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Objective To study the methylation status of the promoter region of several tumor suppressor genes in p53-Bax mitochondrial apoptosis pathway and its role in cholangiocarcinoma. Methods The hypermethylation of the promoter region of tumor suppressors death-associated protein kinase (DAPK), p14, and target of methylation-associoted silencing-1 (TMS1/ASC) were detected by methylation-specific PCR. P53 gene status (exon 5-8 ) were examined by automated sequencing. The relationship between gene mutations and the biological behaviors of cholangiocarcinoma was analyzed. Results Methylation existed in at least one promoter region of tumor suppressor gene in the tumor tissues of 24 patients (66. 7% ). The frequencies of tumor suppressor gene methylation in cholangiocarcinoma were: p14 24%, DAPK 30. 6%, and TMS1/ASC 36. 1%. The frequencies of tumor suppressor gene methylation in the adjacent tissues were: TMS1/ASC 8.3% and DAPK 5.6%. DNA sequencing showed p53 gene mutation was found in 22 of 36 patients (61.1% ), and p53 gene mutation combined with the methylation of tumor suppressor was found in 14 (38.9%) patients, which was significantly correlated with pathologic biology, invasion, and differentiation ( P ＜ 0.05 ). The 1-year, 2-year, and 3-year survival rates were significantly higher in tumor-suppressing genes methylation group ( n = 4) (70%, 43 %, and 28%, respectively)than those in p53 gene mutation group (n = 14) (28%, 5%, and 0%, respectively) (χ2 =9. 060, P =0.03).Conclusions Promoter hypermethylation of p53-Bax mitochondrial apoptosis pathway is a common epigenetic event in cholangiocarcinoma. Although the methylations of TMS1/ASC and DAPK genes in the adjacent tissues are relatively low, they may be informative for the early detection of cholangiocarcinoma. P53 gene mutation combined with the methylation of tumor suppressor may be related with the pathologic biology of cholangiocarcinoma, making the latter trend to be with high malignancy and poor prognosis.
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<p><b>BACKGROUND</b>To study the expression of catalylic subunit of DNA-dependent protein kinase (DNA-PKcs) in non-small cell lung cancer (NSCLC) and its relationship with apoptosis.</p><p><b>METHODS</b>NSCLC tissues from 113 untreated patients were analyzed immnohistochemically with antibodies to DNA-PKcs, p53 and bcl-2.</p><p><b>RESULTS</b>There were expressions of DNA-PKcs, p53 and bcl-2 in NSCLC at different levels. The positive rate of DNA-PKcs, p53 and bcl-2 was 89.38%(101/113), 61.95%(70/113) and 59.29%(67/113) respectively. The expression of DNA-PKcs was significantly related with the histological types. Its expression in squamous carcinoma was significantly lower than that in adenocarcinoma and bronchioloalveolar carcinoma. The expression of DNA-PKcs increased with the increasing differentiated degree of NSCLC ( P < 0.05), but had no relationship with lymph node metastasis. There was no significant relation between the expression of p53 and the pathological type of NSCLC. A significant difference of bcl-2 expression existed in the histological types of lung cancer ( P < 0.01). Its expression in squamous carcinoma was significantly higher than that in adenocarcinoma, bronchioloalveolar carcinoma and adenosquamous carcinoma, but had no relationship with the differentiated degree of lung cancer and lymph node metastasis. The expressions were significantly related between DNA-PKcs and p53 ( P < 0.01), p53 and bcl-2 ( P < 0.05).</p><p><b>CONCLUSIONS</b>The expression of DNA-PKcs is fairly high in NSCLC. The high expression of DNA-PKcs and overexpressions of mutated p53 and bcl-2 may be important causes of radioresistance in NSCLC.</p>
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G protein-coupled receptors(GPCRs) are the largest and most diverse group of trans-membrane proteins involved in signal transduction. They have been playing key roles in drug discover-y. Increasing orphan GPCRs (oGPCRs) whose endogenous ligands and functions are still to be identified have been discovered in recent years. It is obvious that oGPCRs might be the most important targets for innovating drugs.