broadly over-expressed in human cancers than AKR1B10, albeit at a generally lower magnitude. AKR1B1 over-expression was found to be associated with shortened patient survival in acute myelogenous leukemias and multiple myelomas. High AKR1B10 expression tends to predict less aggressive clinical course generally, notably within lung cancers, where it tends to be highly over-expressed compared to normal tissue. These findings suggest that AKR1B1 inhibitors in particular hold great potential as novel cancer therapeutics.

No MeSH data available.


Related in: MedlinePlus

AKR expression in leukemia patients. Expression of AKR1B1 and AKR1B10 mRNA was examined in 2093 human leukemia patients from the Haferlach et al. (2010) study in the Oncomine database. (A) Heatmap display of AKR1B1 (top rows) and AKR1B10 (bottom rows) expression within the indicated leukemia types. Fold changes relative to peripheral blood mononuclear cells (PBMCs) and p-value for that comparison within each leukemia type are listed next to their respective heatmaps. Numbers in parentheses next to the label of each heatmap represent the number of patients contained within that group in this study. (B) AKR1B1 mRNA expression in B-cell acute leukemia patients without (blue box) and with (red box) the presence of the TCF3-PBX1 fusion gene. (C) AKR1B1 mRNA expression in acute myeloid leukemia patients without (blue box) and with (red box) the presence of the PML-RARA fusion gene.
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Figure 1: AKR expression in leukemia patients. Expression of AKR1B1 and AKR1B10 mRNA was examined in 2093 human leukemia patients from the Haferlach et al. (2010) study in the Oncomine database. (A) Heatmap display of AKR1B1 (top rows) and AKR1B10 (bottom rows) expression within the indicated leukemia types. Fold changes relative to peripheral blood mononuclear cells (PBMCs) and p-value for that comparison within each leukemia type are listed next to their respective heatmaps. Numbers in parentheses next to the label of each heatmap represent the number of patients contained within that group in this study. (B) AKR1B1 mRNA expression in B-cell acute leukemia patients without (blue box) and with (red box) the presence of the TCF3-PBX1 fusion gene. (C) AKR1B1 mRNA expression in acute myeloid leukemia patients without (blue box) and with (red box) the presence of the PML-RARA fusion gene.

Mentions: To determine whether the aldo-ketoreductases AKR1B1 and AKR1B10 were differentially expressed between cancerous and normal tissues, we broadly examined microarray data from patient samples contained within the Oncomine database. Results from cancer types where a statistically significant difference in AKR expression between the cancerous and corresponding normal tissue exists are summarized in Table 1. The cancers where gene expression for AKRs was compared to the corresponding normal tissue, but no overall significant difference was found were certain brain tumors (oligodendrogliomas, mixed gliomas), ductal and lobular breast cancers, acute myeloid leukemias, myelomas, and ovarian cancers (not shown). Data for cancers where only one study was available for analysis is also not shown. AKR1B1 expression is significantly elevated compared to the corresponding normal tissue in bladder, brain (astrocytomas and glioblastomas), cervical, esophageal, head and neck, kidney, leukemias (T-cell acute, B-cell acute, and chronic), lymphomas, and melanomas (Table 1; Figure 1A). The fold change in gene expression versus the normal tissue is summarized by study in Table 1, with AKR1B1 expression ranging from ∼1.2- to 5-fold the normal tissue in the majority of cancers where it is significantly over-expressed. The most significant differences between AKR1B1 expression in cancerous and normal tissue are seen in leukemias (Table 1; Figure 1A). AKR1B1 expression is significantly lower than the corresponding normal tissue in prostate cancers (Table 1). As previously reported, AKR1B10 is over-expressed in liver and lung tumors (Table 1; Fukumoto et al., 2005; Woenckhaus et al., 2006; Heringlake et al., 2010; Kang et al., 2011; Schmitz et al., 2011), with fold change relative to normal tissue ranging from 12- to 67-fold in liver cancers; 2- to 75-fold in squamous cell lung cancers; and 1.5- to 5.5-fold in lung adenocarcinomas (Table 1). AKR1B10 is also significantly over-expressed in leukemias (T-cell acute, B-cell acute, and chronic) and pancreatic cancers (Table 1; Figure 1A). AKR1B10 over-expression thus appears to be less common than AKR1B1 over-expression in cancer, and AKR1B10 is under-expressed in colon, gastric, and head and neck cancers (Table 1). It should be noted that these associations are those that hold true across the studies contained within Oncomine, and multiple studies may have individually held a significant association of AKR expression with either the cancerous or normal state, but not in the broader comparison. Our methods also necessarily exclude studies not contained within the Oncomine database.


Expression of the Aldo-Ketoreductases AKR1B1 and AKR1B10 in Human Cancers.

Laffin B, Petrash JM - Front Pharmacol (2012)

AKR expression in leukemia patients. Expression of AKR1B1 and AKR1B10 mRNA was examined in 2093 human leukemia patients from the Haferlach et al. (2010) study in the Oncomine database. (A) Heatmap display of AKR1B1 (top rows) and AKR1B10 (bottom rows) expression within the indicated leukemia types. Fold changes relative to peripheral blood mononuclear cells (PBMCs) and p-value for that comparison within each leukemia type are listed next to their respective heatmaps. Numbers in parentheses next to the label of each heatmap represent the number of patients contained within that group in this study. (B) AKR1B1 mRNA expression in B-cell acute leukemia patients without (blue box) and with (red box) the presence of the TCF3-PBX1 fusion gene. (C) AKR1B1 mRNA expression in acute myeloid leukemia patients without (blue box) and with (red box) the presence of the PML-RARA fusion gene.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368246&req=5

Figure 1: AKR expression in leukemia patients. Expression of AKR1B1 and AKR1B10 mRNA was examined in 2093 human leukemia patients from the Haferlach et al. (2010) study in the Oncomine database. (A) Heatmap display of AKR1B1 (top rows) and AKR1B10 (bottom rows) expression within the indicated leukemia types. Fold changes relative to peripheral blood mononuclear cells (PBMCs) and p-value for that comparison within each leukemia type are listed next to their respective heatmaps. Numbers in parentheses next to the label of each heatmap represent the number of patients contained within that group in this study. (B) AKR1B1 mRNA expression in B-cell acute leukemia patients without (blue box) and with (red box) the presence of the TCF3-PBX1 fusion gene. (C) AKR1B1 mRNA expression in acute myeloid leukemia patients without (blue box) and with (red box) the presence of the PML-RARA fusion gene.
Mentions: To determine whether the aldo-ketoreductases AKR1B1 and AKR1B10 were differentially expressed between cancerous and normal tissues, we broadly examined microarray data from patient samples contained within the Oncomine database. Results from cancer types where a statistically significant difference in AKR expression between the cancerous and corresponding normal tissue exists are summarized in Table 1. The cancers where gene expression for AKRs was compared to the corresponding normal tissue, but no overall significant difference was found were certain brain tumors (oligodendrogliomas, mixed gliomas), ductal and lobular breast cancers, acute myeloid leukemias, myelomas, and ovarian cancers (not shown). Data for cancers where only one study was available for analysis is also not shown. AKR1B1 expression is significantly elevated compared to the corresponding normal tissue in bladder, brain (astrocytomas and glioblastomas), cervical, esophageal, head and neck, kidney, leukemias (T-cell acute, B-cell acute, and chronic), lymphomas, and melanomas (Table 1; Figure 1A). The fold change in gene expression versus the normal tissue is summarized by study in Table 1, with AKR1B1 expression ranging from ∼1.2- to 5-fold the normal tissue in the majority of cancers where it is significantly over-expressed. The most significant differences between AKR1B1 expression in cancerous and normal tissue are seen in leukemias (Table 1; Figure 1A). AKR1B1 expression is significantly lower than the corresponding normal tissue in prostate cancers (Table 1). As previously reported, AKR1B10 is over-expressed in liver and lung tumors (Table 1; Fukumoto et al., 2005; Woenckhaus et al., 2006; Heringlake et al., 2010; Kang et al., 2011; Schmitz et al., 2011), with fold change relative to normal tissue ranging from 12- to 67-fold in liver cancers; 2- to 75-fold in squamous cell lung cancers; and 1.5- to 5.5-fold in lung adenocarcinomas (Table 1). AKR1B10 is also significantly over-expressed in leukemias (T-cell acute, B-cell acute, and chronic) and pancreatic cancers (Table 1; Figure 1A). AKR1B10 over-expression thus appears to be less common than AKR1B1 over-expression in cancer, and AKR1B10 is under-expressed in colon, gastric, and head and neck cancers (Table 1). It should be noted that these associations are those that hold true across the studies contained within Oncomine, and multiple studies may have individually held a significant association of AKR expression with either the cancerous or normal state, but not in the broader comparison. Our methods also necessarily exclude studies not contained within the Oncomine database.

Bottom Line: Using this database, we found that expression of AKR1B1 and AKR1B10 varies greatly by cancer type and tissue of origin, including agreement with previous reports that AKR1B10 is significantly over-expressed in cancers of the lungs and liver.AKR1B1 over-expression was found to be associated with shortened patient survival in acute myelogenous leukemias and multiple myelomas.High AKR1B10 expression tends to predict less aggressive clinical course generally, notably within lung cancers, where it tends to be highly over-expressed compared to normal tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, The School of Medicine, University of Colorado Aurora, CO, USA.

ABSTRACT
The American Cancer Society estimates that there will be more than 1.5 million new cases of cancer in 2011, underscoring the need for identification of new therapeutic targets and development of novel cancer therapies. Previous studies have implicated the human aldo-ketoreductases AKR1B1 and AKR1B10 in cancer, and therefore we examined AKR1B1 and AKR1B10 expression across all major human cancer types using the Oncomine cancer gene expression database (Compendia Biosciences, www.oncomine.com). Using this database, we found that expression of AKR1B1 and AKR1B10 varies greatly by cancer type and tissue of origin, including agreement with previous reports that AKR1B10 is significantly over-expressed in cancers of the lungs and liver. AKR1B1 is more broadly over-expressed in human cancers than AKR1B10, albeit at a generally lower magnitude. AKR1B1 over-expression was found to be associated with shortened patient survival in acute myelogenous leukemias and multiple myelomas. High AKR1B10 expression tends to predict less aggressive clinical course generally, notably within lung cancers, where it tends to be highly over-expressed compared to normal tissue. These findings suggest that AKR1B1 inhibitors in particular hold great potential as novel cancer therapeutics.

No MeSH data available.


Related in: MedlinePlus