RESUMEN
Pericytes are perivascular cells related to vessel structure and angiogenesis that can interact with neoplastic cells, interfering with cancer progression and outcomes. This study focused on the characterization of pericytes in oral squamous cell carcinoma (OSCC) using clinical samples and a transgenic mouse model of oral carcinogenesis. Nestin-/NG2+ (type-1) and nestin+/NG2+ (type-2) pericytes were analyzed by direct fluorescence after induction of oral carcinogenesis (4-nitroquinoline-1-oxide). Gene expression of neuron glial antigen-2 (NG2), platelet-derived growth factor receptor beta (PDGFR-ß), and cluster of differentiation 31 (CD31) was examined in human OSCC tissues. The protein expression of von Willebrand factor and NG2 was assessed in oral leukoplakia (i.e., oral potentially malignant disorders) and OSCC samples. Additionally, clinicopathological aspects and survival data were correlated and validated by bioinformatics using The Cancer Genome Atlas (TCGA). Induction of carcinogenesis in mice produced an increase in both NG2+ pericyte subsets. In human OSCC, advanced-stage tumors showed a significant reduction in CD31 mRNA and von Willebrand factor-positive vessels. Low PDGFR-ß expression was related to a shorter disease-free survival time, while NG2 mRNA overexpression was associated with a reduction in overall survival, consistent with the TCGA data. Herein, oral carcinogenesis resulted in an increase in NG2+ pericytes, which negatively affected survival outcomes.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Ratones , Humanos , Animales , Pericitos/metabolismo , Carcinoma de Células Escamosas/metabolismo , Nestina/metabolismo , Neoplasias de la Boca/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Factor de von Willebrand/genética , Factor de von Willebrand/metabolismo , Ratones Transgénicos , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Carcinogénesis/patología , Neoplasias de Cabeza y Cuello/patología , ARN Mensajero/metabolismoRESUMEN
To evaluate molecular epithelial changes, we investigated whether a profile of survivin, cyclin dependent kinase inhibitor 2A (CDKN2A), epidermal growth factor receptor (EGFR), polo like kinase 1 (PLK1), p63, p40 (Δnp63 isoform), cyclin D1 (CCND1) and BCL2 apoptosis regulator (BCL2) proteins could predict malignant transformation. Different tissue segments (tumor adjacent epithelium; dysplasia and tumor) from a total of 109 patients were analyzed by immunohistochemistry. An increased expression of survivin (p < 0.001), PLK1 (p = 0.001), and p63 (p < 0.001) in parallel to reduced immunostaining of p40 (p < 0.001) and BCL2 (p = 0.029) was observed among the tissue segments analyzed. Our study revealed that survivin, PLK1, p63, p40 and BCL2 play a role in oral tumorigenesis and represent promising biomarkers able to recognize mesenchymal phenotype induction in the transition from nonmalignant cells to tumor cells. These results reveals critical interaction between survivin, PLK1, p63, p40 promising proteins during invasive carcinoma development.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Mucosa Bucal/metabolismo , Neoplasias de la Boca/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/patología , Proteínas de Ciclo Celular/metabolismo , Transformación Celular Neoplásica/patología , Ciclina D1/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Receptores ErbB/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Isoformas de Proteínas , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Survivin/metabolismo , Factores de Transcripción/metabolismo , Quinasa Tipo Polo 1RESUMEN
OBJECTIVE: The aim of this study was to evaluate the application of in situ hybridization using E6/E7 mRNA probes to identify the frequency of high-risk HPV transcriptionally active and the use of HPV status as a prognostic biomarker in oral cavity squamous cell carcinoma (OCSCC). METHODS: Ninety-nine OCSCC samples were evaluated from Hospital Santa Rita de Cassia, Hospital Universitário Cassiano Antônio de Moraes and University Hospitals Coventry and Warwickshire NHS Trust. After tissue microarray construction, the slides were submitted to an in situ hybridization detection method for HPV E6/E7 mRNA. HPV status was designated a binary classification. Multiple logistic regression examined the association of HPV with clinical features and other risk factors, using SPSS® software. For all hypothesis tests, a significance level of pâ¯≤â¯0.05 was considered. RESULTS: HPV frequency in oral squamous cell carcinoma was 8%. There was no association between HPV and clinical variables and between the main prognostic features and known risk factors. There was no difference in the prevalence of HPV for oral cavity squamous cell carcinoma by geography (Brazil vs UK). CONCLUSIONS: A low frequency of E6/E7 mRNA by RNA in situ hybridization was found in oral cavity squamous cell carcinoma, which supports the evidence that HPV-driven cancer of the oral cavity is uncommon.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Papillomaviridae , Infecciones por Papillomavirus , ARN Mensajero , Brasil , Neoplasias de Cabeza y Cuello/virología , Humanos , Hibridación in Situ , Papillomaviridae/patogenicidad , Infecciones por Papillomavirus/diagnóstico , ARN ViralRESUMEN
BACKGROUND: The prevalence of high-risk human papillomavirus (HPV) DNA in cases of oral cavity squamous cell carcinoma (SCC) varies widely. The aim of this study is to investigate the frequency of high-risk HPV DNA in a large Brazilian cohort of patients with oral cavity SCC. METHODS: Biopsy and resected frozen and formalin-fixed paraffin-embedded specimens of oral cavity SCC were available from 101 patients who were recruited at two Brazilian centres. Stringent measures with respect to case selection and prevention of sample contamination were adopted to ensure reliability of the data. Nested PCR using MY09/MY11 and GP5+/GP6+ as well as PGMY09/11 L1 consensus primers were performed to investigate the presence of HPV DNA in the tumours. HPV-positive cases were subjected to direct sequencing. Shapiro-Wilk and Student t test were used to evaluate data normality and to compare the means, respectively. Qualitative variables were analysed by logistic regression. RESULTS: Our results demonstrate that the frequency of high-risk HPV types in oral cavity SCC is very low and is less than 4%. All HPV-positive cases were HPV16. In addition, our results do not show a significant association between the tumour clinical features and the risk factors (tobacco, alcohol and HPV) for oral cavity SCC. CONCLUSION: In the current study, we observed an overlapping pattern of risk factors that are related to tumour development. This, along with a low frequency of high-risk HPV DNA, supports the findings that HPV is not involved in the genesis of oral cavity SCC in Brazilian population.