RESUMEN

Oral squamous cell carcinoma (OSCC) is the most common oral malignancy, representing 90% of all malignant neoplasms in the head and neck region. Patients with this aggressive tumor have an overall 5-year survival rate of approximately 50%, which drops to less than 30% when tumors are diagnosed at advanced clinical stages. Over decades, several studies provided high-level evidence of the impact of histopathological features on treatment guidelines and prognosis of OSCC. The 8th American Joint Committee on Cancer (AJCC) TNM staging system recognized the importance of depth of invasion to the T category and extranodal extension to the N category for OSCC. This review provides the current knowledge on emerging histopathological parameters identified as potential biomarkers for OSCC, such as depth of invasion, tumor thickness, the pattern of invasion, inflammatory profile, and tumor-stroma ratio, evaluating their clinical relevance on patient outcomes. Analysis, limitations, and potential biological mechanisms are highlighted and discussed. Assessing and reporting these markers are cost-effective and can be incorporated into daily practice.

Asunto(s)

Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/patología , Pronóstico , Estadificación de Neoplasias , Neoplasias de Cabeza y Cuello/patología , Estudios Retrospectivos

RESUMEN

BACKGROUND: The expression of heat-shock protein 47 (HSP47) has been linked to collagen synthesis control and implicated in fibrotic disorders, but more recent studies have demonstrated its role in solid tumors. In this study, we explored the prognostic impact of HSP47 in oral squamous cell carcinomas (OSCC) and determined the in vitro effects of its loss-of-function on viability, proliferation, migration, invasion, and resistance to cisplatin of OSCC cells. METHODS: The HSP47 expression in tumor samples was assessed by immunohistochemistry in two independent cohorts totaling 339 patients with OSCC, and protein levels were associated with clinicopathological features and survival outcomes. The OSCC cell lines HSC3 and SCC9 were transduced with lentivirus expressing short hairpin RNA to stably silence HSP47 and used in assays to measure cellular viability, proliferation, migration, and invasion. RESULTS: HSP47 was overexpressed in OSCC samples, and its overexpression was significantly and independently associated with poor disease-specific survival and shortened disease-free survival in both OSCC cohorts. The knockdown of HSP47 showed no effects on cell viability or cisplatin sensitivity, but impaired significantly proliferation, migration, and invasion of OSCC cells, with stronger effects on SCC9 cells. CONCLUSION: Our results show a significant prognostic impact of HSP47 overexpression in OSCC and reveal that HSP47 inhibition impairs the proliferation, migration, and invasion of OSCC cells. HSP47 may represent a potential therapeutic target for OSCC.

Asunto(s)

Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas de Cabeza y Cuello , Proteínas del Choque Térmico HSP47/genética , Proteínas del Choque Térmico HSP47/metabolismo , Neoplasias de la Boca/patología , Cisplatino/farmacología , Línea Celular Tumoral , Proliferación Celular/genética , Movimiento Celular/genética

RESUMEN

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.

Asunto(s)

Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Carcinoma de Células Escamosas/patología , Moléculas de Adhesión Celular/genética , Humanos , Neoplasias de la Boca/patología , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello , Trofoblastos/metabolismo , Trofoblastos/patología

RESUMEN

Objective: Although there have been remarkable achievements in the molecular landscape of oral squamous cell carcinoma (OSCC) in recent years, bringing advances in the understanding of its pathogenesis, development and progression, little has been applied in the prognosis and choosing the optimal treatment. In this study, we explored the influence of the stress induced phosphoprotein 1 (STIP1), which is frequently reported to be highly expressed in many cancers, in OSCCs. Methods: STIP1 expression was assessed in the TCGA database and in two independent cohorts by immunohistochemistry. Knockdown strategy was applied in OSCC cell lines to determine the impact of STIP1 on viability, proliferation, migration and invasion. The zebrafish model was applied for studying tumor formation and metastasis in vivo. The association of STIP1 and miR-218-5p was explored by bioinformatics and mimics transfection. Results: STIP1 was highly expressed in OSCCs and significantly associated with shortened survival and higher risk of recurrence. STIP1 down-regulation decreased proliferation, migration and invasion of tumor cells, and reduced the number of metastases in the Zebrafish model. STIP1 and miR-218-5p were inversely expressed, and the transfection of miR-218-5p mimics into OSCC cells decreased STIP1 levels as well as proliferation, migration and invasion. Conclusion: Our findings show that STIP1 overexpression, which is inversely associated with miR-218-5p levels, contributes to OSCC aggressiveness by controlling proliferation, migration and invasion and is a determinant of poor prognosis.

RESUMEN

OBJECTIVE: Over many decades, studies on histopathological features have not only presented high-level evidence of contribution for treatment directions and prognosis of oral squamous cell carcinoma (OSCC) but also provided inconsistencies, making clinical application difficult. The 8th TNM staging system of OSCC has acknowledged the importance of some histopathological features, by incorporating depth of invasion (DOI) to T category and extranodal extension (ENE) to N category. The aim of this systematic review with meta-analysis is to determine the most clinically relevant histopathological features for risk assessment and treatment planning of OSCC and to elucidate gaps in the literature. METHODS: A systematic review was conducted using PRISMA guidelines, and the eligibility criteria were based on population, exposure, comparison, outcome, and study type (PECOS). PubMed, Cochrane, Scopus, and Web of Science were searched for articles exploring the impact of histopathological features on OSCC outcomes with Cox multivariate analysis. Pooled data were subjected to an inverse variance method with random effects or fixed effect model, and the risk of bias was evaluated using quality in prognosis studies (QUIPS). Quality of evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. RESULTS: The study included 172 articles published from 1999 to 2021. Meta-analyses confirmed the prognostic potential of DOI, ENE, perineural invasion, lymphovascular invasion, and involvement of the surgical margins and brought promising results for the association of bone invasion, tumor thickness, and pattern of invasion with increased risk for poor survival. Although with a small number of studies, the results also revealed a clinical significance of tumor budding and tumor-stroma ratio on predicted survival of patients with OSCC. Most of the studies were considered with low or moderate risk of bias, and the certainty in evidence varied from very low to high. CONCLUSION: Our results confirm the potential prognostic usefulness of many histopathological features and highlight the promising results of others; however, further studies are advised to apply consistent designs, filling in the literature gaps to the pertinence of histopathological markers for OSCC prognosis. SYSTEMATIC REVIEW REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO), identifier CRD42020219630.

RESUMEN

Juvenile nasopharyngeal angiofibroma (JNA) is a rare fibrovascular benign tumor showing an invasive growth pattern and affecting mainly male adolescents. We investigated the role of epithelial-mesenchymal transition (EMT) and WNT signaling pathways in JNA. Gene expression profiles using nine JNA paired with four inferior nasal turbinate samples were interrogated using a customized 2.3K microarray platform containing genes mainly involved in EMT and WNT/PI3K pathways. The expression of selected genes (BCL2, CAV1, CD74, COL4A2, FZD7, ING1, LAMB1, and RAC2) and proteins (BCL2, CAV1, CD74, FZD7, RAF1, WNT5A, and WNT5B) was investigated by RT-qPCR (28 cases) and immunohistochemistry (40 cases), respectively. Among 104 differentially expressed genes, we found a significantly increased expression of COL4A2 and LAMB1 and a decreased expression of BCL2 and RAC2 by RT-qPCR. The immunohistochemistry analysis revealed a low expression of BCL2 and a negative to moderate expression of FZD7 in most samples, while increased CAV1 and RAF1 expression were detected. Moderate to strong CD74 protein expression was observed in endothelial and inflammatory cells. A significant number of JNAs (78%) presented reduced WNT5A and increased WNT5B expression. Overall, the transcript and protein profile indicated the involvement of EMT and WNT pathways in JNA. These candidates are promising druggable targets for treating JNA.

RESUMEN

other: Pathological parameters have been indicated as tumor prognostic factors in oral carcinoma. OBJECTIVE: The objective of this study was to investigate the impact of pathological parameters on prognosis of patients affected only by tongue and/or floor of the mouth squamous cell carcinoma (SCC). METHODOLOGY: In total, 380 patients treated in the Brazilian National Cancer Institute (INCA) from 1999 to 2006 were included. These patients underwent radical resection followed by neck dissection. The clinical and pathological characteristics were recorded. The Kaplan-Meier method and Cox proportional hazards model were used in survival analysis. Overall survival (OS), cancer-specific survival (CSS) and disease-free interval (DFI) were estimated. Cox residuals were evaluated using the R software version 3.5.2. Worst OS, CSS and DFI were observed in patients with tumors in advanced pathological stages (p<0.001), with the presence of perineural invasion (p<0.001) and vascular invasion (p=0.005). RESULTS: Advanced pathological stage and the presence of a poorly differentiated tumor were independent prognostic factors for OS and CSS. However, advanced pathological stage and perineural invasion were independent predictors of a shorter OS, DFI and CSS. CONCLUSION: Pathological stage and perineural invasion were the most significant pathological variables in survival analysis in tongue and/or floor of the mouth SCC.

Asunto(s)

Carcinoma de Células Escamosas/patología , Suelo de la Boca/patología , Neoplasias de la Boca/patología , Neoplasias de la Lengua/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/cirugía , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/mortalidad , Neoplasias de la Boca/cirugía , Disección del Cuello/métodos , Clasificación del Tumor/métodos , Estadificación de Neoplasias , Análisis de Regresión , Factores de Tiempo , Neoplasias de la Lengua/mortalidad , Neoplasias de la Lengua/cirugía , Adulto Joven

RESUMEN

Abstract Pathological parameters have been indicated as tumor prognostic factors in oral carcinoma. Objective: The objective of this study was to investigate the impact of pathological parameters on prognosis of patients affected only by tongue and/or floor of the mouth squamous cell carcinoma (SCC). Methodology: In total, 380 patients treated in the Brazilian National Cancer Institute (INCA) from 1999 to 2006 were included. These patients underwent radical resection followed by neck dissection. The clinical and pathological characteristics were recorded. The Kaplan-Meier method and Cox proportional hazards model were used in survival analysis. Overall survival (OS), cancer-specific survival (CSS) and disease-free interval (DFI) were estimated. Cox residuals were evaluated using the R software version 3.5.2. Worst OS, CSS and DFI were observed in patients with tumors in advanced pathological stages (p<0.001), with the presence of perineural invasion (p<0.001) and vascular invasion (p=0.005). Results: Advanced pathological stage and the presence of a poorly differentiated tumor were independent prognostic factors for OS and CSS. However, advanced pathological stage and perineural invasion were independent predictors of a shorter OS, DFI and CSS. Conclusion: Pathological stage and perineural invasion were the most significant pathological variables in survival analysis in tongue and/or floor of the mouth SCC.

Asunto(s)

Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Neoplasias de la Boca/patología , Neoplasias de la Lengua/patología , Carcinoma de Células Escamosas/patología , Suelo de la Boca/patología , Disección del Cuello/métodos , Factores de Tiempo , Neoplasias de la Boca/cirugía , Neoplasias de la Boca/mortalidad , Neoplasias de la Lengua/cirugía , Neoplasias de la Lengua/mortalidad , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/mortalidad , Análisis de Regresión , Supervivencia sin Enfermedad , Estimación de Kaplan-Meier , Clasificación del Tumor/métodos , Estadificación de Neoplasias

RESUMEN

Nanosilver immobilized on TiO2 nanometric fibers (Ag/TiO2) was produced by solution blow spinning and characterized using scanning electron microscopy, transmission electron microscopy, N2 adsorption/desorption, X-ray diffraction, X-ray photoelectron spectroscopy, water contact angle, and inductively coupled plasma emission spectroscopy analyses. The in vitro antimicrobial and anticancer activities of the produced nanofibers was also investigated. Ag/TiO2 nanofibers revealed a crystalline structure compatible with the rutile crystalline phase, as well as a mesoporous and superhydrophilic nature. XPS profiles showed Ti4+ and Ag0, indicating a strong interaction between the Ag nanoparticles and TiO2. The Ag/TiO2 nanofibers presented antimicrobial activity against Staphylococcus aureus, Enterococcus faecalis, and Escherichia coli. The release of silver ions from 5 mg∙mL-1 and 50 mg∙mL-1 of Ag/TiO2 nanofibers was approximately 0.08 µg∙mL-1 and 0.18 µg∙mL-1, respectively. The nanofiber cytotoxicity in both macrophages (ATCC RAW 264.7) and cancer cells (murine AT-84 oral squamous carcinoma cells) was dose-dependent. A concentration of 5 mg∙mL-1 induced partial suppression growth and migration of cancer cells, while a concentration of 50 mg∙mL-1 resulted in complete inhibition of proliferation and migration of murine AT-84 cells. The overall results indicate that Ag/TiO2 nanofibers can selectively inhibit the cellular mechanism of AT-84 by apoptosis with DNA damage and cell death. The antimicrobial and anticancer performance of Ag/TiO2 nanofibers is probably the result of its nanometric dimension, high surface reactivity, and the interaction between TiO2 and Ag. Electron transfer at the metal-semiconductor interface and reactive oxygen species production, in addition to the biological activity of released silver ions, confirm the potential for use as an agent in antimicrobial and anticancer therapy.

Asunto(s)

Antiinfecciosos/química , Antineoplásicos/química , Nanopartículas del Metal/química , Nanofibras/química , Plata/química , Titanio/química , Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Bacterias/efectos de los fármacos , Pruebas de Sensibilidad Microbiana/métodos , Microscopía Electrónica de Rastreo/métodos , Microscopía Electrónica de Transmisión/métodos , Espectroscopía de Fotoelectrones/métodos , Difracción de Rayos X/métodos

RESUMEN

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.

Asunto(s)

Biomarcadores de Tumor/análisis , Carcinoma de Células Escamosas/mortalidad , Neoplasias de la Boca/mortalidad , Recurrencia Local de Neoplasia/diagnóstico , Proteómica/métodos , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patología , Toma de Decisiones Clínicas , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Metástasis Linfática , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/patología , Recurrencia Local de Neoplasia/prevención & control , Péptidos/análisis , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Saliva/química , Tasa de Supervivencia

RESUMEN

BACKGROUND: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. METHODS: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. RESULTS: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. CONCLUSION: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.

Asunto(s)

Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Adulto , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Biología Computacional/métodos , Reparación de la Incompatibilidad de ADN , Femenino , Efecto Fundador , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Variación Genética , Mutación de Línea Germinal , Humanos , América Latina/epidemiología , Masculino , Persona de Mediana Edad , Vigilancia de la Población , Empalme del ARN , Sistema de Registros , Factores de Riesgo

RESUMEN

Breast cancer biomarkers that can precisely predict the risk of progression of non-invasive ductal carcinoma in situ (DCIS) lesions to invasive disease are lacking. The identification of molecular alterations that occur during the invasion process is crucial for the discovery of drivers of transition to invasive disease and, consequently, biomarkers with clinical utility. In this study, we explored differences in gene expression in mammary epithelial cells before and after the morphological manifestation of invasion, i.e., early and late stages, respectively. In the early stage, epithelial cells were captured from both pre-invasive lesions with distinct malignant potential [pure DCIS as well as the in situ component that co-exists with invasive breast carcinoma lesions (DCIS-IBC)]; in the late stage, epithelial cells were captured from the two distinct morphological components of the same sample (in situ and invasive components). Candidate genes were identified using cDNA microarray and rapid subtractive hybridization (RaSH) cDNA libraries and validated by RT-qPCR assay using new samples from each group. These analyses revealed 26 genes, including 20 from the early and 6 from the late stage. The expression profile based on the 20 genes, marked by a preferential decrease in expression level towards invasive phenotype, discriminated the majority of DCIS samples. Thus, this study revealed a gene expression signature with the potential to predict DCIS progression and, consequently, provides opportunities to tailor treatments for DCIS patients.

Asunto(s)

Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma in Situ/genética , Carcinoma in Situ/patología , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patología , Transcriptoma , Biomarcadores de Tumor , Progresión de la Enfermedad , Células Epiteliales/metabolismo , Femenino , Perfilación de la Expresión Génica , Estudios de Asociación Genética , Humanos , Estadificación de Neoplasias , Reproducibilidad de los Resultados

RESUMEN

BACKGROUND: Some single-nucleotide polymorphisms are associated with higher risk of colorectal cancer development and are suggested to explain part of the genetic contribution to Lynch syndrome. AIM: To evaluate the mutL homolog 1 (MLH1) I219V polymorphism in 124 unrelated South American individuals suspected of having Lynch syndrome, based on frequency, association with pathogenic MLH1 and mutS homolog 2 (MSH2) mutation and clinical features. MATERIALS AND METHODS: DNA was obtained from peripheral blood and polymerase chain reaction (PCR) was performed, followed by direct sequencing. RESULTS: The Val allelic of the I219V polymorphism was found in 51.61% (64/124) of the individuals, with an allelic frequency of 0.3. MLH1 or MHS2 pathogenic mutations were found in 32.81% (21/64) and in 23.33% (14/60) of Val-carriers and non-carriers, respectively. CONCLUSION: The Val-carrying genotype was frequent in the studied population; however, it does not appear to exert any modifier effect on MLH1 or MSH2 pathogenic mutations and the development of colorectal cancer.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Proteínas Nucleares/genética , Polimorfismo Genético , Adulto , Anciano , Secuencia de Bases , Neoplasias Colorrectales/genética , Femenino , Frecuencia de los Genes , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , América del Sur

RESUMEN

BACKGROUND: HOX genes encode homeodomain-containing transcription factors involved in the regulation of cellular proliferation and differentiation during embryogenesis. However, members of this family demonstrated oncogenic properties in some malignancies. The present study investigated whether genes of the HOXA cluster play a role in oral cancer. METHODS: In order to identify differentially expressed HOXA genes, duplex RT-PCR in oral samples from healthy mucosa and squamous cell carcinoma was used. The effects of HOXA1 on proliferation, apoptosis, adhesion, invasion, epithelial-mesenchymal transition (EMT) and anchorage-independent growth were assessed in cells with up- and down-regulation of HOXA1. Immunohistochemical analysis using a tissue microarray (TMA) containing 127 oral squamous cell carcinomas (OSCC) was performed to determine the prognostic role of HOXA1 expression. RESULTS: We showed that transcripts of HOXA genes are more abundant in OSCC than in healthy oral mucosa. In particular, HOXA1, which has been described as one of the HOX members that plays an important role in tumorigenesis, was significantly more expressed in OSCCs compared to healthy oral mucosas. Further analysis demonstrated that overexpression of HOXA1 in HaCAT human epithelial cells promotes proliferation, whereas downregulation of HOXA1 in human OSCC cells (SCC9 cells) decreases it. Enforced HOXA1 expression in HaCAT cells was not capable of modulating other events related to tumorigenesis, including apoptosis, adhesion, invasion, EMT and anchorage-independent growth. A high number of HOXA1-positive cells was significantly associated with T stage, N stage, tumor differentiation and proliferative potential of the tumors, and was predictive of poor survival. In multivariate analysis, HOXA1 was an independent prognostic factor for OSCC patients (HR: 2.68; 95% CI: 1.59-2.97; p = 0.026). CONCLUSION: Our findings indicate that HOXA1 may contribute to oral carcinogenesis by increasing tumor cell proliferation, and suggest that HOXA1 expression might be helpful as a prognostic marker for patients with OSCC.

Asunto(s)

Carcinoma de Células Escamosas/metabolismo , Genes Homeobox/fisiología , Proteínas de Homeodominio/metabolismo , Neoplasias de la Boca/metabolismo , Factores de Transcripción/metabolismo , Apoptosis/fisiología , Western Blotting , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Adhesión Celular/fisiología , Proliferación Celular , Transición Epitelial-Mesenquimal , Femenino , Expresión Génica , Proteínas de Homeodominio/fisiología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Supervivencia , Factores de Transcripción/fisiología

RESUMEN

BACKGROUND: Oral squamous cell carcinoma affects mainly patients between the fifth and sixth decades of life, being rare in the young (≤40 years old). METHODS: Demographic, clinical, and pathologic features, and the long-term survival of 125 patients younger than 41 years of age were compared with 250 control patients older than 50 years old. Data were submitted to Kaplan-Meier and log-rank tests. RESULTS: The percentage of nonsmokers was higher in the younger patients (p = .04). In the younger patients, tumors at advanced clinical stage (p < .01) and poorly differentiated tumors (p = .01) were associated with a higher risk of recurrence. The relapse rate was higher in the younger patients (p = .02); however, there was no significant difference on overall survival (p = .86). The younger patients diagnosed after the 1990s had less advanced clinical stage tumors, had an increase in the use of combination of surgery, radiotherapy, and chemotherapy, and their overall survival was improved. CONCLUSION: This study emphasizes the importance of early diagnosis and aggressive treatment of oral squamous cell carcinoma.

Asunto(s)

Carcinoma de Células Escamosas/mortalidad , Neoplasias de la Boca/mortalidad , Recurrencia Local de Neoplasia/patología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Brasil/epidemiología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Estudios de Casos y Controles , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Humanos , Persona de Mediana Edad , Neoplasias de la Boca/patología , Neoplasias de la Boca/terapia , Disección del Cuello , Pronóstico , Radioterapia Adyuvante , Estudios Retrospectivos , Fumar/epidemiología

RESUMEN

Head and neck squamous cell carcinoma (HNSCC) is associated with environmental factors, especially tobacco and alcohol consumption. Most of the carcinogens present in tobacco smoke are converted into DNA-reactive metabolites by cytochrome P450 (CYPs) enzymes and detoxification of these substances is performed by glutathione S-transferases (GSTs). It has been suggested that genetic alterations, such as polymorphisms, play an important role in tumorigenesis and HNSCC progression. The aim of this study was to investigate CYP1A1, CYP1A2, CYP2E1, GSTM1, and GSTT1 polymorphisms as risk factors in HNSCC and their association with clinicopathologic data. The patients comprised 153 individuals with HNSCC (cases) and 145 with no current or previous diagnosis of cancer (controls). Genotyping of the single nucleotide polymorphisms (SNPs) of the CYP1A1, CYP1A2, and CYP2E1 genes was performed by PCR-RFLP and the GSTM1 and GSTT1 copy number polymorphisms (CNPs) were analyzed by PCR-multiplex. As expected, a significant difference was detected for tobacco and alcohol consumption between cases and controls (P<0.001). It was observed that the CYP1A2*1D (OR=16.24) variant and GSTM1 null alleles (OR=0.02) confer increased risk of HNSCC development (P<0.001). In addition, head and neck cancer alcohol consumers were more frequently associated with the CYP2E1*5B variant allele than control alcohol users (P<0.0001, OR=190.6). The CYP1A2*1C polymorphism was associated with tumor recurrence (log-rank test, P=0.0161). The CYP2E1*5B and GSTM1 null alleles were significantly associated with advanced clinical stages (T3+T4; P=0.022 and P=0.028, respectively). Overall, the findings suggested that the genetic polymorphisms studied are predictors of risk and are also associated with tumor recurrence, since they are important for determining the parameters associated with tumor progression and poor outcomes in HNSCC.

Asunto(s)

Carcinoma de Células Escamosas/genética , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP2E1/genética , Glutatión Transferasa/genética , Neoplasias de Cabeza y Cuello/genética , Consumo de Bebidas Alcohólicas/genética , Brasil , Estudios de Casos y Controles , Citocromo P-450 CYP1A1/genética , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Nucleótido Simple , Pronóstico , Factores de Riesgo , Fumar/genética

RESUMEN

Overexpression of fatty acid synthase (FASN) and ErbB2 has been described in oral squamous cell carcinomas (OSCC). FASN is the key lipogenic enzyme responsible for the endogenous synthesis of fatty acids and its expression can be regulated by ErbB2. The deubiquitinating enzyme (DUB) ubiquitin-specific protease 2a (USP2a) plays a critical role in prostate cancer cell survival by stabilizing the FASN protein. This study investigates whether the gene expression and the immunohistochemical status of FASN, ErbB2, and USP2a correlate with the clinicopathological characteristics of OSCC cases. A strong positive correlation among ErbB2, FASN, and USP2a expression (p=0.001) was observed by qRT-PCR in laser capture microdissected OSCC samples. Perineural infiltration was associated with ErbB2 mRNA expression (p=0.046). The presence of metastatic cervical lymph nodes was associated with FASN (p=0.002), ErbB2 (p=0.001), and USP2a (p=0.006) mRNA levels. ErbB2 staining at the cell membranes was stronger in well-differentiated lesions while a cytoplasmic positivity was found in poorly differentiated tumors. Most of the OSCC (97.06%) that showed a high positivity for FASN were also labeled for ErbB2 at the cell membranes (p=0.001). FASN and ErbB2 positivity was associated with tumor thickness and lymphatic embolization (p=0.006 and p=0.035, p=0.006 and p=0.024 respectively). The membrane expression of ErbB2 as well as FASN and Ki-67 staining were significantly associated with a high risk of recurrence by predicting both disease free survival (log-rank test, p=0.0056, p=0.0011, and p=0.0004, respectively) and overall survival (log-rank test, p=0.0005, p=0.0062, and p=0.0001, respectively). Taken together, the results presented here suggest a molecular connection among FASN, ErbB2, and USP2a in OSCC since their mRNA and protein levels were associated with tumor progression and poor prognosis.

Asunto(s)

Carcinoma de Células Escamosas/metabolismo , Endopeptidasas/metabolismo , Ácido Graso Sintasas/metabolismo , Neoplasias de la Boca/metabolismo , Proteínas de Neoplasias/metabolismo , Receptor ErbB-2/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Brasil , Carcinoma de Células Escamosas/patología , Femenino , Expresión Génica , Humanos , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Pronóstico , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Proteasas Ubiquitina-Específicas

RESUMEN

Several lines of evidence demonstrated that the stroma surrounding the tumors plays an important role in the growth and progression of several neoplasms, including oral squamous cell carcinomas (OSCC). We evaluated the presence of myofibroblasts in OSCC and determined whether their presence is associated with clinicopathological features of the tumors. We also investigated the mutual paracrine effects of tumor cells and myofibroblasts on fibroblast-myofibroblast transdifferentiation and tumor cell proliferation. Immunohistochemical analysis showed the approximately 60% of the OSCCs contained myofibroblasts in the stroma of the tumor. Abundant presence of myofibroblasts significantly correlated with N stage, disease stage, regional recurrence, and proliferative potential of the tumor cells. Using OSCC cell lines and primary oral normal fibroblasts (ONF), we demonstrated that tumor cells induced transdifferentiation of ONFs to myofibroblasts via secretion of transforming growth factor-beta 1 (TGF-beta 1). In turn, myofibroblasts secreted factors that stimulated OSCC cell proliferation, as revealed by measuring BrdU incorporation and Ki67 expression. The results of the study suggest that during tumor invasion OSCC-derived TGF-beta 1 promote fibroblast-myofibroblast transdifferentiation, and that tumor cellular proliferation can be induced by factors released from myofibroblasts, which may favor tumor growth.

Asunto(s)

Carcinoma de Células Escamosas/patología , Transformación Celular Neoplásica/patología , Fibroblastos/citología , Neoplasias de la Boca/patología , Comunicación Paracrina/fisiología , Factor de Crecimiento Transformador beta/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/metabolismo , Proliferación Celular , Transdiferenciación Celular , Transformación Celular Neoplásica/química , Transformación Celular Neoplásica/metabolismo , Femenino , Fibroblastos/fisiología , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/metabolismo , Fenotipo , Células del Estroma/patología , Células Tumorales Cultivadas/citología