RESUMEN
OBJECTIVE: To evaluate and compare the expression of E-cadherin, Snail1 and Twist1 in pleomorphic adenomas (PAs), adenoid cystic carcinomas (AdCCa) and carcinoma ex-pleomorphic adenomas (CaexPA) of salivary glands, as well as investigate possible associations with clinicopathological parameters. STUDY DESIGN: E-cadherin, Snail1 and Twist1 antibody immunostaining were analyzed semiquantitatively in 20 PAs, 20 AdCCas and 10 CaexPAs. Cases were classified as low and high expression for analysis of the association with clinicopathological parameters. RESULTS: Compared to PAs, AdCCas and CaexPAs exhibited higher nuclear expression of Snail1 (p = 0.021 and p = 0.028, respectively) and Twist1 (p = 0.009 and p = 0.001). Membranous and cytoplasmic expression of E-cadherin were positively correlated in PAs, AdCCas and CaexPAs (r = 0.645, p = 0.002; r = 0.824, p < 0.001; r = 0.677, p = 0.031). In PAs, positive correlation was found between nuclear expression of Snail1 and membrane expression of E-cadherin (r = 0.634; p = 0.003), as well as between nuclear expression of Snail1 and Twist1 (r = 0.580; p = 0.007). Negative correlations were detected between membrane expression of E-cadherin and cytoplasmic expression of Snail1 in AdCCas (r = - 0.489; p = 0.029). CONCLUSIONS: E-cadherin, Twist1, and Snail1 may participate in modulating events related to cell differentiation and adhesion in PAs and to biological behavior in AdCCas and CaexPAs, which indicates the involvement of EMT in these processes. Furthermore, the expression of these proteins in these carcinomas may reflect the plasticity feature of EMT.
Asunto(s)
Adenoma Pleomórfico , Cadherinas , Carcinoma Adenoide Quístico , Transición Epitelial-Mesenquimal , Proteínas Nucleares , Neoplasias de las Glándulas Salivales , Factores de Transcripción de la Familia Snail , Proteína 1 Relacionada con Twist , Humanos , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo , Cadherinas/metabolismo , Femenino , Masculino , Proteína 1 Relacionada con Twist/metabolismo , Persona de Mediana Edad , Carcinoma Adenoide Quístico/patología , Carcinoma Adenoide Quístico/metabolismo , Proteínas Nucleares/metabolismo , Adulto , Adenoma Pleomórfico/metabolismo , Adenoma Pleomórfico/patología , Anciano , Factores de Transcripción Twist/metabolismo , Inmunohistoquímica , Factores de Transcripción/metabolismo , Biomarcadores de Tumor/metabolismoRESUMEN
OBJECTIVE: Pleomorphic adenoma (PA), mucoepidermoid carcinoma (MEC), and adenoid cystic carcinoma (ACC) are the most prevalent salivary gland tumors. Their pathogenesis has been recently associated with complex molecular cascades, including the TGFß signaling pathway. The aim of this study was to evaluate the expression of genes associated with the TGFß signaling pathway (TGFB1, ITGB6, SMAD2, SMAD4, FBN1, LTBP1, and c-MYC) to map possible downstream alterations in the TGFß cascade. DESIGN: Thirteen PA, 17 MEC, 13 ACC, and 10 non-neoplastic salivary gland samples were analyzed by real-time RT-PCR. RESULTS: Cases of PA presented increased TGFB1, LTPB1, c-MYC, and FBN1 expressions, whereas SMAD2 expression was decreased when compared to non-neoplastic tissue. MEC patients displayed increased expressions of TGFB1, ITGB6, FBN1, and c-MYC and decreased expressions of SMAD2 and SMAD4. ACC cases exhibited elevated expressions of the investigated genes except TGFB1. The present results suggest that decreased expression of SMAD2 and SMAD4 does not impede the transcriptional regulation of c-MYC, especially in PA and MEC. Increased expressions of ITGB6, TGFB1, LTBP1, and FBN1 appear to be related to the regulation of the TGFß signaling pathway in these tumors. Additionally, we observed a higher expression of SMAD4 in ACC and a raised expression of ITGB6 and lowered expression of SMAD2 in MEC. CONCLUSIONS: Our study demonstrated the differential expression of TGFß cascade members in salivary gland tumors such as SMAD2/SMAD4 and c-MYC as well as the participation of ITGB6, TGFB1, LTBP1, and FBN1, contributing to the understanding of the mechanisms involved in tumor progression.
Asunto(s)
Adenoma Pleomórfico , Carcinoma Adenoide Quístico , Carcinoma Mucoepidermoide , Neoplasias de las Glándulas Salivales , Factor de Crecimiento Transformador beta , Humanos , Adenoma Pleomórfico/genética , Adenoma Pleomórfico/metabolismo , Adenoma Pleomórfico/patología , Biomarcadores de Tumor/metabolismo , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Mucoepidermoide/metabolismo , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Adenoid cystic carcinoma (ACC) has been reported as the second most common carcinoma of the salivary glands. Few studies have associated miRNA expression with ACC aggressiveness. In this study, we evaluated the miRNA profile of formalin-fixed, paraffin-embedded (FFPE) samples of salivary gland ACC patients using the NanoString platform. We studied the miRNA expression levels associated with the solid growth pattern, the more aggressive histologic feature of ACCs, compared with the tubular and cribriform growth patterns. Moreover, the perineural invasion status, a common clinicopathological feature of the disease that is frequently associated with the clinical progression of ACC, was investigated. The miRNAs showing significant differences between the study groups were selected for target prediction and functional enrichment, which included associations with the disease according to dedicated databases. We observed decreased expression of miR-181d, miR-23b, miR-455, miR-154-5p, and miR-409 in the solid growth pattern compared with tubular and cribriform growth patterns. In contrast, miR-29c, miR-140, miR-195, miR-24, miR-143, and miR-21 were overexpressed in patients with perineural invasion. Several target genes of the miRNAs identified have been associated with molecular processes involved in cell proliferation, apoptosis, and tumor progression. Together, these findings allowed the characterization of miRNAs potentially associated with aggressiveness in salivary gland adenoid cystic carcinoma. Our results highlight important new miRNA expression profiles involved in ACC carcinogenesis that could be associated with the aggressive behavior of this tumor type.
Asunto(s)
Carcinoma Adenoide Quístico , MicroARNs , Neoplasias de las Glándulas Salivales , Humanos , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/patología , MicroARNs/genética , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/patología , Glándulas Salivales/metabolismo , Carcinogénesis/genéticaRESUMEN
OBJECTIVE: Local recurrence, distant metastasis, and perineural invasion (PNI) viciously occur in salivary adenoid cystic carcinoma (SACC), resulting in a poor prognosis. This study aimed to explore the mechanism by which circular RNA RNF111 (circ-RNF111) regulates PNI in SACC by targeting the miR-361-5p/high mobility group box 2 (HMGB2) axis. METHOD: Circ-RNF111 and HMGB2 were highly expressed in SACC specimens, while miR-361-5p was underexpressed. Functional experiments showed that ablating circ-RNF111 or promoting miR-361-5p hindered the biological functions and PNI of SACC-LM cells. RESULTS: HMGB2 overexpression induced the reversal of SACC-LM cell biological functions and PNI caused by circ-RNF111 knockout. Furthermore, reduction of circ-RNF111 suppressed PNI in a SACC xenograft model. Circ-RNF111 regulated HMGB2 expression through targeted modulation of miR-361-5p. CONCLUSION: Taken together, circ-RNF111 stimulates PNI in SACC by miR-361-5p/HMGB2 axis and may serve as a potential therapeutic target for SACC.
Asunto(s)
Carcinoma Adenoide Quístico , MicroARNs , Neoplasias de las Glándulas Salivales , Humanos , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/patología , ARN Circular/genética , Proteína HMGB2/genética , Proteína HMGB2/metabolismo , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/patología , Factores de Transcripción/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Línea Celular Tumoral , Invasividad Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genética , Proliferación Celular , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: Mitochondrial fission and fusion processes are known as mitochondrial dynamics and the occurrence of imbalances in the mitochondrial activity is related to the pathogenesis of many human cancers. However, the importance of mitochondrial dynamics in malignant salivary gland tumours remains unknown. Therefore, we aimed to investigate its prognostic significance in adenoid cystic carcinoma. METHODS: Fifty-seven formalin-fixed paraffin-embedded cases were retrieved and disposed in tissue microarray. Histological sections were submitted to immunohistochemical reactions against AMT, DRP1, FIS1, MFN1, MFN2 and OPA1 proteins. Clinical data were retrieved from the patients' medical files, including specific and disease-free survival data. RESULTS: It was observed that 50.9% of the cases were strongly positive for AMT and DRP1, and 49.1%, 21.1%, 22.8% and 24.6% strongly positive for FIS1, MFN1, MFN2 and OPA1, respectively. Reactions were observed in both epithelial and myoepithelial components of the tumour. The higher expression of MFN2 was associated with solid microscopic pattern (p = 0.016). DRP1 overexpression showed a trend towards a shorter overall survival (p = 0.054), while negative/weak OPA1 showed a trend towards a lower disease-free survival (p = 0.051) in the univariate analysis, but no mitochondrial marker represented an independent prognostic determinant under multivariate analysis. CONCLUSION: In conclusion, mitochondrial dynamics markers do not seem to carry a prognostic significance for adenoid cystic carcinoma patients, but these proteins may play an important role in its pathogenesis.
Asunto(s)
Carcinoma Adenoide Quístico , Dinámicas Mitocondriales , Carcinoma Adenoide Quístico/metabolismo , Humanos , MitocondriasRESUMEN
BACKGROUND: Among cancers affecting the oral cavity, adenoid cystic carcinoma (ACC) is a relatively common malignant neoplasm. It has high rates of metastasis and recurrence and is associated with significant morbidity. During the progression of ACC, the oxygen concentration is reduced in specific areas of the tumour microenvironment, leading to intratumoural hypoxia. The expression of NOTCH1, a disintegrin and metalloproteinase 12 (ADAM-12), hypoxia-inducible factor 1 alpha (HIF-1α), and heparin-binding epidermal growth factor (HB-EGF) under hypoxic conditions has been implicated in invadopodia formation, tumour invasiveness, and metastasis. The aim of this study was to analyse the expression of these proteins to elucidate the mechanisms underlying ACC invasiveness. METHODS: Fifteen ACC samples and 10 normal-looking salivary gland (SG) samples were used to investigate the expression of these proteins by immunohistochemistry. Primary antibodies against NOTCH1, ADAM-12, HIF-1α, and HB-EGF were used. RESULTS: The immunoexpression of all proteins was higher in ACC samples than in SG samples (p < 0.05). CONCLUSIONS: There was increased expression of proteins associated with hypoxia and tumour invasiveness in ACC samples, which indicates a possible role of these proteins in the biological behaviour of this tumour.
Asunto(s)
Carcinoma Adenoide Quístico/patología , Hipoxia de la Célula/fisiología , Neoplasias de las Glándulas Salivales/patología , Microambiente Tumoral/fisiología , Adulto , Anciano , Carcinoma Adenoide Quístico/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de las Glándulas Salivales/metabolismoRESUMEN
OBJECTIVE: Malignant salivary gland tumors (MSGTs) present different phenotypic characteristics and various clinical outcomes, which proved to be a diagnostic challenge. Considering the heterogeneity of MSGT, this study aims to identify molecule related to the nature of MSGT. METHODS: For screening, proteomic analysis comparing MSGT with pleomorphic adenoma (PA) and salivary gland was performed. The MSGT-associated protein which presented in the higher number in the Gene Expression Omnibus (GEO) database was selected. To validate the data, immunohistochemistry (IHC) was performed in 14 patients with PA, 22 patients with MSGT, and 14 controls. RESULTS: 16 proteins were associated with MSGT. ANXA2 was the primary protein, according to GEO database analyses. ANXA2 was most expressed in the cell membrane. However, some ANXA2 staining was also observed in the cytoplasm and nucleus. ANXA2 was highly expressed in MSGT in comparison with control. Also, ANXA2 has a higher expression in adenocarcinoma not otherwise specified (ANOS) and myoepithelial carcinoma (MC) in comparison with PA. CONCLUSION: In conclusion, this study demonstrated that MSGT presented higher levels of ANXA2 in comparison with normal salivary glands. Also, ANXA2 might be interesting as a molecular marker of ANOS and MS.
Asunto(s)
Adenoma Pleomórfico/metabolismo , Anexina A2/metabolismo , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Mucoepidermoide/metabolismo , Neoplasias de las Glándulas Salivales/metabolismo , Adenoma Pleomórfico/patología , Biomarcadores de Tumor/metabolismo , Carcinoma Adenoide Quístico/patología , Carcinoma Mucoepidermoide/patología , Estudios de Casos y Controles , Humanos , Proteoma , Proteómica , Neoplasias de las Glándulas Salivales/patologíaRESUMEN
The presence of a translocation involving MYB and NFIB genes have been described in adenoid cystic carcinoma (AdCC) from different anatomical regions. However, the exact frequency of this genetic event and its prognostic impact for patient survival remain obscure. The aim of this study was to carry out a systematic review to address the prevalence and the prognostic potential of t(6;9)(MYB-NFIB) in head and neck AdCC. Quantitative analysis was done to determine the prevalence of the translocation. A total of 1,107 articles were initially retrieved with 36 remaining for data extraction. The prevalence of t(6;9)(MYB-NFIB) varied significantly (16%-100%), especially due to methodological heterogeneity among studies. A total of 11 studies attempted to determine the prognostic importance of the translocation, but no study found any significant association with survival rates; only three studies observed a significant association with age, sex, tumour location and the presence of recurrences and metastases. The prevalence of t(6;9)(MYB-NFIB) in head and neck AdCC varies according to the laboratorial methods used, and the best evidence available demonstrates that t(6;9)(MYB-NFIB) does not seem to be a prognostic determinant.
Asunto(s)
Carcinoma Adenoide Quístico/genética , Neoplasias de Cabeza y Cuello/genética , Recurrencia Local de Neoplasia/genética , Proteínas de Fusión Oncogénica/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Carcinoma Adenoide Quístico/metabolismo , Genes myb , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Hibridación Fluorescente in Situ , Factores de Transcripción NFI , Prevalencia , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Salivary gland cancers represent a rare group of tumors composed by over 20 histological subtypes. Initially treated as one single disease, its diagnosis, prognosis, and treatment are currently being stratified based on morphology. More recently, insight has been provided on the molecular characterization of each subtype, further improving diagnostic accuracy and paving the way for personalized therapy. In this article, we provide a comprehensive review of recent breakthroughs, preliminary results of novel therapy, and future directions on the treatment of these complex malignancies.
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Neoplasias de las Glándulas Salivales , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/terapia , Carcinoma Ductal/genética , Carcinoma Ductal/metabolismo , Carcinoma Ductal/terapia , Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/metabolismo , Carcinoma Mucoepidermoide/terapia , Análisis Mutacional de ADN , Perfilación de la Expresión Génica , Humanos , Mutación , Conductos Salivales/patología , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/terapiaRESUMEN
PURPOSE: To compare the immunohistochemical expression of matrix metalloproteinases-2, -7, -9 and -26 and tissue inhibitors of metalloproteinases-1 and -2 in pleomorphic adenomas and adenoid cystic carcinomas of the minor salivary glands. METHODS: Twenty cases of pleomorphic adenomas and 20 cases of adenoid cystic carcinomas were evaluated for the immunohistochemical expression of matrix metalloproteinases-2, -7, -9, and -26 and tissue inhibitors-1 and -2 in tumor parenchyma. RESULTS: Most pleomorphic adenomas and adenoid cystic carcinomas showed high expression of matrix metalloproteinases and tissue inhibitors, predominantly located in the tumor cells. There was no statistically significant difference in the expression of the metalloproteinases-2 (p = 0.359), -7 (p = 0.081), and -26 (p = 0 553), as well as the tissue inhibitors-1 (p = 0.657), and -2 (p = 0.248) between the parenchyma of the studied tumors. Only matrix metalloproteinase-9 showed a significant difference in expression between the two tumors, with adenoid cystic carcinoma showing a more intense staining for this gelatinase (p = 0.041). CONCLUSIONS: The expression of the studied metalloproteinases suggests the involvement of these enzymes in the tissue remodeling process in pleomorphic adenomas and adenoid cystic carcinomas, but only MMP-9, significantly expressed in the adenoid cystic carcinomas, appears to be involved in the process of invasiveness and more aggressive behavior of these tumors. Additionally, results point that TIMPs-1 and -2 may have more complex functions besides metalloproteinase inhibition, which may be related to the pathogenesis and biological behavior of salivary gland tumors.
Asunto(s)
Adenoma Pleomórfico/metabolismo , Carcinoma Adenoide Quístico/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Neoplasias de las Glándulas Salivales/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Adenoma Pleomórfico/patología , Carcinoma Adenoide Quístico/patología , Humanos , Inmunohistoquímica , Neoplasias de las Glándulas Salivales/patología , Glándulas Salivales Menores/metabolismo , Glándulas Salivales Menores/patologíaRESUMEN
PURPOSE: Adenoid cystic carcinoma (ACC) is an intriguing lesion because it shows a slow growth in the beginning, but a late poor prognosis due to perineural invasion, metastasis and recurrence. This study aimed to investigate whether Akt signaling would be deregulated in adenoid cystic carcinoma and its consequence in the expression of associated proteins. METHODS: The expression of the Akt, p-Akt, NFκB, ß-catenin, cyclin D1 and COX-2 was assessed by immunohistochemistry in 10 cases of ACC, 17 cases of pleomorphic adenoma (PA), and 7 cases of normal salivary gland (NSG). RESULTS: p-Akt was overexpressed in ACC when compared to NSG. NFκB, ß-catenin, and COX-2 were overexpressed in ACC and PA when compared to NSG. Most proteins were slightly higher expressed in ACC than in PA, but they never reached significance. p-Akt expression positively correlated with NFκB, ß-catenin, cyclin D1 and COX-2 in ACC and PA, while this correlation trended to be negative in for these proteins (except for NFκB) in NSG using Person's correlation analysis, but without reaching significance. CONCLUSIONS: Our results indicate an abnormal activation of Akt signaling pathway, which can be an important regulator of tumor biology in ACC. Activated Akt correlated with the expression of NFκB, ß-catenin and COX-2, which can potentially influence cell survival in ACC.
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Adenoma Pleomórfico/metabolismo , Carcinoma Adenoide Quístico/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de las Glándulas Salivales/metabolismo , Adenoma Pleomórfico/patología , Carcinoma Adenoide Quístico/patología , Ciclina D1/metabolismo , Ciclooxigenasa 2/metabolismo , Humanos , Inmunohistoquímica , Subunidad p50 de NF-kappa B/metabolismo , Neoplasias de las Glándulas Salivales/patología , Glándulas Salivales/patología , Transducción de Señal , beta Catenina/metabolismoRESUMEN
PURPOSE: Salivary gland tumors are complex and have a great histomorphological diversity; more than 30 histological subtypes are currently described and the study of proteins that help understand and differentiate these tumors is essential. We aimed to analyze the immunoexpression of cyclooxygenase-2 (COX-2) and cyclin D1 proteins in pleomorphic adenomas (PA), mucoepidermoid carcinomas (MEC) and adenoid cystic carcinomas (AdCC) of salivary glands. METHODS: A total of 38 PA, 12 AdCC and 12 MEC underwent immunohistochemical study by the polymeric biotin-free technique. Immunopositive cells were analyzed semi-quantitatively. For statistical analysis, a significance level was set at p ≤ 0.05. RESULTS: Overall, these tumors were more prevalent in women (n = 37). The mean age of these patients was 58-year-old and the parotid gland was the most affected anatomic site (n = 33). All cases of AdCC and MEC showed immunopositivity to cyclin D1; however, 39.5% of the PAs were negative (p < 0.001). Regarding COX-2 immunoexpression, we observed that all cases of CME were positive, whereas 60.5% of the PA and 75% of the CAC analyzed were completely negative (p = 0.042). CONCLUSIONS: The overexpression of COX-2, observed only in MEC, emphasizes that salivary gland tumors have different profiles. Cyclin D1 is more immunoexpressed in malignant tumors. Together, these immunohistochemical findings may be useful in differentiating the studied tumors.
Asunto(s)
Adenoma Pleomórfico/metabolismo , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Mucoepidermoide/metabolismo , Ciclina D1/metabolismo , Ciclooxigenasa 2/metabolismo , Neoplasias de las Glándulas Salivales/metabolismo , Adenoma Pleomórfico/patología , Adulto , Biomarcadores de Tumor/metabolismo , Carcinoma Adenoide Quístico/patología , Carcinoma Mucoepidermoide/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de las Glándulas Salivales/patologíaRESUMEN
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that was first known as responsible for sustain the growth, function, and plasticity of neural cells. BDNF exerts its effects by binding to the tyrosine kinase receptor B (TrkB). The BDNF/TrkB axis has been reported to be overexpressed in several neurogenic and non-neurogenic tumors. Its higher expression was associated with a poor prognosis to patients affected by different human malignancies, tumor growth, invasion, and metastasis; epithelial-mesenchymal transition and resistance to chemotherapy. BDNF/TrkB represent promising targets to the development of novel anticancer therapies. Some clinical trials are currently evaluating the efficacy of Trk protein-target drugs in different types of solid tumors. To date, few groups have evaluated the DNF/TrkB pathway in head and neck malignancies. The aims of this study were to review the literature concerning the role of BDNF/TrkB activation in head and neck squamous cell carcinoma and malignant salivary gland tumors and to discuss future perspectives of BDNF/TrkB-target therapy.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Receptor trkB/metabolismo , Antineoplásicos/farmacología , Carcinoma Adenoide Quístico/tratamiento farmacológico , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/patología , Carcinoma Mucoepidermoide/tratamiento farmacológico , Carcinoma Mucoepidermoide/metabolismo , Carcinoma Mucoepidermoide/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Cisplatino/farmacología , Resistencia a Antineoplásicos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Humanos , Invasividad Neoplásica , PronósticoAsunto(s)
Envejecimiento/genética , Carcinoma Adenoide Quístico/genética , Cromatina/metabolismo , Cisplatino/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Células Madre Neoplásicas/metabolismo , Carcinoma Adenoide Quístico/metabolismo , Cisplatino/farmacología , Humanos , Células Madre Neoplásicas/patologíaRESUMEN
This study aimed to evaluate and compare the immunoexpression of glucose transporter-1 (GLUT-1) and angiogenic index between pleomorphic adenomas (PAs), adenoid cystic carcinomas (ACCs), and mucoepidermoid carcinomas (MECs) of the salivary glands, and establish associations with the respective subtype/histological grade. Twenty PAs, 20 ACCs, and 10 MECs were submitted to morphological and immunohistochemical analysis. GLUT-1 expression was semi-quantitatively evaluated and angiogenic index was assessed by microvessel counts using anti-CD34 antibody. Higher GLUT-1 immunoexpression was observed in the MECs compared to PAs and ACCs (p = 0.022). Mean number of microvessels was 66.5 in MECs, 40.4 in PAs, and 21.2 in ACCs (p < 0.001). GLUT-1 expression and angiogenic index showed no significant correlation in the tumors studied. Results suggest that differences in biological behavior of the studied tumors are related to GLUT-1. Benign and malignant salivary gland tumors differ in the angiogenic index; however, angiogenesis may be independent of the tumor cell's metabolic demand.
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Adenoma Pleomórfico/metabolismo , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Mucoepidermoide/metabolismo , Transportador 2 de Aminoácidos Excitadores/metabolismo , Neovascularización Patológica , Neoplasias de las Glándulas Salivales/metabolismo , Adenoma Pleomórfico/irrigación sanguínea , Adenoma Pleomórfico/patología , Biomarcadores de Tumor/metabolismo , Carcinoma Adenoide Quístico/irrigación sanguínea , Carcinoma Adenoide Quístico/patología , Carcinoma Mucoepidermoide/irrigación sanguínea , Carcinoma Mucoepidermoide/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Microvasos/patología , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias de las Glándulas Salivales/irrigación sanguínea , Neoplasias de las Glándulas Salivales/patología , Glándulas Salivales/patologíaRESUMEN
OBJECTIVE: Despite their similar cellular origin, pleomorphic adenomas (PA) and adenoid cystic carcinomas (ACC) present distinct behaviors. This study aimed to analyze the immunoexpression of E-cadherin in PA and ACC of salivary glands, and to investigate differences in its expression in relation to E-cadherin gene (CDH1) -160C/A polymorphism. DESIGN: Twenty-four PA (15 cell-rich and 9 cell-poor tumors) and 24 ACC (10 tubular, 8 cribriform and 6 solid tumors) were selected for the analysis of pattern of distribution, and cellular localization of E-cadherin. In addition, E-cadherin expression was evaluated using the H-score scoring system. The CDH1 -160C/A polymorphism was investigated by PCR-RFLP. RESULTS: No significant differences in pattern of distribution (p=0.181) and cellular localization (p=0.192) of E-cadherin were observed between PA and ACC. Comparison of PA and ACC cases revealed a higher median H-score in the latter (p=0.036). Cell-rich PA presented a higher H-score than cell-poor tumors (p=0.013), whereas no significant differences in E-cadherin expression were observed between ACC subtypes (p=0.254). The heterozygous genotype of the CDH1 -160C/A polymorphism was detected in only one PA and one ACC. H-scores for tumors carrying the polymorphism were below the lower quartile of their respective groups. CONCLUSIONS: The results suggest that E-cadherin expression in PA and ACC is mainly related to cellular composition (epithelial cells versus myoepithelial cells) and degree of differentiation of myoepithelial cells in these tumors. The CDH1 -160C/A polymorphism does not seem to significantly influence the expression of E-cadherin in PA and ACC of salivary glands.
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Adenoma Pleomórfico/genética , Cadherinas/genética , Carcinoma Adenoide Quístico/genética , Neoplasias de las Glándulas Salivales/genética , Adenoma Pleomórfico/metabolismo , Antígenos CD , Cadherinas/metabolismo , Carcinoma Adenoide Quístico/metabolismo , Electroforesis en Gel de Poliacrilamida , Genotipo , Humanos , Técnicas para Inmunoenzimas , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción , Neoplasias de las Glándulas Salivales/metabolismoAsunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma Adenoide Quístico/metabolismo , Transformación Celular Neoplásica/patología , Gotas Lipídicas/patología , Neoplasias de las Glándulas Salivales/metabolismo , Adulto , Carcinoma Adenoide Quístico/diagnóstico , Proliferación Celular , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Pronóstico , Neoplasias de las Glándulas Salivales/diagnósticoRESUMEN
Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is strongly expressed in malignant tumors and has been associated with their aggressive behavior. The aim of this study was to evaluate the presence of IMP3 in a series of salivary gland tumors. The sample consisted of 9 pleomorphic adenomas (PA), 14 adenoid cystic carcinomas (ACC), and 13 mucoepidermoid carcinomas (MEC) that were investigated by immunohistochemical technique. All cases of PA and MEC were positive for IMP3 particularly in the cytoplasm. PA showed 4 cases as high expression and 6 as low expression. MEC showed 10 cases as low expression and 3 as high expression. For ACC, 4 cases were high expression, whereas 6 cases were low expression. No significant difference was observed between tumors (P>0.05, Fisher's test) when both scores of IMP3 were compared. This study showed that MEC seems to be more sensitive to IMP3 than ACC and provided an insight into this protein in salivary gland tumors. Furthermore, although IMP3 is not a specific diagnostic marker to distinguish the tumors studied, it seems to mediate cell adhesion and migration in these tumors. Further studies should be performed to better understand the IMP3 biology in salivary gland tumors.
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Proteínas de Unión al ARN/metabolismo , Neoplasias de las Glándulas Salivales/metabolismo , Adenoma Pleomórfico/metabolismo , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Mucoepidermoide/metabolismo , HumanosRESUMEN
Introdução: As neoplasias das glândulas salivares têm amplo espectro histológico resultante da múltipla diferenciação celular tumoral. O adenoma pleomórfico (AP) e o carcinoma adenoide cístico (CAC) são as mais comuns neoplasias benignas e malignas provenientes do ducto intercalado, respectivamente, além de serem compostas por estruturas luminais e células mioepiteliais. Em estudo realizado previamente pelo nosso grupo, detectamos que a proteína c-kit está envolvida nos processos da morfogênese das glândulas salivares e no adenoma pleomórfico. A proteína c-Kit tem papel importante no desenvolvimento de muitos processos embrionários, incluindo a gametogênese, melanogênese e hematopoiese, e também na biologia de tumores. Sua ativação induz diversas respostas intracelulares através de cascatas de sinalização de vias como PI3K/AKT e MAPK. Em tumores da glândula salivar ainda há poucos estudos sobre as alterações do gene KIT e das proteínas relacionadas a sua via de sinalização, assim como sua regulação pós-transcricional, realizada principalmente por meio dos microRNAs. O presente estudo avaliou, em APs e CACs (a) a localização das proteínas das vias PI3K/AKT/mTOR e MAPK por meio da técnica de imunoistoquímica; (b) a expressão dos microRNAs 221 e 222, relacionados ao gene KIT (c) a associação dos achados laboratoriais com variáveis clínicas, patológicas e sobrevida. Resultados: Nos casos de AP a proteína c-Kit foi identificada em formações luminais e em raras células isoladas no parênquima tumoral. Já nos CAC, observou-se positividade na membrana das células ductais. Para a via de PI3K/AKT/mTOR, no AP, a proteína PI3K beta mostrou-se parcialmente positiva no citoplasma das células próximas à capsula tumoral, e as proteínas AKT e mTOR fosforiladas, foram expressas especialmente nas células epiteliais e em poucas células mioepiteliais. Já no CAC, a proteína PI3K beta e AKT fosforilada mostraram-se negativas na maioria dos casos, e a proteína mTOR fosforilada foi expressa no citoplasma das células epiteliais e em algumas células mioepiteliais. Para a via MAPK, as proteínas RAS, MEK-1 fosforilada e ERK 1/2 foram negativas na maioria dos AP e CAC; B-Raf e MEK-2 fosforilada foram observadas nas células luminais dos AP. Nos CAC, estruturas luminais neoplásicas foram positivas para a proteína MEK-2 fosforilada; B-Raf foi positivo nas células luminais e mioepiteliais. Além disso, os pacientes que expressaram as proteínas mTOR e MEK-2 fosforilada apresentaram sobrevida câncer-específica significativamente aumentada (p=0,040 e p=0,005, respectivamente). Na análise do microRNAs, a expressão do miR-221 foi variável nas 13 amostras analisadas, tendo baixa expressão em 30,77% dos casos, expressão normal em 38,46 e expressão aumentada em 30,77% dos casos. Já nos APs o miR-221 foi detectado em 19 amostras, sendo 36,84% com baixa expressão, 52,63% com expressão normal e expressão aumentada foi vista em 10,53% dos casos. A expressão do miR-222 foi detectada em 14 CACs, sendo que a maioria dos casos (8 casos 57,1%) a expressão do miR-222 foi semelhante ao observado nas amostras não neoplásicas. Nos APs, o miR-222 foi detectado em 22 amostras, sendo 31,8% com baixa expressão, 31,8% com expressão normal e 36,4% com expressão aumentada. Conclusão: Apesar de a proteína c-Kit ser expressa em ambas as neoplasias AP e CAC, sua influência sobre as vias de sinalização MAPK e PI3K/AKT/mTOR ainda permanece por ser estabelecida. Ainda, os microRNAs 221 e 222 não mostram correlação consistente com a expressão de c-Kit nos tipos tumorais estudados.
Introduction: Salivary gland tumors present broad histological spectrum resulting from multiple tumor cell differentiation. Pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC) are the commonest benign and malignant salivary gland neoplasms originated from the intercalated duct region, respectively, and are composed by luminal structures and myoepithelial cells. In a previous study we detected that protein c-kit is involved in the process of salivary gland morphogenesis and PA. c-Kit protein is important during embryogenesis, including gametogenesis, melanogeneis and hematopoiesis as well as in tumorigenesis. Its activation induces various intracellular responses through pathways such as MAPK and PI3K/AKT/mTOR signaling cascades. In salivary gland neoplasms, only a few reports have shown that alterations in KIT gene are present and proteins related to its signaling pathway as well as its post-transcriptional regulation. This study has aimed at evaluating in PA and ACC: (a) the proteins location of PI3K/AKT/mTOR and MAPK pathways using immunohistochemistry (IHC); (b) expression of miR-221 and miR-222, related to KIT gene; and (c) the association of these findings with clinical, pathological and survival data of patients. Results: In PA c-kit was positive in isolated luminal cells; in ACC, neoplastic luminal structures were positive for c-Kit. In PA, PI3K beta protein was shown to be partially positive in the cytoplasm of cells near the tumor capsule and phosphor AKT and phospho mTOR, are specifically expressed in epithelial cells and in a few myoepithelial. In ACC, PI3K and phosphor AKT protein showed to be negative in most of cases. Phospho mTOR protein was expressed in the cytoplasm of epithelial cells and some myoepithelial cells. In MAPK pathway, Ras, ERK1/2 and phosphor MEK-1 proteins were negative in most PAs and CACs; B-Raf and phospho MEK-2 were detected in luminal cells of PA. In ACC neoplastic luminal structures were positive for phospho MEK-2; B-Raf was also positive in myoepithelial and epithelial cells. In addition, cases with expressed phospho-mTOR and phosphor MEK-2 proteins were significantly associated with higher cancer-specific survival (p = 0.040 and p = 0.005, respectively). Moreover, expression of miR-221 was detected in 13 CAC samples and 19 PA samples. In CAC, expression of miR-221 was downregulated in 30,77% of the samples, upregulated in 30,77% samples, and normal in 38,46% samples. In PA, miR-221 expression was downregulated in 36,84% samples, upregulated in 10,53% samples, and normal in 52,63% samples. Expression of miR-222 was detected in 14 CAC samples and 22 PA samples. In the majority of CAC samples, the expression of miR-222 was similar to that observed in non-neoplastic samples. In PA samples, expression of miR-222 was downregulated in 31,8% samples, upregulated in 36,4% samples, and normal in 31,8% samples. Conclusion: Although c-Kit expression is detected in PA and ACC, its influence on the MAPK e PI3K/AKT/mTOR signaling cascades remains to be established. miR-221 e -222 did not show a robust correlation with c-Kit expression in the tumors studied.
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Humanos , Masculino , Femenino , Niño , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Adulto Joven , Neoplasias de las Glándulas Salivales/genética , Carcinoma Adenoide Quístico/genética , Adenoma Pleomórfico/genética , Proteínas Proto-Oncogénicas c-kit/genética , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/patología , Expresión Génica , Análisis de Supervivencia , Regulación de la Expresión Génica , Proteínas Proto-Oncogénicas/fisiología , Proteínas Proto-Oncogénicas/metabolismo , ADN Complementario , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/patología , Adenoma Pleomórfico/metabolismo , Adenoma Pleomórfico/patología , Proteínas Proto-Oncogénicas c-kit/fisiología , Proteínas Proto-Oncogénicas c-kit/metabolismo , MicroARNs , MutaciónRESUMEN
We investigated the effects of gossypol acetic acid (GAA) on the proliferation, apoptosis, and expression of DNA methyltransferase 1 (DNMT1) mRNA in human adenoid cystic carcinoma (ACC-M) cells in vitro. The proliferation and apoptosis of ACC-M cells after treatment with different concentrations of GAA were detected using Cell Counting Kit-8 and flow cytometry, respectively. DNMT1 mRNA expression was measured by real-time fluorescence quantitative polymerase chain reaction. The growth of ACC-M cells was inhibited after treatment with GAA for 24, 48, and 72 h. The apoptotic rates of ACC-M cells after treatment with GAA for 72 h were higher than those of control cells (without treatment) (P < 0.05). DNMT1 mRNA expression in ACC-M after treatment with GAA for 72 h was lower than that in control cells (P < 0.05). GAA had inhibitory effects on the proliferation and induced apoptosis of human ACC-M cells, while GAA also reduced the expression level of DNMT1 mRNA in ACC-M cells.