Limits...
Up-regulated Dicer expression in patients with cutaneous melanoma.

Ma Z, Swede H, Cassarino D, Fleming E, Fire A, Dadras SS - PLoS ONE (2011)

Bottom Line: The expression of Dicer was significantly higher in melanomas compared to benign melanocytic nevi (P<0.0001).In patients with cutaneous melanomas, Dicer up-regulation was found to be significantly associated with an increased tumor mitotic index (P = 0.04), Breslow's depth of invasion (P = 0.03), nodal metastasis (P = 0.04) and a higher American Joint Committee on Caner (AJCC) clinical stage (P = 0.009).Understanding deregulation of Dicer and its influence on miRNA maturation is needed to predict the susceptibility of melanoma patients to miRNA-based therapy in the future.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT

Background: MicroRNAs (miRNAs) are small non-coding RNAs (18-24 nucleotides) that have recently been shown to regulate gene expression during cancer progression. Dicer, a central enzyme in the multi-component miRNA biogenesis pathway, is involved in cutting precursor miRNAs to functionally mature forms. Emerging evidence shows that Dicer expression is deregulated in some human malignancies and it correlates with tumor progression, yet this role has not yet been investigated in skin cancers.

Methods and findings: Using an anti-human monoclonal antibody against Dicer and immunohistochemistry, we compared the expression of Dicer protein among 404 clinically annotated controls and skin tumors consisting of melanocytic nevi (n = 71), a variety of melanomas (n = 223), carcinomas (n = 73) and sarcomas (n = 12). Results showed a cell-specific up-regulated Dicer in 81% of cutaneous, 80% of acrolentiginous and 96% of metastatic melanoma specimens compared to carcinoma or sarcoma specimens (P<0.0001). The expression of Dicer was significantly higher in melanomas compared to benign melanocytic nevi (P<0.0001). In patients with cutaneous melanomas, Dicer up-regulation was found to be significantly associated with an increased tumor mitotic index (P = 0.04), Breslow's depth of invasion (P = 0.03), nodal metastasis (P = 0.04) and a higher American Joint Committee on Caner (AJCC) clinical stage (P = 0.009). Using western blot analysis, we confirmed the cell-specific up-regulation of Dicer protein in vitro. A pooled-analysis on mRNA profiling in cutaneous tumors showed up-regulation of Dicer at the RNA level in cutaneous melanoma, also showing deregulation of other enzymes that participate in the biogenesis and maturation of canonical miRNAs.

Conclusions: Increased Dicer expression may be a clinically useful biomarker for patients with cutaneous melanoma. Understanding deregulation of Dicer and its influence on miRNA maturation is needed to predict the susceptibility of melanoma patients to miRNA-based therapy in the future.

Show MeSH

Related in: MedlinePlus

Enzymes involved in the canonical miRNA biogenesis are deregulated during melanoma progression.Combined Dicer immunoreactivity, presented herein (denoted by asterisk ‘*’), and mRNA transcriptional profiling [21], [22] examined for Dicer and other enzymes in the miRNA biogenesis showed a global change in their expression levels during tumor progression. Enzymes shown in red are up-regulated and those in green are down-regulated. Up-regulation of Dicer (italicized) from common melanocytic nevus to invasive melanoma was found both in our study and others [21], [22]. Dicer, DGCR8 and Gemin4 ranked among the top 20 percentile of most significantly altered genes.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3117784&req=5

pone-0020494-g006: Enzymes involved in the canonical miRNA biogenesis are deregulated during melanoma progression.Combined Dicer immunoreactivity, presented herein (denoted by asterisk ‘*’), and mRNA transcriptional profiling [21], [22] examined for Dicer and other enzymes in the miRNA biogenesis showed a global change in their expression levels during tumor progression. Enzymes shown in red are up-regulated and those in green are down-regulated. Up-regulation of Dicer (italicized) from common melanocytic nevus to invasive melanoma was found both in our study and others [21], [22]. Dicer, DGCR8 and Gemin4 ranked among the top 20 percentile of most significantly altered genes.

Mentions: Since the expression of Dicer is significantly altered from common to dysplastic nevi to melanoma in situ to invasive and to metastatic melanoma, we interrogated the same combined dataset, which included 20 different disease groups and 25, 135 genes, for the mRNA levels of all the known enzymes involved in canonical miRNA biogenesis by performing a pooled analysis mining published whole genome oligo-microarray dataset [21], [22]. Enzymes tested in the canonical miRNA biogenesis pathway included Drosha, DGCR8, RAN, XPO5, Dicer1, GEMIN3, GEMIN4, EIF2C2, Ago2 and TRBP (Table S1). Dicer1, DGCR8 and Gemin4 ranked among the top ∼20 percentile of most significantly altered genes. We represent this data with respect to a linear, step-wise progression model for melanomagenesis, plotting changes in the expression level of the enzyme detected in our own immunostaining (protein) and in microarray pooled analysis (mRNA) (Fig. 6). This analysis suggests that the biogenesis of mature miRNAome maybe enhanced in the early steps of melanocyte transformation and melanoma formation raising the possibility that Dicer may play a central role in the melanocyte transformation and metastasis. Surprisingly, Dicer, Drosha and Gemin4 are down-regulated in melanoma in situ compared to invasive melanoma; in addition, Dicer is down-regulated in dysplastic nevi compared to common nevi, suggesting a global repression of miRNA biogenesis in these steps.


Up-regulated Dicer expression in patients with cutaneous melanoma.

Ma Z, Swede H, Cassarino D, Fleming E, Fire A, Dadras SS - PLoS ONE (2011)

Enzymes involved in the canonical miRNA biogenesis are deregulated during melanoma progression.Combined Dicer immunoreactivity, presented herein (denoted by asterisk ‘*’), and mRNA transcriptional profiling [21], [22] examined for Dicer and other enzymes in the miRNA biogenesis showed a global change in their expression levels during tumor progression. Enzymes shown in red are up-regulated and those in green are down-regulated. Up-regulation of Dicer (italicized) from common melanocytic nevus to invasive melanoma was found both in our study and others [21], [22]. Dicer, DGCR8 and Gemin4 ranked among the top 20 percentile of most significantly altered genes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3117784&req=5

pone-0020494-g006: Enzymes involved in the canonical miRNA biogenesis are deregulated during melanoma progression.Combined Dicer immunoreactivity, presented herein (denoted by asterisk ‘*’), and mRNA transcriptional profiling [21], [22] examined for Dicer and other enzymes in the miRNA biogenesis showed a global change in their expression levels during tumor progression. Enzymes shown in red are up-regulated and those in green are down-regulated. Up-regulation of Dicer (italicized) from common melanocytic nevus to invasive melanoma was found both in our study and others [21], [22]. Dicer, DGCR8 and Gemin4 ranked among the top 20 percentile of most significantly altered genes.
Mentions: Since the expression of Dicer is significantly altered from common to dysplastic nevi to melanoma in situ to invasive and to metastatic melanoma, we interrogated the same combined dataset, which included 20 different disease groups and 25, 135 genes, for the mRNA levels of all the known enzymes involved in canonical miRNA biogenesis by performing a pooled analysis mining published whole genome oligo-microarray dataset [21], [22]. Enzymes tested in the canonical miRNA biogenesis pathway included Drosha, DGCR8, RAN, XPO5, Dicer1, GEMIN3, GEMIN4, EIF2C2, Ago2 and TRBP (Table S1). Dicer1, DGCR8 and Gemin4 ranked among the top ∼20 percentile of most significantly altered genes. We represent this data with respect to a linear, step-wise progression model for melanomagenesis, plotting changes in the expression level of the enzyme detected in our own immunostaining (protein) and in microarray pooled analysis (mRNA) (Fig. 6). This analysis suggests that the biogenesis of mature miRNAome maybe enhanced in the early steps of melanocyte transformation and melanoma formation raising the possibility that Dicer may play a central role in the melanocyte transformation and metastasis. Surprisingly, Dicer, Drosha and Gemin4 are down-regulated in melanoma in situ compared to invasive melanoma; in addition, Dicer is down-regulated in dysplastic nevi compared to common nevi, suggesting a global repression of miRNA biogenesis in these steps.

Bottom Line: The expression of Dicer was significantly higher in melanomas compared to benign melanocytic nevi (P<0.0001).In patients with cutaneous melanomas, Dicer up-regulation was found to be significantly associated with an increased tumor mitotic index (P = 0.04), Breslow's depth of invasion (P = 0.03), nodal metastasis (P = 0.04) and a higher American Joint Committee on Caner (AJCC) clinical stage (P = 0.009).Understanding deregulation of Dicer and its influence on miRNA maturation is needed to predict the susceptibility of melanoma patients to miRNA-based therapy in the future.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT

Background: MicroRNAs (miRNAs) are small non-coding RNAs (18-24 nucleotides) that have recently been shown to regulate gene expression during cancer progression. Dicer, a central enzyme in the multi-component miRNA biogenesis pathway, is involved in cutting precursor miRNAs to functionally mature forms. Emerging evidence shows that Dicer expression is deregulated in some human malignancies and it correlates with tumor progression, yet this role has not yet been investigated in skin cancers.

Methods and findings: Using an anti-human monoclonal antibody against Dicer and immunohistochemistry, we compared the expression of Dicer protein among 404 clinically annotated controls and skin tumors consisting of melanocytic nevi (n = 71), a variety of melanomas (n = 223), carcinomas (n = 73) and sarcomas (n = 12). Results showed a cell-specific up-regulated Dicer in 81% of cutaneous, 80% of acrolentiginous and 96% of metastatic melanoma specimens compared to carcinoma or sarcoma specimens (P<0.0001). The expression of Dicer was significantly higher in melanomas compared to benign melanocytic nevi (P<0.0001). In patients with cutaneous melanomas, Dicer up-regulation was found to be significantly associated with an increased tumor mitotic index (P = 0.04), Breslow's depth of invasion (P = 0.03), nodal metastasis (P = 0.04) and a higher American Joint Committee on Caner (AJCC) clinical stage (P = 0.009). Using western blot analysis, we confirmed the cell-specific up-regulation of Dicer protein in vitro. A pooled-analysis on mRNA profiling in cutaneous tumors showed up-regulation of Dicer at the RNA level in cutaneous melanoma, also showing deregulation of other enzymes that participate in the biogenesis and maturation of canonical miRNAs.

Conclusions: Increased Dicer expression may be a clinically useful biomarker for patients with cutaneous melanoma. Understanding deregulation of Dicer and its influence on miRNA maturation is needed to predict the susceptibility of melanoma patients to miRNA-based therapy in the future.

Show MeSH
Related in: MedlinePlus