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Cancer Res ; 73(16): 5040-52, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23774208


The DNA repair protein damaged DNA-binding 2 (DDB2) has been implicated in promoting cell-cycle progression by regulating gene expression. DDB2 is selectively overexpressed in breast tumor cells that are noninvasive, but not in those that are invasive. We found that its overexpression in invasive human breast tumor cells limited their motility and invasiveness in vitro and blocked their ability to colonize lungs in vivo, defining a new function for DDB2 in malignant progression. DDB2 overexpression attenuated the activity of NF-κB and the expression of its target matrix metalloprotease 9 (MMP9). Mechanistic investigations indicated that DDB2 decreased NF-κB activity by upregulating expression of IκBα by binding the proximal promoter of this gene. This effect was causally linked to invasive capacity. Indeed, knockdown of DDB2-induced IκBα gene expression restored NF-κB activity and MMP9 expression, along with the invasive properties of breast tumor cells overexpressing DDB2. Taken together, our findings enlighten understanding of how breast cancer cells progress to an invasive phenotype and underscore potential clinical interest in DDB2 as a prognostic marker or therapeutic target in this setting.

Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , NF-kappa B/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Células MCF-7 , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Invasividade Neoplásica , Prognóstico , Regiões Promotoras Genéticas , Transcrição Genética , Regulação para Cima/genética
Free Radic Biol Med ; 50(12): 1771-9, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21419216


A high basal expression of manganese superoxide dismutase (MnSOD) has been reported in aggressive breast cancer cells, according to an unknown mechanism, and contributes to their invasive abilities. Here, we report the involvement of Sp1 and nuclear factor-κB (NF-κB) transcription factors in this high basal expression of MnSOD in aggressive breast cancer cells. Suppression or inactivation of Sp1 showed that it plays an essential role in the high MnSOD expression in aggressive breast cancer cells through a unique binding site identified by chromatin immunoprecipitation (ChIP) assay and functional analysis of the MnSOD proximal promoter. Treatment of cells with a specific NF-κB inhibitor peptide decreased significantly high basal MnSOD expression. A ChIP assay showed binding of a constitutive p50/p65 NF-κB complex to the MnSOD intronic enhancer element, associated with hyperacetylation of the H3 histone. Finally, high basal expression of MnSOD resulted in the lack of expression of Damaged DNA binding 2 (DDB2) protein in aggressive breast cancer cells. DDB2 overexpression prevented the binding of Sp1 as well as of NF-κB to their respective elements on the MnSOD gene. These results contribute to a better understanding of MnSOD up-regulation, which may be clinically important in the prediction of breast tumor progression.

Neoplasias da Mama/genética , Proteínas de Ligação a DNA/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Fator de Transcrição Sp1/metabolismo , Superóxido Dismutase/genética , Acetilação , Sequência de Bases , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos , Feminino , Radicais Livres , Histonas/genética , Histonas/metabolismo , Humanos , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Estudos Retrospectivos , Fator de Transcrição Sp1/genética , Superóxido Dismutase/biossíntese , Superóxido Dismutase/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima
Int J Oncol ; 29(6): 1601-10, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17089002


Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormone receptor family. In colon, this transcription factor is involved in differentiation of absorptive cells. PPARgamma participates also in colon carcinogenesis and cancer progression. Two isoforms, namely PPARgamma1 and PPARgamma2, have been described. Recently, new PPARgamma1 transcripts whose translation raises PPARgamma1 protein have been characterised. They differ from each other by combination of untranslated exons localised in the 5' UTR of the PPARG gene. Here, we studied whether such a diversity of PPARgamma transcripts occurs in human colon cell models. Based on bioinformatic analysis, putative untranslated exons were identified in the human PPARG gene. By RT-PCR analysis, we have demonstrated that several of these untranslated exons are included in PPARgamma transcripts from colon-derived cell lines or in those derived from other tissue. Using HT-29 cells, changes in PPARgamma1 mRNA levels were observed after treatment with PPARgamma agonists such as pioglitazone and troglitazone. These modifications correlated with particular PPARgamma transcripts excluding the untranslated exon A2. HT-29 cells treatment with actinomycin D or cycloheximide showed that the presence of PPARgamma mRNA including exon A2 was dependent on de novo protein synthesis. We concluded that diverse PPARgamma1 mRNA exist in colorectal cells. Levels of PPARgamma1 transcript varied according to the phenotype of colon cell model used. We suggest that regulation of PPARgamma1 mRNA levels could be dependent in part on the composition of untranslated exon(s) in the 5' UTR of PPARgamma1 mRNA.

Neoplasias do Colo/genética , PPAR gama/genética , Sequência de Bases , Células CACO-2 , Cromanos/farmacologia , Mapeamento Cromossômico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Cicloeximida/farmacologia , Dactinomicina/farmacologia , Éxons , Células HCT116 , Células HT29 , Humanos , PPAR gama/agonistas , PPAR gama/metabolismo , Pioglitazona , Isoformas de Proteínas , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Tiazolidinedionas/farmacologia , Troglitazona , Regiões não Traduzidas