RESUMEN
BACKGROUND: Acetylation and deacetylation are the most studied covalent histone modifications resulting in transcriptional regulation with histone deacetylases (HDAC) and histone acetyltransferases (HAT) as the main associated enzymes. These enzymes overexpression induces abnormal transcription of key genes that regulate important cellular functions, such as proliferation, cell cycle regulation, and apoptosis. Thus, the expression of different HATs and HDACs has been evaluated in various cancers. OBJECTIVE: To investigate HDAC1, HDAC2 and HAT1 expression in lip squamous cell carcinoma (LSCC) and actinic cheilitis (AC) and to demonstrate their correlation with DNA metyltransferases (DNMTs). MATERIAL AND METHODS: Thirty cases of lip squamous cell carcinoma (LSCC), thirty cases of actinic cheilitis (AC), and 28 cases of non-neoplastic epithelium as control were selected for immunohistochemical investigation. RESULTS: Nuclear HDAC2 immunopositivity was significantly higher in AC (75.07% ± 29.70) when compared with LSCC (51.06% ± 39.02). HDAC1 and HAT1 nuclear immunostaining were higher in AC, with no statistical significance. When comparing data with our previous study, we found a positive correlation between HDAC1 X DNMT1/DNMT3b, HDAC2 X DNMT3b, and HAT1 X DNMT1/DNMT3b for certain studied groups. CONCLUSION: This study showed higher levels of nuclear HDAC2 immunopositivity in AC, possibly indicating that this enzyme plays a key role in lip photocarcinogenesis early stages.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/enzimología , Queilitis/enzimología , Histona Acetiltransferasas/metabolismo , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/metabolismo , Neoplasias de los Labios/enzimología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , Preescolar , Metilasas de Modificación del ADN/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: This study aimed to evaluate apoptosis by assessing cleaved caspase-3 immunoexpression in hyperplastic, potentially malignant disorder (PMD), and malignant tumors in intraoral and lower lip sites. MATERIAL AND METHODS: A retrospective study using paraffin blocks with tissues from patients with inflammatory fibrous hyperplasia (IFH), actinic cheilitis, oral leukoplakia, lower lip and intraoral squamous cell carcinoma (SCC) was performed. The tissues were evaluated by immunohistochemical analysis with anti-cleaved caspase-3 antibody. Apoptotic area index was then correlated with lesion type. RESULTS: From 120 lesions assessed, 55 (46%) were cleaved caspase-3-positive. The SCC samples (n=40) had the highest apoptotic area indices (n=35; 87.5%). Significant differences were detected between SCCs and PMDs (p=0.0003), as well as SCCs and IFHs (p=0.001), regarding caspase-3 immunopositivity. Carcinomas of the lower lip had lower apoptotic area indices than intraoral cancer (p=0.0015). CONCLUSIONS: Cleaved caspase-3 immunoexpression showed differences in oral SCCs and PMDs and demonstrated a distinct role of apoptosis in carcinogenesis of intraoral and lower lip cancer. In future, the expression of cleaved caspase-3 with other target molecules in oral cancer may be helpful in delineating the prognosis and treatment of these tumors.
Asunto(s)
Apoptosis , Carcinoma de Células Escamosas/patología , Caspasa 3/análisis , Leucoplasia Bucal/patología , Neoplasias de los Labios/patología , Neoplasias de la Boca/patología , Carcinogénesis/patología , Carcinoma de Células Escamosas/enzimología , Queilitis/enzimología , Queilitis/patología , Humanos , Hiperplasia/enzimología , Hiperplasia/patología , Inmunohistoquímica , Leucoplasia Bucal/enzimología , Neoplasias de los Labios/enzimología , Neoplasias de la Boca/enzimología , Adhesión en Parafina , Pronóstico , Estudios Retrospectivos , Estadísticas no ParamétricasRESUMEN
ABSTRACT Objective This study aimed to evaluate apoptosis by assessing cleaved caspase-3 immunoexpression in hyperplastic, potentially malignant disorder (PMD), and malignant tumors in intraoral and lower lip sites. Material and Methods A retrospective study using paraffin blocks with tissues from patients with inflammatory fibrous hyperplasia (IFH), actinic cheilitis, oral leukoplakia, lower lip and intraoral squamous cell carcinoma (SCC) was performed. The tissues were evaluated by immunohistochemical analysis with anti-cleaved caspase-3 antibody. Apoptotic area index was then correlated with lesion type. Results From 120 lesions assessed, 55 (46%) were cleaved caspase-3-positive. The SCC samples (n=40) had the highest apoptotic area indices (n=35; 87.5%). Significant differences were detected between SCCs and PMDs (p=0.0003), as well as SCCs and IFHs (p=0.001), regarding caspase-3 immunopositivity. Carcinomas of the lower lip had lower apoptotic area indices than intraoral cancer (p=0.0015). Conclusions Cleaved caspase-3 immunoexpression showed differences in oral SCCs and PMDs and demonstrated a distinct role of apoptosis in carcinogenesis of intraoral and lower lip cancer. In future, the expression of cleaved caspase-3 with other target molecules in oral cancer may be helpful in delineating the prognosis and treatment of these tumors.
Asunto(s)
Humanos , Leucoplasia Bucal/patología , Neoplasias de los Labios/patología , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas/patología , Apoptosis , Caspasa 3/análisis , Pronóstico , Leucoplasia Bucal/enzimología , Neoplasias de los Labios/enzimología , Neoplasias de la Boca/enzimología , Inmunohistoquímica , Carcinoma de Células Escamosas/enzimología , Queilitis/enzimología , Queilitis/patología , Estudios Retrospectivos , Adhesión en Parafina , Estadísticas no Paramétricas , Carcinogénesis/patología , Hiperplasia/enzimología , Hiperplasia/patologíaRESUMEN
BACKGROUND: Epigenetic modifications, including DNA methylation of tumor suppressor genes carried out by DNA methyltransferases (DNMTs), are important events in carcinogenesis. Although there are studies concerning to its expression in several cancer types, DNMTs expression pattern is not known in photoinduced lip carcinogenesis. The aim of this study was to investigate the immunoexpression of DNMTs 1, 3a, and 3b in lip precancerous lesion (actinic cheilitis) and cancer. METHODS: Thirty cases of actinic cheilitis (AC), thirty cases of lip squamous cell carcinoma (LSCC), and twenty cases of non-neoplastic tissue (NNT) were selected for immunohistochemical investigation of DNMTs 1, 3a, and 3b. RESULTS: Nuclear DNMT 1 immunoreactivity was significantly higher in the LSCC group (68.6%) compared with NNT (47%), and nuclear DNMT 3b was higher in LSCC (70.9%) than in NNT (37.9%) and in AC (44%). Only DNMT 3a showed both higher nuclear and cytoplasmic expression in AC (35.9% and 35.5%, respectively) than in NNT (4.4% and 16.1%, respectively) and LSCC (8.8% and 13.2%, respectively) (P < 0.05). CONCLUSIONS: The results suggested that DNMT 3a could play a key role in the methylation process of initial steps of UV carcinogenesis present in AC while DNMT 3b could be responsible for de novo methylation in already established lip cancer.
Asunto(s)
Carcinoma de Células Escamosas/enzimología , Queilitis/enzimología , ADN (Citosina-5-)-Metiltransferasas/biosíntesis , Neoplasias de Cabeza y Cuello/enzimología , Neoplasias de los Labios/enzimología , Proteínas Represoras/biosíntesis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinogénesis/inmunología , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Queilitis/inmunología , Queilitis/patología , Niño , Preescolar , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Femenino , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/patología , Humanos , Inmunohistoquímica , Neoplasias de los Labios/inmunología , Neoplasias de los Labios/patología , Masculino , Persona de Mediana Edad , Proteínas Represoras/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello , Adulto Joven , ADN Metiltransferasa 3BRESUMEN
Actinic cheilitis exhibits a potential of malignant transformation in 10-20 % of cases. The objective of this study was to compare the expression of MDM2 and SUMO-1 proteins between actinic cheilitis (AC) and squamous cell carcinoma (SCC) of the lip. The sample consisted of lower lip mucosa specimens obtained from cases with a clinical and histopathological diagnosis of AC (n = 26) and SCC (n = 25) and specimens of labial semi-mucosa (n = 15) without clinical alterations or inflammation. The tissue samples were stained with hematoxylin-eosin and anti-MDM2 and anti-SUMO-1 antibodies. Data were analyzed by the Kruskal-Wallis and Dunn's tests (5 %). The median expression of MDM2 (kW = 36.8565; df = 3-1 = 2; p = 0.0001) and SUMO-1 (kW = 32.7080; df = 3-1 = 2; p = 0.0001) was similar in cases of AC and SCC of the lip, but differed significantly from that observed for normal labial semi-mucosa. Despite the limitations of the present study, immunohistochemistry demonstrated the overexpression of important proteins (MDM2 and SUMO-1) related to regulatory mechanisms of apoptosis in AC and SCC of the lip, but further studies are needed.
Asunto(s)
Carcinoma de Células Escamosas/enzimología , Queilitis/enzimología , Neoplasias de los Labios/enzimología , Mucosa Bucal/enzimología , Proteínas Proto-Oncogénicas c-mdm2/análisis , Proteína SUMO-1/análisis , Adulto , Anciano , Biopsia , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Queilitis/patología , Femenino , Humanos , Inmunohistoquímica , Neoplasias de los Labios/patología , Masculino , Persona de Mediana Edad , Mucosa Bucal/patología , Regulación hacia ArribaRESUMEN
Actinic cheilitis (AC) is an early keratocyte neoplasia with inflammation that occurs in the lip vermillion with the potential to develop into invasive squamous cell carcinoma (SCC). The expression of the intracellular enzyme indoleamine 2,3-dioxygenase (IDO) by antigen-presenting cells and/or tumor cells has been described to arrest T cell proliferation by degrading the essential amino acid tryptophan from the environment. The expression of IDO in AC may support cancer progression by inhibiting T cell-mediated rejection responses. The aim of this study was to identify the cellular nature and extent of IDO expression in early keratocye neoplasia of the lower lip (n=25), and to correlate IDO expression to the severity of epithelial atypia (KIN I°- KIN III°) and to the extent of actinic inflammation. The expression of IDO was analyzed together with expression markers for T-cells (CD3), myeloid DCs (S100, CD11c), macrophages (CD68, CD11c), and Langerhans cells (CD1a) by immunohistochemistry and immunofluorescence analysis. Analyses showed that IDO was expressed in myeloid S100(+) CD11c(+) DCs. The expression of IDO correlated significantly with the degree of epithelial atypia (P=0.0005) but not to the extent of inflammation (P=0.4283). Expression of IDO in early atypic skin epithelial conditions might be a predictor to promote carcinogenesis.
Asunto(s)
Queilitis/enzimología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Labio/enzimología , Piel/enzimología , Queilitis/patología , Humanos , Inflamación/enzimología , Inflamación/patología , Labio/patología , Índice de Severidad de la Enfermedad , Piel/patologíaRESUMEN
BACKGROUND: Actinic cheilitis (AC) is characterized by epithelial and connective tissue alterations caused by ultraviolet sunlight overexposure known as photodamage. Fibroblasts have been linked to photodamage and tumor progression during skin carcinogenesis; however, their role in early lip carcinogenesis remains unknown. The aim of this study was to assess the density of fibroblasts in AC and normal lip (NL) samples and determine their association with markers of lip photodamage. METHODS: Fibroblasts, mast cells, p53, COX-2, and elastin were detected in NL (n = 20) and AC (n = 28) biopsies using immunohistochemistry/histochemistry. Mast cell and fibroblast density and epithelial p53 and COX-2 expression scores were then obtained. Elastosis was scored 1-4 according to elastin fiber density and tortuosity. RESULTS: Fibroblasts, mast cells, p53, COX-2, and elastosis were increased in AC as compared to NL (P < 0.001). Multivariate analysis showed an association between fibroblast and mast cell density at the papillary and reticular areas of AC and NL (P < 0.05). Papillary fibroblast density was also associated with epithelial p53 and COX-2 expression (P < 0.05). Increased fibroblast density, both papillary and reticular, was found in the high elastosis group (scores 3-4) as compared to the low elastosis group (scores 1-2) (P < 0.01). Increased reticular mast cell density was detected only in the high elastosis group (P < 0.01). CONCLUSIONS: Fibroblasts are increased in AC, and they are associated with mast cell density, epithelial p53 and COX-2 expression, and actinic elastosis. Therefore, fibroblasts may contribute to lip photodamage and could be considered useful markers of early lip carcinogenesis.
Asunto(s)
Queilitis/patología , Ciclooxigenasa 2/análisis , Fibroblastos/patología , Mastocitos/patología , Enfermedades de la Piel/patología , Triptasas/análisis , Proteína p53 Supresora de Tumor/análisis , Adulto , Biomarcadores/análisis , Recuento de Células , Queilitis/enzimología , Colorantes , Elastina/análisis , Epitelio/patología , Femenino , Humanos , Inmunohistoquímica , Labio/patología , Masculino , Mastocitos/enzimología , Persona de Mediana Edad , Envejecimiento de la Piel/patología , Enfermedades de la Piel/enzimologíaRESUMEN
BACKGROUND: Actinic cheilitis (AC) is a pre-malignant lesion caused by ultraviolet (UV) radiation and characterized by epithelial and connective tissue alterations. Mast cells (MCs), key contributors to solar elastosis in murine UV-irradiated skin, were characterized in order to assess their potential contribution to connective tissue degeneration in AC. METHODS: Actinic cheilitis (n = 15) and normal lip (n = 8) biopsies were stained immunohistochemically for tryptase and enzymehistochemically for chymase to determine MC density and protease content. MC subpopulations (i.e. MC(T) containing only tryptase, and MC(TC) containing chymase and tryptase) and their distribution were also determined. RESULTS: Mast cells and their proteases were increased in AC as compared with normal lip (P < 0.0001), and appeared degranulated especially around elastotic areas. MC(T) predominated over MC(TC) in AC and normal lip (P < 0.05). However, in AC MC(T) were increased in the epithelium/connective junction and connective area (P < 0.05), while in normal lip MC(T) predominated in connective and submucosal areas (P < 0.05). CONCLUSION: The results suggest that increased MC density and protease content may contribute to elastosis formation in AC. In addition, changes in MC(T) distribution may favor AC malignization.