Death-associated Protein Kinase Gene Research Articles

Differential gene expression analysis after DAPK1 knockout in hepatocellular carcinoma cells.

BackgroundThe mechanism through which death-associated protein kinase 1 (DAPK1) causes hepatocellular carcinoma (HCC) progression remains unclear. In this study, we aimed to identify key proteins that were altered after DAPK1 knockout.MethodsStable DAPK1 knockout HCC cell lines were established, then the differentially expressed genes (DEGs) of HCC were screened using the NetworkAnalyst database and enriched using the Metascape software. Protein-protein interaction networks (PPIs) were analyzed and visualized using the STRING database expansion.ResultsIn total, 732 differentially expressed genes were identified, including 415 upregulated genes and 317 downregulated genes. Through Cytoscape software scoring, 10 pivotal genes were found to be closely related to changes in DAPK1 expression; Kininogen-1 (KNG1), Complement C3 (C3), Metalloproteinase inhibitor 1 (TIMP1), and Alpha-2-HS-glycoprotein (AHSG) were the most strongly associated with DAPK1 expression changes. Moreover, western blot analysis results revealed that changes in the levels of proteins encoded by the four key genes after DAPK1 knockout were consistent with those seen in the database screening.ConclusionsThese results provide a direction for further studies on the DAPK1 gene and on the mechanism through which DAPK1 leads to hepatocellular carcinoma development.

Blocking ERK-DAPK1 Axis Attenuates Glutamate Excitotoxicity in Epilepsy.

Glutamate excitotoxicity induces neuronal cell death during epileptic seizures. Death-associated protein kinase 1 (DAPK1) expression is highly increased in the brains of epilepsy patients; however, the underlying mechanisms by which DAPK1 influences neuronal injury and its therapeutic effect on glutamate excitotoxicity have not been determined. We assessed multiple electroencephalograms and seizure grades and performed biochemical and cell death analyses with cellular and animal models. We applied small molecules and peptides and knocked out and mutated genes to evaluate the therapeutic efficacy of kainic acid (KA), an analog of glutamate-induced neuronal damage. KA administration increased DAPK1 activity by promoting its phosphorylation by activated extracellular signal-regulated kinase (ERK). DAPK1 activation increased seizure severity and neuronal cell death in mice. Selective ERK antagonist treatment, DAPK1 gene ablation, and uncoupling of DAPK1 and ERK peptides led to potent anti-seizure and anti-apoptotic effects in vitro and in vivo. Moreover, a DAPK1 phosphorylation-deficient mutant alleviated glutamate-induced neuronal apoptosis. These results provide novel insight into the pathogenesis of epilepsy and indicate that targeting DAPK1 may be a potential therapeutic strategy for treating epilepsy.

Clinicopathological significance of DAPK gene promoter hypermethylation in non-small cell lung cancer: A meta-analysis.

Death-associated protein kinase (DAPK) has a strong function of tumor suppression involving apoptosis regulation, autophagy, and metastasis inhibition. Hypermethylation of CpG islands in DAPK gene promoter region is one of the important ways to inactivate this tumor suppressor gene, which might promote lung carcinogenesis. However, the clinicopathological significance of the DAPK promoter hypermethylation in lung cancer remains unclear. In this study, we performed a meta-analysis trying to estimate the clinicopathological significance of DAPK promoter hypermethylation in non-small cell lung cancer (NSCLC). A detailed literature search for publications relevant to DAPK gene promoter methylation and NSCLC was made in PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, CSTJ, Wanfang databases, and SinoMed (CBM). The random-effects model and fixed-effects model were utilized to pool the relative ratio based on the heterogeneity test in the meta-analysis. A total of 41 studies with 3348 patients were included. The frequency of DAPK methylation was significantly higher in NSCLC than in non-malignant control (odds ratio (OR) = 6.88, 95% confidence interval (CI): 4.17-11.35, P < 0.00001). The pooled results also showed that DAPK gene promoter hypermethylation was significantly associated with poor prognosis for overall survival in patients with NSCLC (hazard ratio: 1.23, 95% CI:1.01-1.52, P = 0.04). Moreover, DAPK gene promoter hypermethylation was significantly associated with squamous cell carcinoma (OR: 1.25, 95% CI: 1.01-1.54, P = 0.04) and smoking behavior (OR: 1.42, 95% CI: 1.04-1.93, P = 0.03) but not with TNM stage, tumor differentiation, age, or gender. DAPK promoter hypermethylation might be a candidate diagnostic and prognostic tumor marker for NSCLC.

Meta-analysis: Assocation between promoter hypermethylation of DAPK (Death-Associated Protein Kinase) and cervical cancer

Purpose: Death-associated protein kinase (DAPK or DAPK1) is an important tumor suppressor protein that involved in the regulation of cell activities. The aberrant methylation of DAPK promoter has been reported in patients with cervical cancer. However, the association between of DAPK1 and cervical cancer was not always unification, in previous studies. Therefore, in current study, a meta-analysis was performed for association of between DAPK gene’s promoter hypermethylated and cervical cancer.&#x0D; Methods: A systematic literature analysis was conducted based on the previous studies published in PubMed, PubMed Central (NCBI), Google by using following keywords: cervical cancer, cervical carcinoma, Methylation, by the end of January, 2018. The association between DAPK promoter methylation and cervical cancer was evaluated by odds ratio (ORs) and 95% confidence intervals (CI). To evaluate the potential sources of heterogeneity, the meta-regression analysis and subgroup analysis were conducted.&#x0D; Results: A total of 21 case-control studies which relevant to the association between DAPK1 gene’s promoter methylation frequency and cervical cancer, that including 1600 cancer cases and 1011 control cases (non-cancerous cases). The analysis results indicated that the characteristic of candidate gene’s promoter methylation increased the cervical cancer risk through the calculation of OR value (OR = 21.25; 95% CI = 8.73 – 52.97; p &lt; 0.001; Random effect model). The association between DAPK1 gene’s promoter hypermethylation was confirmed in all the subgroups analyses, including materials and assays methods, ethnicity. Furthermore, this association is higher in cervical squamous cell carcinoma than cervical adenocarcinoma and is a characteristic of late-stage disease.&#x0D; Conclusion: The hypermethylated DAPK1 gene’s promoter was also one of etiological factor, lead to the cervical tumorigenesis.

Analysis of Promoter Hypermethylation of DAPK and BAX Apoptotic Genes in Iranian Gastric Cancer Patients Undergoing Chemotherapy

Background: The apoptotic route is mostly damaged in gastric cancer tumor cells. DNA methylation of promoter associated CpG islands inactivates tumor suppressor genes. The objective of the present study was to analyze the hypermethylation of death-associated protein kinase (DAPK) and Bcl-2-associated X protein (BAX) genes in individuals suffering from gastric cancer and undergoing chemotherapy. Methods: Genomic DNA was extracted from blood samples and the tissue fixed in the paraffin of 30 patients and normal individuals. Hypermethylation investigation of DAPK and BAX genes was conducted via methylation specific PCR technique, the outcomes of which were analyzed through electrophoresis and SPSS software version 20. Results: Methylation of both BAX and DAPK genes with a frequency of (28.3%, 21.7%) in blood and (23.3%, 23.3%) in tissue, respectively, had a significant relationship with gastric cancer (P˂0.01). A significant relationship was also observed between the methylation of BAX gene in tissue and tumor type (12, 35.3% and P˂0.01). No relationship was found between methylation and grade, stage, node, age, sex, and other pathologic and clinical data of the patients (P>0.05). There was a significant association between simultaneous methylation of DAPK and BAX genes in tumor and typical tissues with methylation a frequency of 40% and 95.83%, respectively (P˂ 0.01). Conclusion: Methylation of the BAX and DAPK genes can be used as a biomarker in bloodand an approach in the early detection of malignity and illness management. Methylation inhibitors with the potential for drug targeting of DAPK and BAX can further be employed in pharmacotherapy.

Association of Protein Expression and Methylation of DAPK1 with Clinicopathological Features in Invasive Ductal Carcinoma Patients from Kashmir

Aims:Death-associated protein kinase-1 (DAPK1) is a pro-apoptotic Ser/Thr kinase that participates in cell apoptosis and tumor suppression. DAPK1 is frequently lost in many different tumor types including breast cancer. The aim of this study was to evaluate the promoter methylation status of DAPK1 and a possible correlation with the expression of DAPK1 and standard clinicopathological features in invasive ductal breast carcinoma patients (IDC).Methods:Methylation Specific PCR (MSP) was carried out to investigate the promoter methylation status of DAPK1 from 128 breast cancer patients. The effect of promoter methylation on protein expression was evaluated by immunohistochemistry (n=128) and western blotting (n=56).Results:We found significant difference in DAPK1 promoter methylation frequency among breast tumors when compared with the corresponding normal tissues. Hypermethylation of DAPK1 is significantly correlated with the loss of DAPK1 protein expression (P < .001, rs= -0.361). The loss of DAPK1 protein was significantly associated with estrogen receptor (ER) negativity (p= 0.003), triple negative breast cancer (TNB) (p= 0.024) and advanced tumor stages (P = 0.001). Moreover, age at diagnosis (p= 0.041), tumor stage (p= 0.034), ER negativity (p= 0.004) and TNB cancers (p=0.003) correlated significantly with the hypermethylation of the DAPK1 promoter.Coclusion:This study indicates that DAPK1 is methylated in IDC and promoter hypermethylation could be attributed to silencing of DAPK1 gene expression in breast cancer. Thus, we consider DAPK1 inactivation by promoter hypermethylation likely plays a role in the development and progression of breast cancer.

Death-associated Protein Kinase 1 Impairs the Hippocampo-prefrontal Cortical Circuit and Mediates Post-stroke Depression

Post-stroke depression (PSD) is a common and complex post-stroke neuropsychiatric disorder, which not only delays functional recovery but also increases mortality, and which currently lacks effective drug therapy. The pathogenesis of PSD is associated with impairment of the subcortical neural circuits and alterations of synaptic plasticity and neurotransmitters, but the exact mechanisms of PSD remain unknown. Our previous work indicates that the death-associated protein kinase 1 (DAPK1) mediates neuronal death after stroke. Genetic deletion of DAPK1 gene or blocking DAPK1 signal in the PSD mouse model can not only alleviate cerebral ischemic injury but also relieve PSD-like behaviors. Our previous work has also demonstrated the following results. First, the neural circuit of dorsal CA1 (dCA1) to medial prefrontal cortex (mPFC) (dCA1-mPFC) is selectively impaired after stroke. Second, the DAPK1 signal is involved in the impairment of dCA1-mPFC neural circuit after stroke. Third, genetic deletion of the DAPK1 gene or blocking of the DAPK1 signal alleviates the injury of dCA1-mPFC neural circuit after stroke and improves PSD-like behaviors. In conclusion, we hypothesize that activated DAPK1 signal after stroke induces apoptosis in the hippocampal dCA1 neurons, leading to loss of the dCA1-mPFC glutamatergic projections, synaptic injury, decrease of glutamate release, inhibition of mPFC neurons, and finally onset of PSD. We hope to further replenish the mechanisms of PSD and provide new insights for PSD treatment.

The prognostic value of DAPK1 hypermethylation in gliomas: A site-specific analysis

Background and aimsThe gene of death associated protein kinase 1 (DAPK1) has been reported to be methylated in various cancers including gliomas. However, its prognostic value for gliomas is still controversy, and the methylation at specific CpG sites of DAPK1 has not been investigated. The aim of this study was to prognostically evaluate the methylation level of different CpG sites within DAPK1 promoter region in gliomas. MethodsBased on sodium bisulfite treated DNA products, we made use of DNA pyrosequencing method to evaluate overall and site-specific methylation of DAPK1 in 143 gliomas and 26 benign tumors (meningeomas) or normal brain tissues. We both statistically analyzed the association between methylation levels of each CpG site and the clinicopathological characteristics, and estimated the prognosis predictive value of site-specific methylation for glioma patients. ResultsMethylation status of DAPK1 site −1527, −1543, and the overall five sites concerned was higher in gliomas than controlled subjects (p < 0.001). Hypermethylation at site −1527 or together with site −1543 associated with better survival in patients taken postoperative therapies (−1527: p = 0.002; −1527 & −1543: p = 0.023), as well as in patients just underwent radiotherapy after surgery (-1527: p = 0.015; −1527 & −1543: p = 0.030). However, Cox regression analysis indicated the site-specific methylation was not independent contributor for gliomas prognosis. ConclusionAnalysis of DAPK1 gene promoter by quantitative pyrosequencing provided more detailed information of methylation status of CpG sites. DAPK1 methylation level is associated with gliomas clinical features and outcomes. Interestingly, the hypermethylation at site −1527 or together with site −1543 indicated good sensitivity of postoperative therapies, especially radiotherapy. Thus, site specifically analysis of DAPK1 methylation may be a valuable diagnostic and prognostic estimation for gliomas.

Relationship between DAPK methylation and gene inactivation in papillary thyroid carcinoma

To investigate the relationship between the methylation of death-associated protein kinase (DAPK) promoter and gene inactivation in papillary thyroid carcinoma, the technique of methylation-specific polymerase chain reaction (PCR (MSP)) was applied to detect the methylation status of DAPK gene promoter in 70 cases of papillary thyroid carcinoma (study group) and in 50 cases of corresponding adjacent tissues (control group). Immunohistochemical method was used to detect the protein expression; besides, the relationship of DAPK methylation and gene inactivation with pathological factors of papillary thyroid cancer was analyzed. The methylation rate of DAPK was 16% (8/50) in the control group and 71.4% (50/70) in the study group with the difference being statistically significant (χ2 = 19.724, P &lt; 0.01). The methylation of DAPK gene promoter was not associated with age, sex, tumor size, TNM stage, and thyroid capsular infiltration in the study group with papillary thyroid carcinoma ( P &gt; 0.05), but was associated with lymph node metastasis ( P &lt; 0.05). Spearman’s rank correlation analysis showed that the methylation of DAPK promoter was negatively correlated with the expression of DAPK (r = −0.793, P &lt; 0.01). The methylation of CpG island in the promoter region of DAPK gene can lead to gene inactivation and may be involved in the occurrence of papillary thyroid carcinoma.

IDENTIFICATION OF FREQUENT PROMOTER METHYLATION OF DEATH-ASSOCIATED PROTEIN KINASE IN LIQUID-BASED PAPANICOLAOUS TEST SAMPLES IN VIETNAMESE POPULATION

Objective: The infection of high-risk human papillomavirus (HPV) genotypes, particularly HPV-16 and HPV-18, is known to cause cervical cancer (CC); however, aberrant DNA methylation of death-associated protein kinase (DAPK), a member of tumor suppressor gene family, are required for cervical tumorigenesis. The aim of our study was to evaluate the hypermethylation frequency of CpG belonged to DAPK promoter, in Vietnamese patients, as well as to study about the association between hypermethylation, and high-risk HPV infection leading to CC.Methods: Methylation-specific-polymerase chain reaction (MSP) was performed to analyze methylation status from 109 liquid-based papanicolaous test samples, collected from local hospital and were identified whether HPV/or non-HPV, high-risk/low-risk HPV infection, then was confirmed by sequencing.Results: In the case of high-risk HPV infection, the frequency of DAPK gene hypermethylation was 66.67% (24 of 36 cases). Meanwhile, low hypermethylation status was found in low-risk and non-HPV infection, counting for 12.0% (3 of 25 cases), 2.1% (1 of 48 cases), respectively. Significant association of DAPK hypermethylation with high-risk, low-risk, and non-HPV infection was observed (p&lt;0.0001). The DAPK hypermethylation increased the possibility to CC in the case of high-risk HPV infected with high incidence: Odds ratio=34.5 (95% confidence interval [CI]=10.15-117.23, p&lt;0.01), relative risk=12.2 (95% CI=4.56-32.42, p&lt;0.01).Conclusion: Based on those data, it suggested that MSP carried out on noninvasive samples will lead to potential method to screening, diagnosis and early diagnosis of cervical carcinoma in Vietnamese population.

Rs4878104 contributes to Alzheimer's disease risk and regulates DAPK1 gene expression.

In 2006, a candidate gene study reported death-associated protein kinase 1 (DAPK1) rs4878104 variant to be significantly associated with Alzheimer's disease (AD) risk. However, the following studies showed inconsistent association results. Here, we conducted an updated analysis to investigate the potential association between rs4878104 and AD using a total of 60,751 samples (20,161 AD cases and 40,590 controls). In the pooled population, the results based on the allele and genotype genetic models show that rs4878104 variant is not significantly associated with AD risk. Interestingly, we identified rs4878104 variant to be significantly associated with AD risk in American population and Chinese population in subgroup analysis. Using multiple large-scale expression quantitative trait loci datasets, we further found that rs4878104 T allele could significantly regulate increased DAPK1 expression in European population. These findings suggest that rs4878104 may contribute AD susceptibility by modifying DAPK1 expression in European population.

Promoter methylation and expression of death-associated protein kinase gene in acute leukemia

To study the clinical implications of death-associated protein kinase (DAPK) promoter methylation and DAPK gene expression in untreated patients with acute leukemia. Methylation-specific PCR and RT-PCR were employed to detect the DAPK gene methylation and mRNA expression in the bone marrow of 60 patients with acute myeloid leukemia (AML), 55 patients with acute lymphocytic leukemia (ALL), and 17 normal subjects. The positivity rate of DAPK methylation was significantly higher in ALL patients (29.1%) than in AML patients group (5%) and normal subjects (0%) (P<0.01). No correlation was found between DAPK gene methylation and the clinical features in ALL patients (P>0.05). DAPK mRNA expression level differed significantly among the 3 groups (P=0.000), and was the highest in normal subjects and the lowest in ALL patients. In ALL patients, the expression level of DAPK mRNA showed a significant inverse correlation with DAPK promoter methylation (P<0.05). The methylation rate of DAPK gene is higher in untreated ALL patients than in AML patients and normal subjects. DAPK gene methylation is not correlated with the clinical features of ALL patients but is probably related with the low gene expression level of DAPK in these patients.

Association between promoter methylation of DAPK gene and HNSCC: A meta-analysis.

BackgroundThe death-associated protein kinase (DAPK) is a tumor suppressor gene, which is a mediator of cell death of INF-γ–induced apoptosis. Aberrant methylation of DAPK promoter has been reported in patients with head and neck squamous cell carcinoma (HNSCC). However, the results of these studies are inconsistent. Hence, the present study aimed to evaluate the association between the promoter methylation of DAPK gene and HNSCC.MethodsRelevant studies were systematically searched in PubMed, Web of Science, Ovid, and Embase. The association between DAPK promoter methylation and HNSCC was assessed by odds ratio (ORs) and 95% confidence intervals (CI). To evaluate the potential sources of heterogeneity, we conducted the meta-regression analysis and subgroup analysis.ResultsEighteen studies were finally included in the meta-analysis. The frequency of DAPK promoter methylation in patients with HNSCC was 4.09-fold higher than the non-cancerous controls (OR = 3.96, 95%CI = 2.26–6.95). A significant association between DAPK promoter methylation and HNSCC was found among the Asian region and the Non-Asia region (Asian region, OR = 4.43, 95% CI = 2.29–8.58; Non-Asia region, OR = 3.39, 95% CI = 1.18–9.78). In the control source, the significant association between DAPK promoter methylation and HNSCC was seen among the autologous group and the heterogeneous group (autologous group, OR = 2.71, 95% CI = 1.49–4.93; heterogeneous group, OR = 9.50, 95% CI = 2.98–30.27). DAPK promoter methylation was significantly correlated with alcohol status (OR = 1.85, 95% CI = 1.07–3.21).ConclusionThe results of this meta-analysis suggested that aberrant methylation of DAPK promoter was associated with HNSCC.

Promoter methylation of p16 and DAPK genes in brushing, blood, and tissue samples from patients with nasopharyngeal carcinoma: a systematic meta-analysis

Background: Promoter methylation of tumor suppressor genes (TSGs) p16 and death-associated protein kinase ( DAPK ) has been reported in various carcinomas. However, the correlation between p16 or DAPK promoter methylation and the detection of nasopharyngeal carcinoma (NPC) in different sample types remains unclear. Methods: A systematic literature research was conducted to identify available studies. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated and analyzed. Results: Eleven eligible papers on p16 promoter methylation and seven eligible papers on DAPK promoter methylation were included in this analysis. The pooled OR of p16 and DAPK promoter methylation was significantly higher in samples of NPC tissues than in nontumorous (OR =5.49, P 0.1). Conclusions: Our findings suggested that p16 and DAPK promoter methylation may be associated with the carcinogenesis of NPC. Promoter methylation of p16 or DAPK may become a noninvasive biomarker for NPC detection in blood and brushing samples. DAPK or p16 promoter methylation was not correlated with tumor stage. Conducting additional studies is essential in the future to confirm our results.

Epigenetic Silencing of Death-Associated Protein Kinase Gene May Promote Mesenteric Metastasis in Primary Ovarian Cancer

Epigenetic Silencing of Death-Associated Protein Kinase Gene May Promote Mesenteric Metastasis in Primary Ovarian Cancer

Methylation and mRNA expression levels of P15, death-associated protein kinase, and suppressor of cytokine signaling-1 genes in multiple myeloma.

The aim of this study was to investigate the methylation status and mRNA expression levels of P15, death-associated protein kinase (DAPK), and suppressor of cytokine signaling-1 (SOCS1) genes in multiple myeloma (MM). The bone marrow samples of 54 MM patients were collected and the methylation status of the P15, DAPK, and SOCS1 gene promoter regions was determined by methylation-specific polymerase chain reaction. Automated sequencing technology was used to sequence the amplified products in order to analyze the base methylation sites. mRNA expression levels were determined using real-time fluorescent quantitative polymerase chain reaction. Among the 54 MM patients, the positive methylation rates of the P15, DAPK, and SOCS1 genes were 27.78%, 18.52%, and 16.67%, respectively. The methylation results were confirmed by sequencing. The positive methylation rates of the P15, DAPK, and SOCS1 genes showed no correlation with patient gender, age, typing, staging, and grouping (P>0.05). There was no significant difference in the mRNA expression levels of the P15, DAPK, and SOCS1 genes between the MM patient group and the control group (P>0.05). Aberrant methylation of the P15, DAPK, and SOCS1 genes exists in MM, and these genes may play certain roles in pathogenesis of MM. There was no significant difference in mRNA expression levels between the methylated group and the non-methylated group, suggesting that these genes are regulated by other mechanisms during their transcription.

Methylation ofDAPKandTHBS1genes in esophageal gastric-type columnar metaplasia

To explore methylation of DAPK, THBS1, CDH-1, and p14 genes, and Helicobacter pylori (H. pylori) status in individuals harboring esophageal columnar metaplasia. Distal esophageal mucosal samples obtained by endoscopy and histologically diagnosed as gastric-type (non-specialized) columnar metaplasia, were studied thoroughly. DNA was extracted from paraffin blocks, and methylation status of death-associated protein kinase (DAPK), thrombospondin-1 (THBS1), cadherin-1 (CDH1), and p14 genes, was examined using a methyl-sensitive polymerase chain reaction (MS-PCR) and sodium bisulfite modification protocol. H. pylori cagA status was determined by PCR. In total, 68 subjects (33 females and 35 males), with a mean age of 52 years, were included. H. pylori cagA positive was present in the esophageal gastric-type metaplastic mucosa of 18 individuals. DAPK, THSB1, CDH1, and p14 gene promoters were methylated by MS-PCR in 40 (58.8%), 33 (48.5%), 46 (67.6%), and 23 (33.8%) cases of the 68 esophageal samples. H. pylori status was associated with methylation of DAPK (P = 0.003) and THBS1 (P = 0.019). DNA methylation occurs in cases of gastric-type (non-specialized) columnar metaplasia of the esophagus, and this modification is associated with H. pylori cagA positive infection.

DAPK and P16 Methylation and HPV and EBV Infection in Small Cell Carcinoma of Cervix: A Case Report

Purpose: Small cell carcinoma (SMCC) of the cervix is rare and aggressive tumor, often diagnosed in an advanced stage and their prognosis is generally poor. A case of SMCC showing Human Papillomavirus (HPV) and Epstein barr virus (EBV) infection and Death-associated protein kinase (DAPK) and p16 genes methylation is presented. A 74-year-old woman was diagnosed as having stage IB2 of SMCC. Methods: HPV and EBV infection and DAPK and p16 gene methylation were found using molecular approaches. Results: The sample was positive for HPV and EBV infection and showed DAPK and p16 promoter regions methylated Conclusion: Methylation of DAPK and p16 gene could be used as a molecular marker in cervical cancer.

Retraction Note to: Promoter methylation of DAPK gene may contribute to the pathogenesis of nonsmall cell lung cancer: a meta-analysis.

We performed a meta-analysis of cohort studies to determine whether promoter methylation of the death-associated protein kinase (DAPK) gene contributes to the pathogenesis of nonsmall cell lung cancer (NSCLC). A range of electronic databases were searched: MEDLINE (1966 ∼ 2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980 ∼ 2013), CINAHL (1982 ∼ 2013), Web of Science (1945 ∼ 2013), and the Chinese Biomedical Database (CBM; 1982 ∼ 2013) without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude odds ratio (OR) with 95 % confidence interval (95 % CI) was calculated. Our meta-analysis integrated results from 12 clinical cohort studies that met all inclusion criteria with a total of 1,027 NSCLC patients. We observed that the frequency of DAPK gene methylation in cancer tissues were significantly higher than that in the adjacent normal and benign tissues (cancer tissues vs. benign tissues: OR = 8.50, 95 % CI = 5.88 ∼ 12.28, P < 0.001; cancer tissues vs. adjacent tissues: OR = 5.95, 95 % CI = 4.11 ∼ 8.60, P < 0.001; cancer tissues vs. normal tissues: OR = 4.75, 95 % CI = 3.28 ∼ 6.87, P < 0.001; respectively). Subgroup analysis by ethnicity demonstrated that DAPK gene methylation was closely associated with the development and progression of NSCLC among both Asians and Caucasians (all P < 0.05). Furthermore, we conducted a subgroup analysis based on sample source and discovered that DAPK gene methylation was implicated in the pathogenesis of NSCLC in both blood and tissue subgroups (all P < 0.05). Our results suggest that DAPK promoter methylation may be involved in NSCLC carcinogenesis. Thus, the detection of aberrant DAPK methylation may be helpful in the diagnosis and prognosis of NSCLC.

Increased hypermethylation of glutathione S-transferase P1, DNA-binding protein inhibitor, death associated protein kinase and paired box protein-5 genes in triple-negative breast cancer Saudi females.

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) with higher metastatic rate and both local and systemic recurrence compared to non-TNBC. The generation of reactive oxygen species (ROS) secondary to oxidative stress is associated with DNA damage, chromosomal degradation and alterations of both hypermethylation and hypomethylation of DNA. This study concerns differential methylation of promoter regions in specific groups of genes in TNBC and non-TNBC Saudi females in an effort to understand whether epigenetic events might be involved in breast carcinogenesis, and whether they might be used as markers for Saudi BCs. Methylation of glutathione S-transferase P1 (GSTP1), T-cadherin (CDH13), Paired box protein 5 (PAX5), death associated protein kinase (DAPK), twist-related protein (TWIST), DNA-binding protein inhibitor (ID4), High In Normal-1 (HIN-1), cyclin-dependent kinase inhibitor 2A (p16), cyclin D2 and retinoic acid receptor-β (RARβ1) genes was analyzed by methylation specific polymerase chain reaction (MSP) in 200 archival formalin- fixed paraffin embedded BC tissues divided into 3 groups; benign breast tissues (20), TNBC (80) and non-TNBC (100). The relationships between methylation status, and clinical and pathological characteristics of patients and tumors were assessed. Higher frequencies of GSTP1, ID4, TWIST, DAPK, PAX5 and HIN-1 hypermethylation were found in TNBC than in non-TNBC. Hypermethylation of GSTP1, CDH13, ID4, DAPK, HIN-1 and PAX5 increased with tumor grade increasing. Other statistically significant correlations were identified with studied genes. Data from this study suggest that increased hypermethylation of GSTP1, ID4, TWIST, DAPK, PAX5 and HIN-1 genes in TNBC than in non-TNBC can act as useful biomarker for BCs in the Saudi population. The higher frequency of specific hypermethylated genes paralleling tumor grade, size and lymph node involvement suggests contributions to breast cancer initiation and progression.