Single CpG island methylation is not sufficient to maintain the silenced expression of CASPASE-8 apoptosis-related gene among women with epithelial ovarian cancer

Braga, Letícia da Conceição; Silva, Luciana Maria; Ramos, Ana Paula Álvares da Silva; Piedade, Josiane Barbosa; Vidigal, Paula Vieira Teixeira; Traiman, Paulo; Filho, Agnaldo Lopes da Silva

doi:10.1016/j.biopha.2013.12.004

Cited by 7 publications

(4 citation statements)

References 26 publications

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“…The majority of them are amplifications of the CASP8 gene (www.cbioportal.org). Braga et al evaluated the expression levels and epigenetic alterations of caspase-8 in normal ovarian tissues, ovarian serous cystadenoma tumors, and epithelial ovarian cancer [26]. The study found 25 times higher expression levels of caspase-8 in metastatic cancers (50.8) as compared to ovarian serous cystadenoma (2.0) and primary EOC (2.16).…”

Section: Apoptotic and Non-apoptotic Functions Of Caspase-8mentioning

confidence: 99%

“…The significant differences in the expression and methylation of caspase-8 in the metastatic EOCs as compared to the primary tumor and normal tissue could be associated with its non-apoptotic functions leading to apoptosis resistance, dysregulated proliferation, and enhanced activation of NF-κB, PKB/Akt, and MAPKs. However, the promotor DNA methylation was not associated with the expression levels of caspase-8, suggesting additional mechanisms, regulating the gene expression [26]. Furthermore, RNA-seq analysis had confirmed the upregulated caspase-8 in ovarian adenocarcinoma, when compared to normal ovaries (www.ebi.ac.…”

Section: Apoptotic and Non-apoptotic Functions Of Caspase-8mentioning

confidence: 99%

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The role of caspase-8 in the tumor microenvironment of ovarian cancer

Kostova

Mandal

Becker

et al. 2020

Cancer Metastasis Rev

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Caspase-8 is an aspartate-specific cysteine protease, which is best known for its apoptotic functions. Caspase-8 is placed at central nodes of multiple signal pathways, regulating not only the cell cycle but also the invasive and metastatic cell behavior, the immune cell homeostasis and cytokine production, which are the two major components of the tumor microenvironment (TME). Ovarian cancer often has dysregulated caspase-8 expression, leading to imbalance between its apoptotic and non-apoptotic functions within the tumor and the surrounding milieu. The downregulation of caspase-8 in ovarian cancer seems to be linked to high aggressiveness with chronic inflammation, immunoediting, and immune resistance. Caspase-8 plays therefore an essential role not only in the primary tumor cells but also in the TME by regulating the immune response, B and T lymphocyte activation, and macrophage differentiation and polarization. The switch between M1 and M2 macrophages is possibly associated with changes in the caspase-8 expression. In this review, we are discussing the non-apoptotic functions of caspase-8, highlighting this protein as a modulator of the immune response and the cytokine composition in the TME. Considering the low survival rate among ovarian cancer patients, it is urgently necessary to develop new therapeutic strategies to optimize the response to the standard treatment. The TME is highly heterogenous and provides a variety of opportunities for new drug targets. Given the variety of roles of caspase-8 in the TME, we should focus on this protein in the development of new therapeutic strategies against the TME of ovarian cancer.

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Section: Apoptotic and Non-apoptotic Functions Of Caspase-8mentioning

confidence: 99%

Section: Apoptotic and Non-apoptotic Functions Of Caspase-8mentioning

confidence: 99%

The role of caspase-8 in the tumor microenvironment of ovarian cancer

Kostova

Mandal

Becker

et al. 2020

Cancer Metastasis Rev

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“…Alternatively, different CGIs or CpG sites within a CGI could have differential effects on gene expression ( 20 , 21 ). Moreover, single CGI methylation is not sufficient to maintain silencing ( 22 ). It could be speculated that other sites instead of the regions analyzed in the present study may be directly associated with NMES1 expression.…”

Section: Resultsmentioning

confidence: 99%

Hypermethylation of normal mucosa of esophagus‑specific�1 is associated with an unfavorable prognosis in patients with non‑small cell lung cancer

2018

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Lung cancer is the leading cause of cancer-associated mortality due to high incidence and poor survival rates, irrespective of global variations in its biology and treatment. Changes in DNA methylation are frequent in cancer and constitute an important mechanism in tumorigenesis. Normal mucosa of esophagus-specific 1 (NMES1) is expressed in epithelial tissue and is believed to be a tumor suppressor gene. The present study investigated the methylation status of the NMES1 promoter in 178 cases of primary non-small cell lung cancer (NSCLC) by pyrosequencing and evaluated the prognostic value of this methylation. NMES1 methylation-positive tumors above the background threshold for non-malignant tissue were found in 15 cases (8.4%) and were detected exclusively in malignant tissues. In addition, univariate and multivariate analyses showed that methylation-positive patients experienced worse overall survival rate (OSR) compared with methylation-negative patients (adjusted hazard ratio, 2.62; 95% confidence interval, 1.20–5.69; P=0.02). Notably, within the methylation-positive group, patients with strong methylation tended to experience worse OSR compared with those with weak methylation (adjusted hazard ratio, 2.45 vs. 3.05; Ptrend=0.02). These findings suggest that NMES1 may serve an important role in lung cancer pathogenesis, and its methylation could be considered a prognostic marker for NSCLC. Further studies with large numbers of samples are required to confirm this conclusion.

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“…Previous studies from our group described different apoptosis-related genes as EOC biomarkers associated with disease prognosis [11][12][13]. Considering that aberrant miRNAs expression plays a key pathogenic role in different stages of the carcinogenesis process and is involved in the deregulation of several biological processes, including apoptosis, miRNA profile analysis may reveal new biomarkers that can be used for EOC prognosis and chemorresistance [14].…”

Section: Introductionmentioning

confidence: 99%

Three-Dimensional Cellular Arrangement in Epithelial Ovarian Cancer Cell Lines TOV-21G and SKOV-3 is Associated with Apoptosis-Related miRNA Expression Modulation

Lima

Silva

Gonçales

et al. 2018

Cancer Microenvironment

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Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, and the lack of chemoresistance biomarkers contributes to the poor prognosis. Cancer stem cells (CSC) have been investigated in EOC to understand its relationship with chemoresistance and recurrence. In this context, in vitro cultivation-models are important tools for CSC studies. MicroRNAs (miRNAs) play key roles in cancer, CSC regulation and apoptosis. Thus, this study aims to evaluate the tumorsphere model as CSC-enrichment method in EOC studies and investigate apoptosis-related miRNAs in tumorspheres-derived EOC cell lines. TOV-21G and SKOV-3 were cultured in monolayer and tumorspheres. Genetic profiles of cell lines were obtained using COSMIC database. CD24/CD44/CD146/CD177 and ALDH1 markers were evaluated in cell lines and tumorspheres-derived by flow cytometry. Eleven miRNAs were selected by in silico analysis for qPCR analysis. According to COSMIC, TOV-21G and SKOV-3 have eight and nine cancer-related mutations, respectively. TOV-21G showed a CD44/CD24/CD117/CD146/ALDH1 profile in both culture models; thus, no significant difference between cultivation models was identified. SKOV-3 showed a CD44/CD24/ CD117/CD146/ALDH1 profile in both culture models, although the tumorsphere model showed a significant increase in CD24 subpopulation (ovarian CSC-like). Among eleven miRNAs, we observed differences in miRNA expression between culture models. MiR-26a was overexpressed in TOV-21G tumorspheres, albeit downregulated in SKOV-3 tumorspheres. MiR-125b-5p, miR-17-5p and miR-221 was downregulated in tumorsphere model in both cell lines. Given that tumorsphere-derived SKOV-3 had a higher ratio of CD24 cells, we suggest that miR-26a, miR-125b-5p, miR-17-5p and miR-221 downregulation could be related to poor EOC prognosis.

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Single CpG island methylation is not sufficient to maintain the silenced expression of CASPASE-8 apoptosis-related gene among women with epithelial ovarian cancer

Cited by 7 publications

References 26 publications

The role of caspase-8 in the tumor microenvironment of ovarian cancer

The role of caspase-8 in the tumor microenvironment of ovarian cancer

Hypermethylation of normal mucosa of esophagus‑specific�1 is associated with an unfavorable prognosis in patients with non‑small cell lung cancer

Three-Dimensional Cellular Arrangement in Epithelial Ovarian Cancer Cell Lines TOV-21G and SKOV-3 is Associated with Apoptosis-Related miRNA Expression Modulation

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