[Promoter methylation status and protein expression of p14ARF gene in squamous cell carcinoma and adenocarcinoma of the lung].
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Recently, the p14 ARF gene has emerged as a new putative tumor suppressor gene, and the alteration of p14 ARF gene is closely related to development of multiple human tumors. The aberrant promoter methylation as a mechanism of inactivation of p14 ARF gene might participate in tumorigenesis. The aim of this study is to investigate promoter methylation status and protein expression of p14 ARF gene in pulmonary squamous cell carcinoma and adenocarcinoma, and to value the role of p14 ARF promoter methylation in carcinogenesis of non-small cell lung cancer.Promoter methylation status and protein expression of p14 ARF gene were analyzed in 40 cases of pulmonary squamous cell carcinoma and adenocarcinoma by methylation specific polymerase chain reaction (MSP), restriction enzyme-related polymerase chain reaction (RE-PCR) and immunohistochemistry (IHC).The positive rate of p14 ARF promoter methylation in tumor tissues and normal tissues adjacent to cancer was 17.5% (7/40) and 2.5% (1/40) respectively (P= 0.025 ). The results of RE-PCR were consistent with the above. The positive rate of p14 ARF protein in tumor tissues was significantly lower than that in normal tissues adjacent to cancer (P=0.003). Promoter methylation and protein expression of p14 ARF gene showed a significantly negative correlation (r=-0.56, P= 0.001 ), and both of them did not correlate statistically with the clinicopathologic characteristics of patients such as histological classification, TNM stages, differentiation grade and lymph node involvement.Promoter methylation is a crucial mechanism of inactivation of p14 ARF gene. Promoter methylation of p14 ARF gene might be involved in carcinogenesis of non-small cell lung cancer, and it is an early event in development process of non-small cell lung cancer.Keywords:
p14arf
Bisulfite sequencing
Aim:To investigate the abnormal methylation of p16,Rb and p27 gene promoter region in colorectal carcinoma tissue and the significance.Methods:Methylation-specific polymerase chain reaction(MSP) was used to detect the methylation status of p16,Rb and p27 gene promoter region in 56 cases of colorectal carcinoma and the matched normal mucosa epithelium,and 42 cases of adenoma tissue.Results: Compared to that of normal mucosa epithelium,the methylation rates of p16 and p27 gene promoter region in colorectal adenoma and carcinoma tissues increased significantly (χ2=4.680,9.091 and 4.008,10.618,P0.05),while that of Rb gene maintained low level(χ2=2.513 and 3.125,P0.05).The methylation status of p16 and p27 gene promoter region were negatively correlated with their proteins(rP was 0.894 and 0.920,P0.001),but there was no correlation between methylation status of Rb gene and the expression of Rb protein(rP=0.026,P=0.661).The hypermethylation of p16 gene promoter region was significantly related to the degree of differentiation,the depth of infiltration and the metastasis of lymph node (χ2=10.757,6.229 and 5.707,P0.05),while that of p27 gene was only related to the metastasis of lymph node(χ2=10.475,P0.001).Conclusion: Hypermethylation of p16 and p27 gene promoter region may play important roles in the carcinogenesis,progression and metastasis of colorectal carcinoma.
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Objective To investigate the value of RUNX3 gene promoter methylation in diagnosis of non-small cellular lung cancer(NSCLC). Methods The methylation of RUNX3 gene promoter was analyzed in 58 NSCLC tissues and tumor-adjacent normal lung tissues by methylation-specific-PCR. The correlation between methylation of RUNX3 gene promoter and clinicopathological characteristics was statistically analyzed as well.Results Twenty-six(44.8%) tissues with methylation of RUNX3 gene promoter in 58 NSCLC tissues was detected,which was significantly higher than 10(17.2%) tumor-adjacent normal lung tissues(P0.01).The methylation of RUNX3 gene promoter was closely relatedtoclinical stage,lymph node metastasis and differentiation degree of NSCLC(P0.05). Conclusion The high methylation rate of RUNX3 gene promoter exists in NSCLC tissues.The methylation of RUNX3 gene promoter is closely related to clinical stage,lymph node metastasis and differentiation degree and has an important significance in the diagnosis and evaluation of prognosis of NSCLC.
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Objective To explore the clinical correlation between p14ARF promoter methylation and primary liver cancer through analysis of p14ARF promoter methylation in primary liver cancer in the population of North China.Methods By the method of methylation specific PCR(MSP),the detection of p14ARF promoter methylation in 111 cases of primary liver cancer and 22 cases of adjacent non-tumor tissue were carried out,and then correlated with different clinical variables,such as tumor type,tumor stages,differentiation of tumor cell and with or without HBV infection in tumor.Results Significant difference(P=0.010)of p14ARF promoter methylation between hepatocellular carcinomas(HCC) and adjacent non-tumor tissue was found,with the ratio of 33.7%(29/86)in primary liver cancer and 5.0%(1/20)in non-tumor tissue.Higher frequency of p14ARF promoter methylation was identified in HCC with tumor stage of TNM1 compared with tumor stage of more than TNM1(P=0.027).No correlation was found between p14ARF promoter methylation and differentiation of tumor cell and with or without HBV infection in HCC,as well as between p14ARF promoter methylation and tumor stages,differentiation of tumor cell and with or without HBV infection in intrahepatic cholangiocellular carcinoma(ICC).Conclusion p14ARF promoter methylation may constitute one of the important mechanism in inactivation of p14ARF gene and maybe involved in the development and progression of HCC.
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Liver Cancer
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BACKGROUND:Primary liver cancer is a common malignant tumor that causes serious damage to human health. DNA methylation is common in epigenetics. DNA methylation plays an important role in the process of primary liver cancer occurrence and development. The P14ARF gene is an important tumor suppressor gene. It was found that P14ARF methylation is associated with the degree of malignancy in multiple tumors. Therefore, this study aimed to investigate the relationship between P14ARF methylation level and primary liver cancer malignant degree. MATERIAL AND METHODS:Carcinoma tissues and adjacent tissues were collected from 87 primary liver cancer patients. Pyrosequencing was applied to obtain P14ARF methylation. Real-time PCR was used to detect P14ARF mRNA level. RESULTS:P14ARF methylation level in cancerous tissue was significantly higher than in the adjacent tissue (t=76.54, P<0.001). P14ARF methylation showed no significant difference in patients with different age, sex, smoking status, or drinking status. It did not present an obvious difference in tumors with different size. Its methylation level increased following the improvement of TNM stage (P<0.05). Compared with the adjacent tissue, P14ARF mRNA in carcinoma tissue decreased by 31% (t=28.91, P<0.001). P14ARF methylation showed a significant negative correlation with mRNA expression in cancerous tissue (r=–0.43, P<0.01). CONCLUSIONS:P14ARF mRNA level is regulated by DNA methylation in primary liver cancer. P14ARF gene DNA methylation may be associated with the occurrence of primary liver cancer occurrence and TNM staging.
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Primary (astronomy)
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Objective To investigate aberrant methylation in the promoter area of p16 gene and p16 protein expression in human pancreatic carcinoma and in the corresponding tumor-adjacent tissues,and evaluate their role in the carcinogenesis and progression of tumor and its clinical significance.Methods Immunohistochemistry and MSP(methylation-specific PCR)were performed on 46 samples of pancreatic carcinoma and their corresponding tumor-adjacent tissue specimens for p16 and its methylation.Results Expression rate of p16 protein was 41.3%(19/46)in pancreatic carcinomas,95.7%(44/46)in corresponding tumor-adiucent tissues.Through MSP,the methylation rate in pancreatic carcinomas was 39.1%.No gene methylation was found in 19 cases expressing p16 protein.p16 gene methylation was closely related to p16 protein expression in pancreatic carcinoma(P0.05).The expression of p16,the aberrant methylation in the promoter area of p16 gene were no relationship with clinicopathological characteristics,such as tumor size,patient's sex and age(P0.05);but were significantly related to the PTNM staging,histological differentiation,distant metastasis and lymph node metastasis(P0.05).Conclusions Methylation in the promoter of p16 gene and p16 protein expression were associated with the development of pancreatic carcinoma and could be used as a putative prognostic indicator for malignancy.
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Abstract Hypermethylation of cytosines in CpG‐rich islands of the promoter regions of regulatory genes has been discovered as a common mechanism of gene silencing during carcinogenesis. We analysed 64 primary lung carcinomas for promoter methylation of the tumour suppressor genes (TSGs) p16 ( p16 INK4a / CDKN2A ) and p14 ( p14 ARF ) by methylation‐specific PCR, in order to evaluate aberrant methylation as a potential biomarker for epigenetic alterations in tobacco‐related lung cancer. Methylation of p16 was observed in 34% (22/64) of the lung tumours examined. In particular, p16 methylation occurred in nonsmall cell lung cancer (NSCLC) only, with 41 % (22/54) of the tumours being positive. The highest frequency was found in large cell carcinoma (5/7, 71%), followed by adenocarcinoma (9/25, 36%) and squamous cell carcinoma (7/21, 33%). Methylation of the p14 gene was less frequent in lung cancer (4/52, 8%). When association with tobacco smoking was analysed, 42% (21/50) of NSCLC from ever smokers exhibited p16 methylation. Interestingly, the analysis revealed a significantly higher risk of p16 methylation in former smokers as compared to current smokers [odds ratio (OR) 5.1; 95% confidence interval (CI) 1.3–22]. The difference was retained after adjustment for age (OR 3.7; 95% CI 0.9–17). The promoter methylation results were then combined with data on genetic alterations determined previously in the same set of tumours. This data similarly showed that p16 methylation in parallel with p53 gene mutation or p14 methylation occurred more frequently in former smokers than in current smokers (44% vs. 14%; P = 0.035). Taken together, our data suggest that analysis of promoter methylation in TSGs may provide a valuable biomarker for identification of groups with an elevated risk of cancer, such as smokers and ex‐smokers. © 2003 Wiley‐Liss, Inc.
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Abnormal hypermethylation of the CDKN2A (p14ARF and p16INK4a) gene can lead to repression of gene expression and contribute to carcinogenesis and tumor progression.In esophageal squamous cell carcinoma (ESCC), the promoter methylation of the p14ARF and p16INK4a gene was investigated in 38 cases by methylation-specific PCR and the expression of each gene in 18 cases was quantified by real-time quantitative reverse transcription-PCR.Aberrant methylation of p14ARF and of p16INK4a was detected in 23 (61%) and 29 (76%) cases, respectively. No relationship was found between clinicopathological variables and p14ARF or p161NK4a promoter methylation. A statistically significant association between p14ARF methylation status and mRNA expression was found (p=0.0441). Regarding p14ARF, a low expression group showed a significantly higher proportion of cases with deep invasion of tumor, lymph node metastasis, and a high TNM stage of disease (p=0.0474, 0.0474, and 0.0441, respectively), and a significantly poor prognosis (p=0.0402). Regarding p161NK4a, no relationship was found among the methylation status, mRNA expression and clinicopathological variables, including survival.Our results suggest that methylation is the predominant mechanism of inactivation of the p14ARF gene in ESCC. The decrease in p14ARF gene expression associated with invasive and metastatic phenotypes may be significant as an indicator of the malignant potential of human ESCC.
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(1) To investigate the promoter methylation status of gene p16(INK4a) and gene RB in breast carcinoma and the adjacent non-neoplastic hyperplastic epithelial tissue. (2) To study the correlation of p16(INK4a) gene expression at protein level with the abnormal gene methylation, the clinical manifestation and the pathological parameters.Methylation status of promoters of p16(INK4a) gene and RB gene was detected by using methylation specific PCR in 46 cases of breast cancer, 22 cases of the adjacent non-neoplastic hyperplastic epithelium tissue and 7 cases of normal breast tissue. In addition, the p16(INK4a) gene protein expression level was also detected using immunohistochemical technique(SP method) in 46 cases of breast cancer and 22 cases of the adjacent hyperplastic epithelial tissue.The methylation rate of p16(INK4a) gene was 23.9% (11/46) in breast cancer, 18.2% (4/22) in the adjacent non-neoplastic hyperplastic epithelial tissue and 1/7 in normal breast tissue, respectively. The methylation rate of RB gene was relatively low, which was 10.8% (5/46), 9.1% (2/22) and 0(0/7) in the above 3 groups, respectively. Methylation rate of p16(INK4a) gene and RB gene was not significantly different among the breast cancer, the adjacent non-neoplastic hyperplastic tissue and the normal tissues (P > 0.05). However, the methylation status of p16(INK4a) gene was closely correlated with its protein expression level and the negative ER expression result of the breast cancer (P < 0.05), but not correlated with the size of the cancer, differentiation status, lymph node metastasis, and age. The methylation status of RB gene was correlated with lymph node metastasis, but not with the size, the differentiation status, ER expression of the breast cancer and the age of the patients.The abnormal methylation of p16(INK4a) gene may not play a significant role in the early stage of breast cancinogenesis, but may play a role of in the progression of the cancer. RB gene methylation may also be a indicator in choice to identify the progression and prognosis of breast cancer.
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