Tumor risk markers in recurrent respiratory papillomatosis

Abstract Objectives: This study aims to investigate the pattern of immunoexpression of proteins p16, p53 and Ki-67 in RRP, as well as to evaluate its influence on the number of surgeries that patients have undergone to date and to analyze the benefit of immunohistochemistry in this disease. Methods: Clinical-demographic data and tumor samples were obtained from 33 patients with RRP. The expression of proteins p16, p53 and Ki-67 was analyzed by immunohistochemical method. Results: Most patients had already undergone more than one surgery. The p16 marker was negative in 24.2% of the cases, with little positivity in 27.3% of the cases, moderate in 36.4% and intense in 12.1%. The p53 marker was positive in all cases, with little immunoexpression in 39.4% of cases, moderate in 36.4% and intense in 24.2%. The Ki-67 marker showed nuclear positivity in all lesions, although in varying degrees, with a mean proliferative index ±SD (standard deviation) of 51.7±26. Conclusions: The papillomatous lesions had varying degrees of immunoexpression of proteins p16, p53 and Ki-67, but no specific immunohistochemical pattern was observed. It was found, with statistical difference, that the number of surgeries was higher in cases with greater intensity of p53 expression, without correlation with the other markers. The benefit of immunohistochemistry in recurrent respiratory papillomatosis may lie in the prognostic assessment. However, further studies are needed to evaluate the use of this technique for this purpose. Level of evidence:: 4.

The Expression and clinical Significance of p53、p16 protein in advanced gastric carcinoma / 中国基层医药

Objective To investigate the expressions of p53,p16 protein and the clinical significance in advanced gastric carcinoma. Methods The expressions of p.53 ,p16 were detected by using immunohistochemistry in 24 specimens of normal gastric mucosa and 55 specimens of gastric carcinoma. Results The positive rate of p53 ,p16 in normal gastric mucosa and gastric carcinoma tissues were 0,100% ;67.3% ,30. 9%, respectively (P <0. 05). The positive rate of p53, p16 in non-differentiated、low- differentiated and moderate- differentiated 、high- differentiated gastric carcinoma tissues were 80. 0% ,56.7% and 48. 0% ,56. 0% ,respectively(P <0. 05). Conclusions The abnormal expressions of p53 and p16 play an important role in the course and prognosis of gastric carcinoma. The positive expression of p53 was correlated with the degree of defferentiation of gastric carcinoma. No correlation between the expression of p16 and grade of differentiation was observed.

The significance of p16 protein and Ki-67 antigen expression in gastric mucosa-associated lymphoid tissue lymphoma / 中华内科杂志

To detect the expression of p16 protein and Ki-67 antigen in gastric mucosa-associated lymphoid tissue lymphoma(MALTL)and normal gastric mucosa and to investigate the clinical significance of their expression in the occurrence and development of gastric MALTL.Methods 47 samples of gastric MALTL diagnosed pathologically in the department of pathology of the PLA General Hospital from March 1993 to June 2005 were collected.By using immunohistochemial methods,the expression of p16 protein and Ki-67 antigen was detected in 20 samples of normal gastric tissue and the 47 samples of gastric MALTL.Results The positive rate of p16 protein Was 21.3%(10/47)and 90.0% in gastric MALTL and normal gastric tissue respectively.The positive rate of p16 protein in gastric MALTL was lower than that in normal gastric tissue(P<0.05).The expression of p16 was related to the degree of lymph node metastasis.The positive rate of Ki-67 labelling index(LI)in gnstric MALTL was hiigher than that in normal gastric tissue.A negative correlation was found between the expression of p16 protein and Ki-67 LI(P<0.05). Conclusions Detection p16 and Ki-67 may help to predict the possibility of lymph node metastasis and prognosis in gastric MALTL.

The effect of pigment epithelium-derived factor on apoptosis of glioma cells / 中华检验医学杂志

Objective To assess the impact of pigment epithelium-derived factor(PEDF)on the proliferation and apoptosis of the glioma cells by detecting expression of apoptosis related proteins.Methods U87 cells were treated with PEDF(1000μg/ml,U87PEDF),or without PEDF(U87com0),cell proliferation assays were performed by MTT assay to test the effect of PEDF on proliferation of glioma cells;Apoptosis assays were performed by flow-cytometric analysis;Western-blot Was used for evaluating the expression of p16 protein.Results The induced inhibitony rates of glioma cells by PEDF were(54.29±0.62)% Compaxed with the control(t=2.63,P<0.05).The apoptosis assay showed that(21.84±0.36)% of PI- negative/annexin V-positive Was present in the U87 PEDF cells.The appoptosis was associated with the incteases of p16 protein(0.82±0.09)compared with tlle control(0.43±0.03,P<0.05).Conciusion PEDF may play a significant role in apoptosis regulation and proliferation of glioma cell accompanied with the increase of the p16 protein.

The Loss of p16(ink4)Expression is Strongly Associated with Hyperme thylation-Related Inactivation in Breast Carcinoma / 한국유방암학회지

PURPOSE: The loss of p16 protein has been frequently detected in breast carcinoma, but genetic alterations are infrequent. CpG islands of methylation within the p16 promotor have been identified as a mechanism that inactivates the p16 expression. The object of this study is to investigate the relationship between the loss of p16 protein and methylation as a molecular mechanism of the p16 gene inactivation in mammary tumorigenesis. METHODS : We performed an immunohistochemical assay of p16 protein in 70 cases of mammary carcinomas, and we tested for DNA methylation of p16 using methylation-specific PCR, and we then analyzed its correlation with the histopathologic variables. RESULTS : Among the 70 cases, the p16 expression was lost in 32 cases (45.7%), which was not significantly correlated with the pathologic variables. Twenty-three cases with and 27 cases without loss of p16 expression were tested for DNA methylation of p16. Twenty-one of the 23 interpretable cases with loss of p16 expression (91%) showed hypermethylation on p16, but there was no hypermethylation in any of the cases that were without the loss of the p16 expression. CONCLUSION: These findings suggest that the loss of the p16 expression is one of the common abnormalities observed in breast carcinoma and that methylation on the 5'CpG island of the p16 promoter is a major process for p16 ink4 inactivation in breast carcinoma.

Genetic Analysis of Epstein-Barr Virus Latent Membrane Protein 1 and Immunohistochemical Expression of Transforming Growth Factor (TGF)-beta1, TGF-betaRII, p21, p16, E2F1, Thymidylate Synthase, and NF-kappaB in Epstein-Barr Virus Encoded RNA-positive Gast

BACKGROUND :Although clinicopathologic differences have been described between Epstein-Barr virus (EBV)-positive and negative gastric adenocarcinomas, the pathogenetic basis for these differences remains unclear. In this study, efforts were made to confirm that expression of EBV-latent membrane protein (LMP1) and immunohistochemical characteristics of EBVpositive gastric adenocarcinomas. METHODS: We investigated genomic deletion, and RNA & protein expression of the EBV-LMP1, as well as immunohistochemical protein expression of transforming growth factor (TGF)-beta1, TGF-bata RII, p21, p16, E2F1, thymidylate synthase, and NF-kappaB in relation to EBV positive gastric adenocarcinoma. RESULTS: A total of 38 Epstein-Barr Virus Encoded RNA-positive and 80 negative gastric carcinomas were examined. A 30 bp DNA deletion in the EBV-LMP1 gene, initiating at codon 342, was detected in 94.4% of EBVpositive cases. By RT-PCR and western blotting, EBV-LMP1 mRNA and protein expressions were absent in all cases, re-gardless of DNA deletion. No significant differences in TGF-bata1, TGF-betaRII, p21, NF-kappaB, E2F1, or thymidylate synthase expression were identified. However, the decreased expression of p16 was found in 84.2% of EBV-positive carcinomas, relative to only 57.5% of EBV-negative tumors (p=0.024). CONCLUSION: EBV-LMP1 DNA deletion, mRNA and protein losses are highly prevalent in EBV-positive gastric adenocarcinoma among Korean patients, along with decreased p16 expression.

Epstein-Barr Virus and p16INK4A Methylation in Squamous Cell Carcinoma and Precancerous Lesions of the Cervix Uteri

Methylation of p16 is an important mechanism in cervical carcinogenesis. However, the relationship between cervical squamous cell carcinoma (SCC) and Epstein-Barr virus (EBV) remains controversial. Here, we explored whether EBV infection and/or p16 gene inactivation would play any role in cervical carcinogenesis. Eighty-two specimens included 41 invasive SCCs, 30 cervical intraepithelial neoplasm (CIN; CIN 1, 11 cases, CIN II, 3 cases, CIN III 16 cases) and 11 nonneoplastic cervices. EBV was detected by polymerase chain reaction (PCR) for EBNA-1 and in situ hybridization for EBER-1. The p16 methylation-status and the expression of p16 protein were studied by methylation-specific PCR and immunohistochemistry, respectively. The materials were divided into four groups: 1) nonneoplastic cervices, 2) CIN I, 3) CIN II-III and 4) invasive SCCs. p16 methylation and p16 immunoexpressions increased in CIN and invasive SCCs than nonneoplastic tissue. p16-methylation and p16-immunoreactivities were higher in the EBV-positive group (p=0.009, p<0.001) than in the EBV-negative group. EBV was detected more frequently in CIN and SCCs than nonneoplastic cervices. In conclusion, a correlation between p16 methylation, p16 immunoreactivity and the detection of EBV strongly suggested that the cooperation of EBV and p16 gene may play a synergic effect on cell cycle deregulation.

Immunocytochemical Staining for p16 of Atypical Squamous Cells in Cervicovaginal Smear / 대한세포병리학회지

It was reported that the main cause of intraepithelial neoplasm and squamous cell carcinoma of the uterine cervix is human papilloma virus infection, and that the expression of p16 is increased in cells infected by human papilloma virus. We performed an immunocytochemical staining for protein p16 in 17 cases of cervocovaginal smears initially diagnosed as atypical squamous cells of undetermined significance, to know whether the staining could help the differentiation of neoplastic cells from reactive atypical cells. Of 17 smears, 6 were diagnosed finally as high grade intraepithelial neoplasm or invasive squamous cell carcinoma by follow-up biopsy and smear, and 5 of the 6 were positive for p16. Three were diagnosed as koilocytosis, and one of them was weakly positive for p16. Eight were diagnosed as reactive atypical cells, and all of them were negative for p16. We thought that immunocytochemical staining of p16 in cervocovaginal smears could help the differentiation of neoplastic cells from reactive atypical cells.

Immunohistochemical Expressions of p16 and p21 Proteins in Laryngeal Squamous Cell Carcinomas / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Cyclin-dependent kinase inhibitor (CDKI) is known to play an important role in oncogenesis, but its clinical effect in head and neck cancer has not been reported yet. This study was designed to investigate the prognostic relevance of p16 and p21 protein expressions by evaluating the correlation between the expression pattern of p16 and p21 proteins, and tumor progress in laryngeal squamous cell carcinoma. MATERIALS AND METHODS: Paraffin-embedded tissue specimens from 54 patients, who were diagnosed with laryngeal squamous cell carcinoma between 1993 and 2002, were immunohistochemically stained for p16 and p21 proteins. The clinical features from these patients were retrospectively evaluated. The percentages of positive nuclei that stained positive for tumor were determined. RESULTS: In p16 protein, the proportion of strong expression was higher than that of weak expression in early tumor stage (T1, T2) and clinical stages (stage I, II): the proportion of weak expression was higher in the advanced tumor stage (T3, T4) and the clinical stages (stage III, IV): the correlations between the expressions of p16 protein and tumor clinical stages were significant (p0.05). In p16 and p21 protein, the proportion of weak expression was higher in nodal stage with neck metastasis than in nodal stage without neck metastasis: but the correlation between expression of p16 or p21 protein and nodal stage was not significant, respectively (p>0.05). CONCLUSION: There was a significant correlation between weak expression of p16 protein and more advanced tumor clinical stages. The expression of p16 protein may have prognostic value restrictively in laryngeal squamous cell carcinoma. Further study will be needed to understand the role of p16 and p21 protein in oncogenesis of laryngeal squamous cell carcinoma.

Detection of expression level of protein P16 in lung neoplasms biopsy samples by flow cytometry / 中华检验医学杂志

Objective To improve the sensitivity of detection of protein P16 by FCM.Methods Protein P16 of blood cells and tumor cells in biopsy samples were labeled simultaneously with anti-CD45 and anti-P16 fluorescent antibody.The rates of CD45+P16+ cells and CD45-P16+ cells were calculated by FCM.Results The low expression rates of protein P16 in normal blood cells and in tumor cells in biopsy samples were 15.39%(6/39) and 69.23%(27/39),respectively, which had a significant differences (P

Expression of G1/S Phase Checkpoint Proteins in Breast Carcinoma: Relationship to Clinicopathologic Factors andSurvival Rate / Journal of the Korean Cancer Association, 대한암학회지

The retinoblastoma protein (pRb)/cyclin D1/ p16 pathway plays a critical role in controlling the progression from G1 to S phase of the cell cycle. Abnormal expression of the individual components of the pathway has been reported in many human cancers, including the breast. Our aim was to investigate the role of this pathway in tumorigenesis and tumor progression, and to evaluate the value of these oncoproteins as potential prognostic factors in breast cancer. MATERIALS AND METHODS: We examined the significance of the p16, pRb, and cyclin D1 expression in 128 cases of invasive breast carcinomas using immunohistochemistry on formalin fixed, paraffin sections. The results correlated with the survival rate and clinicopathologic variables, including age, histologic grade, lymph node status, tumor size, estrogen receptor (ER) and progesterone receptor (PR) content. The negative finding for nuclear staining for pRb and p16 were defined as abnormal. RESULTS: Abnormal expression of the p16 and pRb were seen in 21% and 43% of tumors, respectively. There was a significant inverse relationship between the p16 and pRb expressions. There was no association between the p16 staining and any other parameters, including survival rate, cyclin D1, or clinicopathologic variables. Surprisingly, there was a trend for pRb positive tumors to be grade III ductal carcinomas. Cyclin D1 positivity was noted in 46% of cases. The expression of cyclin D1 protein was significantly higher in lower histologic grades, and with higher ER and PR expressions. CONCLUSION: These findings suggest the p16 may be negatively regulated by the pRb, and that cyclin D1 is involved in the tumor progression in well-differentiated tumors and could be an ER and PR related protein. In a Cox multivariate analysis, the p16, pRb, and cyclin D1 were not independent predictors of patient outcome.

Early Diagnosis of Lung Carcinoma:A Correlative study of P53?P16 Protein Expression to CT Appearance in Lung Carcinoma / 实用放射学杂志

Objective The main purpose of the present study was to reveal the correlation among the CT and p53?p16 protein of non-small cell lung carcinoma(NSCLC).Methods The expression of p53?p16 protein in 52 cases by SABC immunohistochemical technique and the relationship to CT appearance were analysed.Results (1)The experssion of p53 protein of NSCLC was significantly higher than that of their adjacent tissues and their normal lung tissues(?

The relationship between the expression of CD44v6,P16 protein and invasion and metastasis in gastric carcinoma / 中国医师杂志

Objective To explore the relationship between the expression of CD44v6,P16 protein and the invasion and metastasis in gastric carcinoma and to investigate the correlation between the expression of CD44v6 and P16 protein.Methods Immunohistochemical methods were used to detect the expression of CD44v6 and P16 protein in 110 cases of gastric carcinoma.Results In 110 cases of gastric carcinoma,the expression of CD44v6 and P16 protein were 72.7%(80/110)and 47.3%(52/110)respectively. The high level expression of CD44v6 protein and low level expression of P16 protein were positively correlated with the TNM staging,serosa infiltration,lympho node and liver metastasis of gastric carcinoma(P

Expression of cyclin D1 and p16 protein in vulvar white lesion / 中华妇产科杂志

0.05). Conclusions Cyclin D1 and p16 are important factors modulating cell cycle. The interrupt of balance between these two factors derived from abnormal expression of cyclin D1 may be one of the causes of vulvar white lesion.

K-ras Gene Mutations and Expression of K-ras, p16, Cyclin D1 and p53 in Synchronous Lesions of The Colon Adenoma-Carcinoma Sequences

BACKGROUND: The colorectal adenoma-carcinoma sequence represents a well-known para-digm for the sequential development of cancer driven by the accumulation of genomic defects. Although the colorectal adenoma-carcinoma sequence has been well investigated, the studies about tumors of different dignity co-existent in the same patient are rare. K-ras mutation is an early genetic change in colon cancer. The genes involved in the cell cycle such as cyclin D1, p16, and p53 are important in the tumorigenesis of the colon. The aims of this study were to determine K-ras gene mutation and expression of K-ras, p16, cyclin D1 and p53 in synchronous lesions of the colon adenoma-carcinoma sequences and their possible relationship with K-ras mutation. METHODS: The materials included 45 colonic adenocarcinomas which were accompanied by adenoma (22 low grade and 26 high grade). By using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP), we detected K-ras mutation of codon 12. An aberrant K-ras, p16, cyclin D1 and p53 expressions were stained using an immunohistochemical method. RESULTS: K-ras mutation was 52.4% (11/21) of high grade adenomas. K-ras expression was 65.4% (17/26) of high grade adenomas. p16 and cyclin D1 expressions were 50% (11/22) and 90.9% (20/22) of low grade adenomas, respectively. p53 expression was 75.6% (34/45) of adenocarcinomas. There were statistical correlations among K-ras, p16 and cyclin D1. CONCLUSIONS: These results indicate that the ras gene mutation is an early event and the overexpressions of p16, cyclin D1 and p53 are associated with K-ras mutation and expression in adenoma-carcinoma sequences.

Expression of Cyclin D1, CDK4, p16 and Rb Proteins in Human Soft Tissue Sarcomas

BACKGROUND: Altered cell cycle regulation may underlie the development and/or progression of human malignancies. The purpose of this study is to determine if the oncogenesis of soft tissue sarcomas could be better explained by examining the components involved in G1 phase progression. METHODS: Sixty-seven soft tissue sarcomas were studied for the immunohistochemical expression of cdk4, cyclin D1, retinoblastoma (Rb) and p16 proteins. For Rb and p16, samples showing either negative or heterogeneous (<80% of tumor cells) staining were considered to be altered. RESULTS: The cdk4 protein was observed in 64 cases (95.5%). Cyclin D1 was expressed in 14 cases (20.9%). The Rb expression was altered in 48 (71.6%). Sixty-three (94%) sarcomas demonstrated altered p16 expressions. All of the samples displayed altered expressions of either Rb or p16. A high percentage of the tumors with altered Rb were observed in relapsed patients (p<0.05). CONCLUSIONS: Disturbance in the cell cycle regulatory system involving the Rb/p16/cdk4/cyclin D1 pathway appears to be relatively frequent in soft tissue sarcomas and may play an important role in the tumorigenesis of these tumors. It is noteworthy that the reduced Rb expression correlates with tumor relapse, suggesting its prognostic significance.

Expression of the G1-S Modulators in Hepatitis B Virus-Related Hepatocellular Carcinoma and Dysplastic Nodule: Association of Cyclin D1 and p53 Proteins with the Progression of Hepatocellular Carcinoma

Deranged expression of cell cycle modulators has been reported to contribute to the development and progression of hepatocellular carcinoma (HCC). However, their expression patterns remain poorly understood in hepatitis B virus (HBV)-related HCC, which constitutes about 65-70% of HCC in Korea. The aims of this study were to evaluate the expressions of G1-S modulators in HBV-related HCCs and dysplastic nodules (DNs), and to correlate with the histopathologic features of HCCs. Immunohistochemical expressions of cyclin D1, cyclin E, p53, p27, p21, p16, Rb, and PCNA proteins were investigated in 80 HCCs and 22 DNs. Cyclin D1 overexpression showed positive relationships with advanced tumor stage, poor differentiation, larger tumor size, microvascular invasion, intrahepatic meta-stasis, no tumor capsule formation, infiltrative growth, aberrant p53 expression, and high PCNA labeling index (LI) of HCC (p<0.05). Aberrant p53 expression showed positive relationship with poor differentiation of HCC (p<0.01). Expression of cyclin D1 or p53 was not observed in DNs. The p27 LI and p16 LI were lower in HCCs with intrahepatic metastasis (p<0.05). Cyclin D1 overexpression and aberrant p53 expression could be associated with the progression of HBV-related HCC, and might have a less crucial role in the DN-HCC sequence. In addition, elevated expression of p27 and p16 proteins might have inhibitory action to the intrahepatic metastasis of HBV-related HCC.

Expression of p16 and Rb in 9,10-Dimethyl-1,2-Benzanthracene Induced Rat Ovarian Carcinogenesis

BACKGROUND: In order to investigate the roles of p16 and Rb, their expression was evaluated in 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced ovarian cancers of rats. METHODS: DMBA-coated silk was inserted into both ovaries of 20 9-week-old Sprague-Dawley rats. The experimental period lasted 20 weeks. The tumor histology was classified and the expression of p16 and Rb in the ovarian tumors was analyzed by immunohistochemistry and Western blot. RESULTS: The p16 and Rb labeling index was significantly lower in the ovarian cancers than the normal ovarian surface epithelium of a rat. There were no differences among the cancer types. In Western blot analysis, the expressions of p16 and Rb in ovarian cancers were lower than those in normal ovarian tissue. No correlation was present between p16 and Rb. CONCLUSION: The abnormal expression of p16 and Rb occurs in DMBA-induced rat ovarian cancer and might be involved in carcinogenesis.

Expression of pRb, p16, Cyclin D1 and Cyclin E in Infiltrating Duct Carcinoma of the Breast

BACKGROUND: Inactivation of the retinoblastoma protein (pRb) is a mechanism by which tumor cells can subdue normal growth control. Among the molecules involved in control of pRb phosphorylation, cyclin D1 and cyclin E have been found to be deregulated and overexpressed in various types of cancers. METHODS: Immunohistochemical stains for pRb, p16, cyclin D1 and cyclin E were performed in 73 cases of infiltrating duct carcinomas of the breast. In addition to analysis of their expression rates, the relationships between their expressions and the clinicopathologic parameters were evaluated. RESULTS: pRb, p16, cyclin D1 and cyclin E were positive in 64.7% (44 out of 68 cases), 24.6% (15 out of 61 cases), 43.8% (32 out of 73 cases) and 61.6% (45 out of 73 cases), respectively. Their expression rates were not significantly associated with clinicopathologic prognostic factors. 33 out of 38 cases with p16-negative reactions were pRb positive, while 10 out of 15 cases with pRb-negative reactions were p16 positive. There was a significant inverse relationship between pRb and p16 expressions (P<0.005). 25 out of 32 cases with cyclin E-positive reactions were cyclin D1-positive, and 25 out of 45 cases with cyclin D1-positive reactions were cyclin E-positive. A statistically significant association was observed between cyclin D1 and cyclin E expressions (P<0.05). CONCLUSIONS: The main mechanism during tumorigenesis of breast carcinoma depends on the cyclin D1/p16/pRb pathway, but cyclin E might play a role in the absence of cyclin D1. The inverse correlation between the pRb and p16 expressions may represent one of the important mechanisms in tumorigenesis, as well.

Expression of P16/cyclin D1 and their relationship with cervical lymph node metastasis of tongue carcinoma / 实用口腔医学杂志

0.05),cyclin D1 was positively and P16 negatively associated with the differentiation and the lymph node metastasis of tongue cancer(P