Epigenetic Regulation of APAF-1 Through DNA Methylation in Pancreatic Cancer

Lukošiūtė-Urbonienė, Aušra; Mažeikė, Augustina; Kazokaitė, Mintautė; Šilkūnienė, Giedrė; Šilkūnas, Mantas; Barauskas, Vidmantas; Barauskas, Giedrius; Gulbinas, Antanas; Daukša, Albertas; Dambrauskas, Žilvinas

doi:10.21873/anticanres.14366

Cited by 7 publications

(4 citation statements)

References 24 publications

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“…While this is cell biologically very interesting, it raises a fundamental question: in which situation does such inflammatory cell death occur? There are a few reports where caspase-activation in cancer cells may be altered, mostly by down-regulation of Apaf-1 in melanoma (although with unknown frequency [ 12 ]) and in pancreatic cancer [ 13 ], and cardiomyocytes have been reported to express little Apaf-1 and to generate only low caspase-activity [ 14 ]. However, a lack of caspases or a block of caspase-activation downstream of mitochondria seems very rare in human cells, and the non-inflammatory nature of apoptotic cell death has for decades been regarded as a hallmark of apoptosis [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?

Häcker

Haimovici

2022

Cell Death Differ

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One of the tasks of mitochondria is the rule over life and death: when the outer membrane is permeabilized, the release of intermembrane space proteins causes cell death by apoptosis. For a long time, this mitochondrial outer membrane permeabilization (MOMP) has been accepted as the famous step from which no cell returns. Recent results have however shown that this quite plainly does not have to be the case. A cell can also undergo only a little MOMP, and it can efficiently repair damage it has incurred in the process. There is no doubt now that such low-scale permeabilization occurs. A major unclarified issue is the biological relevance. Is small-scale mitochondrial permeabilization an accident, a leakiness of the apoptosis apparatus, perhaps during restructuring of the mitochondrial network? Is it attempted suicide, where cell death by apoptosis is the real goal but the stimulus failed to reach the threshold? Or, more boldly, is there a true biological meaning behind the event of the release of low amounts of mitochondrial components? We will here explore this last possibility, which we believe is on one hand appealing, on the other hand plausible and supported by some evidence. Recent data are consistent with the view that sub-lethal signals in the mitochondrial apoptosis pathway can drive inflammation, the first step of an immune reaction. The apoptosis apparatus is almost notoriously easy to trigger. Sub-lethal signals may be even easier to set off. We suggest that the apoptosis apparatus is used in this way to sound the call when the first human cell is infected by a pathogen.

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Section: Introductionmentioning

confidence: 99%

Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?

Häcker

Haimovici

2022

Cell Death Differ

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“…As numerous studies have shown, colon adenocarcinoma is not the only cancer type to have reduced expression of Apaf-1 protein. Lukosiute-Urbonieniehas shown that in pancreatic ductal adenocarcinoma (PDAC) downregulation of Apaf-1 expression was detected both at mRNA and protein levels [24]. Decreased level of Apaf-1 was also found in serum samples of patients [25].…”

Section: Discussionmentioning

confidence: 95%

The Prognostic Significance of Apoptotic Protease Activating Factor (Apaf-1) Protein Expression in Colon Adenocarcinoma Tissue-Preliminary Report

Brzozowa-Zasada¹,

Matysiak²,

Piecuch³

et al. 2023

Front. Biosci. (Landmark Ed)

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Background:The Apoptotic protease activating factor 1 (Apaf-1) protein, as one of the factors involved in the activation of the mitochondrial apoptotic pathway, plays an important role in cancer biology. Apaf-1 expression in tumour cells has been shown to be downregulated, with significant implications for tumour progression. Hence, we investigated the expression of Apaf-1 protein in the Polish population of patients with colon adenocarcinoma without any therapy prior to radical surgery. Moreover, we assessed the relation between Apaf-1 protein expression and the clinicopathological factors. The prognostic activity of this protein was analyzed in relation to 5-year survival of patients. In order to show the localization of Apaf-1 protein at the cellular level, the immunogold labelling method was used. Methods: The study was conducted using the colon tissue material from patients with histopathologically confirmed colon adenocarcinoma. Immunohistochemical expression of Apaf-1 protein was performed using Apaf-1 antibody at dilution 1:600. The associations between the immunohistochemistry (IHC) expression of Apaf-1 and clinical parameters were analyzed using the Chi 2 test and Chi 2 Yatesa test. Kaplan-Meier analysis and the log-rank test were used to verify the relationship between the intensity of Apaf-1 expression and 5-year survival rate of patients. The results were considered statistically significant when p < 0.05. Results: Apaf-1 expression was evaluated by immunohistochemical staining in whole tissue sections. Thirty-nine (33.23%) samples had strong Apaf-1 protein expression and 82 (67.77%) samples were characterized by low expression. The high expression of Apaf-1 was clearly correlated with the histological grade of the tumour (p = 0.001), proliferating cell nuclear antigen (PCNA) immunohistochemical expression (p = 0.005), age (p = 0.015), depth of invasion (p < 0.001) and angioinvasion (p < 0.001). The 5-year survival rate was significantly higher in the group of patients with high expression of this protein (log-rank, p < 0.001). Conclusions: We can conclude that Apaf-1 expression is positively correlated with reduced survival of colon adenocarcinoma patients.

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“…Moreover, the DNA methylation of the CDKN2A promoter was a more frequent event in aggressive prostatic tumors with PNI [41]. Several other studies demonstrated an association between the epigenetic regulation of specific candidate genes by altered DNA methylation and the development of PNI [42][43][44][45][46][47][48][49][50]. Still, the DNA methylation status in head and neck squamous cell carcinoma has not yet been studied sufficiently [50].…”

Section: Discussionmentioning

confidence: 99%

Establishment of a Machine Learning Model for the Risk Assessment of Perineural Invasion in Head and Neck Squamous Cell Carcinoma

Weusthof

Burkart

Metzger

et al. 2023

IJMS

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Perineural invasion is a prevalent pathological finding in head and neck squamous cell carcinoma and a risk factor for unfavorable survival. An adequate diagnosis of perineural invasion by pathologic examination is limited due to the availability of tumor samples from surgical resection, which can arise in cases of definitive nonsurgical treatment. To address this medical need, we established a random forest prediction model for the risk assessment of perineural invasion, including occult perineural invasion, and characterized distinct cellular and molecular features based on our new and extended classification. RNA sequencing data of head and neck squamous cell carcinoma from The Cancer Genome Atlas were used as a training cohort to identify differentially expressed genes that are associated with perineural invasion. A random forest classification model was established based on these differentially expressed genes and was validated by inspection of H&E-stained whole image slides. Differences in epigenetic regulation and the mutational landscape were detected by an integrative analysis of multiomics data and single-cell RNA-sequencing data were analyzed. We identified a 44-gene expression signature related to perineural invasion and enriched for genes mainly expressed in cancer cells according to single-cell RNA-sequencing data. A machine learning model was trained based on the expression pattern of the 44-gene set with the unique feature to predict occult perineural invasion. This extended classification model enabled a more accurate analysis of alterations in the mutational landscape and epigenetic regulation by DNA methylation as well as quantitative and qualitative differences in the cellular composition in the tumor microenvironment between head and neck squamous cell carcinoma with or without perineural invasion. In conclusion, the newly established model could not only complement histopathologic examination as an additional diagnostic tool but also guide the identification of new drug targets for therapeutic intervention in future clinical trials with head and neck squamous cell carcinoma patients at a higher risk for treatment failure due to perineural invasion.

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Epigenetic Regulation of APAF-1 Through DNA Methylation in Pancreatic Cancer

Cited by 7 publications

References 24 publications

Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?

Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?

The Prognostic Significance of Apoptotic Protease Activating Factor (Apaf-1) Protein Expression in Colon Adenocarcinoma Tissue-Preliminary Report

Establishment of a Machine Learning Model for the Risk Assessment of Perineural Invasion in Head and Neck Squamous Cell Carcinoma

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