Hypermethylation of the Death-Associated Protein (DAP) Kinase Promoter and Aggressiveness in Stage I Non-Small-Cell Lung Cancer

Tang, Ximing; Khuri, Fadlo R.; Lee, John; Kemp, Bonnie L.; Liu, Diane; Hong, Waun Ki; Li, Mao

doi:10.1093/jnci/92.18.1511

Cited by 290 publications

(170 citation statements)

References 28 publications

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“…In addition, concordant results were also obtained after studying noncancerous and cancerous lung samples collected in these seven patients by a methylation-specific PCR method (data not shown). The frequency of TFPI-2 gene promoter methylation (30%) was relatively high compared to frequencies previously published for other methylated genes in primary lung tumours such as MGMT, DAPK, E-cadherin, RASSF1A, TIMP-3 and p16 (Esteller et al, 1999;Tang et al, 2000;Zochbauer-Muller et al, 2002;Yanagawa et al, 2003). Silencing of the TFPI-2 gene associated with hypermethylation of the promoter has recently been described in several cancer cell lines derived from choriocarcinoma (Hube et al, 2003b), glioma (Konduri et al, 2003), fibrosarcoma, breast and prostate cancers .…”

Section: Discussionmentioning

confidence: 66%

Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer

et al. 2005

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Tissue factor pathway inhibitor-2 (TFPI-2) is a Kunitz-type serine proteinase inhibitor that inhibits plasmin-dependent activation of several metalloproteinases. Downregulation of TFPI-2 could thus enhance the invasive potential of neoplastic cells in several cancers, including lung cancer. In this study, TFPI-2 mRNA was measured using a real-time PCR method in tumours of 59 patients with nonsmall-cell lung cancer (NSCLC). Tumour TFPI-2 mRNA levels appeared well correlated with protein expression evaluated by immunohistochemistry and were 4 -120 times lower compared to those of nonaffected lung tissue in 22 cases (37%). Hypermethylation of the TFPI-2 gene promoter was demonstrated by restriction enzyme-polymerase chain reaction in 12 of 40 cases of NSCLC (30%), including nine of 17 for whom tumour TFPI-2 gene expression was lower than in noncancerous tissue. In contrast, this epigenetic modification was shown in only three of 23 tumours in which no decrease in TFPI-2 synthesis was found (P ¼ 0.016). Decreased TFPI-2 gene expression and hypermethylation were more frequently associated with stages III or IV NSCLC (eight out of 10, P ¼ 0.02) and the TFPI-2 gene promoter was more frequently hypermethylated in patients with lymph node metastases (eight out of 16, P ¼ 0.02). These results suggest that silencing of the TFPI-2 gene by hypermethylation might contribute to tumour progression in NSCLC.

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Section: Discussionmentioning

confidence: 66%

Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer

et al. 2005

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“…DAPK is absent in highly metastatic variants of mouse lung cancer cell lines, and is present in the low metastatic variants of those same cell lines (Inbal et al, 1997). In lung and head and neck cancers, DAPK promoter methylation was associated with aggressive disease and poor survival (Sanchez-Cespedes A new paradigm in cell signaling and cancer therapy D Goldschneider and P Mehlen et al, 2000;Tang et al, 2000;Kim et al, 2001;Kong et al, 2005). DRAL was initially characterized as a downregulated gene in rhabdomyosarcoma (Genini et al, 1997).…”

Section: Drs Are Altered During Tumor Progressionmentioning

confidence: 99%

Dependence receptors: a new paradigm in cell signaling and cancer therapy

2010

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Dependence receptors (DRs) now form a family of more than a dozen membrane receptors that are not linked by their structure, but by common functional traits. The most notable is their ability to trigger two opposite signaling pathways: in the presence of ligand, these receptors activate classic signaling pathways implicated in cell survival, migration and differentiation. In the absence of ligand, they do not stay inactive, rather they elicit an apoptotic signal. Thus, cells expressing this kind of receptor are dependent on the presence of ligand in the extracellular environment to survive. This review will recapitulate the increasing data regarding the molecular mechanisms associated with DRs, their potential implication during development, as well as their deregulation during tumorigenesis and, finally, their emergence as new possible therapeutic targets for cancer treatment.

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“…In lung cancers, DAPk promoter methylation was associated with aggressive disease and poor survival. [35][36][37][38] Lung tumors that were positive for DAPk hypermethylation showed advanced pathological stage, larger tumor size and lymph node involvement. 35 Similarly, DAPk hypermethylation in head and neck cancer correlated with lymph node involvement and advanced disease stage.…”

Section: Dapk Family and Cancer: A Novel Tumor Suppressor Family Of Pmentioning

confidence: 99%

DAPk Protein Family and Cancer

Gözüaçık¹,

Kimchi²

2006

Autophagy

186

170

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The Death-Associated Protein kinase (DAPk) family contains three closely related serine/threonine kinases, named DAPk, ZIPk and DRP-1, which display a high degree of homology in their catalytic domains. The recent discovery of protein-protein interactions and kinase/substrate relationships among these family members suggests that the three kinases may form multi-protein complexes capable of transmitting apoptotic or autophagic cell death signals in response to various cellular stresses including the misregulated expression of oncogenes in premalignant cells. Several lines of evidence indicate that the most studied member of the family, DAPk, has tumor and metastasis suppressor properties. Here we present an overview of the data connecting the DAPk family of proteins to cell death and malignant transformation and discuss the possible involvement of the autophagic cell death-inducing capacity of DAPk in its tumor suppressor activity.

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Hypermethylation of the Death-Associated Protein (DAP) Kinase Promoter and Aggressiveness in Stage I Non-Small-Cell Lung Cancer

Abstract: Hypermethylation of the DAP kinase promoter is a common abnormality in early-stage NSCLC. This abnormality is strongly associated with survival, suggesting that DAP kinase plays an important role in determining the biologic aggressiveness of early-stage NSCLC.

Cited by 290 publications

References 28 publications

Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer

Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer

Dependence receptors: a new paradigm in cell signaling and cancer therapy

DAPk Protein Family and Cancer

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