Expression of p27 and p16 and their clinical significance in gastric cancer

Background Deregulated expression of cell cycle regulators p27 and p16 is associated with cancer progression. p27kip1 and p16INKa are a cyclin dependent kinase inhibitor whose major target is the cyclinE/CDK2 and cyclinD/CDK4/6 complex, respectively, that governs cell cycle transition from late G1 to S phase. Methods We recruited biopsies of a total of 84 subjects including 72 primary tumor biopsies from histopathologically proven gastric carcinoma, 8 adjacent controls and 12 independent controls. We used gastric cancer cell line, AGS, for validation of our data. Expression profiling at transcript level was done by semi-quantitative RT-PCR and at proteome level by immunohistochemistry and immunofluorescence. Receiver operator characteristics analysis was done for determining the diagnostic utility of p27 and p16 with respect to the sensitivity and specificity. Results We demonstrate that p27 and p16 are frequently over expressed in early stages of gastric carcinoma. Our semi-quantitative data show a significant upregulation of p27 (Mean ± SEM, 0.4771 ± 0.0895; p = 0.0001) and p16 (Mean ± SEM, 0.4676 ± 0.04305; p = 0.0001) at mRNA level. Concordant to semi-quantitative data, immunohistochemistry data also showed a significant upregulation of p27 (Mean ± SEM, 196.4 ± 10.84; p < 0.0001) and p16 (Mean ± SEM, 100.4 ± 23.71; p < 0.0001) at protein level. Conclusions The present study showed that the significant upregulation of p27 and p16 were associated with early events in gastric carcinogenesis. Our data suggests that clinical correlation of these differentially expressed genes may be useful as diagnostic biomarkers for early detection of gastric carcinoma and promising therapeutics target for GC patients (AU)

CDKN2A inhibits cell proliferation and invasion in cervical cancer through LDHA-mediated AKT/mTOR pathway

Purpose The current study aims to explore the effects of CDKN2A on cell proliferation and cycle, and investigate the underlying mechanisms. Methods Expression of CDKN2A in cervical cancer cell lines was evaluated by real-time quantitative PCR (RT-qPCR) and western blotting. Apoptotic rate was detected by Annexin V assay. MTT assay, Transwell assay and cell cycle assay kit were applied to examine the effect of CDKN2A on cell viability, invasion and cell cycle. Co-immunoprecipitation and western blotting were devoted to explore the mechanism by which CDKN2A contributes to cell function. Results CDKN2A was expressed at a low level in cervical cancer cell lines. Overexpression of CDKN2A inhibited cell proliferation and invasion, and caused cell cycle arrest in the G1 phase. CDKN2A mediates the AKT–mTOR signaling pathway by suppressing lactate dehydrogenase (LDHA). Taken together, our data revealed that CDKN2A can be applied as a therapeutic target for the treatment of cervical cancer in future. Conclusions CDKN2A inhibits cell proliferation and invasion in cervical cancer through LDHA-mediated AKT–mTOR pathway (AU)

Preclinical and clinical development of palbociclib and future perspectives

Cyclin-dependent kinases (CDKs) play a key role in cell cycle regulation, which makes them a clear therapeutic target to interfere with cell division and proliferation in cancer patients. Palbociclib, a specific inhibitor of CDK4/6 with outstanding clinical efficacy data and limited toxicity, has been recently approved for the treatment of hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer, either in combination with an aromatase inhibitor or in combination with fulvestrant in women who have received prior endocrine therapy. This review describes the mechanism of action, preclinical experiences and clinical data of palbociclib, with a special focus on integrating this data with the positioning of palbociclib in the current clinical guidelines for advanced HR-positive/HER2-negative breast cancer. Aspects of the ongoing major studies are also presented, as well as future prospects in the development of palbociclib

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Gamma-Tocotrienol prevents cell cycle arrest in aged human fibroblast cells through p16INK4a pathway

Human diploid fibroblasts (HDFs) proliferation in culture has been used as a model of aging at the cellular level. Growth arrest is one of the most important mechanisms responsible for replicative senescence. Recent researches have been focusing on the function of vitamin E in modulating cellular signaling and gene expression. Therefore, the aim of this study was to elucidate the effect of palm γ-tocotrienol (vitamin E) in modulating cellular aging through p16INK4a pathway in HDF cells. Primary culture of senescent HDFs was incubated with 70 μM of palm γ-tocotrienol for 24 hours. Silencing of p16INK4a was carried out by siRNA transfection. RNA was extracted from the different treatment groups and gene expression analysis was carried out by real-time reverse transcription polymerase chain reaction. Proteins that were regulated by p16INK4a were determined by western blot technique. The finding of this study showed that p16INK4a mRNA was overexpressed in senescent HDFs, and hypophosphorylated-pRb and cyclin D1 protein expressions were increased (p < 0.05). However, downregulation of p16INK4a and hypophosphorylated-pRb and cyclin D1 protein expressions (p < 0.05) by γ-tocotrienol led to modulation of the cell cycle regulation during cellular aging. In conclusion, senescent HDFs showed change in biological process specifically in cell cycle regulation with elevated expression of genes and proteins which may contribute to cell cycle arrest. Palm γ-tocotrienol may delay cellular senescence of HDFs by regulating cell cycle through downregulation of p16INK4a and hypophosphorylated-pRb and cyclin D1 protein expressions (AU)

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Tinción dual p16 + ki 67. Un paso más en cuanto a la especificidad de citologías ginecológicas / p16/Ki-67 dual staining. A step forward in the specificity of gynecological cytology

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Papel de p16 en lesiones preinvasivas e invasivas de cáncer de cuello uterino. Aplicación de la técnica a citología convencional / Role of p16 expression in preinvasive and invasive cervical lesions: application of conventional cytology

Introducción: La detección de la sobreexpresión de la proteína p16 mediante técnicas inmunohistoquímicas e inmunocitoquímicas es un valor seguro en la identificación de lesiones epiteliales cervicales de alto grado, sirviendo al mismo tiempo para detectar aquellas lesiones de bajo grado cito o histológico con integración viral, firmes candidatas a la progresión a lesión de alto grado. Material y métodos: Hemos evaluado la eficacia de la detección inmunohistoquímica e inmunocitoquímica de la sobreexpresión de la proteína p16 sobre muestras de cérvix uterino. Para ello hemos recurrido a 58 casos de biopsias de cérvix y 53 citologías con diagnóstico de positividad para la infección por el virus del papiloma humano. Resultados: Hemos observado cómo el 100% de las lesiones de alto grado eran teñidas mientras que so ́lo un porcentaje de las de bajo grado hacían lo propio. Los resultados obtenidos en citología fueron extrapolados a las citologías (correspondientes a las mismas pacientes que las biopsias) obteniendo similares resultados. Conclusiones: La identificación de la sobreexpresión de la proteína p16 por métodos inmunocitoquímicos sobre citologías cervicovaginales convencionales muestra resultados superponibles a los obtenidos sobre muestras histológicas (AU)

Introduction: Detection of p16 expression by immunohistochemistry and immunocytochemistry is a good standard for the identification of high-grade cervical epithelial lesions and low-grade lesions with DNA HPV viral integration (with a tendency for progression). Material and methods: We evaluated p16 expression in 58 HPV-positive cervical biopsies and 53 conventional cytological samples that tested HPV-positive with immunohistochemical and immunocytochemical techniques. Results: All high-grade lesions were positive for p16 while only some of the low-grade lesions were positive. The results obtained in histological samples could be extrapolated to cytological samples from the same patients. Conclusions: p16 expression in conventional cytology provides similar results to those in histological samples (AU)

Expresión inmunohistoquímica de p53, p21, p16 y Ciclina D1 en el cáncer de vejiga superficial. Estudio en un soporte de tissue microarray / Immunohistochemical expression of P53, P21, P16, and cyclin D1 in superficial Bladder cancer. A tissue microarray study

Introducción y objetivos: Evaluar, de forma retrospectiva, la relación entre la expresión inmunohistoquímica de p53, p21, p16 y ciclina D1, con la recurrencia, progresión tumoral y supervivencia en los carcinomas vesicales superficiales. Métodos: 163 pacientes sometidos a resección transuretral de tumor vesical superficial entre febrero de 1995 y marzo de 2004. Las muestras tumorales evaluadas estaban contenidas en un soporte de tissue microarray, al que se le realizaron varias secciones consecutivas para tinción inmunohistoquímica. La asociación del grado y estadio tumoral con los marcadores se valoró según el test de Chi-cuadrado y para valorar la relación con la recurrencia, progresión y supervivencia se utilizaron las curvas de Kaplan-Meier y se compararon con el log-rank test. Resultados: No se observaron diferencias estadísticamente significativas en la expresión de los marcadores según el grado y estadio tumoral a excepción de la Ciclina D1, que sí mostraba diferencias significativas según el estadio tumoral (p=0,030). La expresión de p21 se relacionó con la recurrencia tumoral (p=0,035), progresión (p=0,008) y supervivencia (p=0,034). La expresión de p16 también se relacionó con la recurrencia (p=0,048) y supervivencia (p=0,047), pero no con la progresión tumoral (p=0,116). La expresión de p53 y ciclina D1 no mostraron asociación estadísticamente significativa con la recurrencia y progresión tumoral ni con la supervivencia. Conclusiones: En nuestra experiencia, sólo los marcadores p16 y p21 pueden ser útiles en el manejo de los tumores vesicales superficiales por ser predictores de recurrencia y supervivencia en pacientes con estadios Ta y T1

Introduction and objectives: To retrospectively assess the relationship between immunohistochemical expression of p53, p21, p16, and cyclin D1, with recurrence, progression and survival in superficial bladder cancer. Methods: 163 patients undergoing transurethral resection for superficial bladder cancer between February 1995 and March 2004. Tumor samples were included in a tissue microarray support that was serially sectioned for immunohistochemical staining. Grade and stage associations for each marker were evaluated by the Chi-square test. Assessment of the relationship with recurrence, progression, and survival Kaplan-Meier curves and log-rank test were used. Results: There were no statistically significant differences in marker expression depending on tumor grade and stage, with the exception of Cyclin D1, that was significantly different depending on tumor stage (p=0.030). p21 expression was related to tumor recurrence (p=0.035), progression (p=0.008) and survival (p=0.034). p16 expression was also related to recurrence (p=0.048) and survival (p=0.047), but not to tumor progression (p=0.116). p53 and Cyclin D1 were not statistically associated with tumor recurrence, progression or survival. Conclusions: In our experience, only p16 and p21 may be useful in the management of superficial bladder tumors, as they are predictors of recurrence and survival in Ta and T1 patients

El papel modulador de p16ink4a en la infección por el virus del papiloma humano / Modulator role of p16ink4a in human papillomavirus infection

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Genética molecular de los astrocitomas / Molecular genetics of astrocytomas

Los astrocitomas son el grupo de tumores intracraneales más frecuentes. De ellos, el glioblastoma es el más agresivo. En esta revisión nos centramos en describir las anomalías genéticas más frecuentes en astrocitomas. Para ello hacemos referencia a los genes del preceptor del factor de crecimiento epidérmico (EGFR) p53, p16, PTEN y DMBT1. Asimismo presentamos ciertos aspectos genéticos que influyen en la progresión tumoral hacia glioblastomas (AU)