Overexpression of CDC7 in malignant salivary gland tumors correlates with tumor differentiation / Superexpressão de CDC7 em tumores malignos de glândulas salivares correlaciona-se com a diferenciação dos tumores

Abstract Introduction: Cell division cycle-7 protein is a serine/threonine kinase that has a basic role in cell cycle regulation and is a potential prognostic or therapeutic target in some human cancers. Objectives: This study investigated the expression of cell division cycle-7 protein in benign and malignant salivary gland tumors and also its correlation with clinicopathologic factors. Methods: Immunohistochemical expression of cell division cycle-7 was evaluated in 46 cases, including 15 adenoid cystic carcinoma, 12 mucoepidermoid carcinoma, 14 pleomorphic adenoma, and 5 normal salivary glands. Cell division cycle-7 expression rate and intensity were compared statistically. Results: The protein was expressed in almost all tumors. The intensity and mean of cell division cycle-7 expression were higher in malignant tumors in comparison with pleomorphic adenomas (p = 0.000). The protein expression was correlated with tumor grades (p = 0.000). Conclusions: The present study demonstrated cell division cycle-7 overexpression in malignant salivary gland tumors in comparison with pleomorphic adenomas, and also a correlation with tumor differentiation. Therefore, this protein might be a potential prognostic and therapeutic target for salivary gland tumors.

Resumo Introdução: A cell division cycle-7 é uma serina/treonina quinase que tem um papel básico na regulação do ciclo celular e é um potencial marcador prognóstico ou terapêutico em alguns tipos de câncer humano. Objetivos: Este estudo investigou a expressão de cell division cycle-7 em tumores de glândulas salivares benignos e malignos e também sua correlação com fatores clínico-patológicos. Método: A expressão imuno-histoquímica de cell division cycle-7 foi avaliada em 46 casos, incluindo 15 carcinomas adenoide císticos, 12 carcinomas mucoepidermoides, 14 adenomas pleomórficos e 5 glândulas salivares normais. A taxa de expressão e a intensidade da proteína cell division cycle-7 foram comparadas estatisticamente. Resultados: A proteína foi expressa em quase todos os tumores. A intensidade e a média da expressão de cell division cycle-7 foram maiores em tumores malignos em comparação com adenoma pleomórfico (p = 0,000). A expressão da proteína foi correlacionada com os graus do tumor (p = 0,000). Conclusões: O presente estudo demonstrou a superexpressão de cell division cycle-7 em tumores malignos de glândulas salivares quando comparada com o adenoma pleomórfico, além de uma correlação com a diferenciação de tumores. Portanto, essa proteína pode ser um potencial marcador prognóstico e terapêutico para tumores de glândulas salivares.

In situ carcinoma developed over oral lichen planus: a case report with analysis of BUB3, p16, p53, Ki67 and SOX4 expression

AbstractOral lichen planus (OLP) represents a common mucocutaneous disease. Various authors have suggested that OLP has malignant potential; however, the mechanisms involved in malignant transformation have not yet been elucidated. A 79-year-old man presented a white lesion for five months in the buccal mucosa diagnosed as OLP. After two months using 0.05% clobetasol ointment for treatment, the lesion became ulcerated. A new biopsy of the same lesion was performed, and histological analysis showed an in situ oral carcinoma (ISOC). An immunohistochemistry panel was performed, and p16 expression was negative in OLP, however, it showed weak cytoplasmic staining in ISOC. There was strong nuclear BUB3 staining in both OLP and ISOC areas. p53 showed less intense nuclear staining in both regions. Ki67 was negative in OLP area, but showed nuclear staining in the ISOC. SOX4 was negative in both studied areas. BUB3 expression, first reported in this case, and the p16 expression may suggest some influence of these genes on pathogenesis or malignant potential of OLP.

Clinicopathological values of NBS1 and DNA damage response genes in epithelial ovarian cancers

Epithelial ovarian cancers (EOCs) are highly lethal gynecological malignancies with a high recurrence rate. Therefore, developing prognostic markers for recurrence after chemotherapy is crucial for the treatment of ovarian cancers. As ovarian cancers frequently respond to DNA-damaging agents, we assessed the clinicopathological significance of key double-strand DNA break (DSB) repair genes, including BRCA1, BRCA2, BARD1, ATM, RAD51 and NBS1 in EOC cell lines and paraffin-embedded tissue sections from 140 EOC patients treated with cytoreductive surgery, followed by platinum-based chemotherapy. These samples were analyzed for the clinicopathological impact of DSB genes by western blot analysis, immunohistochemistry and quantitative real-time PCR. Of the DSB repair genes, BRCA1, ATM and NBS1, which are involved in the homologous recombination-mediated repair pathway, were related to aggressive parameters in EOC. When survival analysis was performed, NBS1 expression exhibited an association with EOC recurrence. Specifically, increased NBS1 expression was found in 107 out of 140 cases (76.0%) and correlated with advanced stage (P=0.001), high grade (P=0.001) and serous histology (P=0.008). The median recurrence-free survival in patients with positive and negative expression of NBS1 was 30 and 78 months, respectively (P=0.0068). In multivariate analysis, NBS1 was an independent prognostic factor for the recurrence of EOC. Together, these results suggest that NBS1 is a marker of poor prognosis for the recurrence of EOC and is associated with aggressive clinicopathological parameters.

Expression of the cell cycle regulation proteins p53 and p21WAF1 in different types of non-dysplastic leukoplakias

OBJECTIVES: The aim of this study was to analyze the immunolabeling of two cell cycle protein regulators, p53 and p21WAF1, in non-dysplastic leukoplakias with different epithelial alterations: acanthosis, hyperkeratosis and acanthosis combined with hyperkeratosis, and compare them with dysplastic leukoplakias. MATERIAL AND METHODS: This was a prospective cohort study involving 36 patients with oral homogeneous leukoplakias. excisional biopsies were performed and the patients remain under clinical follow-up. The leukoplakias were divided into four groups: 6 acanthosis, 9 hyperkeratosis, 10 acanthosis combined with hyperkeratosis, and 11 epithelial dysplasias. Paraffin-embebeded sections were immunostained for p53 and p21WAF1. Five hundred cells from the basal layer and 500 from the parabasal layer were counted to determine the percentage of positive cells. A qualitative analysis was also carried out to determine the presence or absence of immunohistochemical staining in the intermediate and superficial layers. Groups were compared with ANOVA (p<0.05). Pearson's correlation coefficient was used to test for associations between the two markers, p53 and p21WAF1. RESULTS: No leukoplakia recurred and no malignant transformation was observed whitin a follow-up period of 3-6 years. The mean percentage of p53 staining in the basal and parabasal layers was similar in all groups. p21WAF1 staining differed between layers was as follows: in the basal, only 3 to 4% of cells were stained, while in the parabasal, between 16 and 28% of the epithelial cells were stained in the four different studied groups with no statistically significant difference (p>0.05). CONCLUSIONS: Our findings failed to differentiate the non-dysplastic lesions by means of p53 and p21WAF1 immunostaining, notwithstanding similar profiles between non-dysplastic and dysplastic leukoplakias were observed.

Minichromosome maintenance 2 and 5 expressions are increased in the epithelium of hereditary gingival fibromatosis associated with dental abnormalities

INTRODUCTION: Gingiva fibromatosis is a relatively rare condition characterized by diffuse enlargement of the gingiva, which is caused by expansion and accumulation of the connective tissue. OBJECTIVE: The aim of the present study was to investigate proliferative and apoptotic biomarker expression in normal gingiva and two forms of gingival fibromatosis. METHODS: Archived tissue specimens of hereditary gingival fibromatosis, gingival fibromatosis and dental abnormality syndrome and normal gingiva were subject to morphological analysis and immunohistochemical staining. The results were analyzed statistically. RESULTS: Proteins associated with proliferation were found in the nuclei of epithelial cells from the basal and suprabasal layers, whereas apoptotic proteins were detected in the cytoplasm of the upper layers of the epithelium. Increased expressions of minichromosome maintenance proteins 2 and 5 were observed in the gingival fibromatosis and dental abnormality syndrome samples. In contrast, geminin expression was higher in normal gingiva samples. No difference in the expression of apoptotic proteins was observed among the groups. CONCLUSION: Our findings support a role for augmented proliferation of epithelial cells within the overgrown tissues associated with gingival fibromatosis or dental abnormality syndrome. However, our data suggest that different biological mechanisms may account for the pathogenesis of different types of gingival fibromatosis.

Involvement of mitogen-activated protein kinases and p21Waf1 in hydroxyurea-induced G1 arrest and senescence of McA-RH7777 rat hepatoma cell line

Hydroxyurea is commonly used to treat hematologic disorders and some type of solid tumors, but the mechanism for its therapeutic effect is not clearly known. In this study, we examined the effect of hydroxyurea on rat hepatoma McA-RH7777 cells, specifically, on the role of mitogen-activated protein (MAP) kinase signal transduction pathways and p21Waf1, p27Kip1 and p53. Rat hepatoma McA-RH7777 cells treated with hydroxyurea for 7 days, caused the inhibition of cell growth in a dose-dependent manner. But, this growth inhibition was not caused by necrosis or apoptosis but instead was associated with cell senescence-like change as evidenced by senescence associated-beta-galactosidase staining, and cells arrest at G1 phase of cell cycle. Phosphorylation of MAP kinases, such as ERK, JNK, and p38, was found to be decreased after treatment of cells with hydroxyurea. But, the expression of p21Waf1 was increased, while p27Kip1 and p53 were not detected in hydroxyurea treated rat hepatoma cells. Hydroxyurea treatment induced G1 arrest and a senescence-like changes in rat hepatoma McA-RH7777 cells may be the likely results of signal disruption of MAP kinases (ERK, JNK, and p38 MAP kinase) and p21Waf1 over-expression.

Cyclin E, p27 and Mutant p53 do not Predict the Prognosis in AJCC Stage II Colorectal Carcinomas / 대한소화기학회지

BACKGROUND/AIMS: Carcinogenesis is characterized by the abnormal regulation of cell cycle. The abnormal expression of the regulators of cell cycle may be related to the prognosis. Since the clinical significance of the expression of the three proteins in colorectal carcinomas is still controversial, we evaluated the prognostic value of the expression of cyclin E, p27 and mutant p53 in stage II colorectal cancer. METHODS: The expression levels of cyclin E, p27 and mutant p53 proteins in 41 patients with stage II colorectal carcinomas were analyzed by immunohistochemistry. RESULTS: In the univariate analysis, the level of CEA at diagnosis was associated with disease relapse. In the multivariate analysis, the clinicopathological variables such as age, gender, site of primary tumor, tumor size, state of tumor differentiation and preoperative plasma CEA level were not associated with disease relapse. When Kaplan-Meier survival curves were constructed to determine the prognosis, cyclin E, p27 and mutant p53 expressions did not predict poor prognosis. CONCLUSIONS: Our results suggested that the expression of cyclin E, p27 and mutant p53 proteins did not predict the clinical outcome in the stage II colorectal carcinomas.