The death associated protein kinase DAPK is an actin
The death-associated protein kinase (DAPK) is an actin-associated, calcium/calmodulin-dependent enzyme with serine/threonine kinase activity , . DAPK is a pro-apoptotic gene and participates in various apoptotic systems, such as TNF-α- and Fas-triggered apoptosis , IFN-γ-induced cell death , and TGF-β- and p19ARF/p53-mediated apoptosis , . DAPK suppresses tumor growth and metastasis by increasing the occurrence of apoptosis in vivo, and therefore has been characterized as a tumor suppressor gene .
Inactivation of DAPK by hypermethylation has been described in a variety of gastrointestinal malignancies , , , , , , , , . Because alterations of pro-apoptotic UO 126 might cause instability in the balance of cell-turnover during chronic inflammatory processes such as UC, epigenetic silencing of DAPK might be involved in carcinogenesis of UCC.
Materials and methods
Conflict of interest
Acknowledgements The authors thank all patients and their attending physicians for their participation in this study. We thank N. Wiest, C. Miethke, C. Kügler, S. Staeck, H. Scharfenort, and A. Schinlauer for their reliable technical assistance, and B. Wüsthoff for editing the manuscript. The work was supported by a research grant from the “Deutsche Morbus Crohn/Colitis ulcerosa Vereinigung e.V.”, Germany.
Introduction The incidence of ovarian cancer (OvCa) is in the range of 4 to 14 cases per 100,000 women depending on the geographical region . The 5-year survival rate is dependent on tumor stage and declines from 90% for FIGO stage I to 13% for FIGO stage IV tumors . The overall survival rate of only 37% is due to the predominantly late diagnosis of ovarian cancer and reflects the lack of adequate screening opportunities. OvCa has the highest mortality rate of all gynecological malignancies . Measurement of serum CA125 concentration and transvaginal sonography (TVS) are the only routinely available noninvasive procedures to examine women with suspicious symptoms or adnexal masses. On their own both methods do not fulfill the specifications required in a screening setting (sensitivity >75%, specificity >99.6%) , . However promising data were obtained in the UKCTOCS prevalence screening trial in which the combined screening program consisted of ultrasonography for women with raised CA125 levels. This multimodal screening program exhibited a specificity of 99.8% and sensitivity of 89.4% . Data on the influence of this screening program on the mortality rate are not yet available. The identification of new sensitive and specific screening markers and procedures is hampered by the late occurrence of clinical symptoms, missing pre-cancerous stages and moreover by the heterogeneous histological subtypes of ovarian cancer. The adequacy of various biomarkers for OvCa screening is the subject of multiple studies , . In particular circulating DNA shed from the tumor into the blood stream could be used as a marker . Importantly the presence of such DNA was also shown for ovarian cancer patients by genetic analyzes , . However no common genetic alterations useful for OvCa screening could be identified until now. The ability of epigenetic modifications besides gene alterations to promote the tumorigenic process is accepted , . Thus, epigenetic markers are potentially useful for early diagnosis of cancer . The best known epigenetic alterations is the methylation of CpG dinucleotides , . Scattered CpG dinucleotides in repetitive elements are mostly methylated in the genome of normal cells but become hypomethylated in cancer cells thus contributing to an increased genomic instability . In contrast sequences with increased CpG content (CpG islands) which are often located within promotor regions become hypermethylated during carcinogenesis , . Hypermethylation of promotor regions stably suppresses gene expression by recruiting histone modification enzymes thus potentially inhibiting tumor suppressor gene activation . Furthermore DNA hypermethylation also affects genes already silenced by polycomb repressor complexes enabling a stable “embryonic stem cell” like state of tumor cells , . Altogether DNA methylation contributes to the tumorigenic phenotype and could be used for characterization and detection of tumor cells.