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Cytoplasmic accumulation of NCoR in malignant melanoma: consequences of altered gene repression and prognostic significance.

Gallardo F, Padrón A, Garcia-Carbonell R, Rius C, González-Perez A, Arumí-Uria M, Iglesias M, Nonell L, Bellosillo B, Segura S, Pujol RM, Lopez-Bigas N, Bertran J, Bigas A, Espinosa L - Oncotarget (2015)

Bottom Line: Nuclear corepressor (NCoR) is an essential regulator of gene transcription, and its function has been found deregulated in different types of cancer.We found that loss of nuclear NCoR results in upregulation of a specific cancer-related genetic signature, and is significantly associated with MM progression.Analysis of public database demonstrated that inactivating NCoR mutations are highly prevalent in MM, showing features of driver oncogene.

View Article: PubMed Central - PubMed

Affiliation: Dermatology Department, Parc de Salut Mar-Hospital del Mar, Barcelona, Spain.

ABSTRACT
Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy available in advanced stages. Nuclear corepressor (NCoR) is an essential regulator of gene transcription, and its function has been found deregulated in different types of cancer. In colorectal cancer cells, loss of nuclear NCoR is induced by Inhibitor of kappa B kinase (IKK) through the phosphorylation of specific serine residues. We here investigate whether NCoR function impacts in MM, which might have important diagnostic and prognostic significance. By IHC, we here determined the subcellular distribution of NCoR in a cohort of 63 primary invasive MM samples, and analyzed its possible correlation with specific clinical parameters. We therefore used a microarray-based strategy to determine global gene expression differences in samples with similar tumor stage, which differ in the presence of cytoplasmic or nuclear NCoR. We found that loss of nuclear NCoR results in upregulation of a specific cancer-related genetic signature, and is significantly associated with MM progression. Inhibition of IKK activity in melanoma cells reverts NCoR nuclear distribution and specific NCoR-regulated gene transcription. Analysis of public database demonstrated that inactivating NCoR mutations are highly prevalent in MM, showing features of driver oncogene.

No MeSH data available.


Related in: MedlinePlus

Loss of nuclear NCoR is associated with MM progression(A) IHC analysis of NCoR distribution in MM samples at different stages of tumor progression. (B) Quantification of the percent of cells containing detectable nuclear NCoR in tumors with different Breslow Index. (C) Histoscore index showing the proportion of cells carrying nuclear (active) p65-NF-κB and nuclear NCoR in the indicated MM groups. (D) IHC analysis of p65-NF-κB distribution in nevi and MM samples at different stages of tumor progression.
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Figure 1: Loss of nuclear NCoR is associated with MM progression(A) IHC analysis of NCoR distribution in MM samples at different stages of tumor progression. (B) Quantification of the percent of cells containing detectable nuclear NCoR in tumors with different Breslow Index. (C) Histoscore index showing the proportion of cells carrying nuclear (active) p65-NF-κB and nuclear NCoR in the indicated MM groups. (D) IHC analysis of p65-NF-κB distribution in nevi and MM samples at different stages of tumor progression.

Mentions: By IHC, we found that NCoR protein exhibits a nuclear distribution in melanocytes of nevi samples. However, malignant melanocytes in MM samples showed a variable distribution, which in some cases resulted in the loss of nNCoR, occasionally associated with its cytoplasmic accumulation. More specifically, we observed that all in situ MM samples contained nNCoR similar to benign nevi. In contrast, the number of cells that lost nNCoR at the time of diagnosis correlated with increased tumor staging (Figure 1A and 1B), whereas the vast majority of metastatic samples disclosed an absent or minimal number of melanocytic cells with nNCoR. To determine the predictive value of loss of nNCoR in the primary tumors, we analyzed NCoR distribution in 63 primary tumor samples from MM patients with different Breslow index using the non-parametric Spearman test. We found an inverse correlation (–0.628) between the percentages of nNCoR and the Breslow index (p < 0.001), with samples showing lower percentage of nNCoR positive cells corresponding to the greater Breslow index (Figure 1B, Table 1). Next, we analyzed the possible relationship between loss of nNCoR and other prognostic indicators of MM. The analysis demonstrated a significant association between loss of nNCoR localization and higher mitotic index (p < 0.01) and a statistical trend with ulceration (p = 0.051) (see Table 1). However, no differences in other histopathological features (regression or prevalence of inflammatory component), age and gender were recorded between MM with nNCoR or cNCoR. Moreover, we did not detect any significant association between BRAF mutational status and NCoR distribution in 18 samples analyzed (all samples with available material).


Cytoplasmic accumulation of NCoR in malignant melanoma: consequences of altered gene repression and prognostic significance.

Gallardo F, Padrón A, Garcia-Carbonell R, Rius C, González-Perez A, Arumí-Uria M, Iglesias M, Nonell L, Bellosillo B, Segura S, Pujol RM, Lopez-Bigas N, Bertran J, Bigas A, Espinosa L - Oncotarget (2015)

Loss of nuclear NCoR is associated with MM progression(A) IHC analysis of NCoR distribution in MM samples at different stages of tumor progression. (B) Quantification of the percent of cells containing detectable nuclear NCoR in tumors with different Breslow Index. (C) Histoscore index showing the proportion of cells carrying nuclear (active) p65-NF-κB and nuclear NCoR in the indicated MM groups. (D) IHC analysis of p65-NF-κB distribution in nevi and MM samples at different stages of tumor progression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496217&req=5

Figure 1: Loss of nuclear NCoR is associated with MM progression(A) IHC analysis of NCoR distribution in MM samples at different stages of tumor progression. (B) Quantification of the percent of cells containing detectable nuclear NCoR in tumors with different Breslow Index. (C) Histoscore index showing the proportion of cells carrying nuclear (active) p65-NF-κB and nuclear NCoR in the indicated MM groups. (D) IHC analysis of p65-NF-κB distribution in nevi and MM samples at different stages of tumor progression.
Mentions: By IHC, we found that NCoR protein exhibits a nuclear distribution in melanocytes of nevi samples. However, malignant melanocytes in MM samples showed a variable distribution, which in some cases resulted in the loss of nNCoR, occasionally associated with its cytoplasmic accumulation. More specifically, we observed that all in situ MM samples contained nNCoR similar to benign nevi. In contrast, the number of cells that lost nNCoR at the time of diagnosis correlated with increased tumor staging (Figure 1A and 1B), whereas the vast majority of metastatic samples disclosed an absent or minimal number of melanocytic cells with nNCoR. To determine the predictive value of loss of nNCoR in the primary tumors, we analyzed NCoR distribution in 63 primary tumor samples from MM patients with different Breslow index using the non-parametric Spearman test. We found an inverse correlation (–0.628) between the percentages of nNCoR and the Breslow index (p < 0.001), with samples showing lower percentage of nNCoR positive cells corresponding to the greater Breslow index (Figure 1B, Table 1). Next, we analyzed the possible relationship between loss of nNCoR and other prognostic indicators of MM. The analysis demonstrated a significant association between loss of nNCoR localization and higher mitotic index (p < 0.01) and a statistical trend with ulceration (p = 0.051) (see Table 1). However, no differences in other histopathological features (regression or prevalence of inflammatory component), age and gender were recorded between MM with nNCoR or cNCoR. Moreover, we did not detect any significant association between BRAF mutational status and NCoR distribution in 18 samples analyzed (all samples with available material).

Bottom Line: Nuclear corepressor (NCoR) is an essential regulator of gene transcription, and its function has been found deregulated in different types of cancer.We found that loss of nuclear NCoR results in upregulation of a specific cancer-related genetic signature, and is significantly associated with MM progression.Analysis of public database demonstrated that inactivating NCoR mutations are highly prevalent in MM, showing features of driver oncogene.

View Article: PubMed Central - PubMed

Affiliation: Dermatology Department, Parc de Salut Mar-Hospital del Mar, Barcelona, Spain.

ABSTRACT
Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy available in advanced stages. Nuclear corepressor (NCoR) is an essential regulator of gene transcription, and its function has been found deregulated in different types of cancer. In colorectal cancer cells, loss of nuclear NCoR is induced by Inhibitor of kappa B kinase (IKK) through the phosphorylation of specific serine residues. We here investigate whether NCoR function impacts in MM, which might have important diagnostic and prognostic significance. By IHC, we here determined the subcellular distribution of NCoR in a cohort of 63 primary invasive MM samples, and analyzed its possible correlation with specific clinical parameters. We therefore used a microarray-based strategy to determine global gene expression differences in samples with similar tumor stage, which differ in the presence of cytoplasmic or nuclear NCoR. We found that loss of nuclear NCoR results in upregulation of a specific cancer-related genetic signature, and is significantly associated with MM progression. Inhibition of IKK activity in melanoma cells reverts NCoR nuclear distribution and specific NCoR-regulated gene transcription. Analysis of public database demonstrated that inactivating NCoR mutations are highly prevalent in MM, showing features of driver oncogene.

No MeSH data available.


Related in: MedlinePlus