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1.
Mol Cell Endocrinol ; 528: 111230, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33675864

RESUMO

Despite advances in treatment of lethal prostate cancer, the incidence of prostate cancer brain metastases is increasing. In this sense, we analyzed the molecular profile, as well as the functional consequences involved in the reciprocal interactions between prostate tumor cells and human astrocytes. We observed that the DU145 cells, but not the LNCaP cells or the RWPE-1 cells, exhibited more pronounced, malignant and invasive phenotypes along their interactions with astrocytes. Moreover, global gene expression analysis revealed several genes that were differently expressed in our co-culture models with the overexpression of GLIPR1 and SPARC potentially representing a molecular signature associated with the invasion of central nervous system by prostate malignant cells. Further, these results were corroborated by immunohistochemistry and in silico analysis. Thus, we conjecture that the data here presented may increase the knowledge about the molecular mechanisms associated with the invasion of CNS by prostate malignant cells.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Osteonectina/genética , Osteonectina/metabolismo , Neoplasias da Próstata/genética , Células A549 , Animais , Astrócitos/química , Astrócitos/citologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Neoplasias da Próstata/metabolismo , Regulação para Cima
2.
J Mater Chem B ; 8(4): 703-714, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31867589

RESUMO

Here we describe the assembly and pH-driven operation of two nanocarriers based on non-functionalized (MCM-41) and carboxylate-functionalized (MCM-41-COOH) containers loaded with the anticancer drug doxorubicin (DOX) and capped by quaternary ammonium pillar[5]arene (P[5]A) nanogates. MCM-41 and MCM-41-COOH containers were synthesized and transmission and scanning electron microscopies showed nanoparticles with spherical morphology and dimensions of 85 ± 13 nm. The nanochannels of MCM-41 loaded with DOX were gated through the electrostatic interactions between P[5]A and the silanolate groups formed at the silica-water interface, yielding the MCM-41-DOX-P[5]A nanocarrier. The second nanocarrier was gated through the electrostatic interactions between the carboxylate groups mounted on the surface of MCM-41 and P[5]A, resulting in the MCM-41-COO-DOX-P[5]A nanocarrier. The DOX release profiles from both nanocarriers were investigated by UV-vis spectroscopy at different pH values (2.0, 5.5 and 7.4) and also in the presence of ions, such as citrate3- (19 mmol L-1) and Zn2+ (1.2 and 50 mmol L-1) at 37 °C. MCM-41-COO-DOX-P[5]A can be turned on and off eight times through the formation and breaking of electrostatic interactions. In vitro studies show that MCM-41-COO-DOX-P[5]A can penetrate and release DOX in the nucleus of human breast adenocarcinoma MCF-7 cancer cells leading to a pronounced cytotoxic effect. Therefore, the fabricated nanocarrier based on a water-soluble cationic pillar[5]arene nanogate, which is reversibly opened and closed by electrostatic interactions, can be considered as a promising drug transport and delivery technique for future cancer therapy.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Calixarenos/química , Doxorrubicina/farmacologia , Compostos de Amônio Quaternário/química , Dióxido de Silício/química , Antibióticos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Teste de Materiais , Nanopartículas/química , Tamanho da Partícula , Porosidade , Relação Estrutura-Atividade , Propriedades de Superfície , Células Tumorais Cultivadas
3.
Artigo em Inglês | MEDLINE | ID: mdl-30719063

RESUMO

Benign Prostatic Hyperplasia (BPH) affects mainly older men. It is estimated to affect 50% of 51-60-year-old men and 70% of 61-70-year-old men. BPH is a nonmalignant proliferation of epithelial and stromal cells of the prostate gland regions. Despite the use of conventional pharmacological therapy, herbal medicines are used in BPH therapy, and several mechanisms of action have been suggested based on their complex chemical composition. Considering the ethnomedicinal uses of Kalanchoe gastonis-bonnieri (KGB), we evaluated the inhibitory effects on the proliferation of stromal cells from primary benign prostatic hyperplasia (BPH) of four different aqueous extracts from this plant: underground parts from specimens in flower (T1 treatment), leaves from specimens in flower (T2 treatment), and flowers (T3 treatment) and leaves from specimens not in flower (T4 treatment). T1, T2, T3, and T4 treatments at 250 µg/ml for 72 hours inhibited BPH cells by 56.7%, 29.2%, 39.4%, and 13.5%, respectively, showing that the KGB underground parts extract (T1 treatment) was the most active. Our findings show that the extract of the KGB underground parts (150 and 250 µg/ml) stimulates important changes in the BPH cells, modulating crucial processes such as proliferation, viability, and apoptosis. HPLC-DAD-MS/MS analysis provided a tentative identification of glycosylated syringic acid derivatives, glycosylated forms of volatile compounds, and lignans in this extract. Finally, these results suggest that there is a potential therapeutic use for KGB in BPH, which could improve the clinical management of the disease.

4.
Oncotarget ; 9(24): 16634-16647, 2018 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-29682174

RESUMO

Esophageal squamous cell carcinoma (ESCC) presents poor prognosis, and patients diagnosed with this tumor currently lack target treatments. Therefore, in order to identify potential targets for ESCC treatment, we carried out a transcriptome analysis with ESCC and paired nonmalignant surrounding mucosa samples, followed by a master regulator analysis, and further explored the role of the identified central regulatory genes through in vivo and in vitro assays. Among the transcription factors deregulated/enriched in ESCC, we focused on FOXM1 because of its involvement in the regulation of critical biological processes. A new transcriptome analysis performed with ESCC cell lineage TE-1 showed that the modulation of FOXM1 expression resulted in PIK3R3 expression changes, whereas chromatin immunoprecipitation assay revealed that FOXM1 was capable of binding onto PIK3R3 promoter, thus demonstrating that PIK3R3 is a new FOXM1 target. Furthermore, FOXM1 overexpression resulted in the activation of PIK3/AKT signaling pathway through PIK3R3-mediated AKT phosphorylation. Finally, the analysis of the clinic-pathological data of ESCC patients revealed that overexpression of both FOXM1 and PIK3R3 was associated with poor prognosis, but only the latter was an independent prognosis factor for ESCC patients. In conclusion, our results show that FOXM1 seems to play a central role in ESCC carcinogenesis by upregulating many oncogenes found overexpressed in this tumor. Furthermore, PIK3R3 is a novel FOXM1 target that triggers the activation of the PI3K/AKT pathway in ESCC cells.

5.
Cell Biol Int ; 41(11): 1239-1245, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28477422

RESUMO

Cancer has been mainly treated by traditional therapeutic approaches which do not consider the human genetic diversity and present limitations, probably as a consequence of a poor knowledge of both patient's genetic background and tumor biology. Due to genome project conclusion and large-scale gene analyses emergence, the therapeutic management of several prevalent and aggressive tumors has dramatically improved and represents the closest examples of a precision medicine intervention in this field. Nonetheless, prostate cancer (PCa) remains as a challenge to personalized medicine implementation, probably due to its notorious heterogeneous molecular profile. Cancer treatment personalized approaches rely on the premise that a well-defined panorama of tumor molecular alterations can help selecting new and specific therapeutic targets for its treatment and potentially discriminate tumors which behave differentially. Lately, molecular and genetic studies have been investigating PCa basis, revealing multiple recurrent genomic alterations that include mutations, DNA copy-number variations, rearrangements, and gene fusions, among others. In addition to the increment on PCa molecular biology knowledge, mapping the molecular alterations pattern of this neoplasia, especially the differences existent between tumors displaying distinct behaviors, could represent a great improvement concerning the identification of new targets, personalized medicine, and patients' management and prognosis.


Assuntos
Medicina de Precisão/métodos , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Terapia de Alvo Molecular , Prognóstico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/terapia
6.
Clin Epigenetics ; 9: 130, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29296124

RESUMO

Background: Esophageal squamous cell carcinoma (ESCC) is one of the 10 most incident cancer types in the world, and it is mainly associated with tobacco and alcohol consumption. ESCC mortality rates stand very close to its incidence, which is a direct consequence of a late diagnosis and an inefficient treatment. Although this scenery is quite alarming, the major molecular alterations that drive this carcinogenesis process remain unclear. We have previously shown through the first ESCC methylome analysis that TFF1 promoter is frequently hypermethylated in ESCC. Here, to evaluate TFF1 methylation as a potential biomarker of early ESCC diagnosis, we investigated the status of TFF1 promoter methylation and its expression in ESSC and histologically normal tumor surrounding tissue of ESCC patients in comparison to healthy esophagus of non-cancer individuals. Results: Analysis of TFF1 promoter methylation, and gene and protein expression in 65 ESCC patients and 88 controls revealed that TFF1 methylation levels were already increased in histologically normal tumor surrounding tissue of ESCC patients when compared to healthy esophagus of non-cancer individuals. This increase in DNA methylation was followed by the reduction of TFF1 mRNA expression. Interestingly, TFF1 expression was capable of distinguishing tumor surrounding normal tissue from normal mucosa of healthy individuals with 92% accuracy. In addition, TFF1 protein was undetectable both in tumor and surrounding mucosa by immunohistochemistry, while submucosa glands of the healthy esophagus showed positive staining. Furthermore, treatment of TE-1 and TE-13 ESCC cell lines with decitabine led to a reduction of promoter methylation and consequent upregulation of TFF1 gene and protein expression. Finally, using TCGA data we showed that TFF1 loss is observed in ESCC, but not in esophageal adenocarcinoma, highlighting the different molecular mechanisms involved in the development of each histological subtype of esophageal cancer. Conclusions: This study shows that TFF1 expression is silenced in early phases of ESCC development, which seems to be mediated at least in part by promoter hypermethylation, and provides the basis for the use of TFF1 expression as a potential biomarker for early ESCC detection.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Metilação de DNA , Regulação para Baixo , Neoplasias Esofágicas/diagnóstico , Fator Trefoil-1/genética , Fator Trefoil-1/metabolismo , Adulto , Idoso , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Decitabina , Regulação para Baixo/efeitos dos fármacos , Detecção Precoce de Câncer , Epigênese Genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas
7.
Oncotarget ; 7(40): 65876-65887, 2016 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-27588470

RESUMO

The esophageal squamous cell carcinoma (ESCC) is widely known as a highly lethal and poor understood cancer, then requiring the search for novel molecular markers to improve its management and patients survival. Recently, ubiquitin-conjugating enzyme E2C (UBE2C) has been figuring as a prominent tumor biomarker candidate, once it has been recognized as a key player in cell cycle progression. In this way, the aim of this study was to evaluate the expression profile of UBE2C gene and protein in ESCC samples, as well as its diagnostic and prognostic marker potential, and its contribution to ESSC genesis and/or progression by performing in vitro functional assays. The analysis of UBE2C gene expression in 52 paired ESCC samples (tumor and respective histologically normal surrounding tissue), by qRT-PCR, revealed that this gene is overexpressed in 73% of ESCC samples. Subsequently, immunohistochemical analysis confirmed that UBE2C protein expression was upregulated in all ESCC cases, but absent in the histologically normal tumor surrounding tissues. Moreover, we showed that UBE2C mRNA expression was able to accurately discriminate ESCC tissue from both healthy esophageal and histologically normal tumor surrounding tissues, pointing out its role as a diagnostic marker for this cancer. Finally, we report that UBE2C affects proliferation rates and cell cycle profile of ESCC cell lines, by directly interfering with cyclin B1 protein levels, suggesting its involvement in crucial steps of ESCC carcinogenesis.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , Enzimas de Conjugação de Ubiquitina/metabolismo , Adulto , Idoso , Apoptose , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/cirurgia , Ciclo Celular , Progressão da Doença , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Enzimas de Conjugação de Ubiquitina/genética
8.
Cell Cycle ; 15(18): 2410-3, 2016 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-27484584

RESUMO

We have recently shown that HMGA2 is overexpressed in esophageal squamous cell carcinoma (ESCC) and its detection allows to discriminate between cancer and normal surrounding tissue proposing HMGA2 as a novel diagnostic marker. Interestingly, esophageal adenocarcinoma shows an opposite behavior with the overexpression of HMGA1 but not HMGA2. Moreover, we show that the suppression of HMGA2 in 2 ESCC cell lines reduces the malignant phenotype. Then, this paper highlights a differential induction of the HMGA proteins, depending on the cancer histological type, and reinforces the perspective of an innovative esophageal cancer therapy based on the suppression of the HMGA protein function and/or expression.


Assuntos
Neoplasias Esofágicas/metabolismo , Proteínas HMGA/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Carcinogênese/metabolismo , Carcinogênese/patologia , Epigênese Genética , Neoplasias Esofágicas/patologia , Humanos , Modelos Biológicos
9.
Oncotarget ; 7(18): 25872-84, 2016 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-27027341

RESUMO

Esophageal Squamous Cell Carcinoma (ESCC) is the most common esophageal tumor worldwide. However, there is still a lack of deeper knowledge about biological alterations involved in ESCC development. High Mobility Group A (HMGA) protein family has been related with poor outcome and malignant cell transformation in several tumor types. In this way, the aim of this study was to analyze the expression of HMGA1 and HMGA2 expression in ESCC and their role in crucial cellular features. We evaluated HMGA1 and HMGA2 mRNA expression in 52 paired ESCC and normal surrounding tissue samples by qRT-PCR. Here, we show that HMGA2, but not HMGA1, is overexpressed in ESCC samples. This result was further confirmed by the immunohistochemical analysis. Indeed, accordingly to mRNA expression data, HMGA2, but not HMGA1, was overexpressed in approximately 90% of ESCC samples, while it was barely expressed in the respective control. Conversely, HMGA1, but not HMGA2, was overexpressed in esophageal adenocarcinoma samples. Interestingly, HMGA2 abrogation attenuated the malignant phenotype of two ESCC cell lines, suggesting that HMGA2 overexpression is involved in ESCC progression.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Proteína HMGA2/metabolismo , Adulto , Idoso , Área Sob a Curva , Biomarcadores Tumorais/análise , Progressão da Doença , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC
10.
Histol Histopathol ; 31(8): 933-42, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26853489

RESUMO

Endometriosis is a benign gynecological disease affecting approximately 10-15% of women of reproductive age and 25-50% of all infertile women. It is characterized by the presence of glands and/or endometrial stroma outside the uterine cavity. Angiogenesis is a crucial process for the development and maintenance of endometriotic lesions. The Wnt/ß-catenin pathway is a major promoter of angiogenesis in both physiological and pathological conditions. In the present study, we evaluated the expression of molecules related to the Wnt/ß-catenin pathway in a rat model of peritoneal endometriosis. mRNA analyses showed significantly increased expression of Wnt4 and Wnt7b and decreased expression of Gsk3beta and E-cadherin in endometriotic lesions. However, there were no differences in ß-catenin and Fzd2 mRNA expression. In addition, we observed a significant increase of nuclear ß-catenin in endometriotic lesions, a hallmark of Wnt/ ß-catenin pathway activation. Stromal ß-catenin staining was found in 45.4% of endometrial tissues and 77.8% of endometriotic lesions. ß-catenin nuclear localization was found in 18.2% of the endometrial tissues and 33.3% of endometriotic lesions. Finally, the expression of galectin-3, a regulator of this pathway, was increased in endometriosis. In summary, this pattern of Wnt/ß-catenin components expression suggests an increased activity of this pathway in endometriosis.


Assuntos
Endometriose/metabolismo , Via de Sinalização Wnt/fisiologia , Animais , Western Blotting , Modelos Animais de Doenças , Endometriose/fisiopatologia , Feminino , Imunofluorescência , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma , beta Catenina/metabolismo
11.
Clin Exp Metastasis ; 31(4): 461-74, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24488147

RESUMO

Tumor establishment, growth, and survival are supported by interactions with microenvironment components. Here, we investigated whether the interactions between prostate cancer cells and cortical astrocytes are associated to a potential role for astrocytes in tumor establishment. We demonstrate that astrocytes interact in vitro with prostatic cancers cells derived from different metastatic sites. Astrocytes and their secreted extracellular matrix, stimulate DU145 cell (a brain-derived prostate tumor cell line) proliferation while inhibiting cell death and modulating the expression of several genes related to prostate cancer progression, suggesting the activation of EMT process in these cells. In contrast, DU145 cells and their conditioned medium inhibited cell proliferation and induced cell death of astrocytes. On the other hand, the astrocytes were unable to significantly induce an increment of LNCaP cell (a lymph node-derived prostate tumor cell line) proliferative activity. In addition, LNCaP cells were also unable to induce cell death of astrocytes. Thus, we believe that DU145 cells, but not LNCaP cells, present an even more aggressive behavior when interacting with astrocytes. These results provide an important contribution to the elucidation of the cellular mechanisms involved in the brain microenvironment colonization.


Assuntos
Astrócitos/patologia , Neoplasias Encefálicas/secundário , Comunicação Celular , Movimento Celular , Neoplasias da Próstata/patologia , Apoptose , Astrócitos/metabolismo , Neoplasias Encefálicas/genética , Proliferação de Células , Perfilação da Expressão Gênica , Humanos , Masculino , Neoplasias da Próstata/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Microambiente Tumoral
12.
Biosci Rep ; 33(4)2013 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-23837802

RESUMO

EC (oesophageal cancer) is one of the ten most frequent and fatal tumours worldwide and ESCC (oesophageal squamous cell carcinoma) accounts for about 80% of the cases. The first symptoms of ESCC arise late during the progression of the disease and, therefore, the diagnosis is usually done in advanced stages. This leads to an inefficient treatment and consequently to a poor prognosis. Thus, a comprehensive knowledge of ESCC biology is of major importance to identify risk factors, especially in high-incidence areas and biomarkers which could enable ESCC prevention and interventions throughout the natural history of the disease. In this review, we present the current knowledge regarding ESCC aetiology as well as the different genetic and epigenetic alterations already described in this tumour. We also discuss how these alterations could be used to anticipate ESCC diagnosis as well as how they can help improving treatment. A molecular natural history of the disease is proposed pointing out potential markers that may improve interventions at different points of ESCC development. Only when the different layers of complexity behind this tumour are elucidated, it will be possible to successfully perform prevention at different levels.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Esofágicas/diagnóstico , Animais , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/terapia , Detecção Precoce de Câncer , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago , Humanos , Mutação , Infecções por Papillomavirus/complicações , Fatores de Risco , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
13.
Cell Cycle ; 11(24): 4570-8, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23165212

RESUMO

Thymine DNA glycosylase (TDG) belongs to the superfamily of uracil DNA glycosylases (UDG) and is the first enzyme in the base-excision repair pathway (BER) that removes thymine from G:T mismatches at CpG sites. This glycosylase activity has also been found to be critical for active demethylation of genes involved in embryonic development. Here we show that wild-type p53 transcriptionally regulates TDG expression. Chromatin immunoprecipitation (ChIP) and luciferase assays indicate that wild-type p53 binds to a domain of TDG promoter containing two p53 consensus response elements (p53RE) and activates its transcription. Next, we have used a panel of cell lines with different p53 status to demonstrate that TDG mRNA and protein expression levels are induced in a p53-dependent manner under different conditions. This panel includes isogenic breast and colorectal cancer cell lines with wild-type or inactive p53, esophageal squamous cell carcinoma cell lines lacking p53 or expressing a temperature-sensitive p53 mutant and normal human bronchial epithelial cells. Induction of TDG mRNA expression is accompanied by accumulation of TDG protein in both nucleus and cytoplasm, with nuclear re-localization occurring upon DNA damage in p53-competent, but not -incompetent, cells. These observations suggest a role for p53 activity in TDG nuclear translocation. Overall, our results show that TDG expression is directly regulated by p53, suggesting that loss of p53 function may affect processes mediated by TDG, thus negatively impacting on genetic and epigenetic stability.


Assuntos
Timina DNA Glicosilase/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Epigênese Genética/genética , Epigênese Genética/fisiologia , Humanos , Microscopia Confocal , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/fisiologia , Ligação Proteica , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Timina DNA Glicosilase/genética , Proteína Supressora de Tumor p53/genética
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