RESUMO
BACKGROUND: Trophoblast cell surface antigen 2 (TROP2) has unclear clinical role in oral squamous cell carcinomas (OSCC). Here, we investigated the association of TROP2 immunoexpression with clinicopathological parameters and survival of OSCC patients. SUBJECTS AND METHODS: Cancer-specific survival (CSS) and disease-free survival (DFS) were assessed in a cohort composed of 266 OSCC. An independent cohort with 88 OSCC samples matched with the normal oral tissue, as well as 17 metastatic lymph nodes, was used for validation. RESULTS: Multivariate analysis showed TROP2 as an independent marker of favorable prognosis for both CSS (HR: 0.60, 95% CI: 0.40-0.90, p = .01) and DFS (HR: 0.57, 95% CI: 0.36-0.89, p = .01). Furthermore, TROP2 protein expression was significantly higher in morphologically normal tissues compared to primary tumors (p < .0001) and lymph node metastases (p = .001), and it was significantly associated with CSS (HR: 0.26, 95% CI: 0.09-0.74, p = .008) in the validation cohort. A pooled mRNA analysis performed on the Oncomine™ database confirmed the underexpression in OSCC compared with normal tissues (p = .014). CONCLUSIONS: In summary, our results point to a favorable prognostic significance of TROP2 overexpression in a large cohort of oral cancer patients, suggesting it as an attractive clinical marker.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Carcinoma de Células Escamosas/patologia , Moléculas de Adesão Celular/genética , Humanos , Neoplasias Bucais/patologia , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Trofoblastos/metabolismo , Trofoblastos/patologiaRESUMO
Stanniocalcin 2 (STC2), a glycoprotein that regulates calcium and phosphate homeostasis during mineral metabolism, appears to display multiple roles in tumorigenesis and cancer progression. This study aimed to access the prognostic value of STC2 in oral squamous cell carcinoma (OSCC) and its implications in oral tumorigenesis. STC2 expression was examined in 2 independent cohorts of OSCC tissues by immunohistochemistry. A loss-of-function strategy using shRNA targeting STC2 was employed to investigate STC2 in vitro effects on proliferation, apoptosis, migration, invasion, epithelial-mesenchymal transition (EMT) and possible activation of signaling pathways. Moreover, STC2 effects were assessed in vivo in a xenograft mouse cancer model. High expression of STC2 was significantly associated with poor disease-specific survival (HR: 2.67, 95% CI: 1.37-5.21, p = 0.001) and high rate of recurrence with a hazard ratio of 2.80 (95% CI: 1.07-5.71, p = 0.03). In vitro downregulation of STC2 expression in OSCC cells attenuated proliferation, migration and invasiveness while increased apoptotic rates. In addition, the STC2 downregulation controlled EMT phenotype of OSCC cells, with regulation on E-cadherin, vimentin, Snail1, Twist and Zeb2. The reactivation of STC2 was observed in the STC2 knockdown cells in the in vivo xenograft model, and no influence on tumor growth was observed. Modulation of STC2 expression levels did not alter consistently the phosphorylation status of CREB, ERK, JNK, p38, p70 S6K, STAT3, STAT5A/B and AKT. Our findings suggest that STC2 overexpression is an independent marker of OSCC outcome and may contribute to tumor progression via regulation of proliferation, survival and invasiveness of OSCC cells.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Bucais/metabolismo , Recidiva Local de Neoplasia/metabolismo , Adulto , Idoso , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/patologia , Recidiva Local de Neoplasia/genéticaRESUMO
AIMS: Previous studies have demonstrated that the tumour-stroma ratio (TSR) and tumour budding are of prognostic value for oral squamous cell carcinomas (OSCCs). The aim of this study was to evaluate the prognostic significance of those histological parameters, individually and in combination, for OSCC. METHODS AND RESULTS: The TSR and tumour budding (the presence of five or more buds at the invasive front) were estimated in 254 patients with OSCC. The clinicopathological association was investigated with a chi-square test, and the prognostic significance (cancer-specific survival and disease-free survival) was verified with Kaplan-Meier analysis and the Cox proportional hazard model. The TSR (≥50%, stroma-rich) was significantly and independently associated with both shortened cancer-specific survival and poor disease-free survival, whereas tumour budding was significantly associated with reduced cancer-specific survival. The TSR/tumour budding model was independently associated with a high risk of cancer mortality and recurrence (disease-free survival). In patients with early-stage tumours (clinical stage I and II, n = 103), the TSR, tumour budding and the TSR/tumour budding model were significantly associated with both cancer-related death and recurrence, whereas, in advanced-stage tumours (clinical stage III and IV, n = 144), only the TSR and the TSR/tumour budding model were significantly associated with cancer-specific survival. CONCLUSIONS: The TSR, tumour budding and their combination provide significant information on OSCC outcome, suggesting that their incorporation in the routine evaluation of histopathological specimens might be useful in prognostication for OSCC patients.
Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidadeRESUMO
BACKGROUND: Rho-associated coiled-coil kinase 2 (ROCK2) is an oncoprotein that controls cytoskeleton organization and acts as prognostic marker in different types of solid tumors. ROCK2 overexpression is also observed in cancer-associated fibroblasts (CAF), which suggests its relevance within the tumor microenvironment. This study aimed to access the prognostic value of ROCK2 in oral squamous cell carcinomas (OSCCs) and its association with CAF density. METHODS: Rho-associated coiled-coil kinase 2 immunohistochemical analysis was applied in 93 OSCC samples from 2 centers in Brazil and Finland. The samples were also stained for isoform α of smooth muscle actin (α-SMA) to characterize the presence of CAF in the tumor stroma. Clinicopathological associations were analyzed using Chi-squared test, survival curves were constructed according to the Kaplan-Meier method, and Cox proportional hazard model was applied for multivariate survival analysis. RESULTS: Advanced clinical stage (P = .002) and increased density of CAF (P = .002) were significantly associated with high ROCK2 expression. The high expression of ROCK2 was also associated with shortened disease-specific survival (HR: 2.22, 95% CI: 1.15-4.38, P = .04), but the association did not withstand the Cox multivariate survival analysis. CONCLUSIONS: The findings suggest that high ROCK2 expression in OSCC is associated with advanced disease and follows the increase in CAF density, which may be important for tumor progression.
Assuntos
Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/enzimologia , Neoplasias Bucais/patologia , Quinases Associadas a rho/metabolismo , Actinas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas , Biomarcadores Tumorais/análise , Brasil , Fibroblastos Associados a Câncer/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/cirurgia , Feminino , Finlândia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/mortalidade , Neoplasias Bucais/cirurgia , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Fumar , Análise de Sobrevida , Microambiente TumoralRESUMO
OBJECTIVES: Oral squamous cell carcinoma (OSCC) predominantly affects males in the fifth decade of life; nevertheless, an increased incidence in young patients has been reported worldwide, and the clinical and behavioral characteristics of tumors in this group are controversial, and the literature shows divergent results. PURPOSE: To investigate the clinicopathological features and prognostic significance of the immunoexpression of cell cycle and local invasion proteins in OSCC affecting young patients (≤40 years old). METHODS: A tissue microarray was performed with 132 OSCC samples (61 cases of young patients vs 71 cases of elderly patients) and submitted to immunohistochemical reactions with Ki67, p53, p16, Bcl-2, Cyclin D1, C-ErbB2, p21, Myc, EGFR, MMP-9, SMA, Cathepsin K and FGF-2 antibodies. RESULTS: Clinicopathological features and survival rates were similar in both groups. Although overexpression of EGFR (P=.042) and MMP-9 (P=.001) was more frequent in young patients, only C-ErbB-2 (P=.048) and SMA (P=.048) expression correlated with lower disease-free survival (DFS) in this group of patients. CONCLUSION: Clinicopathological features and survival rates are similar between younger and older patients with OSCC. The different patterns of C-ErbB2, EGFR, MMP-9, and SMA expression between the groups merits further investigation to understand their role in the early tumor onset in young patients.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias Bucais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Catepsina K/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Ciclina D1/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Intervalo Livre de Doença , Células Epiteliais/patologia , Receptores ErbB/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptor ErbB-2/metabolismo , Taxa de Sobrevida , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Oral tongue squamous cell carcinoma (OTSCC) metastasises early, especially to regional lymph nodes. There is an ongoing debate on which early stage (T1-T2N0) patients should be treated with elective neck dissection. We need prognosticators for early stage tongue cancer. METHODS: Mice immunisation with human mesenchymal stromal cells resulted in production of antibodies against tenascin-C (TNC) and fibronectin (FN), which were used to stain 178 (98 early stage), oral tongue squamous cell carcinoma samples. Tenascin-C and FN expression in the stroma (negative, moderate or abundant) and tumour cells (negative or positive) were assessed. Similar staining was obtained using corresponding commercial antibodies. RESULTS: Expression of TNC and FN in the stroma, but not in the tumour cells, proved to be excellent prognosticators both in all stages and in early stage cases. Among early stages, when stromal TNC was negative, the 5-year survival rate was 88%. Correspondingly, when FN was negative, no cancer deaths were observed. Five-year survival rates for abundant expression of TNC and FN were 43% and 25%, respectively. CONCLUSIONS: Stromal TNC and, especially, FN expressions differentiate patients into low- and high-risk groups. Surgery alone of early stage primary tumours might be adequate when stromal FN is negative. Aggressive treatments should be considered when both TNC and FN are abundant.
Assuntos
Carcinoma de Células Escamosas/patologia , Fibronectinas/metabolismo , Células Estromais/metabolismo , Tenascina/metabolismo , Neoplasias da Língua/patologia , Carcinoma de Células Escamosas/metabolismo , Gerenciamento Clínico , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Neoplasias da Língua/metabolismoRESUMO
An important role has been attributed to cancer-associated fibroblasts (CAFs) in the tumorigenesis of oral squamous cell carcinoma (OSCC), the most common tumor of the oral cavity. Previous studies demonstrated that CAF-secreted molecules promote the proliferation and invasion of OSCC cells, inducing a more aggressive phenotype. In this study, we searched for differences in the secretome of CAFs and normal oral fibroblasts (NOF) using mass spectrometry-based proteomics and biological network analysis. Comparison of the secretome profiles revealed that upregulated proteins involved mainly in extracellular matrix organization and disassembly and collagen metabolism. Among the upregulated proteins were fibronectin type III domain-containing 1 (FNDC1), serpin peptidase inhibitor type 1 (SERPINE1), and stanniocalcin 2 (STC2), the upregulation of which was validated by quantitative PCR and ELISA in an independent set of CAF cell lines. The transition of transforming growth factor beta 1 (TGF-ß1)-mediating NOFs into CAFs was accompanied by significant upregulation of FNDC1, SERPINE1, and STC2, confirming the participation of these proteins in the CAF-derived secretome. Type I collagen, the main constituent of the connective tissue, was also associated with several upregulated biological processes. The immunoexpression of type I collagen N-terminal propeptide (PINP) was significantly correlated in vivo with CAFs in the tumor front and was associated with significantly shortened survival of OSCC patients. Presence of CAFs in the tumor stroma was also an independent prognostic factor for OSCC disease-free survival. These results demonstrate the value of secretome profiling for evaluating the role of CAFs in the tumor microenvironment and identify potential novel therapeutic targets such as FNDC1, SERPINE1, and STC2. Furthermore, type I collagen expression by CAFs, represented by PINP levels, may be a prognostic marker of OSCC outcome.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Neoplasias Bucais/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular , Linhagem Celular Tumoral , Intervalo Livre de Doença , Matriz Extracelular/patologia , Feminino , Fibroblastos/patologia , Glicoproteínas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Neoplasias Bucais/patologia , Proteínas de Neoplasias/metabolismo , Fragmentos de Peptídeos/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Pró-Colágeno/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Microambiente Tumoral/fisiologia , Regulação para Cima/fisiologiaRESUMO
Poor prognosis associated with the dysregulated expression of activin A in a number of malignancies has been related to with numerous aspects of tumorigenesis, including angiogenesis. The present study investigated the prognostic significance of activin A immunoexpression in blood vessels and cancer cells in a number of oral squamous cell carcinoma (OSCC) cases and applied in vitro strategies to determine the impact of activin A on angiogenesis. In a cohort of 95 patients with OSCC, immunoexpression of activin A in both blood vessels and tumor cells was quantified and the association with clinicopathological parameters and survival was analyzed. Effects of activin A on the tube formation, proliferation and migration of human umbilical vein endothelial cells (HUVECs) were evaluated in gainoffunction (treatment with recombinant activin A) or lossoffunction [treatment with activin Aantagonist follistatin or by stable transfection with short hairpin RNA (shRNA) targeting activin A] conditions. Conditioned medium from an OSCC cell line with shRNAmediated depletion of activin A was also tested. The profile of pro and antiangiogenic factors regulated by activin A was assessed with a human angiogenesis quantitative PCR (qPCR) array. Vascular endothelial growth factor A (VEGFA) and its major isoforms were evaluated by reverse transcriptionqPCR and ELISA. Activin A expression in blood vessels demonstrated an independent prognostic value in the multivariate analysis with a hazard ratio of 2.47 [95% confidence interval (CI), 1.304.71; P=0.006) for diseasespecific survival and 2.09 (95% CI, 1.074.08l: P=0.03) for diseasefree survival. Activin A significantly increased tubular formation of HUVECs concomitantly with an increase in proliferation. This effect was validated by reduced proliferation and tubular formation of HUVECs following inhibition of activin A by follistatin or shRNA, as well as by treatment of HUVECs with conditioned medium from activin Adepleted OSCC cells. Activin Aknockdown increased the migration of HUVECs. In addition, activin A stimulated the phosphorylation of SMAD2/3 and the expression and production of total VEGFA, significantly enhancing the expression of its proangiogenic isoform 121. The present findings suggest that activin A is a predictor of the prognosis of patients with OSCC, and provide evidence that activin A, in an autocrine and paracrine manner, may contribute to OSCC angiogenesis through differential expression of the isoform 121 of VEGFA.
Assuntos
Ativinas/metabolismo , Neoplasias Bucais/patologia , Neovascularização Patológica/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ativinas/análise , Ativinas/antagonistas & inibidores , Ativinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Comunicação Autócrina/efeitos dos fármacos , Comunicação Autócrina/genética , Movimento Celular , Proliferação de Células , Feminino , Folistatina/farmacologia , Folistatina/uso terapêutico , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Neoplasias Bucais/irrigação sanguínea , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/mortalidade , Comunicação Parácrina/efeitos dos fármacos , Comunicação Parácrina/genética , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Prognóstico , Isoformas de Proteínas/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/irrigação sanguínea , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidadeRESUMO
BACKGROUND: The proper estimate of the risk of recurrences in early-stage oral tongue squamous cell carcinoma (OTSCC) is mandatory for individual treatment-decision making. However, this remains a challenge even for experienced multidisciplinary centers. OBJECTIVES: We compared the performance of four machine learning (ML) algorithms for predicting the risk of locoregional recurrences in patients with OTSCC. These algorithms were Support Vector Machine (SVM), Naive Bayes (NB), Boosted Decision Tree (BDT), and Decision Forest (DF). MATERIALS AND METHODS: The study cohort comprised 311 cases from the five University Hospitals in Finland and A.C. Camargo Cancer Center, São Paulo, Brazil. For comparison of the algorithms, we used the harmonic mean of precision and recall called F1 score, specificity, and accuracy values. These algorithms and their corresponding permutation feature importance (PFI) with the input parameters were externally tested on 59 new cases. Furthermore, we compared the performance of the algorithm that showed the highest prediction accuracy with the prognostic significance of depth of invasion (DOI). RESULTS: The results showed that the average specificity of all the algorithms was 71% . The SVM showed an accuracy of 68% and F1 score of 0.63, NB an accuracy of 70% and F1 score of 0.64, BDT an accuracy of 81% and F1 score of 0.78, and DF an accuracy of 78% and F1 score of 0.70. Additionally, these algorithms outperformed the DOI-based approach, which gave an accuracy of 63%. With PFI-analysis, there was no significant difference in the overall accuracies of three of the algorithms; PFI-BDT accuracy increased to 83.1%, PFI-DF increased to 80%, PFI-SVM decreased to 64.4%, while PFI-NB accuracy increased significantly to 81.4%. CONCLUSIONS: Our findings show that the best classification accuracy was achieved with the boosted decision tree algorithm. Additionally, these algorithms outperformed the DOI-based approach. Furthermore, with few parameters identified in the PFI analysis, ML technique still showed the ability to predict locoregional recurrence. The application of boosted decision tree machine learning algorithm can stratify OTSCC patients and thus aid in their individual treatment planning.
Assuntos
Algoritmos , Árvores de Decisões , Neoplasias Bucais/terapia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Aprendizado de Máquina Supervisionado , Neoplasias da Língua/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Brasil/epidemiologia , Quimiorradioterapia , Criança , Estudos de Coortes , Terapia Combinada , Feminino , Finlândia/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Recidiva Local de Neoplasia/classificação , Prognóstico , Máquina de Vetores de Suporte , Neoplasias da Língua/patologia , Adulto JovemRESUMO
Estimation of risk of recurrence in early-stage oral tongue squamous cell carcinoma (OTSCC) remains a challenge in the field of head and neck oncology. We examined the use of artificial neural networks (ANNs) to predict recurrences in early-stage OTSCC. A Web-based tool available for public use was also developed. A feedforward neural network was trained for prediction of locoregional recurrences in early OTSCC. The trained network was used to evaluate several prognostic parameters (age, gender, T stage, WHO histologic grade, depth of invasion, tumor budding, worst pattern of invasion, perineural invasion, and lymphocytic host response). Our neural network model identified tumor budding and depth of invasion as the most important prognosticators to predict locoregional recurrence. The accuracy of the neural network was 92.7%, which was higher than that of the logistic regression model (86.5%). Our online tool provided 88.2% accuracy, 71.2% sensitivity, and 98.9% specificity. In conclusion, ANN seems to offer a unique decision-making support predicting recurrences and thus adding value for the management of early OTSCC. To the best of our knowledge, this is the first study that applied ANN for prediction of recurrence in early OTSCC and provided a Web-based tool.
Assuntos
Aprendizado de Máquina , Recidiva Local de Neoplasia , Redes Neurais de Computação , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Neoplasias da Língua/patologia , Adulto , Idoso , Feminino , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Prognóstico , Sensibilidade e EspecificidadeRESUMO
Different regions of oral squamous cell carcinoma (OSCC) have particular histopathological and molecular characteristics limiting the standard tumor-node-metastasis prognosis classification. Therefore, defining biological signatures that allow assessing the prognostic outcomes for OSCC patients would be of great clinical significance. Using histopathology-guided discovery proteomics, we analyze neoplastic islands and stroma from the invasive tumor front (ITF) and inner tumor to identify differentially expressed proteins. Potential signature proteins are prioritized and further investigated by immunohistochemistry (IHC) and targeted proteomics. IHC indicates low expression of cystatin-B in neoplastic islands from the ITF as an independent marker for local recurrence. Targeted proteomics analysis of the prioritized proteins in saliva, combined with machine-learning methods, highlights a peptide-based signature as the most powerful predictor to distinguish patients with and without lymph node metastasis. In summary, we identify a robust signature, which may enhance prognostic decisions in OSCC and better guide treatment to reduce tumor recurrence or lymph node metastasis.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/mortalidade , Neoplasias Bucais/mortalidade , Recidiva Local de Neoplasia/diagnóstico , Proteômica/métodos , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Tomada de Decisão Clínica , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Metástase Linfática , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/patologia , Recidiva Local de Neoplasia/prevenção & controle , Peptídeos/análise , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Saliva/química , Taxa de SobrevidaRESUMO
Oral squamous cell carcinoma (OSCC) prognosis is related to clinical stage and histological grade. However, this stratification needs to be refined. We conducted a comparative proteome study in microdissected samples from normal oral mucosa and OSCC to identify biomarkers for malignancy. Fascin and plectin were identified as differently expressed and both are implicated in several malignancies, but the clinical impacts of aberrant fascin and plectin expression in OSCCs remains largely unknown. Immunohistochemistry and real-time quantitative PCR were carried out in ex vivo OSCC samples and cell lines. A loss-of-function strategy using shRNA targeting fascin was employed to investigate in vitro and in vivo the fascin role on oral tumorigenesis. Transfections of microRNA mimics were performed to determine whether the fascin overexpression is regulated by miR-138 and miR-145. We found that fascin and plectin are frequently upregulated in OSCC samples and cell lines, but only fascin overexpression is an independent unfavorable prognostic indicator of disease-specific survival. In combination with advanced T stage, high fascin level is also an independent factor of disease-free survival. Knockdown of fascin in OSCC cells promoted cell adhesion and inhibited migration, invasion and EMT, and forced expression of miR-138 in OSCC cells significantly decreased the expression of fascin. In addition, fascin downregulation leads to reduced filopodia formation and decrease on paxillin expression. The subcutaneous xenograft model showed that tumors formed in the presence of low levels of fascin were significantly smaller compared to those formed with high fascin levels. Collectively, our findings suggest that fascin expression correlates with disease progression and may serve as a prognostic marker and therapeutic target for patients with OSCC.