Cancer Stem Cells, DNA Methylation and DNA Sequences: Their Diagnostic and Therapeutical Applications

Topic Information

Dear Colleagues,

DNA methylation is an essential epigenetic mechanism for controlling gene expression in both embryonic and adult stem cells. There is a fine-tuned balance between the regulation of gene activation and repression during normal cellular activity, and either hypo- or hypermethylation could induce the expression or inhibition of genes, respectively. Changes in methylation status are acknowledged to be hallmarks for cancer initiation and progression, with the potential to transform normal stem cells into a cancer stem cell (CSC) phenotype. The basic function of the immune system is to provide the host with protection from invading foreign antigens in parallel with the state of self-tolerance, i.e., maintaining its unique antigenic profile. Cellular structures such as nuclei and mitochondria house the vast bulk of DNA. Changes in DNA sequences have gained attention as potential biomarkers since they can be detected as extracellular cell-free DNA (cfDNA) in a wide range of diseases, including cancer. Recently, cfDNA testing has seen a resurgence due to the widespread use of liquid biopsies and the growing need for disease screening, activity monitoring, and drug response assessments. Studies on the immunological effects of cfDNA, in addition to their immunomodulatory or therapeutic advantages, are still in their infancy. The main aim of this Special Issue (Topic) is to discuss the impact of aberrant DNA methylation statuses on CSC functions, including self-renewal, differentiation, drug resistance, and metastasis formation, in addition to analyzing recent findings on the role of different DNA-sensing receptors in the recognition of foreign or self-DNA sequences as potent danger-associated molecular patterns. Further, emphasizing the immunomodulatory as well as pro- and anti-tumor capacities of different DNA sequences, and thus their subsequent potential for anticancer therapy, this Special Issue (Topic) also intends to summarize the results of recent experimental studies.

Dr. Ferenc Sipos
Dr. Györgyi Műzes
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomedicines biomedicines	3.9	5.2	2013	14.6 Days	CHF 2600
Cancers cancers	4.5	8.0	2009	17.4 Days	CHF 2900
Cells cells	5.1	9.9	2012	17 Days	CHF 2700
Journal of Clinical Medicine jcm	3.0	5.7	2012	16 Days	CHF 2600
Pharmaceutics pharmaceutics	4.9	7.9	2009	15.5 Days	CHF 2900
Reports reports	0.8	-	2018	18.6 Days	CHF 1400

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Published Papers (5 papers)

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All Biomedicines Cancers Cells JCM Pharmaceutics Reports

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Open AccessArticle

Assessing the Methylation Status of Two Potential Key Factors Involved in Cervical Oncogenesis

by Alina Fudulu, Marinela Bostan, Iulia Virginia Iancu, Adriana Pleșa, Adrian Albulescu, Irina Liviana Stoian, Demetra Gabriela Socolov, Gabriela Anton and Anca Botezatu

Reports 2024, 7(3), 71; https://doi.org/10.3390/reports7030071 - 18 Aug 2024

Viewed by 1482

Abstract

(1) Background: Cervical cancer, caused mainly by high-risk Human Papillomavirus (hrHPV), is a significant global health issue. While a Pap smear remains a reliable method for early detection, identifying new biomarkers to stratify the risk is crucial. For this purpose, extensive research has [...] Read more.

(1) Background: Cervical cancer, caused mainly by high-risk Human Papillomavirus (hrHPV), is a significant global health issue. While a Pap smear remains a reliable method for early detection, identifying new biomarkers to stratify the risk is crucial. For this purpose, extensive research has been conducted on detecting DNA methylation. (2) Methods: This cross-sectional study aimed to assess the expression levels of EIF4G3 and SF3B1 in precursor lesions and cervical tumor tissues through qRT-PCR and evaluate the methylation status of their promoters through bisulfite conversion. (3) Results: Both genes showed similar mRNA expression patterns, with the highest levels observed in squamous cell carcinoma (SCC) samples (p < 0.0001). Additionally, methylation analysis indicated increased percentages in the control group for both factors. Notably, the expression levels of both genes were inversely correlated with promoter methylation (EIF4G3—p = 0.0016; SF3B1—p < 0.0001). (4) Conclusions: Regarding the methylation pattern for both genes, we observe a decreasing trend from NILM to SCC patients. Therefore, we concluded that the decrease in methylation at the promoter level for both genes could be an indicator of abnormal cytology. Full article

(This article belongs to the Topic Cancer Stem Cells, DNA Methylation and DNA Sequences: Their Diagnostic and Therapeutical Applications)

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27 pages, 2265 KiB  

Open AccessReview

Sirtuins Affect Cancer Stem Cells via Epigenetic Regulation of Autophagy

by Ferenc Sipos and Györgyi Műzes

Biomedicines 2024, 12(2), 386; https://doi.org/10.3390/biomedicines12020386 - 7 Feb 2024

Cited by 3 | Viewed by 2504

Abstract

Sirtuins (SIRTs) are stress-responsive proteins that regulate several post-translational modifications, partly by acetylation, deacetylation, and affecting DNA methylation. As a result, they significantly regulate several cellular processes. In essence, they prolong lifespan and control the occurrence of spontaneous tumor growth. Members of the [...] Read more.

Sirtuins (SIRTs) are stress-responsive proteins that regulate several post-translational modifications, partly by acetylation, deacetylation, and affecting DNA methylation. As a result, they significantly regulate several cellular processes. In essence, they prolong lifespan and control the occurrence of spontaneous tumor growth. Members of the SIRT family have the ability to govern embryonic, hematopoietic, and other adult stem cells in certain tissues and cell types in distinct ways. Likewise, they can have both pro-tumor and anti-tumor effects on cancer stem cells, contingent upon the specific tissue from which they originate. The impact of autophagy on cancer stem cells, which varies depending on the specific circumstances, is a very intricate phenomenon that has significant significance for clinical and therapeutic purposes. SIRTs exert an impact on the autophagy process, whereas autophagy reciprocally affects the activity of certain SIRTs. The mechanism behind this connection in cancer stem cells remains poorly understood. This review presents the latest findings that position SIRTs at the point where cancer cells and autophagy interact. Our objective is to highlight the various roles of distinct SIRTs in cancer stem cell-related functions through autophagy. This would demonstrate their significance in the genesis and recurrence of cancer and offer a more precise understanding of their treatment possibilities in relation to autophagy. Full article

(This article belongs to the Topic Cancer Stem Cells, DNA Methylation and DNA Sequences: Their Diagnostic and Therapeutical Applications)

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23 pages, 1454 KiB  

Open AccessReview

Unravelling the Role of PARP1 in Homeostasis and Tumorigenesis: Implications for Anti-Cancer Therapies and Overcoming Resistance

by Taylor Lovsund, Fatemeh Mashayekhi, Amira Fitieh, James Stafford and Ismail Hassan Ismail

Cells 2023, 12(14), 1904; https://doi.org/10.3390/cells12141904 - 21 Jul 2023

Viewed by 2340

Abstract

Detailing the connection between homeostatic functions of enzymatic families and eventual progression into tumorigenesis is crucial to our understanding of anti-cancer therapies. One key enzyme group involved in this process is the Poly (ADP-ribose) polymerase (PARP) family, responsible for an expansive number of [...] Read more.

Detailing the connection between homeostatic functions of enzymatic families and eventual progression into tumorigenesis is crucial to our understanding of anti-cancer therapies. One key enzyme group involved in this process is the Poly (ADP-ribose) polymerase (PARP) family, responsible for an expansive number of cellular functions, featuring members well established as regulators of DNA repair, genomic stability and beyond. Several PARP inhibitors (PARPi) have been approved for clinical use in a range of cancers, with many more still in trials. Unfortunately, the occurrence of resistance to PARPi therapy is growing in prevalence and requires the introduction of novel counter-resistance mechanisms to maintain efficacy. In this review, we summarize the updated understanding of the vast homeostatic functions the PARP family mediates and pin the importance of PARPi therapies as anti-cancer agents while discussing resistance mechanisms and current up-and-coming counter-strategies for countering such resistance. Full article

(This article belongs to the Topic Cancer Stem Cells, DNA Methylation and DNA Sequences: Their Diagnostic and Therapeutical Applications)

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21 pages, 5425 KiB  

Open AccessArticle

Interferon-Alpha Decreases Cancer Stem Cell Properties and Modulates Exosomes in Malignant Melanoma

by María Belén García-Ortega, Ernesto Aparicio, Carmen Griñán-Lisón, Gema Jiménez, Elena López-Ruiz, José Luis Palacios, Gloria Ruiz-Alcalá, Cristina Alba, Antonio Martínez, Houria Boulaiz, Macarena Perán, Michael Hackenberg, José Bragança, Sofia M. Calado, Juan A. Marchal and María Ángel García

Cancers 2023, 15(14), 3666; https://doi.org/10.3390/cancers15143666 - 18 Jul 2023

Cited by 3 | Viewed by 2490

Abstract

Malignant melanoma (MM) can spread to other organs and is resistant in part due to the presence of cancer stem cell subpopulations (CSCs). While a controversial high dose of interferon-alpha (IFN-α) has been used to treat non-metastatic high-risk melanoma, it comes with undesirable [...] Read more.

Malignant melanoma (MM) can spread to other organs and is resistant in part due to the presence of cancer stem cell subpopulations (CSCs). While a controversial high dose of interferon-alpha (IFN-α) has been used to treat non-metastatic high-risk melanoma, it comes with undesirable side effects. In this study, we evaluated the effect of low and high doses of IFN-α on CSCs by analyzing ALDH activity, side population and specific surface markers in established and patient-derived primary cell lines. We also assessed the clonogenicity, migration and tumor initiation capacities of IFN-α treated CSCs. Additionally, we investigated genomic modulations related to stemness properties using microRNA sequencing and microarrays. The effect of IFN-α on CSCs-derived exosomes was also analyzed using NanoSight and liquid chromatography (LC-HRMS)-based metabolomic analysis, among others. Our results showed that even low doses of IFN-α reduced CSC formation and stemness properties, and led to a significant decrease in the ability to form tumors in mice xenotransplants. IFN-α also modulated the expression of genes and microRNAs involved in several cancer processes and metabolomics of released exosomes. Our work suggests the utility of low doses of interferon, combined with the analysis of metabolic biomarkers, as a potential clinical approach against the aggressiveness of CSCs in melanoma. Full article

(This article belongs to the Topic Cancer Stem Cells, DNA Methylation and DNA Sequences: Their Diagnostic and Therapeutical Applications)

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13 pages, 708 KiB  

Open AccessArticle

Aberrant AHRR, ADAMTS2 and FAM184 DNA Methylation: Candidate Biomarkers in the Oral Rinse of Heavy Smokers

by Hernán Guillermo Hernández, Gloria Cristina Aranzazu-Moya and Efraín Hernando Pinzón-Reyes

Biomedicines 2023, 11(7), 1797; https://doi.org/10.3390/biomedicines11071797 - 23 Jun 2023

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Abstract

Objective. To identify DNA methylation patterns of heavy smokers in oral rinse samples. Methods. Genome-wide DNA methylation data was imported from Gene Expression Omnibus GSE70977 using the GEOquery package. Two independent sets were analyzed: (a) 71 epigenomes of cancer-free subjects (heavy smokers n [...] Read more.

Objective. To identify DNA methylation patterns of heavy smokers in oral rinse samples. Methods. Genome-wide DNA methylation data was imported from Gene Expression Omnibus GSE70977 using the GEOquery package. Two independent sets were analyzed: (a) 71 epigenomes of cancer-free subjects (heavy smokers n = 37 vs. non-smokers n = 31); for concordance assessment (b) 139 oral-cancer patients’ epigenomes (heavy smokers n = 92 vs. non-smokers n = 47). Differential DNA methylation for CpG positions and at the regional level was determined using Limma and DMRcate Bioconductor packages. The linear model included sex, age, and alcohol consumption. The statistical threshold was set to p < 0.05. Functional gene prioritization analysis was performed for gene-targeted analysis. Results. In individuals without cancer and heavy smokers, the FAM184B gene was found with two CpG positions differentially hypermethylated (p = 0.012 after FDR adjustment), in a region of 48 bp with an absolute methylation difference >10% between groups (p = 1.76 × 10⁻⁸). In the analysis corresponding to oral-cancer patients, we found AHRR differentially hypomethylated cancer patients, but also in subjects without oral cancer in the targeted analyses. Remarkably, ADAMTS2 was found differentially hypermethylated in heavy smokers without a diagnosis of cancer in two consecutive probes cg05575921 (p = 3.13 × 10⁻⁷) and cg10208897 (p = 1.36 × 10⁻⁵). Conclusions: Differentially methylated AHRR, ADAMTS2, and FAM184B genes are biomarker candidates in oral rinse samples. Full article

(This article belongs to the Topic Cancer Stem Cells, DNA Methylation and DNA Sequences: Their Diagnostic and Therapeutical Applications)

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