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1.
DNA Cell Biol ; 42(6): 274-288, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36576491

RESUMEN

Together with an anti-tumor immune response, oncolysis using a recombinant viral vector promises to eliminate cancer cells by both gene transfer and host-mediated functions. In this study we explore oncolysis induced by nonreplicating adenoviral vectors used for p14ARF and interferon-ß (hIFNß) gene transfer in human melanoma cell lines, revealing an unexpected role for p14ARF in promoting cellular responses predictive of immune stimulation. Oncolysis was confirmed when UACC-62 (p53 wild-type) cells succumbed upon p14ARF gene transfer in vitro, whereas SK-Mel-29 (p53-mutant) benefitted from its combination with hIFNß. In the case of UACC-62, in situ gene therapy in nude mice yielded reduced tumor progression in response to the p14ARF and hIFNß combination. Potential for immune stimulation was revealed where p14ARF gene transfer in vitro was sufficient to induce emission of immunogenic cell death factors in UACC-62 and upregulate pro-immune genes, including IRF1, IRF7, IRF9, ISG15, TAP-1, and B2M. In SK-Mel-29, p14ARF gene transfer induced a subset of these factors. hIFNß was, as expected, sufficient to induce these immune-stimulating genes in both cell lines. This work is a significant advancement for our melanoma gene therapy strategy because we revealed not only the induction of oncolysis, but also the potential contribution of p14ARF to immune stimulation.


Asunto(s)
Melanoma , Proteína p14ARF Supresora de Tumor , Ratones , Animales , Humanos , Proteína p14ARF Supresora de Tumor/genética , Proteína p14ARF Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Ratones Desnudos , Apoptosis/fisiología , Línea Celular , Melanoma/genética , Melanoma/terapia
2.
Ann Surg Oncol ; 20(1): 31-9, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22878614

RESUMEN

PURPOSE: This study was designed to determine the prognostic role of p14ARF in vulvar squamous cell carcinoma (VSCC). METHODS: Immunohistochemistry for p14ARF and p53 and fluorescent in situ hybridization (FISH) for TP53 were performed in 139 cases of VSCC. Human papillomavirus (HPV) genotyping by hybridization was employed in 100 cases. qRT-PCR for p14ARF and p53 transcript assessment was performed in 16 cases. All results were correlated with clinicopathological variables. RESULTS: Immunohistochemistry analysis showed p14ARF and p53 positivity in 16.4% and 53% cases respectively. Positive p14ARF expression was significantly associated with the following variables: shorter cancer-specific survival (P=0.04) and shorter disease-free survival (P=0.02), presence of perineural invasion (P=0.037), vascular invasion (P=0.047), and node metastasis (P=0.031). Also, p14ARF-positive HPV-negative cases had the shortest cancer-specific survival (P=0.03) and disease-free survival (P=0.04). HPV infection was detected in 32.8% of the cases; HPV16 was the most prevalent type. Viral infection was more common in poorly differentiated tumors (P=0.032). qRT-PCR demonstrated that CDKN2A (p14ARF) had higher expression in tumor samples compared with paired noncancerous samples (P<0.001). The opposite relationship was seen in TP53 expression evaluation (P<0.001). FISH demonstrated 4 cases with deleted TP53 (6.3%). CONCLUSIONS: p14ARF represents an important marker of poor prognosis in VSCC. p53 and HPV infection did not show any prognostic importance. Further clinical trials concerning p14ARF positivity may result in important contributions due to its relationship with poor outcome. Mainly due to the relationship of p14ARF with lymph node metastasis, the immunohistochemistry evaluation of this marker may help to identify a subset of patients more suitable to less radical procedures.


Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Papillomavirus Humano 16 , Infecciones por Papillomavirus/complicaciones , Proteína p14ARF Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias de la Vulva/metabolismo , Neoplasias de la Vulva/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Vasos Sanguíneos/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundario , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Nervios Periféricos/patología , ARN Mensajero/metabolismo , Proteína p14ARF Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/genética , Neoplasias de la Vulva/genética , Adulto Joven
3.
Cancer Biomark ; 8(6): 341-50, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-22072122

RESUMEN

The Papanicolaou test (Pap) has been responsible for a significant reduction of cervical cancer-related morbimortality. In order to increase its sensitivity and specificity new markers have been studied and incorporated to cytological and histological methods for diagnosis for cervical cancer, such as p16INK4A that has been considered the immunocytochemical marker of choice for detection of HPV related cancers. We considered that p14ARF could be a complementary marker in order to improve the accuracy of cytological diagnosis because its genetic proximity to p16INK4A. We performed a systematic analysis of several putative cervical cancer markers in order to evaluate their performance in the detection of malignancy, in comparison with p16INK4A and p14ARF, using immunocytochemistry (ICC), immunofluorescence (IF) and Western blot analyses. Most markers were non-specific and could not discriminate HPV infected cancer cell lines from other non HPV malignant. In contrast, nuclear co-expression of p16INK4A and p14ARF was observed only in HPV-transformed cancer cell lines. Notably, in C-33A cervical cancer cells (HPV negative), p14ARF was present in the nucleoli, but p16INK4A was conspicuously absent from the nuclei of these cells. We conclude that both markers; p16INK4A and p14ARF are complementary and should be evaluated jointly in order to improve the accuracy of cytological diagnosis of cervical cancer.


Asunto(s)
Núcleo Celular/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Papillomaviridae/metabolismo , Proteína p14ARF Supresora de Tumor/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Catepsinas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Factor de Transcripción E2F1/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Células HeLa , Humanos , Metaloproteinasas de la Matriz/metabolismo , Proteínas Oncogénicas Virales/genética , Proteínas Oncogénicas Virales/metabolismo , Papillomaviridae/genética , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo , Proteína p14ARF Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/virología
4.
In Vivo ; 23(6): 937-42, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-20023236

RESUMEN

This study was undertaken to investigate, by immunohistochemistry, the expression of some tumor suppressor genes such as p16, p21 and Retinoblastoma (Rb) during 4-Nitroquinoline 1-oxide induced rat tongue carcinogenesis. Male Wistar rats were distributed into three groups of 10 animals each and treated with 50 ppm 4NQO solution through their drinking water for 4, 12 or 20 weeks. Ten animals were used as negative control. Neither histopathological abnormalities were induced in the epithelium after 4 weeks of carcinogen exposure, nor statistically significant differences (p>0.05) in expression of all the tumor suppressor genes were found when compared to the negative control. However, the levels of Rb were increased (p<0.05) in pre-neoplastic lesions at 12 weeks following carcinogen exposure. In well-differentiated squamous cell carcinoma induced after 20 weeks of treatment with 4NQO, p16 and Rb were expressed in some tumor cells. Taken together, the results support the belief that the expression of Rb is closely event-related to malignant transformation and conversion of the oral mucosa, being a reliable biomarker linked to oral cancer pathogenesis.


Asunto(s)
4-Nitroquinolina-1-Óxido/toxicidad , Carcinógenos/toxicidad , Carcinoma de Células Escamosas/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes Supresores de Tumor/efectos de los fármacos , Neoplasias de la Lengua/genética , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/patología , Genes de Retinoblastoma/efectos de los fármacos , Genes Supresores de Tumor/fisiología , Genes p16/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo , Neoplasias de la Lengua/inducido químicamente , Neoplasias de la Lengua/patología , Proteína p14ARF Supresora de Tumor/genética , Proteína p14ARF Supresora de Tumor/metabolismo
5.
Hum Exp Toxicol ; 25(9): 515-22, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17017004

RESUMEN

Oesophageal squamous cell carcinoma (ESCC) is one of the most common malignancies and is the sixth cause of cancer-related death in the world. Inactivation of cell-cycle regulating genes, such as p14ARF and p16INK4a, and cell adhesion genes, such as E-cadherin, is common in cancer, and results from genetic and/or epigenetic alterations. Therefore, we have analysed the mRNA expression of p14ARF, p16INK4a and E-cadherin in 17 matched ESCC and normal mucosal samples obtained from Brazilian patients by semi-quantitative RT-PCR. The expression of p14ARF and p16INK4a was absent or reduced in several ESCC samples. Hypermethylation of CpG islands, caused by the action of DNA methyltransferases (DNMTs), is a major form of epigenetic inactivation of the p14ARF and p16INK4a genes in tumours. Hence, we also investigated the mRNA expression of the human DNA methyltransferases in normal oesophageal mucosa and in the tumour matched samples. All DNMTs were constitutively expressed in the normal oesophageal mucosa but a significantly higher expression of DNMT3B was observed in the tumours. Data analysis by the Spearman rank test showed that the expression of DNMT3B was inversely correlated with that of p14ARF and p16INK4a. Our results suggest that DNMT3B over-expression may be involved in the suppression or lower expression of p14ARF and p16INK4a observed in ESCC.


Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Neoplasias Esofágicas/metabolismo , Proteína p14ARF Supresora de Tumor/metabolismo , Anciano , Cadherinas/genética , Cadherinas/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Regulación hacia Abajo , Esófago/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Análisis por Apareamiento , Metilación , Persona de Mediana Edad , Membrana Mucosa/metabolismo , ARN Mensajero/análisis , Estadísticas no Paramétricas , Células Tumorales Cultivadas , Proteína p14ARF Supresora de Tumor/genética , ADN Metiltransferasa 3B
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