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Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in...
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Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 70378

Special Issue Editor

Dr. Kelly Kiejda

E-Mail Website
Guest Editor
1. Medical Genetics, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
2. Priority Research Centre for Cancer Research, Innovation and Translation, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW 2308, Australia
Interests: breast cancer; metastasis; p53; chemoresistance; miRNAs; epigenetics

Special Issue Information

Dear Colleagues,

Epigenetics is the study of heritable changes in gene expression that does not involve any change in DNA sequence and includes aberrant methylation, histone modifications, as well as altered miRNA or lncRNA expression. Aberrant methylation is a widespread feature in cancer that can lead to transcriptional repression of genes, which is functionally equivalent to the physical deletion of the associated gene(s). Additionally, altered expression of miRNAs and lncRNAs is common in cancer, but the consequences of this are varied and are highly dependent on the target genes regulated. Epigenetic mechanisms of gene regulation hold a great deal of promise both for cancer therapeutics as well as for non-invasive tools to aid cancer diagnosis and prognosis because of their inherently high stability and accessibility in FFPE tissues and blood, ensuring minimal disruption to standard clinical practices. Despite the rising interest and research into epigenetic modifiers in cancer, a significant clinical benefit has not been substantiated from these studies at present; and the key challenge to this is developing an understanding of the biological and clinical consequences of such alterations in cancer.

In this Special Issue, we welcome articles that explore epigenetic changes in cancer as biomarkers or potential therapies, as well as those that advance our understanding of the biological and molecular consequences of these alterations in cancer.

Dr. Kelly Kiejda
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • lncRNA
  • miRNA
  • methylation
  • cancer
  • biomarkers
  • therapy

Published Papers (17 papers)

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Editorial

Jump to: Research, Review

3 pages, 176 KiB  
Editorial
Switching off Cancer: Is There a Role for Epigenetics?
by Kelly A. Avery-Kiejda
Cancers 2021, 13(6), 1272; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13061272 - 12 Mar 2021
Cited by 1 | Viewed by 1403
Abstract
Epigenetics is the study of heritable changes in gene expression that do not involve any change in DNA sequence and include methylation, histone modifications, and altered miRNA or lncRNA expression [...] Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)

Research

Jump to: Editorial, Review

26 pages, 3118 KiB  
Article
Understanding the Molecular Mechanism of miR-877-3p Could Provide Potential Biomarkers and Therapeutic Targets in Squamous Cell Carcinoma of the Cervix
by Saioa Mendaza, Joaquín Fernández-Irigoyen, Enrique Santamaría, Imanol Arozarena, David Guerrero-Setas, Tamara Zudaire, Rosa Guarch, August Vidal, José-Santos Salas, Xavier Matias-Guiu, Karina Ausín, Carmen Gil, Rubén Hernández-Alcoceba and Esperanza Martín-Sánchez
Cancers 2021, 13(7), 1739; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071739 - 06 Apr 2021
Cited by 4 | Viewed by 2746
Abstract
No therapeutic targets and molecular biomarkers are available in cervical cancer (CC) management. In other cancer types, micro-RNA-877-3p (miR-877-3p) has been associated with events relevant for CC development. Thus, we aimed to determine miR-877-3p role in CC. miR-877-3p levels were examined by quantitative-PCR [...] Read more.
No therapeutic targets and molecular biomarkers are available in cervical cancer (CC) management. In other cancer types, micro-RNA-877-3p (miR-877-3p) has been associated with events relevant for CC development. Thus, we aimed to determine miR-877-3p role in CC. miR-877-3p levels were examined by quantitative-PCR in 117 cervical lesions and tumors. Effects on CC cell proliferation, migration, and invasion were evaluated upon anti-miR-877-3p transfection. miR-877-3p dependent molecular mechanism was comprehensively explored by proteomics, dual-luciferase reporter assay, western blot, and immunohistochemistry. Cervical tumors expressed higher miR-877-3p levels than benign lesions. miR-877-3p promoted CC cell migration and invasion, at least partly by modulating cytoskeletal protein folding through the chaperonin-containing T-complex protein 1 complex. Notably, miR-877-3p silencing synergized with paclitaxel. Interestingly, miR-877-3p downregulated the levels of an in silico-predicted target, ZNF177, whose expression and subcellular location significantly distinguished high-grade squamous intraepithelial lesions (HSILs) and squamous cell carcinomas of the cervix (SCCCs). Cytoplasmic ZNF177 was significantly associated with worse progression-free survival in SCCC. Our results suggest that: (i) miR-877-3p is a potential therapeutic target whose inhibition improves paclitaxel effects; (ii) the expression and location of its target ZNF177 could be diagnostic biomarkers between HSIL and SCCC; and (iii) cytoplasmic ZNF177 is a poor-prognosis biomarker in SCCC. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
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29 pages, 7609 KiB  
Article
Regulation of Canonical Oncogenic Signaling Pathways in Cancer via DNA Methylation
by Jennifer Lu, Premila Wilfred, Darren Korbie and Matt Trau
Cancers 2020, 12(11), 3199; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113199 - 30 Oct 2020
Cited by 12 | Viewed by 3390
Abstract
Disruption of signaling pathways that plays a role in the normal development and cellular homeostasis may lead to the dysregulation of cellular signaling and bring about the onset of different diseases, including cancer. In addition to genetic aberrations, DNA methylation also acts as [...] Read more.
Disruption of signaling pathways that plays a role in the normal development and cellular homeostasis may lead to the dysregulation of cellular signaling and bring about the onset of different diseases, including cancer. In addition to genetic aberrations, DNA methylation also acts as an epigenetic modifier to drive the onset and progression of cancer by mediating the reversible transcription of related genes. Although the role of DNA methylation as an alternative driver of carcinogenesis has been well-established, the global effects of DNA methylation on oncogenic signaling pathways and the presentation of cancer is only emerging. In this article, we introduced a differential methylation parsing pipeline (MethylMine) which mined for epigenetic biomarkers based on feature selection. This pipeline was used to mine for biomarkers, which presented a substantial difference in methylation between the tumor and the matching normal tissue samples. Combined with the Data Integration Analysis for Biomarker discovery (DIABLO) framework for machine learning and multi-omic analysis, we revisited the TCGA DNA methylation and RNA-Seq datasets for breast, colorectal, lung, and prostate cancer, and identified differentially methylated genes within the NRF2-KEAP1/PI3K oncogenic pathway, which regulates the expression of cytoprotective genes, that serve as potential therapeutic targets to treat different cancers. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
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16 pages, 269 KiB  
Article
DNA Methylation and Breast Cancer Risk: An Epigenome-Wide Study of Normal Breast Tissue and Blood
by Kaoutar Ennour-Idrissi, Dzevka Dragic, Elissar Issa, Annick Michaud, Sue-Ling Chang, Louise Provencher, Francine Durocher and Caroline Diorio
Cancers 2020, 12(11), 3088; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113088 - 23 Oct 2020
Cited by 18 | Viewed by 2620
Abstract
Differential DNA methylation is a potential marker of breast cancer risk. Few studies have investigated DNA methylation changes in normal breast tissue and were largely confounded by cancer field effects. To detect methylation changes in normal breast epithelium that are causally associated with [...] Read more.
Differential DNA methylation is a potential marker of breast cancer risk. Few studies have investigated DNA methylation changes in normal breast tissue and were largely confounded by cancer field effects. To detect methylation changes in normal breast epithelium that are causally associated with breast cancer occurrence, we used a nested case–control study design based on a prospective cohort of patients diagnosed with a primary invasive hormone receptor-positive breast cancer. Twenty patients diagnosed with a contralateral breast cancer (CBC) were matched (1:1) with 20 patients who did not develop a CBC on relevant risk factors. Differentially methylated Cytosine-phosphate-Guanines (CpGs) and regions in normal breast epithelium were identified using an epigenome-wide DNA methylation assay and robust linear regressions. Analyses were replicated in two independent sets of normal breast tissue and blood. We identified 7315 CpGs (FDR < 0.05), 52 passing strict Bonferroni correction (p < 1.22 × 10−7) and 43 mapping to known genes involved in metabolic diseases with significant enrichment (p < 0.01) of pathways involving fatty acids metabolic processes. Four differentially methylated genes were detected in both site-specific and regions analyses (LHX2, TFAP2B, JAKMIP1, SEPT9), and three genes overlapped all three datasets (POM121L2, KCNQ1, CLEC4C). Once validated, the seven differentially methylated genes distinguishing women who developed and who did not develop a sporadic breast cancer could be used to enhance breast cancer risk-stratification, and allow implementation of targeted screening and preventive strategies that would ultimately improve breast cancer prognosis. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
20 pages, 3874 KiB  
Article
Target Enrichment Enables the Discovery of lncRNAs with Somatic Mutations or Altered Expression in Paraffin-Embedded Colorectal Cancer Samples
by Susana Iraola-Guzmán, Anna Brunet-Vega, Cinta Pegueroles, Ester Saus, Hrant Hovhannisyan, Alex Casalots, Carles Pericay and Toni Gabaldón
Cancers 2020, 12(10), 2844; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102844 - 01 Oct 2020
Cited by 7 | Viewed by 2674
Abstract
Long non-coding RNAs (lncRNAs) play important roles in cancer and are potential new biomarkers or targets for therapy. However, given the low and tissue-specific expression of lncRNAs, linking these molecules to particular cancer types and processes through transcriptional profiling is challenging. Formalin-fixed, paraffin-embedded [...] Read more.
Long non-coding RNAs (lncRNAs) play important roles in cancer and are potential new biomarkers or targets for therapy. However, given the low and tissue-specific expression of lncRNAs, linking these molecules to particular cancer types and processes through transcriptional profiling is challenging. Formalin-fixed, paraffin-embedded (FFPE) tissues are abundant resources for research but are prone to nucleic acid degradation, thereby complicating the study of lncRNAs. Here, we designed and validated a probe-based enrichment strategy to efficiently profile lncRNA expression in FFPE samples, and we applied it for the detection of lncRNAs associated with colorectal cancer (CRC). Our approach efficiently enriched targeted lncRNAs from FFPE samples, while preserving their relative abundance, and enabled the detection of tumor-specific mutations. We identified 379 lncRNAs differentially expressed between CRC tumors and matched healthy tissues and found tumor-specific lncRNA variants. Our results show that numerous lncRNAs are differentially expressed and/or accumulate variants in CRC tumors, thereby suggesting a role in CRC progression. More generally, our approach unlocks the study of lncRNAs in FFPE samples, thus enabling the retrospective use of abundant, well documented material available in hospital biobanks. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
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24 pages, 5679 KiB  
Article
Combined Methylome and Transcriptome Analyses Reveals Potential Therapeutic Targets for EGFR Wild Type Lung Cancers with Low PD-L1 Expression
by Weilei Hu, Guosheng Wang, Lonny B. Yarmus and Yuan Wan
Cancers 2020, 12(9), 2496; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092496 - 03 Sep 2020
Cited by 10 | Viewed by 3752
Abstract
Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have demonstrated remarkable treatment efficacy in advanced non-small cell lung cancer (NSCLC). However, low expression of programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR) wild-type NSCLCs are refractory, and only few therapeutic options exist. Currently, combination [...] Read more.
Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have demonstrated remarkable treatment efficacy in advanced non-small cell lung cancer (NSCLC). However, low expression of programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR) wild-type NSCLCs are refractory, and only few therapeutic options exist. Currently, combination therapy with ICIs is frequently used in order to enhance the treatment response rates. Yet, this regimen is still associated with poor treatment outcome. Therefore, identification of potential therapeutic targets for this subgroup of NSCLC is strongly desired. Here, we report the distinct methylation signatures of this special subgroup. Moreover, several druggable targets and relevant drugs for targeted therapy were incidentally identified. We found hypermethylated differentially methylated regions (DMRs) in three regions (TSS200, TSS1500, and gene body) are significantly higher than hypomethylated ones. Downregulated methylated genes were found to be involved in negative regulation of immune response and T cell-mediated immunity. Moreover, expression of four methylated genes (PLCXD3 (Phosphatidylinositol-Specific Phospholipase C, X Domain Containing 3), BAIAP2L2 (BAR/IMD Domain Containing Adaptor Protein 2 Like 2), NPR3 (Natriuretic Peptide Receptor 3), SNX10 (Sorting Nexin 10)) can influence patients’ prognosis. Subsequently, based on DrugBank data, NetworkAnalyst 3.0 was used for protein–drug interaction analysis of up-regulated differentially methylated genes. Protein products of nine genes were identified as potential druggable targets, of which the tumorigenic potential of XDH (Xanthine Dehydrogenase), ATIC (5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase), CA9 (Carbonic Anhydrase 9), SLC7A11 (Solute Carrier Family 7 Member 11), and GAPDH (Glyceraldehyde-3-Phosphate Dehydrogenase) have been demonstrated in previous studies. Next, molecular docking and molecular dynamics simulation were performed to verify the structural basis of the therapeutic targets. It is noteworthy that the identified pemetrexed targeting ATIC has been recently approved for first-line use in combination with anti-PD1 inhibitors against lung cancer, irrespective of PD-L1 expression. In future work, a pivotal clinical study will be initiated to further validate our findings. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
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16 pages, 2571 KiB  
Article
Tetraspanin CD9 is Regulated by miR-518f-5p and Functions in Breast Cell Migration and In Vivo Tumor Growth
by Danielle R. Bond, Richard Kahl, Joshua S. Brzozowski, Helen Jankowski, Crystal Naudin, Mamta Pariyar, Kelly A. Avery-Kiejda, Christopher J. Scarlett, Claude Boucheix, William J. Muller, Leonie K. Ashman, Murray J. Cairns, Séverine Roselli and Judith Weidenhofer
Cancers 2020, 12(4), 795; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040795 - 26 Mar 2020
Cited by 12 | Viewed by 3602
Abstract
Breast cancer is the most commonly diagnosed and the second leading cause of cancer-related mortality among women worldwide. miR-518f-5p has been shown to modulate the expression of the metastasis suppressor CD9 in prostate cancer. However, the role of miR-518f-5p and CD9 in breast [...] Read more.
Breast cancer is the most commonly diagnosed and the second leading cause of cancer-related mortality among women worldwide. miR-518f-5p has been shown to modulate the expression of the metastasis suppressor CD9 in prostate cancer. However, the role of miR-518f-5p and CD9 in breast cancer is unknown. Therefore, this study aimed to elucidate the role of miR-518f-5p and the mechanisms responsible for decreased CD9 expression in breast cancer, as well as the role of CD9 in de novo tumor formation and metastasis. miR-518f-5p function was assessed using migration, adhesion, and proliferation assays. miR-518f-5p was overexpressed in breast cancer cell lines that displayed significantly lower CD9 expression as well as less endogenous CD9 3′UTR activity, as assessed using qPCR and dual luciferase assays. Transfection of miR-518f-5p significantly decreased CD9 protein expression and increased breast cell migration in vitro. Cd9 deletion in the MMTV/PyMT mouse model impaired tumor growth, but had no effect on tumor initiation or metastasis. Therefore, inhibition of miR-518f-5p may restore CD9 expression and aid in the treatment of breast cancer metastasis. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
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19 pages, 7837 KiB  
Article
VIRMA-Dependent N6-Methyladenosine Modifications Regulate the Expression of Long Non-Coding RNAs CCAT1 and CCAT2 in Prostate Cancer
by Daniela Barros-Silva, João Lobo, Catarina Guimarães-Teixeira, Isa Carneiro, Jorge Oliveira, Elena S. Martens-Uzunova, Rui Henrique and Carmen Jerónimo
Cancers 2020, 12(4), 771; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040771 - 25 Mar 2020
Cited by 63 | Viewed by 4405
Abstract
RNA methylation at position N6 in adenosine (m6A) and its associated methyltransferase complex (MTC) are involved in tumorigenesis. We aimed to explore m6A biological function for long non-coding RNAs (lncRNAs) in prostate cancer (PCa) and its clinical significance. m [...] Read more.
RNA methylation at position N6 in adenosine (m6A) and its associated methyltransferase complex (MTC) are involved in tumorigenesis. We aimed to explore m6A biological function for long non-coding RNAs (lncRNAs) in prostate cancer (PCa) and its clinical significance. m6A and MTC levels in PCa cells were characterized by ELISA and western blot. Putative m6A-regulated lncRNAs were identified and validated by lncRNA profiler qPCR array and bioinformatics analysis, followed by m6A/RNA co-immunoprecipitation. Impact of m6A depletion on RNA stability was assessed by Actinomycin D assay. The association of m6A-levels with PCa prognosis was examined in clinical samples. Higher m6A-levels and VIRMA overexpression were detected in metastatic castration-resistant PCa (mCRPC) cells (p < 0.05). VIRMA knockdown in PC-3 cells significantly decreased m6A-levels (p = 0.0317), attenuated malignant phenotype and suppressed the expression of oncogenic lncRNAs CCAT1 and CCAT2 (p < 0.00001). VIRMA depletion and m6A reduction decreased the stability and abundance of CCAT1/2 transcripts. Higher expression of VIRMA, CCAT1, and CCAT2 as a group variable was an independent predictor of poor prognosis (HR = 9.083, CI95% 1.911–43.183, p = 0.006). VIRMA is a critical factor sustaining m6A-levels in PCa cells. VIRMA downregulation attenuates the aggressive phenotype of PCa by overall reduction of m6A-levels decreasing stability and abundance of oncogenic lncRNAs. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
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11 pages, 291 KiB  
Article
Blood-Based SOX2-Promoter Methylation in Relation to Exercise and PM2.5 Exposure among Taiwanese Adults
by Chun-Lang Su, Disline Manli Tantoh, Ying-Hsiang Chou, Lee Wang, Chien-Chang Ho, Pei-Hsin Chen, Kuan-Jung Lee, Oswald Ndi Nfor, Shu-Yi Hsu, Wen-Miin Liang and Yung-Po Liaw
Cancers 2020, 12(2), 504; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020504 - 21 Feb 2020
Cited by 8 | Viewed by 2986
Abstract
Increased ventilation during exercise in polluted areas could trigger airway inflammation. We evaluated blood DNA methylation of the SOX2-promoter region in relation to exercise and PM2.5 in Taiwanese adults. Data of 948 participants aged 30–70 years were retrieved from the Taiwan Biobank [...] Read more.
Increased ventilation during exercise in polluted areas could trigger airway inflammation. We evaluated blood DNA methylation of the SOX2-promoter region in relation to exercise and PM2.5 in Taiwanese adults. Data of 948 participants aged 30–70 years were retrieved from the Taiwan Biobank Database (2008–2015) and the Air Quality Monitoring Database (2006–2011). PM2.5 was positively associated with SOX2-promoter methylation (β = 0.000216; p < 0.0001). The interaction between PM2.5 and exercise on SOX2-promoter methylation was significant (p = 0.0146). After stratification by exercise habits, PM2.5 was positively associated with SOX2 methylation in only individuals who did regular exercise (β = 0.0003490; p < 0.0001). After stratification by exercise habits and residential areas, SOX2-promoter methylation levels in those who lived in the southern area were higher for both the regular exercise (β = 0.00272; p = 0.0172) and no regular exercise groups (β = 0.002610 and p = 0.0162). SOX2-promoter methylation levels in those who lived in the northern area and did regular exercise were lower; β = -0.00314 (p = 0.0036). In conclusion, PM2.5 was positively associated with SOX2-promoter methylation in participants who did regular exercise. Living in the southern area was positively associated with SOX2-promoter methylation regardless of exercise habits. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)

Review

Jump to: Editorial, Research

27 pages, 2245 KiB  
Review
The Roles of Non-Coding RNAs in Tumor-Associated Lymphangiogenesis
by Khairunnisa’ Md Yusof, Rozita Rosli, Maha Abdullah and Kelly A. Avery-Kiejda
Cancers 2020, 12(11), 3290; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113290 - 06 Nov 2020
Cited by 20 | Viewed by 3431
Abstract
Lymphatic vessels are regarded as the ”forgotten” circulation. Despite this, growing evidence has shown significant roles for the lymphatic circulation in normal and pathological conditions in humans, including cancers. The dissemination of tumor cells to other organs is often mediated by lymphatic vessels [...] Read more.
Lymphatic vessels are regarded as the ”forgotten” circulation. Despite this, growing evidence has shown significant roles for the lymphatic circulation in normal and pathological conditions in humans, including cancers. The dissemination of tumor cells to other organs is often mediated by lymphatic vessels that serve as a conduit and is often referred to as tumor-associated lymphangiogenesis. Some of the most well-studied lymphangiogenic factors that govern tumor lymphangiogenesis are the vascular endothelial growth factor (VEGF-C/D and VEGFR-2/3), neuroplilin-2 (NRP2), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF), to name a few. However, recent findings have illustrated that non-coding RNAs are significantly involved in regulating gene expression in most biological processes, including lymphangiogenesis. In this review, we focus on the regulation of growth factors and non-coding RNAs (ncRNAs) in the lymphatic development in normal and cancer physiology. Then, we discuss the lymphangiogenic factors that necessitate tumor-associated lymphangiogenesis, with regards to ncRNAs in various types of cancer. Understanding the different roles of ncRNAs in regulating lymphatic vasculature in normal and cancer conditions may pave the way towards the development of ncRNA-based anti-lymphangiogenic therapy. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
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25 pages, 1455 KiB  
Review
Unravelling the Epigenome of Myelodysplastic Syndrome: Diagnosis, Prognosis, and Response to Therapy
by Danielle R. Bond, Heather J. Lee and Anoop K. Enjeti
Cancers 2020, 12(11), 3128; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113128 - 26 Oct 2020
Cited by 11 | Viewed by 4027
Abstract
Myelodysplastic syndrome (MDS) is a malignancy that disrupts normal blood cell production and commonly affects our ageing population. MDS patients are diagnosed using an invasive bone marrow biopsy and high-risk MDS patients are treated with hypomethylating agents (HMAs) such as decitabine and azacytidine. [...] Read more.
Myelodysplastic syndrome (MDS) is a malignancy that disrupts normal blood cell production and commonly affects our ageing population. MDS patients are diagnosed using an invasive bone marrow biopsy and high-risk MDS patients are treated with hypomethylating agents (HMAs) such as decitabine and azacytidine. However, these therapies are only effective in 50% of patients, and many develop resistance to therapy, often resulting in bone marrow failure or leukemic transformation. Therefore, there is a strong need for less invasive, diagnostic tests for MDS, novel markers that can predict response to therapy and/or patient prognosis to aid treatment stratification, as well as new and effective therapeutics to enhance patient quality of life and survival. Epigenetic modifiers such as DNA methylation, long non-coding RNAs (lncRNAs) and micro-RNAs (miRNAs) are perturbed in MDS blasts and the bone marrow micro-environment, influencing disease progression and response to therapy. This review focusses on the potential utility of epigenetic modifiers in aiding diagnosis, prognosis, and predicting treatment response in MDS, and touches on the need for extensive and collaborative research using single-cell technologies and multi-omics to test the clinical utility of epigenetic markers for MDS patients in the future. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
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16 pages, 1219 KiB  
Review
Epstein–Barr Virus Promotes B Cell Lymphomas by Manipulating the Host Epigenetic Machinery
by Andrea Di Pietro
Cancers 2020, 12(10), 3037; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12103037 - 19 Oct 2020
Cited by 8 | Viewed by 7009
Abstract
During the past decade, the rapid development of high-throughput next-generation sequencing technologies has significantly reinforced our understanding of the role of epigenetics in health and disease. Altered functions of epigenetic modifiers lead to the disruption of the host epigenome, ultimately inducing carcinogenesis and [...] Read more.
During the past decade, the rapid development of high-throughput next-generation sequencing technologies has significantly reinforced our understanding of the role of epigenetics in health and disease. Altered functions of epigenetic modifiers lead to the disruption of the host epigenome, ultimately inducing carcinogenesis and disease progression. Epstein–Barr virus (EBV) is an endemic herpesvirus that is associated with several malignant tumours, including B-cell related lymphomas. In EBV-infected cells, the epigenomic landscape is extensively reshaped by viral oncoproteins, which directly interact with epigenetic modifiers and modulate their function. This process is fundamental for the EBV life cycle, particularly for the establishment and maintenance of latency in B cells; however, the alteration of the host epigenetic machinery also contributes to the dysregulated expression of several cellular genes, including tumour suppressor genes, which can drive lymphoma development. This review outlines the molecular mechanisms underlying the epigenetic manipulation induced by EBV that lead to transformed B cells, as well as novel therapeutic interventions to target EBV-associated B-cell lymphomas. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
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38 pages, 1904 KiB  
Review
Advances in Prognostic Methylation Biomarkers for Prostate Cancer
by Dilys Lam, Susan Clark, Clare Stirzaker and Ruth Pidsley
Cancers 2020, 12(10), 2993; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102993 - 15 Oct 2020
Cited by 15 | Viewed by 3871
Abstract
There is a major clinical need for accurate biomarkers for prostate cancer prognosis, to better inform treatment strategies and disease monitoring. Current clinically recognised prognostic factors, including prostate-specific antigen (PSA) levels, lack sensitivity and specificity in distinguishing aggressive from indolent disease, particularly in [...] Read more.
There is a major clinical need for accurate biomarkers for prostate cancer prognosis, to better inform treatment strategies and disease monitoring. Current clinically recognised prognostic factors, including prostate-specific antigen (PSA) levels, lack sensitivity and specificity in distinguishing aggressive from indolent disease, particularly in patients with localised intermediate grade prostate cancer. There has therefore been a major focus on identifying molecular biomarkers that can add prognostic value to existing markers, including investigation of DNA methylation, which has a known role in tumorigenesis. In this review, we will provide a comprehensive overview of the current state of DNA methylation biomarker studies in prostate cancer prognosis, and highlight the advances that have been made in this field. We cover the numerous studies into well-established candidate genes, and explore the technological transition that has enabled hypothesis-free genome-wide studies and the subsequent discovery of novel prognostic genes. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
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33 pages, 791 KiB  
Review
Regulating Methylation at H3K27: A Trick or Treat for Cancer Cell Plasticity
by Provas Das and Joseph H. Taube
Cancers 2020, 12(10), 2792; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102792 - 29 Sep 2020
Cited by 28 | Viewed by 4416
Abstract
Properly timed addition and removal of histone 3 lysine 27 tri-methylation (H3K27me3) is critical for enabling proper differentiation throughout all stages of development and, likewise, can guide carcinoma cells into altered differentiation states which correspond to poor prognoses and treatment evasion. In early [...] Read more.
Properly timed addition and removal of histone 3 lysine 27 tri-methylation (H3K27me3) is critical for enabling proper differentiation throughout all stages of development and, likewise, can guide carcinoma cells into altered differentiation states which correspond to poor prognoses and treatment evasion. In early embryonic stages, H3K27me3 is invoked to silence genes and restrict cell fate. Not surprisingly, mutation or altered functionality in the enzymes that regulate this pathway results in aberrant methylation or demethylation that can lead to malignancy. Likewise, changes in expression or activity of these enzymes impact cellular plasticity, metastasis, and treatment evasion. This review focuses on current knowledge regarding methylation and de-methylation of H3K27 in cancer initiation and cancer cell plasticity. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
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27 pages, 1666 KiB  
Review
The Regulatory Role of Mitochondrial MicroRNAs (MitomiRs) in Breast Cancer: Translational Implications Present and Future
by Miguel A. Ortega, Oscar Fraile-Martínez, Luis G. Guijarro, Carlos Casanova, Santiago Coca, Melchor Álvarez-Mon, Julia Buján, Natalio García-Honduvilla and Ángel Asúnsolo
Cancers 2020, 12(9), 2443; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092443 - 28 Aug 2020
Cited by 28 | Viewed by 4384
Abstract
Breast cancer is the most prevalent and incident female neoplasm worldwide. Although survival rates have considerably improved, it is still the leading cause of cancer-related mortality in women. MicroRNAs are small non-coding RNA molecules that regulate the posttranscriptional expression of a wide variety [...] Read more.
Breast cancer is the most prevalent and incident female neoplasm worldwide. Although survival rates have considerably improved, it is still the leading cause of cancer-related mortality in women. MicroRNAs are small non-coding RNA molecules that regulate the posttranscriptional expression of a wide variety of genes. Although it is usually located in the cytoplasm, several studies have detected a regulatory role of microRNAs in other cell compartments such as the nucleus or mitochondrion, known as “mitomiRs”. MitomiRs are essential modulators of mitochondrion tasks and their abnormal expression has been linked to the aetiology of several human diseases related to mitochondrial dysfunction, including breast cancer. This review aims to examine basic knowledge of the role of mitomiRs in breast cancer and discusses their prospects as biomarkers or therapeutic targets. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
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22 pages, 1706 KiB  
Review
DNA Methyltransferases in Cancer: Biology, Paradox, Aberrations, and Targeted Therapy
by Jiayu Zhang, Cheng Yang, Chunfu Wu, Wei Cui and Lihui Wang
Cancers 2020, 12(8), 2123; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082123 - 31 Jul 2020
Cited by 120 | Viewed by 7787
Abstract
DNA methyltransferases are an essential class of modifiers in epigenetics. In mammals, DNMT1, DNMT3A and DNMT3B participate in DNA methylation to regulate normal biological functions, such as embryo development, cell differentiation and gene transcription. Aberrant functions of DNMTs are frequently associated with tumorigenesis. [...] Read more.
DNA methyltransferases are an essential class of modifiers in epigenetics. In mammals, DNMT1, DNMT3A and DNMT3B participate in DNA methylation to regulate normal biological functions, such as embryo development, cell differentiation and gene transcription. Aberrant functions of DNMTs are frequently associated with tumorigenesis. DNMT aberrations usually affect tumor-related factors, such as hypermethylated suppressor genes and genomic instability, which increase the malignancy of tumors, worsen the prognosis for patients, and greatly increase the difficulty of cancer therapy. However, the impact of DNMTs on tumors is still controversial, and therapeutic approaches targeting DNMTs are still under exploration. Here, we summarize the biological functions and paradoxes associated with DNMTs and we discuss some emerging strategies for targeting DNMTs in tumors, which may provide novel ideas for cancer therapy. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
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20 pages, 3680 KiB  
Review
Epigenetics of SFRP1: The Dual Roles in Human Cancers
by Rashidah Baharudin, Francis Yew Fu Tieng, Learn-Han Lee and Nurul Syakima Ab Mutalib
Cancers 2020, 12(2), 445; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020445 - 14 Feb 2020
Cited by 59 | Viewed by 6157
Abstract
Secreted frizzled-related protein 1 (SFRP1) is a gene that belongs to the secreted glycoprotein SFRP family. SFRP1 has been classified as a tumor suppressor gene due to the loss of expression in various human cancers, which is mainly attributed by epigenetic inactivation via [...] Read more.
Secreted frizzled-related protein 1 (SFRP1) is a gene that belongs to the secreted glycoprotein SFRP family. SFRP1 has been classified as a tumor suppressor gene due to the loss of expression in various human cancers, which is mainly attributed by epigenetic inactivation via DNA methylation or transcriptional silencing by microRNAs. Epigenetic silencing of SFRP1 may cause dysregulation of cell proliferation, migration, and invasion, which lead to cancer cells formation, disease progression, poor prognosis, and treatment resistance. Hence, restoration of SFRP1 expression via demethylating drugs or over-expression experiments opens the possibility for new cancer therapy approach. While the role of SFRP1 as a tumor suppressor gene is well-established, some studies also reported the possible oncogenic properties of SFRP1 in cancers. In this review, we discussed in great detail the dual roles of SFRP1 in cancers—as tumor suppressor and tumor promoter. The epigenetic regulation of SFRP1 expression will also be underscored with additional emphasis on the potentials of SFRP1 in modulating responses toward chemotherapeutic and epigenetic-modifying drugs, which may encourage the development of novel drugs for cancer treatment. We also present findings from clinical trials and patents involving SFRP1 to illustrate its clinical utility, extensiveness of each research area, and progression toward commercialization. Lastly, this review provides directions for future research to advance SFRP1 as a promising cancer biomarker. Full article
(This article belongs to the Special Issue Switching Off Cancer: Epigenetic Modifiers (miRNA, lncRNA and Methylation) in Cancers)
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