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Sobhani I, De Oliveira Alves N, Sadeghi M, Charpy C, Bergsten E, Amiot A, Barau C, Brunetti F, Vaysse A, Tournigand C, Chamaillard M, Khashayarsha K, Mestivier D. Poor prognosis in IBD-complicated colon cancer through gut dysbiosis-related immune response failure. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.25.645177. [PMID: 40196693 PMCID: PMC11974894 DOI: 10.1101/2025.03.25.645177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Background Colorectal cancer (CRC) results from the accumulation of mutations and epigenetic changes in gut epithelial cells likely due to gut microbiota dysbiosis. However, limited research has been done to explore the link between host tumour dysbiosis and disease outcome. Methods The mechanisms influencing outcomes of 97 colorectal cancer (CRC) patients, including 13 with Lynch syndrome, 20 with inflammatory bowel disease (IBD), and 64 sporadic cases, were analyzed using a multiomics approach. These patients were categorized into two groups: "disease-free/stable disease" and "progression disease" survival outcomes. The analysis included tumor adherent microbiota composition (16S rRNA), somatic gene mutations (WES), gene expression (RNAseq), immune markers (RNAscope), and immune infiltrate cells (immunohistochemistry). Results IBD-CRC patients had worse outcomes than those with Lynch or sporadic CRC, regardless of TNM staging or treatment. Symbiotic bacteria like Lactococcus lactis were significantly reduced in IBD-CRC tissues. Patient outcomes were influenced by the abundance of virulent ( Escherichia coli ) relative to beneficial bacteria ( Lactococcus lactis ). Although no significant increase in deleterious somatic mutations was found in IBD-CRC. 16sRNA revealed increased virulent- and decreased anti-inflammatory symbiotic-bacteria correlating with the upregulation of oncogenes and downregulation of anti-oncogenes like PHLPP1. The multiplex in situ hybridization of CD8, IFNγ and PHLPP1 an anti-oncogene revealed significant decrease of immune cells with detectable PHLPP1 expression in IBD-CRC tumour tissues as compared to sporadic CRCs. Conclusion The poor outcomes in IBD-CRC patients are likely due to gut dysbiosis and immune cell alterations, possibly triggered by microbiota-related epigenetic pathways. What You Need to Know BACKGROUND AND CONTEXT: Colorectal cancer (CRC) is associated with gut microbiota dysbiosis. Inflammatory bowel disease-related CRC (IBD-CRC) is classified as an environment-related condition.NEW FINDINGS: In relation with patient outcomes, tumour tissues from three types of CRC (Sporadic-, IBD-, and Lynch syndrome-CRC) were analyzed using a multiomic approach. This included examining tissue adherent virulent bacteria, gene analyses, and quantifying immune cell infiltration in the mucosa. IBD-CRC patients had the worst outcomes, associated with the down regulation of PHLPP1 gene, virulent/symbiotic imbalance, and immune response failure.LIMITATIONS: Lack of animal experiments using FMT of fresh stool from IBD-CRC patients.CLINICAL AND TRANSLATIONAL RESEARCH RELEVANCE: Among the different types of CRC, IBD-CRC patients showed a greater imbalance between harmful and beneficial bacteria, along with immune response failure.Lay summary: This study compares the pathological and clinical characteristics of patients with colorectal cancer (CRC) across three distinct etiologies: sporadic CRC, inflammatory bowel disease (IBD)-associated CRC, and Lynch syndrome-associated CRC (LS-CRC). Distinct differences in tumor-adherent microbiota, gene expression and immune response profiles were observed. Notably, IBD-CRC patients demonstrated the poorest prognosis depending on microbe-host gene interaction highlighting potential biomarkers for disease prognosis and treatment strategies.
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Hajebi Khaniki S, Shokoohi F. Data-Driven Identification of Early Cancer-Associated Genes via Penalized Trans-Dimensional Hidden Markov Models. Biomolecules 2025; 15:294. [PMID: 40001597 PMCID: PMC11853217 DOI: 10.3390/biom15020294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/13/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Colorectal cancer (CRC) is a significant worldwide health problem due to its high prevalence, mortality rates, and frequent diagnosis at advanced stages. While diagnostic and therapeutic approaches have evolved, the underlying mechanisms driving CRC initiation and progression are not yet fully understood. Early detection is critical for improving patient survival, as initial cancer stages often exhibit epigenetic changes-such as DNA methylation-that regulate gene expression and tumor progression. Identifying DNA methylation patterns and key survival-related genes in CRC could thus enhance diagnostic accuracy and extend patient lifespans. In this study, we apply two of our recently developed methods for identifying differential methylation and analyzing survival using a sparse, finite mixture of accelerated failure time regression models, focusing on key genes and pathways in CRC datasets. Our approach outperforms two other leading methods, yielding robust findings and identifying novel differentially methylated cytosines. We found that CRC patient survival time follows a two-component mixture regression model, where genes CDH11, EPB41L3, and DOCK2 are active in the more aggressive form of CRC, whereas TMEM215, PPP1R14A, GPR158, and NAPSB are active in the less aggressive form.
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Affiliation(s)
- Saeedeh Hajebi Khaniki
- Department of Biostatistics, School of Health, Mashhad University of Medical Sciences, Mashhad 9137673119, Iran;
| | - Farhad Shokoohi
- Department of Mathematical Sciences, University of Nevada Las Vegas, Las Vegas, NV 89154, USA
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Li T, Luo C, Liu Z, Li J, Han M, Zhang R, Chen Y, Deng H. Nicotinamide mononucleotide protects STAT1 from oxidative stress-induced degradation to prevent colorectal tumorigenesis. MedComm (Beijing) 2024; 5:e70006. [PMID: 39575303 PMCID: PMC11581775 DOI: 10.1002/mco2.70006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 09/04/2024] [Accepted: 09/08/2024] [Indexed: 11/24/2024] Open
Abstract
Colitis, accompanied by the accumulation of reactive oxygen species (ROS) in the intestinal tract, is a risk factor for colorectal cancer (CRC). Our previous studies indicate that nicotinamide mononucleotide (NMN) replenishment reduces chronic inflammation. In this study, we confirm that NMN supplementation reduces inflammatory cytokine levels and oxidative tissue damage in an azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated cancer (CAC) model. Mice treated with NMN developed fewer colon tumors than untreated animals under the same AOM/DSS treatment conditions. Quantitative proteomic analysis revealed a decrease in signal transducer and activator of transcription 1 (STAT1) expression in the CAC model. We demonstrate that STAT1 overexpression induces G1 arrest by downregulating CDK6 expression and suppressing tumor cell proliferation and migration. Of note, H2O2 induced trioxidation of the STAT1 protein and promoted its degradation, which was partially reversed by NMN supplementation. Upon H2O2 treatment, Cys155 in STAT1 was oxidized to sulfonic acid, whereas the mutation of Cys155 to alanine abolished ROS-mediated STAT1 degradation. These results indicate that oxidative stress induces STAT1 degradation in tumor cells and possibly in CAC tissues, whereas supplementation with NMN protects STAT1 from oxidation-induced degradation and prevents tumorigenesis. This study provides experimental evidence for the development of NMN-mediated chemoprevention strategies for CRC.
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Affiliation(s)
- Ting Li
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life SciencesTsinghua UniversityBeijingChina
- School of Life Science and TechnologyWuhan Polytechnic UniversityWuhanChina
| | - Chengting Luo
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life SciencesTsinghua UniversityBeijingChina
- School of Life ScienceYunnan UniversityYunnanChina
| | - Zongyuan Liu
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life SciencesTsinghua UniversityBeijingChina
| | - Jinyu Li
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life SciencesTsinghua UniversityBeijingChina
| | - Meng Han
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life SciencesTsinghua UniversityBeijingChina
| | - Ran Zhang
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life SciencesTsinghua UniversityBeijingChina
| | - Yuling Chen
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life SciencesTsinghua UniversityBeijingChina
| | - Haiteng Deng
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life SciencesTsinghua UniversityBeijingChina
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Fiordoro S, Rosano C, Pechkova E, Barocci S, Izzotti A. Epigenetic modulation of immune cells: Mechanisms and implications. Adv Biol Regul 2024; 94:101043. [PMID: 39305736 DOI: 10.1016/j.jbior.2024.101043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 07/25/2024] [Accepted: 08/02/2024] [Indexed: 12/12/2024]
Abstract
Epigenetic modulation of the immune response entails modifiable and inheritable modifications that do not modify the DNA sequence. While there have been many studies on epigenetic changes in tumor cells, there is now a growing focus on epigenetically mediated changes in immune cells of both the innate and adaptive systems. These changes have significant implications for both the body's response to tumors and the development of potential therapeutic vaccines. This study primarily discusses the key epigenetic alterations, with a specific emphasis on pseudouridination, as well as non-coding RNAs and their transportation, which can lead to the development of cancer and the acquisition of new phenotypic traits by immune cells. Furthermore, the advancement of therapeutic vaccinations targeting the tumor will be outlined.
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Affiliation(s)
- S Fiordoro
- Department of Health Sciences, University of Genova, Via Pastore 1, 16132 Genova, Italy
| | - C Rosano
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy.
| | - E Pechkova
- Department of Experimental Medicine, University of Genoa, 16132 Genova, Italy
| | - S Barocci
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy
| | - A Izzotti
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy; Department of Experimental Medicine, University of Genoa, 16132 Genova, Italy
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Alafaria HAA, Jalal AS. Novel DNA methylation biomarkers for early diagnosis of oral tongue squamous cell carcinoma (OTSCC). J Appl Genet 2024; 65:541-548. [PMID: 38438717 DOI: 10.1007/s13353-024-00830-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/04/2024] [Accepted: 01/08/2024] [Indexed: 03/06/2024]
Abstract
Oral tongue squamous cell carcinoma (OTSCC) is the most common malignancy type among males across the world. However, analysis of molecular markers could be useful in detecting the early-stage OTSCC, which would allow optimal clinical treatments and prolong the survival rate of patients consequently. The study has the objective of detecting the role of salivary biomarkers based on gene promoter hypermethylation. Sample data from 45 OTSCC and normal groups were analyzed to exhibit the methylation levels of salivary biomarkers (TRH, FHIT, MGMT, p16, and RASSF1A). The specificity and sensitivity analysis of methylation biomarkers was conducted in addition to the receiver operating characteristic (ROC) curve for both early-stage and advanced OTSCC stages. Quantitative data findings showed the perfect sensitivity and specificity for TRH, MGMT, p16, and RASSF1A with 100%, and > 90%, respectively. In addition, the results indicated an inefficient area under curves (> 0.7) for these biomarkers to detect the OTSCC. There were no significant differences observed between TRH and FHIT and p16 and MGMT based on the Wilcoxon signed-rank test. The methylation statuses of genes TRH, RASSF1A, p16, and MGMT might become utilized as predictive biomarkers for clinical application in early diagnosis of OTSCC and noninvasive oral cancer screening.
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Affiliation(s)
- Hayat Ali Abdullah Alafaria
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, 11671, Riyadh, Saudi Arabia
| | - Areej Saud Jalal
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, 11671, Riyadh, Saudi Arabia.
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Fialková V, Ďúranová H, Borotová P, Klongová L, Grabacka M, Speváková I. Natural Stilbenes: Their Role in Colorectal Cancer Prevention, DNA Methylation, and Therapy. Nutr Cancer 2024; 76:760-788. [PMID: 38950568 DOI: 10.1080/01635581.2024.2364391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 05/29/2024] [Accepted: 05/31/2024] [Indexed: 07/03/2024]
Abstract
The resistance of colorectal cancer (CRC) to conventional therapeutic modalities, such as radiation therapy and chemotherapy, along with the associated side effects, significantly limits effective anticancer strategies. Numerous epigenetic investigations have unveiled that naturally occurring stilbenes can modify or reverse abnormal epigenetic alterations, particularly aberrant DNA methylation status, offering potential avenues for preventing or treating CRC. By modulating the activity of the DNA methylation machinery components, phytochemicals may influence the various stages of CRC carcinogenesis through multiple molecular mechanisms. Several epigenetic studies, especially preclinical research, have highlighted the effective DNA methylation modulatory effects of stilbenes with minimal adverse effects on organisms, particularly in combination therapies for CRC. However, the available preclinical and clinical data regarding the effects of commonly encountered stilbenes against CRC are currently limited. Therefore, additional epigenetic research is warranted to explore the preventive potential of these phytochemicals in CRC development and to validate their therapeutic application in the prevention and treatment of CRC. This review aims to provide an overview of selected bioactive stilbenes as potential chemopreventive agents for CRC with a focus on their modulatory mechanisms of action, especially in targeting alterations in DNA methylation machinery in CRC.
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Affiliation(s)
- Veronika Fialková
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Hana Ďúranová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Petra Borotová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Lucia Klongová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Maja Grabacka
- Department of Biotechnology and General Technology of Foods, Faculty of Food Technology, University of Agriculture, Cracow, Poland
| | - Ivana Speváková
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
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Mirbahari SN, Fatemi N, Savabkar S, Chaleshi V, Zali N, Taleghani MY, Mirzaei E, Rejali L, Moghadam PK, Mojarad EN. Unmasking early colorectal cancer clues: in silico and in vitro investigation of downregulated IGF2, SOCS1, MLH1, and CACNA1G in SSA polyps. Mol Biol Rep 2024; 51:764. [PMID: 38874740 PMCID: PMC11178608 DOI: 10.1007/s11033-024-09683-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 05/29/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND AND AIM Colorectal cancer (CRC) originates from pre-existing polyps in the colon. The development of different subtypes of CRC is influenced by various genetic and epigenetic characteristics. CpG island methylator phenotype (CIMP) is found in about 15-20% of sporadic CRCs and is associated with hypermethylation of certain gene promoters. This study aims to find prognostic genes and compare their expression and methylation status as potential biomarkers in patients with serrated sessile adenomas/polyps (SSAP) and CRC, in order to evaluate which, one is a better predictor of disease. METHOD This study employed a multi-phase approach to investigate genes associated with CRC and SSAP. Initially, two gene expression datasets were analyzed using R and Limma package to identify differentially expressed genes (DEGs). Venn diagram analysis further refined the selection, revealing four genes from the Weissenberg panel with significant changes. These genes, underwent thorough in silico evaluations. Once confirmed, they proceeded to wet lab experimentation, focusing on expression and methylation status. This comprehensive methodology ensured a robust examination of the genes involved in CRC and SSAP. RESULT This study identified cancer-specific genes, with 8,351 and 1,769 genes specifically down-regulated in SSAP and CRC tissues, respectively. The down-regulated genes were associated with cell adhesion, negative regulation of cell proliferation, and drug response. Four highly downregulated genes in the Weissenberg panel, including CACNA1G, IGF2, MLH1, and SOCS1. In vitro analysis showed that they are hypermethylated in both SSAP and CRC samples while their expressions decreased only in CRC samples. CONCLUSION This suggests that the decrease in gene expression could help determine whether a polyp will become cancerous. Using both methylation status and gene expression status of genes in the Weissenberg panel in prognostic tests may lead to better prognoses for patients.
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Affiliation(s)
- Seyedeh Nasim Mirbahari
- Faculty of Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nayeralsadat Fatemi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sanaz Savabkar
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Chaleshi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Neda Zali
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Yaghoob Taleghani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ebrahim Mirzaei
- Department of Medical Genetics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Leili Rejali
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pardis Ketabi Moghadam
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, P. O. Box: 1985717413, Tehran, Iran
| | - Ehsan Nazemalhosseini Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, P. O. Box: 1985717413, Tehran, Iran.
- Department of Surgery, Leiden University Medical Center, P.O. Box 2333 ZA, Leiden, Netherlands.
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Liu Z, Zhang Q, Zhang H, Yi Z, Ma H, Wang X, Wang J, Liu Y, Zheng Y, Fang W, Huang P, Liu X. Colorectal cancer microbiome programs DNA methylation of host cells by affecting methyl donor metabolism. Genome Med 2024; 16:77. [PMID: 38840170 PMCID: PMC11151592 DOI: 10.1186/s13073-024-01344-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 05/09/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) arises from complex interactions between host and environment, which include the gut and tissue microbiome. It is hypothesized that epigenetic regulation by gut microbiota is a fundamental interface by which commensal microbes dynamically influence intestinal biology. The aim of this study is to explore the interplay between gut and tissue microbiota and host DNA methylation in CRC. METHODS Metagenomic sequencing of fecal samples was performed on matched CRC patients (n = 18) and healthy controls (n = 18). Additionally, tissue microbiome was profiled with 16S rRNA gene sequencing on tumor (n = 24) and tumor-adjacent normal (n = 24) tissues of CRC patients, while host DNA methylation was assessed through whole-genome bisulfite sequencing (WGBS) in a subset of 13 individuals. RESULTS Our analysis revealed substantial alterations in the DNA methylome of CRC tissues compared to adjacent normal tissues. An extensive meta-analysis, incorporating publicly available and in-house data, identified significant shifts in microbial-derived methyl donor-related pathways between tumor and adjacent normal tissues. Of note, we observed a pronounced enrichment of microbial-associated CpGs within the promoter regions of genes in adjacent normal tissues, a phenomenon notably absent in tumor tissues. Furthermore, we established consistent and recurring associations between methylation patterns of tumor-related genes and specific bacterial taxa. CONCLUSIONS This study emphasizes the pivotal role of the gut microbiota and pathogenic bacteria in dynamically shaping DNA methylation patterns, impacting physiological homeostasis, and contributing to CRC tumorigenesis. These findings provide valuable insights into the intricate host-environment interactions in CRC development and offer potential avenues for therapeutic interventions in this disease.
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Affiliation(s)
- Zhi Liu
- Department of Pathogen Biology-Microbiology Division, State Key Laboratory of Reproductive Medicine, Key Laboratory of Pathogen of Jiangsu Province, Key Laboratory of Human Functional Genomics of Jiangsu Province, Center of Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Qingqing Zhang
- Department of Pathogen Biology-Microbiology Division, State Key Laboratory of Reproductive Medicine, Key Laboratory of Pathogen of Jiangsu Province, Key Laboratory of Human Functional Genomics of Jiangsu Province, Center of Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Hong Zhang
- Department of Pathogen Biology-Microbiology Division, State Key Laboratory of Reproductive Medicine, Key Laboratory of Pathogen of Jiangsu Province, Key Laboratory of Human Functional Genomics of Jiangsu Province, Center of Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Zhongyuan Yi
- Department of Pathogen Biology-Microbiology Division, State Key Laboratory of Reproductive Medicine, Key Laboratory of Pathogen of Jiangsu Province, Key Laboratory of Human Functional Genomics of Jiangsu Province, Center of Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Huihui Ma
- Department of Pathogen Biology-Microbiology Division, State Key Laboratory of Reproductive Medicine, Key Laboratory of Pathogen of Jiangsu Province, Key Laboratory of Human Functional Genomics of Jiangsu Province, Center of Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Xiaoyi Wang
- Core Facility Center, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, China
| | - Jingjing Wang
- The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215008, China
| | - Yang Liu
- Department of Pathogen Biology-Microbiology Division, State Key Laboratory of Reproductive Medicine, Key Laboratory of Pathogen of Jiangsu Province, Key Laboratory of Human Functional Genomics of Jiangsu Province, Center of Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Yi Zheng
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Weijia Fang
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Ping Huang
- Department of Surgery, The Third Affiliated Hospital, Nanjing Medical University, Nanjing, 211166, China.
| | - Xingyin Liu
- Department of Pathogen Biology-Microbiology Division, State Key Laboratory of Reproductive Medicine, Key Laboratory of Pathogen of Jiangsu Province, Key Laboratory of Human Functional Genomics of Jiangsu Province, Center of Global Health, Nanjing Medical University, Nanjing, 211166, China.
- The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215008, China.
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Lee MK, Azizgolshani N, Zhang Z, Perreard L, Kolling FW, Nguyen LN, Zanazzi GJ, Salas LA, Christensen BC. Associations in cell type-specific hydroxymethylation and transcriptional alterations of pediatric central nervous system tumors. Nat Commun 2024; 15:3635. [PMID: 38688903 PMCID: PMC11061294 DOI: 10.1038/s41467-024-47943-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 04/16/2024] [Indexed: 05/02/2024] Open
Abstract
Although intratumoral heterogeneity has been established in pediatric central nervous system tumors, epigenomic alterations at the cell type level have largely remained unresolved. To identify cell type-specific alterations to cytosine modifications in pediatric central nervous system tumors, we utilize a multi-omic approach that integrated bulk DNA cytosine modification data (methylation and hydroxymethylation) with both bulk and single-cell RNA-sequencing data. We demonstrate a large reduction in the scope of significantly differentially modified cytosines in tumors when accounting for tumor cell type composition. In the progenitor-like cell types of tumors, we identify a preponderance differential Cytosine-phosphate-Guanine site hydroxymethylation rather than methylation. Genes with differential hydroxymethylation, like histone deacetylase 4 and insulin-like growth factor 1 receptor, are associated with cell type-specific changes in gene expression in tumors. Our results highlight the importance of epigenomic alterations in the progenitor-like cell types and its role in cell type-specific transcriptional regulation in pediatric central nervous system tumors.
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Affiliation(s)
- Min Kyung Lee
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
| | - Nasim Azizgolshani
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
- Department of Surgery, Columbia University Medical Center, New York, NY, USA
| | - Ze Zhang
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Laurent Perreard
- Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Fred W Kolling
- Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Lananh N Nguyen
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - George J Zanazzi
- Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
- Department of Pathology and Laboratory Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Lucas A Salas
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Brock C Christensen
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
- Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
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10
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Chang A, Prabhala S, Daneshkhah A, Lin J, Subramanian H, Roy HK, Backman V. Early screening of colorectal cancer using feature engineering with artificial intelligence-enhanced analysis of nanoscale chromatin modifications. Sci Rep 2024; 14:7808. [PMID: 38565871 PMCID: PMC10987630 DOI: 10.1038/s41598-024-58016-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 03/25/2024] [Indexed: 04/04/2024] Open
Abstract
Colonoscopy is accurate but inefficient for colorectal cancer (CRC) prevention due to the low (~ 7 to 8%) prevalence of target lesions, advanced adenomas. We leveraged rectal mucosa to identify patients who harbor CRC field carcinogenesis by evaluating chromatin 3D architecture. Supranucleosomal disordered chromatin chains (~ 5 to 20 nm, ~1 kbp) fold into chromatin packing domains (~ 100 to 200 nm, ~ 100 to 1000 kbp). In turn, the fractal-like conformation of DNA within chromatin domains and the folding of the genome into packing domains has been shown to influence multiple facets of gene transcription, including the transcriptional plasticity of cancer cells. We deployed an optical spectroscopic nanosensing technique, chromatin-sensitive partial wave spectroscopic microscopy (csPWS), to evaluate the packing density scaling D of the chromatin chain conformation within packing domains from rectal mucosa in 256 patients with varying degrees of progression to colorectal cancer. We found average packing scaling D of chromatin domains was elevated in tumor cells, histologically normal-appearing cells 4 cm proximal to the tumor, and histologically normal-appearing rectal mucosa compared to cells from control patients (p < 0.001). Nuclear D had a robust correlation with the model of 5-year risk of CRC with r2 = 0.94. Furthermore, rectal D was evaluated as a screening biomarker for patients with advanced adenomas presenting an AUC of 0.85 and 85% sensitivity and specificity. artificial intelligence-enhanced csPWS improved diagnostic performance with AUC = 0.90. Considering the low sensitivity of existing CRC tests, including liquid biopsies, to early-stage cancers our work highlights the potential of chromatin biomarkers of field carcinogenesis in detecting early, significant precancerous colon lesions.
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Affiliation(s)
- Andrew Chang
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
| | - Sravya Prabhala
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
| | - Ali Daneshkhah
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
| | | | - Hariharan Subramanian
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
- NanoCytomics, Evanston, IL, USA
| | | | - Vadim Backman
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA.
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11
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Spisak S, Chen D, Likasitwatanakul P, Doan P, Li Z, Bala P, Vizkeleti L, Tisza V, De Silva P, Giannakis M, Wolpin B, Qi J, Sethi NS. Identifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system. Nat Commun 2024; 15:2230. [PMID: 38472198 PMCID: PMC10933491 DOI: 10.1038/s41467-024-46285-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 02/21/2024] [Indexed: 03/14/2024] Open
Abstract
Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer (CRC). To identify functional mediators of these key cellular programs, we engineer a dual endogenous reporter system by genome-editing the SOX9 and KRT20 loci of human CRC cell lines to express fluorescent reporters, broadcasting aberrant stem cell-like and differentiation activity, respectively. By applying a CRISPR screen targeting 78 epigenetic regulators with 542 sgRNAs to this platform, we identify factors that contribute to stem cell-like activity and differentiation in CRC. Perturbation single cell RNA sequencing (Perturb-seq) of validated hits nominate SMARCB1 of the BAF complex (also known as SWI/SNF) as a negative regulator of differentiation across an array of neoplastic colon models. SMARCB1 is a dependency and required for in vivo growth of human CRC models. These studies highlight the utility of biologically designed endogenous reporter platforms to uncover regulators with therapeutic potential.
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Affiliation(s)
- Sandor Spisak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary
| | - David Chen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Pornlada Likasitwatanakul
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Paul Doan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Zhixin Li
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Pratyusha Bala
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Laura Vizkeleti
- Department of Bioinformatics, Faculty of Medicine, Semmelweis University, 1094, Budapest, Hungary
| | - Viktoria Tisza
- Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary
| | - Pushpamali De Silva
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Marios Giannakis
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Brian Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jun Qi
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Nilay S Sethi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA.
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA.
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12
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Shim H, Jang K, Bang YH, Chu HBK, Kang J, Lee JY, Cho S, Lee HS, Jeon J, Hwang T, Joe S, Lim J, Choi JH, Joo EH, Park K, Moon JH, Han KY, Hong Y, Lee WY, Kim HC, Yun SH, Cho YB, Park YA, Huh JW, Shin JK, Pyo DH, Hong H, Lee HO, Park WY, Yang JO, Kim YJ. Comprehensive profiling of DNA methylation in Korean patients with colorectal cancer. BMB Rep 2024; 57:110-115. [PMID: 37605617 PMCID: PMC10910091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/27/2023] [Accepted: 08/21/2023] [Indexed: 08/23/2023] Open
Abstract
Alterations in DNA methylation play an important pathophysiological role in the development and progression of colorectal cancer. We comprehensively profiled DNA methylation alterations in 165 Korean patients with colorectal cancer (CRC), and conducted an in-depth investigation of cancer-specific methylation patterns. Our analysis of the tumor samples revealed a significant presence of hypomethylated probes, primarily within the gene body regions; few hypermethylated sites were observed, which were mostly enriched in promoter-like and CpG island regions. The CpG Island Methylator PhenotypeHigh (CIMP-H) exhibited notable enrichment of microsatellite instability-high (MSI-H). Additionally, our findings indicated a significant correlation between methylation of the MLH1 gene and MSI-H status. Furthermore, we found that the CIMP-H had a higher tendency to affect the right-side of the colon tissues and was slightly more prevalent among older patients. Through our methylome profile analysis, we successfully verified the thylation patterns and clinical characteristics of Korean patients with CRC. This valuable dataset lays a strong foundation for exploring novel molecular insights and potential therapeutic targets for the treatment of CRC. [BMB Reports 2024; 57(2): 110-115].
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Affiliation(s)
- Hyeran Shim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Kiwon Jang
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Yeong Hak Bang
- Department of Digital Health, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul 06355, Korea
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Hoang Bao Khanh Chu
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Jisun Kang
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Jin-Young Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Sheehyun Cho
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Hong Seok Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Jongbum Jeon
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Taeyeon Hwang
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Soobok Joe
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Jinyeong Lim
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06355, Korea
| | - Ji-Hye Choi
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06355, Korea
| | - Eun Hye Joo
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06355, Korea
| | - Kyunghee Park
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea, Seoul 04779, Korea
| | - Ji Hwan Moon
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea, Seoul 04779, Korea
| | - Kyung Yeon Han
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea, Seoul 04779, Korea
| | - Yourae Hong
- Department of Oncology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium, Seoul 04779, Korea
| | - Woo Yong Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Hee Cheol Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Seong Hyeon Yun
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Yong Beom Cho
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Yoon Ah Park
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Jung Wook Huh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Jung Kyong Shin
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Dae Hee Pyo
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Hyekyung Hong
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Hae-Ock Lee
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
- Department of Biomedicine and Health Sciences, Graduate School, The Catholic University of Korea, Seoul 06591, Korea
| | - Woong-Yang Park
- Department of Digital Health, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul 06355, Korea
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06355, Korea
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea, Seoul 04779, Korea
| | - Jin Ok Yang
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Young-Joon Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
- LepiDyne Co., Ltd., Seoul 04779, Korea
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13
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Housini M, Dariya B, Ahmed N, Stevens A, Fiadjoe H, Nagaraju GP, Basha R. Colorectal cancer: Genetic alterations, novel biomarkers, current therapeutic strategies and clinical trials. Gene 2024; 892:147857. [PMID: 37783294 DOI: 10.1016/j.gene.2023.147857] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/22/2023] [Accepted: 09/28/2023] [Indexed: 10/04/2023]
Abstract
Colorectal cancer (CRC) is the third most commonly detected cancer with a serious global health issue. The rates for incidence and mortality for CRC are alarming, especially since the prognosis is abysmal when the CRC is diagnosed at an advanced or metastatic stage. Both type of (modifiable/ non-modifiable) types of risk factors are established for CRC. Despite the advances in recent technology and sophisticated research, the survival rate is still meager due to delays in diagnosis. Therefore, there is urgently required to identify critical biomarkers aiming at early diagnosis and improving effective therapeutic strategies. Additionally, a complete understanding of the dysregulated pathways like PI3K/Akt, Notch, and Wnt associated with CRC progression and metastasis is very beneficial in designing a therapeutic regimen. This review article focused on the dysregulated signaling pathways, genetics and epigenetics alterations, and crucial biomarkers of CRC. This review also provided the list of clinical trials targeting signaling cascades and therapies involving small molecules. This review discusses up-to-date information on novel diagnostic and therapeutic strategies alongside specific clinical trials.
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Affiliation(s)
- Mohammad Housini
- Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX 76107, United States
| | - Begum Dariya
- Center for Drug Design, University of Minnesota, Minneapolis, MN 5545, United States
| | - Nadia Ahmed
- Department of Diagnostic Radiology, Baylor College of Medicine, Houston, TX 77030, United States
| | - Alyssa Stevens
- Missouri Southern State University, Joplin, MO 64801, United States
| | - Hope Fiadjoe
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, United States
| | - Ganji Purnachandra Nagaraju
- Division of Hematology & Oncology, The University of Alabama at Birmingham, Birmingham, AL 35233, United States.
| | - Riyaz Basha
- Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX 76107, United States; Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, United States.
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14
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Spisak S, Chen D, Likasitwatanakul P, Doan P, Li Z, Bala P, Vizkeleti L, Tisza V, De Silva P, Giannakis M, Wolpin B, Qi J, Sethi NS. Utilizing a dual endogenous reporter system to identify functional regulators of aberrant stem cell and differentiation activity in colorectal cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.06.21.545895. [PMID: 38293113 PMCID: PMC10827082 DOI: 10.1101/2023.06.21.545895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2024]
Abstract
Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer (CRC). To identify functional mediators that regulate these key cellular programs in CRC, we developed an endogenous reporter system by genome-editing human CRC cell lines with knock-in fluorescent reporters at the SOX9 and KRT20 locus to report aberrant stem cell-like activity and differentiation, respectively, and then performed pooled genetic perturbation screens. Constructing a dual reporter system that simultaneously monitored aberrant stem cell-like and differentiation activity in the same CRC cell line improved our signal to noise discrimination. Using a focused-library CRISPR screen targeting 78 epigenetic regulators with 542 sgRNAs, we identified factors that contribute to stem cell-like activity and differentiation in CRC. Perturbation single cell RNA sequencing (Perturb-seq) of validated hits nominated SMARCB1 of the BAF complex (also known as SWI/SNF) as a negative regulator of differentiation across an array of neoplastic colon models. SMARCB1 is a dependency in CRC and required for in vivo growth of human CRC models. These studies highlight the utility of a biologically designed endogenous reporter system to uncover novel therapeutic targets for drug development.
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Affiliation(s)
- Sandor Spisak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Institute of Enzymology, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary
| | - David Chen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Pornlada Likasitwatanakul
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand
| | - Paul Doan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Zhixin Li
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Pratyusha Bala
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Laura Vizkeleti
- Department of Bioinformatics, Faculty of Medicine, Semmelweis University, 1094 Budapest, Hungary
| | - Viktoria Tisza
- Institute of Enzymology, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary
| | - Pushpamail De Silva
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Marios Giannakis
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Brian Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jun Qi
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Nilay S. Sethi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
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15
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Bagheri R, Ghorbian M, Ghorbian S. Tumor circulating biomarkers in colorectal cancer. Cancer Treat Res Commun 2023; 38:100787. [PMID: 38194840 DOI: 10.1016/j.ctarc.2023.100787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/11/2023] [Accepted: 12/21/2023] [Indexed: 01/11/2024]
Abstract
CRC is a major global health concern and is responsible for a significant number of cancer-related deaths each year. The successful treatment of CRC becomes more difficult when it goes undetected until it has advanced to a later stage. Diagnostic biomarkers can play a critical role in the early detection of CRC, which leads to improved patient outcomes and increased survival rates. It is important to develop reliable biomarkers for the early detection of CRC to enable timely diagnosis and treatment. To date, CRC detection methods such as endoscopy, blood, and stool tests are imperfect and often only identify cases in the later stages of the disease. To overcome these limitations, researchers are turning to molecular biomarkers as a promising avenue for improving CRC detection. Diagnostic information can be provided more reliably through a noninvasive approach using biomarkers such as mRNA, circulating cell-free DNA, micro-RNA, long non-coding RNA, and proteins. These biomarkers can be found in blood, tissue, feces, and volatile organic compounds. The identification of molecular biomarkers with high sensitivity and specificity for early detection of CRC that are safe, cost-effective, and easily measurable remains a significant challenge for researchers. In this article, we will explore the latest advancements in blood-based diagnostic biomarkers for CRC and their potential impact on improving patient survival rates.
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Affiliation(s)
- Raana Bagheri
- Department of Molecular Genetics, Ahar Branch, Islamic Azad University, Ahar, Iran
| | - Mohsen Ghorbian
- Department of Computer Engineering, Qom Branch, Islamic Azad University, Qom, Iran
| | - Saeid Ghorbian
- Department of Molecular Genetics, Ahar Branch, Islamic Azad University, Ahar, Iran.
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16
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Alotaibi N, Alotaibi MO, Alshammari N, Adnan M, Patel M. Network Pharmacology Combined with Molecular Docking, Molecular Dynamics, and In Vitro Experimental Validation Reveals the Therapeutic Potential of Thymus vulgaris L. Essential Oil (Thyme Oil) against Human Breast Cancer. ACS OMEGA 2023; 8:48344-48359. [PMID: 38144096 PMCID: PMC10734022 DOI: 10.1021/acsomega.3c07782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/22/2023] [Accepted: 11/29/2023] [Indexed: 12/26/2023]
Abstract
Breast cancer is a major global health issue for women. Thyme oil, extracted from Thymus vulgaris L., has shown promising anticancer effects. In the present study, we investigated how Thyme oil can influence breast cancer treatment using a multimethod approach. We used network pharmacology to identify the active compounds of Thyme oil, their molecular targets, and the pathways involved in breast cancer. We found that Thyme oil can modulate several key proteins (EGFR, AKT1, ESR1, HSP90AA1, STAT-3, SRC, IL-6, HIF1A, JUN, and BCL2) and pathways (EGFR tyrosine kinase inhibitor resistance, prolactin signaling pathway, HIF-1 signaling pathway, estrogen signaling pathway, ERBB signaling pathway, AGE-RAGE signaling pathway, JAK-STAT signaling pathway, FoxO signaling pathway, and PI3K-AKT signaling pathway) related to breast cancer progression. We then used molecular docking and dynamics to study the interactions and stability of the Thyme oil-compound complexes. We discovered three potent compounds (aromadendrene, α-humulene, and viridiflorene) that can bind strongly to important breast cancer proteins. We also performed in vitro experiments on MCF-7 cells to confirm the cytotoxicity and antiproliferative effects of Thyme oil. We observed that Thyme oil can inhibit cancer cell growth and proliferation at a concentration of 365.37 μg/mL. Overall, our results provide a comprehensive understanding of the pharmacological mechanism of Thyme oil in breast cancer treatment and suggest its potential as a new or adjuvant therapy. Further studies are needed to validate and optimize the therapeutic efficacy of Thyme oil and its active compounds.
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Affiliation(s)
- Nahaa
M. Alotaibi
- Department
of Biology, College of Science, Princess
Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Modhi O. Alotaibi
- Department
of Biology, College of Science, Princess
Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Nawaf Alshammari
- Department
of Biology, College of Science, University
of Ha’il, P.O. Box 2440, Ha’il 55473, Saudi Arabia
| | - Mohd Adnan
- Department
of Biology, College of Science, University
of Ha’il, P.O. Box 2440, Ha’il 55473, Saudi Arabia
| | - Mitesh Patel
- Research
and Development Cell, Department of Biotechnology, Parul Institute
of Applied Sciences, Parul University, Vadodara 391760, India
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17
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Dastafkan Z, Rezvani N, Amini S. Diagnostic value of FOXF1 gene promoter-methylated DNA in the plasma samples of patients with colorectal cancer. Int J Biol Markers 2023; 38:194-202. [PMID: 37847578 DOI: 10.1177/03936155231207109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2023]
Abstract
BACKGROUND Epigenetic modifications such as DNA methylation in the CpG islands of genes occur at a high rate. In this study, we measured the methylation level of the promoter region of the FOXF1 gene as a new blood biomarker for the detection of colorectal cancer in the early stages. METHODS The methylation level of the promoter region of the FOXF1 gene was measured in the plasma samples of 50 colorectal cancer patients and 50 normal individuals. DNA was extracted after exposure to sodium bisulfite by the MethyLight polymerase chain reaction (PCR) method. The percentage of promoter region was measured in all samples, and statistical analysis was done using SPSS v24 software. RESULTS The average promoter region between the plasma samples of colorectal cancer patients and healthy individuals had a significant difference (P < 0.001). The average promoter region of the FOXF1 gene in tumor plasma samples was 7.1 and in the control samples was 0.48. The sensitivity and specificity of the sample plasma levels were 78% and 89.5%, respectively. CONCLUSION The promoter region value of the FOXF1 gene in plasma samples using the MethyLight PCR method had high sensitivity and specificity as a non-invasive method for colorectal cancer diagnosis. This research is the first report that has been presented regarding the investigation of FOXF1 gene methylation in plasma samples in colorectal cancer. Therefore, it is necessary to conduct more studies with larger size samples to evaluate the efficiency of the gene under investigation.
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Affiliation(s)
- Zahra Dastafkan
- Medical Genetics Laboratory, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Nayebali Rezvani
- Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sabrieh Amini
- Department of Biology, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran
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18
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Qian C, Zou X, Li W, Li Y, Yu W. The outpost against cancer: universal cancer only markers. Cancer Biol Med 2023; 20:j.issn.2095-3941.2023.0313. [PMID: 38018033 PMCID: PMC10690883 DOI: 10.20892/j.issn.2095-3941.2023.0313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 10/12/2023] [Indexed: 11/30/2023] Open
Abstract
Cancer is the leading cause of death worldwide. Early detection of cancer can lower the mortality of all types of cancer; however, effective early-detection biomarkers are lacking for most types of cancers. DNA methylation has always been a major target of interest because DNA methylation usually occurs before other detectable genetic changes. While investigating the common features of cancer using a novel guide positioning sequencing for DNA methylation, a series of universal cancer only markers (UCOMs) have emerged as strong candidates for effective and accurate early detection of cancer. While the clinical value of current cancer biomarkers is diminished by low sensitivity and/or low specificity, the unique characteristics of UCOMs ensure clinically meaningful results. Validation of the clinical potential of UCOMs in lung, cervical, endometrial, and urothelial cancers further supports the application of UCOMs in multiple cancer types and various clinical scenarios. In fact, the applications of UCOMs are currently under active investigation with further evaluation in the early detection of cancer, auxiliary diagnosis, treatment efficacy, and recurrence monitoring. The molecular mechanisms by which UCOMs detect cancers are the next important topics to be investigated. The application of UCOMs in real-world scenarios also requires implementation and refinement.
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Affiliation(s)
- Chengchen Qian
- Shanghai Epiprobe Biotechnology Co., Ltd, Shanghai 200233, China
| | - Xiaolong Zou
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Wei Li
- Shanghai Epiprobe Biotechnology Co., Ltd, Shanghai 200233, China
- Shandong Epiprobe Medical Laboratory Co., Ltd, Heze 274108, China
| | - Yinshan Li
- People’s Hospital of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan 750002, China
| | - Wenqiang Yu
- Shanghai Public Health Clinical Center & Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
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19
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Fadul SM, Arshad A, Mehmood R. CRISPR-based epigenome editing: mechanisms and applications. Epigenomics 2023; 15:1137-1155. [PMID: 37990877 DOI: 10.2217/epi-2023-0281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2023] Open
Abstract
Epigenomic anomalies contribute significantly to the development of numerous human disorders. The development of epigenetic research tools is essential for understanding how epigenetic marks contribute to gene expression. A gene-editing technique known as CRISPR (clustered regularly interspaced short palindromic repeats) typically targets a particular DNA sequence using a guide RNA (gRNA). CRISPR/Cas9 technology has been remodeled for epigenome editing by generating a 'dead' Cas9 protein (dCas9) that lacks nuclease activity and juxtaposing it with an epigenetic effector domain. Based on fusion partners of dCas9, a specific epigenetic state can be achieved. CRISPR-based epigenome editing has widespread application in drug screening, cancer treatment and regenerative medicine. This paper discusses the tools developed for CRISPR-based epigenome editing and their applications.
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Affiliation(s)
- Shaima M Fadul
- Department of Life Sciences, College of Science & General Studies, Alfaisal University, Riyadh, 11533, Kingdom of Saudi Arabia
| | - Aleeza Arshad
- Medical Teaching Insitute, Ayub Teaching Hospital, Abbottabad, 22020, Pakistan
| | - Rashid Mehmood
- Department of Life Sciences, College of Science & General Studies, Alfaisal University, Riyadh, 11533, Kingdom of Saudi Arabia
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Chang A, Prabhala S, Daneshkhah A, Lin J, Subramanian H, Roy HK, Backman V. Early screening of colorectal cancer using feature engineering with artificial intelligence-enhanced analysis of nanoscale chromatin modifications. RESEARCH SQUARE 2023:rs.3.rs-3500134. [PMID: 37961494 PMCID: PMC10635400 DOI: 10.21203/rs.3.rs-3500134/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Colonoscopy is accurate but inefficient for colorectal cancer (CRC) prevention due to the low (~ 7-8%) prevalence of target lesions, advanced adenomas. We leveraged rectal mucosa to identify patients who harbor CRC field carcinogenesis by evaluating chromatin 3D architecture. Supranucleosomal disordered chromatin chains (~ 5-20 nm, ~ 1 kbp) fold into chromatin packing domains (~ 100-200 nm, ~ 100-1,000 kbp). In turn, the fractal-like conformation of DNA within chromatin domains and the folding of the genome into packing domains has been shown to influence multiple facets of gene transcription, including the transcriptional plasticity of cancer cells. We deployed an optical spectroscopic nanosensing technique, chromatin-sensitive partial wave spectroscopic microscopy (csPWS), to evaluate the packing density scaling D of the chromatin chain conformation within packing domains from rectal mucosa in 256 patients with varying degrees of progression to colorectal cancer. We found average packing scaling D of chromatin domains was elevated in tumor cells, histologically normal-appearing cells 4 cm proximal to the tumor, and histologically normal-appearing rectal mucosa compared to cells from control patients (p < 0.001). Nuclear D had a robust correlation with the model of 5-year risk of CRC with r2 = 0.94. Furthermore, rectal D was evaluated as a screening biomarker for patients with advanced adenomas presenting an AUC of 0.85 and 85% sensitivity and specificity. Artificial Intelligence (AI)-enhanced csPWS improved diagnostic performance with AUC = 0.90. Considering the low sensitivity of existing CRC tests, including liquid biopsies, to early-stage cancers our work highlights the potential of chromatin biomarkers of field carcinogenesis in detecting early, significant precancerous colon lesions.
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21
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Chang A, Prabhala S, Daneshkhah A, Lin J, Subramanian H, Roy HK, Backman V. Early screening of colorectal cancer using feature engineering with artificial intelligence-enhanced analysis of nanoscale chromatin modifications. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.10.30.23297790. [PMID: 37961299 PMCID: PMC10635240 DOI: 10.1101/2023.10.30.23297790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Colonoscopy is accurate but inefficient for colorectal cancer (CRC) prevention due to the low (~7-8%) prevalence of target lesions, advanced adenomas. We leveraged rectal mucosa to identify patients who harbor CRC field carcinogenesis by evaluating chromatin 3D architecture. Supranucleosomal disordered chromatin chains (~5-20 nm, ~1 kbp) fold into chromatin packing domains (~100-200 nm, ~100-1,000 kbp). In turn, the fractal-like conformation of DNA within chromatin domains and the folding of the genome into packing domains has been shown to influence multiple facets of gene transcription, including the transcriptional plasticity of cancer cells. We deployed an optical spectroscopic nanosensing technique, chromatin-sensitive partial wave spectroscopic microscopy (csPWS), to evaluate the packing density scaling D of the chromatin chain conformation within packing domains from rectal mucosa in 256 patients with varying degrees of progression to colorectal cancer. We found average packing scaling D of chromatin domains was elevated in tumor cells, histologically normal-appearing cells 4 cm proximal to the tumor, and histologically normal-appearing rectal mucosa compared to cells from control patients (p<0.001). Nuclear D had a robust correlation with the model of 5-year risk of CRC with r2=0.94. Furthermore, rectal D was evaluated as a screening biomarker for patients with advanced adenomas presenting an AUC of 0.85 and 85% sensitivity and specificity. Artificial Intelligence (AI)-enhanced csPWS improved diagnostic performance with AUC=0.90. Considering the low sensitivity of existing CRC tests, including liquid biopsies, to early-stage cancers our work highlights the potential of chromatin biomarkers of field carcinogenesis in detecting early, significant precancerous colon lesions.
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Affiliation(s)
- Andrew Chang
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
| | - Sravya Prabhala
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
| | - Ali Daneshkhah
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
| | | | - Hariharan Subramanian
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
- NanoCytomics, Evanston, IL, USA
| | | | - Vadim Backman
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
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22
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Shaygannejad A, Sohrabi B, Rad SR, Yousefisadr F, Darvish H, Soosanabadi M. Promoter methylation of matrix metallopeptidase 9 in peripheral blood mononuclear cells: A novel biomarker in a promising source for noninvasive colorectal cancer diagnosis. J Cancer Res Ther 2023; 19:1797-1802. [PMID: 38376281 DOI: 10.4103/jcrt.jcrt_2188_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 01/03/2022] [Indexed: 11/04/2022]
Abstract
OBJECTIVES Colorectal cancer (CRC) has been described as a "silent disease," which can be readily treated in most patients when discovered in its early stages. Considering the limitations of the current conventional tests for the diagnosis of CRC, researchers strive to find noninvasive and more valid biomarkers for the early detection of CRC. It has been shown that tumor-specific methylation patterns can also be identified in peripheral blood mononuclear cells (PBMCs) and are reliable sources of methylation analysis for CRC screening. MATERIALS AND METHODS We carried out a quantitative methylation analysis on matrix metallopeptidase 9 (MMP9) promoter using methylation quantification endonuclease-resistant DNA (MethyQESD) method. A total of 70 patients with CRC and 70 normal controls were enrolled in this study for methylation analysis in the PBMCs. RESULTS Our findings discovered a considerable hypermethylation of MMP9 promoter in CRC patients compared with healthy controls (mean: 47.30% and 20.31%, respectively; P > 0.001). The sensitivity and specificity of the MMP9 gene for the diagnosis of CRC were 88% and 78%, respectively. In addition, on the basis of area under the curve values, the diagnostic power of the MMP9 gene was 0.976 (P < 0.001). Moreover, our analysis established that MMP9 methylation was significantly different between the different stages of CRC (P: 0.034). CONCLUSIONS Our results showed that MMP9 promoter methylation in PBMCs can be used as an outstanding biomarker for CRC diagnosis. Besides, we confirmed that PBMCs are reliable sources of methylation analysis for CRC screening and MethyQESD is an accurate and fast method for quantitative methylation analyses.
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Affiliation(s)
- Alireza Shaygannejad
- Department of Internal Medicine, Division of Gastrointestinal, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Behnoush Sohrabi
- Department of Biology, Faculty of Sciences, Arak University, Arak, Iran
- Fetal Health Research Center, Hope Generation Foundation, Tehran, Iran
| | - Shima Rahimi Rad
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Farzaneh Yousefisadr
- Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hossein Darvish
- Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mohsen Soosanabadi
- Department of Medical Genetics, Semnan University of Medical Sciences, Semnan, Iran
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23
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Norollahi SE, Vahidi S, Shams S, Keymoradzdeh A, Soleymanpour A, Solymanmanesh N, Mirzajani E, Jamkhaneh VB, Samadani AA. Analytical and therapeutic profiles of DNA methylation alterations in cancer; an overview of changes in chromatin arrangement and alterations in histone surfaces. Horm Mol Biol Clin Investig 2023; 44:337-356. [PMID: 36799246 DOI: 10.1515/hmbci-2022-0043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 01/24/2023] [Indexed: 02/18/2023]
Abstract
DNA methylation is the most important epigenetic element that activates the inhibition of gene transcription and is included in the pathogenesis of all types of malignancies. Remarkably, the effectors of DNA methylation are DNMTs (DNA methyltransferases) that catalyze de novo or keep methylation of hemimethylated DNA after the DNA replication process. DNA methylation structures in cancer are altered, with three procedures by which DNA methylation helps cancer development which are including direct mutagenesis, hypomethylation of the cancer genome, and also focal hypermethylation of the promoters of TSGs (tumor suppressor genes). Conspicuously, DNA methylation, nucleosome remodeling, RNA-mediated targeting, and histone modification balance modulate many biological activities that are essential and indispensable to the genesis of cancer and also can impact many epigenetic changes including DNA methylation and histone modifications as well as adjusting of non-coding miRNAs expression in prevention and treatment of many cancers. Epigenetics points to heritable modifications in gene expression that do not comprise alterations in the DNA sequence. The nucleosome is the basic unit of chromatin, consisting of 147 base pairs (bp) of DNA bound around a histone octamer comprised of one H3/H4 tetramer and two H2A/H2B dimers. DNA methylation is preferentially distributed over nucleosome regions and is less increased over flanking nucleosome-depleted DNA, implying a connection between nucleosome positioning and DNA methylation. In carcinogenesis, aberrations in the epigenome may also include in the progression of drug resistance. In this report, we report the rudimentary notes behind these epigenetic signaling pathways and emphasize the proofs recommending that their misregulation can conclude in cancer. These findings in conjunction with the promising preclinical and clinical consequences observed with epigenetic drugs against chromatin regulators, confirm the important role of epigenetics in cancer therapy.
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Affiliation(s)
- Seyedeh Elham Norollahi
- Cancer Research Center and Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Sogand Vahidi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shima Shams
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Arman Keymoradzdeh
- Department of Neurosurgery, School of Medicine, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Armin Soleymanpour
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Nazanin Solymanmanesh
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Ebrahim Mirzajani
- Department of Biochemistry and Biophysics, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Vida Baloui Jamkhaneh
- Department of Veterinary Medicine, Islamic Azad University of Babol Branch, Babol, Iran
| | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Guilan University of Medical Sciences, Rasht, Iran
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24
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Soltan MA, Alhanshani AA, Shati AA, Alqahtani YA, Alshaya DS, Alharthi J, Altalhi SA, Fayad E, Zaki MSA, Eid RA. Cyclin Dependent Kinase Inhibitor 2A Genetic and Epigenetic Alterations Interfere with Several Immune Components and Predict Poor Clinical Outcome. Biomedicines 2023; 11:2254. [PMID: 37626750 PMCID: PMC10452213 DOI: 10.3390/biomedicines11082254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/27/2023] Open
Abstract
Cyclin dependent kinase inhibitor 2A (CDKN2A) is a well-known tumor suppressor gene as it functions as a cell cycle regulator. While several reports correlate the malfunction of CDKN2A with the initiation and progression of several types of human tumors, there is a lack of a comprehensive study that analyzes the potential effect of CDKN2A genetic alterations on the human immune components and the consequences of that effect on tumor progression and patient survival in a pan-cancer model. The first stage of the current study was the analysis of CDKN2A differential expression in tumor tissues and the corresponding normal ones and correlating that with tumor stage, grade, metastasis, and clinical outcome. Next, a detailed profile of CDKN2A genetic alteration under tumor conditions was described and assessed for its effect on the status of different human immune components. CDKN2A was found to be upregulated in cancerous tissues versus normal ones and that predicted the progression of tumor stage, grade, and metastasis in addition to poor prognosis under different forms of tumors. Additionally, CDKN2A experienced different forms of genetic alteration under tumor conditions, a characteristic that influenced the infiltration and the status of CD8, the chemokine CCL4, and the chemokine receptor CCR6. Collectively, the current study demonstrates the potential employment of CDKN2A genetic alteration as a prognostic and immunological biomarker under several types of human cancers.
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Affiliation(s)
- Mohamed A. Soltan
- Department of Microbiology and Immunology, Faculty of Pharmacy, Sinai University, Ismailia 41611, Egypt
| | - Ahmad A. Alhanshani
- Department of Child Health, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia
| | - Ayed A. Shati
- Department of Child Health, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia
| | - Youssef A. Alqahtani
- Department of Child Health, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia
| | - Dalal Sulaiman Alshaya
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Jawaher Alharthi
- Department of Biotechnology, College of Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Sarah Awwadh Altalhi
- Department of Biotechnology, College of Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Eman Fayad
- Department of Biotechnology, College of Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Mohamed Samir A. Zaki
- Anatomy Department, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia
| | - Refaat A. Eid
- Pathology Department, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia
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25
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Giannopoulou N, Constantinou C. Recent Developments in Diagnostic and Prognostic Biomarkers for Colorectal Cancer: A Narrative Review. Oncology 2023; 101:675-684. [PMID: 37364542 DOI: 10.1159/000531474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 06/02/2023] [Indexed: 06/28/2023]
Abstract
BACKGROUND Colorectal cancer was reported as the second most common cause of cancer death worldwide, in the year 2020. This disease is an important public health problem considering its high incidence and mortality rates. SUMMARY The molecular events that lead to colorectal cancer include genetic and epigenetic abnormalities. Some of the most important molecular mechanisms involved include the APC/β-catenin pathway, the microsatellite pathway, and the CpG island hypermethylation. Evidence in the literature supports a role for the microbiota in the development of colon carcinogenesis, and specific microbes may contribute to or prevent carcinogenesis. Progress in prevention, screening, and management has improved the overall prognosis of the disease when diagnosed at an early stage; yet metastatic disease continues to have a poor long-term prognosis due to late-stage diagnosis and treatment failure. Biomarkers are a key tool for early detection and prognosis and aim to reduce morbidity and mortality associated with colorectal cancer. The main focus of this narrative review is to provide an update on the recent development of diagnostic and prognostic biomarkers in stool, blood, and tumor tissue samples. KEY MESSAGES The review focuses on recent investigations in microRNAs, cadherins, Piwi-interacting RNAs, circulating cell-free DNA, and microbiome biomarkers which can be applied for the diagnosis and prognosis of colorectal cancer.
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Affiliation(s)
- Nefeli Giannopoulou
- Department of Basic and Clinical Sciences, University of Nicosia Medical School, Nicosia, Cyprus
| | - Constantina Constantinou
- Department of Basic and Clinical Sciences, University of Nicosia Medical School, Nicosia, Cyprus
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26
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Abkenar BR, Mohammadi A, Amoli HA, Soleimani AA, Korani M, Mahmoodi H, Najafi M. Non-coding RNAs are correlated to TGF-β receptor type 2 in patients with colorectal cancer. J Gene Med 2023; 25:e3472. [PMID: 36579810 DOI: 10.1002/jgm.3472] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 11/14/2022] [Accepted: 12/21/2022] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Multiple molecular expression alterations, particularly in non-coding RNAs, play fundamental roles in the regulations of cellular processes and may relate to the occurrence and progression of colorectal cancer (CRC). In the present study, we investigated the associations between TGFBR2, miR20a-5p and long non-coding RNA (lncRNA) LAMTOR5-AS1 in CRC patients. METHODS Colorectal cancer and adjacent normal tissue samples (n = 34) were prepared from CRC patients. The associations between TGFBR2, miR20a-5p and lncRNA LAMTOR5-AS1 were predicted using bioinformatics tools. The expression levels of TGFBR2, miR20a-5p and lncRNA LAMTOR5-AS1 were measured using a quantitative real-time polymerase chain reaction technique. The TGFBR2 protein values were measured by western blotting. The clinical importance of lncRNA LAMTOR5-AS1 was assessed using receiver operating characteristic curve. RESULTS The up-regulated levels of TGFBR2 (p = 0.02), TGFBR2 protein (p = 0.008) and lncRNA LAMTOR5-AS1 (p = 0.02) were significantly observed in CRC tissues compared to the adjacent normal tissues. The miR20a-5p expression level (p = 0.009) was downregulated in CRC tissues. In addition, the miR20a-5p expression level was inversely correlated to the TGFBR2 gene (r2 = 0.88, p < 0.0001), protein (r2 = 0.95, p < 0.0001) and lncRNA LAMTOR5-AS1 gene (r2 = 0.93, p < 0.0001) expression levels. Based on the area under curve, the increase of lncRNA LAMTOR5-AS1 expression level with a sensitivity of 64.52% and specificity of 65.52% was considered in CRC patients. CONCLUSIONS We propose that miR20a-5p is inversely related to long non-coding RNA (lncRNA) LAMTOR5-AS, such that it may be involved in the regulation of TGFBR2 expression level in CRC patients.
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Affiliation(s)
| | - Asghar Mohammadi
- Shohada Hospital of Tarom, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Hadi Ahmadi Amoli
- Sina Trauma and Surgery Research Center, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mohsen Korani
- Department of Biochemistry, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Hassan Mahmoodi
- Biochemistry Department, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Najafi
- Biochemistry Department, Iran University of Medical Sciences, Tehran, Iran.,Microbial Biotechnology Research Center, Biochemistry Department, Iran University of Medical Sciences, Tehran, Iran
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27
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Lee MK, Azizgolshani N, Zhang Z, Perreard L, Kolling FW, Nguyen LN, Zanazzi GJ, Salas LA, Christensen BC. Hydroxymethylation alterations in progenitor-like cell types of pediatric central nervous system tumors are associated with cell type-specific transcriptional changes. RESEARCH SQUARE 2023:rs.3.rs-2517758. [PMID: 36909536 PMCID: PMC10002842 DOI: 10.21203/rs.3.rs-2517758/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
Abstract
Although intratumoral heterogeneity has been established in pediatric central nervous system tumors, epigenomic alterations at the cell type level have largely remained unresolved. To identify cell type-specific alterations to cytosine modifications in pediatric central nervous system tumors we utilized a multi-omic approach that integrated bulk DNA cytosine modification data (methylation and hydroxymethylation) with both bulk and single-cell RNA-sequencing data. We demonstrate a large reduction in the scope of significantly differentially modified cytosines in tumors when accounting for tumor cell type composition. In the progenitor-like cell types of tumors, we identified a preponderance differential CpG hydroxymethylation rather than methylation. Genes with differential hydroxymethylation, like HDAC4 and IGF1R, were associated with cell type-specific changes in gene expression in tumors. Our results highlight the importance of epigenomic alterations in the progenitor-like cell types and its role in cell type-specific transcriptional regulation in pediatric CNS tumors.
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Affiliation(s)
- Min Kyung Lee
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Nasim Azizgolshani
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
- Department of Cardiothoracic Surgery, Columbia University Medical Center, New York, NY, USA
| | - Ze Zhang
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Laurent Perreard
- Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Fred W Kolling
- Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Lananh N Nguyen
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - George J Zanazzi
- Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
- Department of Pathology and Laboratory Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Lucas A Salas
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Brock C Christensen
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
- Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
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28
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Zhao S, Zhang D, Liu S, Huang J. The roles of NOP56 in cancer and SCA36. Pathol Oncol Res 2023; 29:1610884. [PMID: 36741964 PMCID: PMC9892063 DOI: 10.3389/pore.2023.1610884] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 01/06/2023] [Indexed: 01/20/2023]
Abstract
NOP56 is a highly conserved nucleolar protein. Amplification of the intron GGCCTG hexanucleotide repeat sequence of the NOP56 gene results in spinal cerebellar ataxia type 36 (SCA36). NOP56 contains an N-terminal domain, a coiled-coil domain, and a C-terminal domain. Nucleolar protein NOP56 is significantly abnormally expressed in a number of malignant tumors, and its mechanism is different in different tumors, but its regulatory mechanism in most tumors has not been fully explored. NOP56 promotes tumorigenesis in some cancers and inhibits tumorigenesis in others. In addition, NOP56 is associated with methylation in some tumors, suggesting that NOP56 has the potential to become a tumor-specific marker. This review focuses on the structure, function, related signaling pathways, and role of NOP56 in the progression of various malignancies, and discusses the progression of NOP56 in neurodegenerative and other diseases.
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Affiliation(s)
- Shimin Zhao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China,Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Dongdong Zhang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China,Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Sicheng Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China,Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jun Huang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China,*Correspondence: Jun Huang,
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Smok-Kalwat J, Mertowska P, Mertowski S, Smolak K, Kozińska A, Koszałka F, Kwaśniewski W, Grywalska E, Góźdź S. The Importance of the Immune System and Molecular Cell Signaling Pathways in the Pathogenesis and Progression of Lung Cancer. Int J Mol Sci 2023; 24:1506. [PMID: 36675020 PMCID: PMC9861992 DOI: 10.3390/ijms24021506] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/04/2023] [Accepted: 01/08/2023] [Indexed: 01/13/2023] Open
Abstract
Lung cancer is a disease that in recent years has become one of the greatest threats to modern society. Every year there are more and more new cases and the percentage of deaths caused by this type of cancer increases. Despite many studies, scientists are still looking for answers regarding the mechanisms of lung cancer development and progression, with particular emphasis on the role of the immune system. The aim of this literature review was to present the importance of disorders of the immune system and the accompanying changes at the level of cell signaling in the pathogenesis of lung cancer. The collected results showed that in the process of immunopathogenesis of almost all subtypes of lung cancer, changes in the tumor microenvironment, deregulation of immune checkpoints and abnormalities in cell signaling pathways are involved, which contribute to the multistage and multifaceted carcinogenesis of this type of cancer. We, therefore, suggest that in future studies, researchers should focus on a detailed analysis of tumor microenvironmental immune checkpoints, and to validate their validity, perform genetic polymorphism analyses in a wide range of patients and healthy individuals to determine the genetic susceptibility to lung cancer development. In addition, further research related to the analysis of the tumor microenvironment; immune system disorders, with a particular emphasis on immunological checkpoints and genetic differences may contribute to the development of new personalized therapies that improve the prognosis of patients.
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Affiliation(s)
- Jolanta Smok-Kalwat
- Department of Clinical Oncology, Holy Cross Cancer Centre, 3 Artwinskiego Street, 25-734 Kielce, Poland
| | - Paulina Mertowska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland
| | - Sebastian Mertowski
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland
| | - Konrad Smolak
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland
| | - Aleksandra Kozińska
- Student Research Group of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland
| | - Filip Koszałka
- Student Research Group of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland
| | - Wojciech Kwaśniewski
- Department of Gynecologic Oncology and Gynecology, Medical University of Lublin, 20-081 Lublin, Poland
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland
| | - Stanisław Góźdź
- Department of Clinical Oncology, Holy Cross Cancer Centre, 3 Artwinskiego Street, 25-734 Kielce, Poland
- Institute of Medical Science, Collegium Medicum, Jan Kochanowski University of Kielce, IX Wieków Kielc 19A, 25-317 Kielce, Poland
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30
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Mishra S, Raval M, Kachhawaha AS, Tiwari BS, Tiwari AK. Aging: Epigenetic modifications. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 197:171-209. [PMID: 37019592 DOI: 10.1016/bs.pmbts.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/15/2023]
Abstract
Aging is one of the most complex and irreversible health conditions characterized by continuous decline in physical/mental activities that eventually poses an increased risk of several diseases and ultimately death. These conditions cannot be ignored by anyone but there are evidences that suggest that exercise, healthy diet and good routines may delay the Aging process significantly. Several studies have demonstrated that Epigenetics plays a key role in Aging and Aging-associated diseases through methylation of DNA, histone modification and non-coding RNA (ncRNA). Comprehension and relevant alterations in these epigenetic modifications can lead to new therapeutic avenues of age-delaying contrivances. These processes affect gene transcription, DNA replication and DNA repair, comprehending epigenetics as a key factor in understanding Aging and developing new avenues for delaying Aging, clinical advancements in ameliorating aging-related diseases and rejuvenating health. In the present article, we have described and advocated the epigenetic role in Aging and associated diseases.
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Maksimova VP, Usalka OG, Makus YV, Popova VG, Trapeznikova ES, Khayrieva GI, Sagitova GR, Zhidkova EM, Prus AY, Yakubovskaya MG, Kirsanov KI. Aberrations of DNA methylation in cancer. ADVANCES IN MOLECULAR ONCOLOGY 2022. [DOI: 10.17650/2313-805x-2022-9-4-24-40] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
DNA methylation is a chromatin modification that plays an important role in the epigenetic regulation of gene expression. Changes in DNA methylation patterns are characteristic of many malignant neoplasms. DNA methylation is occurred by DNA methyltransferases (DNMTs), while demethylation is mediated by TET family proteins. Mutations and changes in the expression profile of these enzymes lead to DNA hypo- and hypermethylation and have a strong impact on carcinogenesis. In this review, we considered the key aspects of the mechanisms of regulation of DNA methylation and demethylation, and also analyzed the role of DNA methyltransferases and TET family proteins in the pathogenesis of various malignant neoplasms.During the preparation of the review, we used the following biomedical literature information bases: Scopus (504), PubMed (553), Web of Science (1568), eLibrary (190). To obtain full-text documents, the electronic resources of PubMed Central (PMC), Science Direct, Research Gate, CyberLeninka were used. To analyze the mutational profile of epigenetic regulatory enzymes, we used the cBioportal portal (https://www.cbioportal.org / ), data from The AACR Project GENIE Consortium (https://www.mycancergenome.org / ), COSMIC, Clinvar, and The Cancer Genome Atlas (TCGA).
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Affiliation(s)
- V. P. Maksimova
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - O. G. Usalka
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; Sechenov First Moscow State Medical University, Ministry of Health of Russia
| | - Yu. V. Makus
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; Peoples’ Friendship University of Russia
| | - V. G. Popova
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; Mendeleev University of Chemical Technology of Russia
| | - E. S. Trapeznikova
- Sechenov First Moscow State Medical University, Ministry of Health of Russia
| | - G. I. Khayrieva
- Sechenov First Moscow State Medical University, Ministry of Health of Russia
| | - G. R. Sagitova
- Sechenov First Moscow State Medical University, Ministry of Health of Russia
| | - E. M. Zhidkova
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - A. Yu. Prus
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; MIREA – Russian Technological University
| | - M. G. Yakubovskaya
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - K. I. Kirsanov
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; Peoples’ Friendship University of Russia
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Essa HYS, Kusaf G, Yuruker O, Kalkan R. Epigenetic Alteration in Colorectal Cancer: A Biomarker for Diagnostic and Therapeutic Application. Glob Med Genet 2022; 9:258-262. [PMID: 36188672 PMCID: PMC9522482 DOI: 10.1055/s-0042-1757404] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
Colorectal cancer (CRC) is the leading cause of cancer death worldwide. A crucial process that initiates and progresses CRC is various epigenetic and genetic changes occurring in colon epithelial cells. Recently, huge progress has been made to understand cancer epigenetics, especially regarding DNA methylation changes, histone modifications, dysregulation of miRNAs and noncoding RNAs. In the "epigenome" of colon cancer, abnormal methylation of genes that cause gene alterations or expression of miRNA has been reported in nearly all CRC; these findings can be encountered in the average CRC methylome. Epigenetic changes, known as driving events, are assumed to play a dominant part in CRC. Furthermore, as epigenetic changes in CRC become properly understood, these changes are being established as clinical biomarkers for therapeutic and diagnostic purposes. Progression in this area indicates that epigenetic changes will often be utilized in the future to prevent and treat CRC.
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Affiliation(s)
| | - Gunay Kusaf
- Department of Medical Genetics, Faculty of Medicine, Near East University, Nicosia, Cyprus
| | - Ozel Yuruker
- Department of Medical Biology, Faculty of Medicine, Kyrenia University, Kyrenia, Cyprus
| | - Rasime Kalkan
- Department of Medical Genetics, Faculty of Medicine, Cyprus Health and Social Sciences University, Guzelyurt, Cyprus
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Double-stranded RNA induction asa potential dynamic biomarkerfor DNA-demethylating agents. MOLECULAR THERAPY - NUCLEIC ACIDS 2022; 29:370-383. [PMID: 36035755 PMCID: PMC9385881 DOI: 10.1016/j.omtn.2022.07.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 07/15/2022] [Indexed: 11/22/2022]
Abstract
Hypomethylating agents (HMAs), such as azacitidine and decitabine, induce cancer cell death by demethylating DNAs to promote the expression of tumor-suppressor genes. HMAs also reactivate the transcription of endogenous double-stranded RNAs (dsRNAs) that trigger the innate immune response and subsequent apoptosis via viral mimicry. However, the expression patterns of endogenous dsRNAs and their relevance in the efficacy of HMAs remain largely uninvestigated. Here, we employ amidine-conjugated spiropyran (Am-SP) to examine the dynamic expression pattern of total dsRNAs regulated by HMAs. By analyzing the bone-marrow aspirates of myelodysplastic syndrome or acute myeloid leukemia patients who received the HMAs, we find a dramatic increase in total dsRNA levels upon treatment only in patients who later benefited from the therapy. We further apply our approach in solid tumor cell lines and show that the degree of dsRNA induction correlates with the effectiveness of decitabine in most cases. Notably, when dsRNA induction is accompanied by increased expression of nc886 RNA, decitabine becomes ineffective. Collectively, our study establishes the potential application of monitoring the total dsRNA levels by a small molecule as an analytical method and a dynamic marker to predict the clinical outcome of the HMA therapy.
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Li J, Li P, Li J, Yang H, Liu G, Shen P, Jiang G. Effects of the Methylation Levels for the Breast Cancer Associated Genes BCSG1 and BRCA1 on Cellular Proliferation and Migration. Genet Test Mol Biomarkers 2022; 26:422-429. [PMID: 36166741 DOI: 10.1089/gtmb.2021.0304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Objective: The aim of this study was to determine whether the methylation patterns of the breast cancer-specific gene 1 (BCSG1) and the breast cancer susceptibility gene 1 (BRCA1) can be used as biomarkers for predicting the occurrence and development of breast cancer. Methods: Methylation-specific polymerase chain reaction (PCR) was used to detect the methylation status of the BCSG1 and BRCA1 genes in ductal infiltrating carcinomas of the breast; carcinoma in situ of the breast; fibroadenoma of the breast and adjacent normal tissues. Quantitative real-time PCR and immunohistochemistry were used to detect the expression levels of BCSG1 and BRCA1. The BCSG1 and BRCA1 genes were knocked down by siRNA to study their effect of BCSG1 and BRCA1 on the behaviour of breast cancer cell lines. Results: The BCSG1 gene was hypomethylated in breast cancer tissues, and its mRNA as well as its protein levels showed elevated expression compared to normal adjacent tissues. In contrast, the BRCA1 gene was hypermethylated in breast cancer tissues and showed correspondingly decreased mRNA and protein expression levels. In vitro experiments demonstrated that BCSG1 could promote the proliferation and migration of breast cancer cells. After inhibiting the methylation, the expression of both the BCSG1 and BRCA1 genes were increased. Conclusion: Abnormal methylation patterns of the BCSG1 and BRCA1 genes are associated with the development of breast cancer. Thus, methylatedion analyses of these genes have biomarker potential for breast cancer prognoses.
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Affiliation(s)
- Junkuo Li
- Department of Pathology, Anyang Tumor Hospital, Anyang, China
| | - Pan Li
- Department of Pathology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jia Li
- Department of Pathology, Anyang Tumor Hospital, Anyang, China
| | - Haijun Yang
- Department of Pathology, Anyang Tumor Hospital, Anyang, China
| | - Guohua Liu
- Department of Pathology, Anyang Tumor Hospital, Anyang, China
| | - Peihong Shen
- Department of Pathology, Zhengzhou University Affiliated Tumor Hospital, Zhengzhou, China
| | - Guozhong Jiang
- Department of Pathology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Amirsasan R, Akbarzadeh M, Akbarzadeh S. Exercise and colorectal cancer: prevention and molecular mechanisms. Cancer Cell Int 2022; 22:247. [PMID: 35945569 PMCID: PMC9361674 DOI: 10.1186/s12935-022-02670-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 08/02/2022] [Indexed: 12/16/2022] Open
Abstract
Exercise and physical activity have been shown to be strongly associated with a decreased incidence rate of various chronic diseases especially numerous human malignancies. A huge number of clinical trials and meta-analysis have demonstrated that exercise is significantly effective in lowering the risk of colorectal cancer. In addition, it is suggested as an effective therapeutic modality against this cancer type. Therefore, in this review, we will review comprehensibly the effects of exercise in preventing, treating, and alleviating the adverse effects of conventional therapeutic options in colorectal cancer. Moreover, the possible mechanisms underlying the positive effects of exercise and physical activity in colorectal cancer, including regulation of inflammation, apoptosis, growth factor axis, immunity, epigenetic, etc. will be also discussed.
Exercise is an effective post-treatment management program in colorectal cancer survivals Exercise improves muscle strength, cardiorespiratory fitness, emotional distress, physical activity, fatigue, and sleep quality in colorectal patients undergoing chemotherapy Targeting and modulating insulin-like growth factor (IGF) system, inflammation, apoptosis, immunity, epigenetic, Leptin and Ghrelin, and signaling pathways are major underlying mechanisms for preventive effects of exercise in colorectal cancer
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Affiliation(s)
- Ramin Amirsasan
- Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, University of Tabriz, Tabriz, Iran
| | - Maryam Akbarzadeh
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Shabnam Akbarzadeh
- Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, University of Tabriz, Tabriz, Iran.
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Epigenetic insights in the diagnosis, prognosis, and treatment selection in CRC, an updated review. Mol Biol Rep 2022; 49:10013-10022. [PMID: 35727475 DOI: 10.1007/s11033-022-07569-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 05/05/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIM The gradual accumulation of genetic and epigenetic alterations can lead to the development of colorectal cancer. In the last decade much research has been done to discover how methylation as an epigenetic alteration leads to carcinogenesis. While Methylation is a biological process, it can influence gene expression by affecting the promoter activity. This article reviews the role of methylation in critical pathways in CRC. METHODS In this study using appropriate keywords, all research and review articles related to the role of methylation on different cancers were collected and analyzed. Also, existing information on methylation detection methods and therapeutic sensitivity or resistance due to DNA methylation were reviewed. RESULTS The results of this survey revealed that while Methylation is a biological process, it can influence gene expression by affecting the promoter activity. Promoter methylation is associated with up or downregulation of genes involved in critical pathways, including cell cycle, DNA repair, and cell adherence. Hence promoter methylation can be used as a molecular tool for early diagnosis, improving treatment, and predicting treatment resistance. CONCLUSION Current knowledge on potential methylation biomarkers for diagnosis and prognoses of CRC has also been discussed. Our survey proposes that a multi-biomarker panel is more efficient than a single biomarker in the early diagnosis of CRC.
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Houschyar KS, Borrelli MR, Rein S, Tapking C, Popp D, Palackic A, Puladi B, Ooms M, Houschyar M, Branski LK, Schmitt L, Modabber A, Rübben A, Hölzle F, Yazdi AS. Head and neck squamous cell carcinoma: a potential therapeutic target for the Wnt signaling pathway. EUROPEAN JOURNAL OF PLASTIC SURGERY 2022. [DOI: 10.1007/s00238-022-01958-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Abstract
Squamous cell carcinoma (SCC) of the head and neck region accounts for 3% of all tumors worldwide. The incidence is higher in men, with most carcinomas found in the oral cavity. At the point of initial diagnosis, distant metastases are rare. The Wnt signaling pathway is critically involved in cell development and stemness and has been associated with SCC. Understanding precisely how Wnt signaling regulates SCC progression and how it can, therefore, be modulated for the therapeutic benefit has enormous potential in the treatment of head and neck SCC. In this review, we will describe the underlying mechanisms of Wnt signaling and outline how Wnt signaling controls cellular processes both in homeostasis and in the development and progression of SCC.Level of evidence: Not gradable.
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Obesity-Associated Differentially Methylated Regions in Colon Cancer. J Pers Med 2022; 12:jpm12050660. [PMID: 35629083 PMCID: PMC9142939 DOI: 10.3390/jpm12050660] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/11/2022] [Accepted: 04/18/2022] [Indexed: 02/01/2023] Open
Abstract
Obesity with adiposity is a common disorder in modern days, influenced by environmental factors such as eating and lifestyle habits and affecting the epigenetics of adipose-based gene regulations and metabolic pathways in colorectal cancer (CRC). We compared epigenetic changes of differentially methylated regions (DMR) of genes in colon tissues of 225 colon cancer cases (154 non-obese and 71 obese) and 15 healthy non-obese controls by accessing The Cancer Genome Atlas (TCGA) data. We applied machine-learning-based analytics including generalized regression (GR) as a confirmatory validation model to identify the factors that could contribute to DMRs impacting colon cancer to enhance prediction accuracy. We found that age was a significant predictor in obese cancer patients, both alone (p = 0.003) and interacting with hypomethylated DMRs of ZBTB46, a tumor suppressor gene (p = 0.008). DMRs of three additional genes: HIST1H3I (p = 0.001), an oncogene with a hypomethylated DMR in the promoter region; SRGAP2C (p = 0.006), a tumor suppressor gene with a hypermethylated DMR in the promoter region; and NFATC4 (p = 0.006), an adipocyte differentiating oncogene with a hypermethylated DMR in an intron region, are also significant predictors of cancer in obese patients, independent of age. The genes affected by these DMR could be potential novel biomarkers of colon cancer in obese patients for cancer prevention and progression.
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Joshi S, Garlapati C, Aneja R. Epigenetic Determinants of Racial Disparity in Breast Cancer: Looking beyond Genetic Alterations. Cancers (Basel) 2022; 14:cancers14081903. [PMID: 35454810 PMCID: PMC9025441 DOI: 10.3390/cancers14081903] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 04/03/2022] [Accepted: 04/04/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary A substantial disparity in breast cancer incidence and mortality exists between African American (AA) and European American (EA) women. However, the basis for these disparities is poorly understood. In this article, we describe that gene–environment interactions mediated through epigenetic modifications may play a significant role in racial disparities in BC incidence and outcomes. Our in silico analyses and an in-depth literature survey suggest that there exists a significant difference in epigenetic patterns between AA and EA women with breast cancer. Herein, we describe the environmental factors that contribute to these epigenetic changes, which may underlie the disparate racial burden in patients with breast cancer. We suggest that AA women with higher basal epigenetic changes, may have higher pre-disposition to cancer onset, and an aggressive disease course. Pre-existing racial differences in epigenetic profiles of breast tissues raises the possibility of examining these profiles for early diagnosis. Abstract Breast cancer (BC) is the most commonly diagnosed cancer in women. Despite advancements in BC screening, prevention, and treatment, BC incidence and mortality remain high among African American (AA) women. Compared with European American (EA) women, AA women tend to be diagnosed with more advanced and aggressive tumors and exhibit worse survival outcomes. Most studies investigating the determinants of racial disparities in BC have focused on genetic factors associated with African ancestry. However, various environmental and social stressors over an individual’s life course can also shape racial stratification in BC. These social and environmental exposures result in long-term changes in gene expression mediated by epigenetic mechanisms. Epigenetics is often portrayed as an intersection of socially patterned stress and genetic expression. The enduring nature of epigenetic changes makes them suitable for studying the effects of different environmental exposures over an individual’s life course on gene expression. The role of differential social and environmental exposures in racial disparities in BC suggests varied epigenetic profiles or signatures associated with specific BC subtypes in AA and EA women. These epigenetic profiles in EA and AA women could be used as biomarkers for early BC diagnosis and disease prognosis and may prove valuable for the development of targeted therapies for BC. This review article discusses the current state of knowledge regarding epigenetic differences between AA and EA women with BC. We also discuss the role of socio-environmental factors, including psychosocial stress, environmental toxicants, and dietary factors, in delineating the different epigenetic profiles in AA and EA patients with BC.
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Affiliation(s)
- Shriya Joshi
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA; (S.J.); (C.G.)
| | | | - Ritu Aneja
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA; (S.J.); (C.G.)
- Department of Clinical and Diagnostics Sciences, School of Health Professions, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Correspondence: or
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Xing W, Zhou PC, Zhang HY, Chen LM, Zhou YM, Cui XF, Liu ZG. Circular RNA circ_GLIS2 suppresses hepatocellular carcinoma growth and metastasis. Liver Int 2022; 42:682-695. [PMID: 34743403 DOI: 10.1111/liv.15097] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/12/2021] [Accepted: 11/02/2021] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is one of the leading causes of tumour-related death. Here, we investigated the molecular mechanism of HCC by studying the function of circ_GLIS2. METHODS Human HCC specimens and cell lines were used. Sanger sequencing, actinomycin D and RNase R treatment were performed to validate circular RNA features of circ_GLIS2. qRT-PCR, western blotting, immunostaining, and IHC were employed to examine levels of circ_GLIS2, GLIS2 mRNA, and EMT-related markers. CCK-8, colony formation, flow cytometry, wound healing assay, and transwell assays were performed to evaluate cancer cell proliferation, apoptosis, migration, and invasion. RIP and RNA pull-down assay were used to validate EIF4A3/GLIS2 mRNA interaction. MSP was performed to measure the methylation status of GLIS2 promoter. Nude mouse xenograft model was used to examine tumour growth and metastasis in vivo. RESULTS Circ_GLIS2 and linear GLIS2 mRNA were reduced in human HCC tissues and cells. Their low levels correlated with a poor survival rate of HCC patients. Overexpression of circ_GLIS2 and GLIS2 suppressed HCC cell proliferation, migration, and invasion but promoted cell apoptosis. GLIS2 promoter region was hypermethylated in HCC cells. EIF4A3 was directly bound with GLIS2 mRNA and promoted circ_GLIS2/GLIS2 expression. Moreover, overexpression of circ_GLIS2 restrained HCC tumour growth and metastasis in vivo. CONCLUSION Circ_GLIS2 suppresses HCC growth and metastasis by inhibiting cell proliferation, migration, and invasion, but promoting cell apoptosis. These findings provide molecular insights into the mechanism of HCC and indicate that circ_GLIS2 could serve as a diagnosis marker or therapeutic target for HCC.
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Affiliation(s)
- Wu Xing
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
| | - Peng-Cheng Zhou
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China
| | - Hao-Ye Zhang
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Li-Min Chen
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yang-Mei Zhou
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xue-Fei Cui
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
| | - Zhen-Guo Liu
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China
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Hypermethylation of PDX1, EN2, and MSX1 predicts the prognosis of colorectal cancer. Exp Mol Med 2022; 54:156-168. [PMID: 35169223 PMCID: PMC8894425 DOI: 10.1038/s12276-022-00731-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 11/12/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023] Open
Abstract
Despite numerous observations regarding the relationship between DNA methylation changes and cancer progression, only a few genes have been verified as diagnostic biomarkers of colorectal cancer (CRC). To more practically detect methylation changes, we performed targeted bisulfite sequencing. Through co-analysis of RNA-seq, we identified cohort-specific DNA methylation markers: CpG islands of the intragenic regions of PDX1, EN2, and MSX1. We validated that these genes have oncogenic features in CRC and that their expression levels are increased in correlation with the hypermethylation of intragenic regions. The reliable depth of the targeted bisulfite sequencing data enabled us to design highly optimized quantitative methylation-specific PCR primer sets that can successfully detect subtle changes in the methylation levels of candidate regions. Furthermore, these methylation levels can divide CRC patients into two groups denoting good and poor prognoses. In this study, we present a streamlined workflow for screening clinically significant differentially methylated regions. Our discovery of methylation markers in the PDX1, EN2, and MSX1 genes suggests their promising performance as prognostic markers and their clinical application in CRC patients. An experimental strategy for detecting patterns of DNA modification reveals gene-specific alterations associated with worse outcomes in colorectal cancer patients. Many genomic regions undergo a process of chemical modification called methylation, which can strongly affect the expression of nearby genes. Many cancers exhibit abnormal methylation, and South Korean researchers led by Tae-You Kim of Seoul National University and Lark Kyun Kim of Yonsei University College of Medicine, Seoul, have developed a strategy for identifying such tumor-specific modifications. They identified a trio of genes that undergo excessive methylation in colorectal cancer, and show that this ‘signature’ is associated with more advanced metastatic tumors and shorter overall survival. The results from this study could give clinicians an additional diagnostic tool, and highlight the potential utility of performing such methylation profiling in other cancer types.
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Houschyar KS, Borrelli MR, Rein S, Tapking C, Popp D, Puladi B, Ooms M, Schulz T, Maan ZN, Branski LK, Siemers F, Philipp-Dormston WG, Yazdi AS, Duscher D. Wnt ligand expression in malignant melanoma: new insights. EUROPEAN JOURNAL OF PLASTIC SURGERY 2022. [DOI: 10.1007/s00238-022-01941-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Novel Diagnostic Biomarkers in Colorectal Cancer. Int J Mol Sci 2022; 23:ijms23020852. [PMID: 35055034 PMCID: PMC8776048 DOI: 10.3390/ijms23020852] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 12/27/2021] [Accepted: 01/03/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is still a leading cause of cancer death worldwide. Less than half of cases are diagnosed when the cancer is locally advanced. CRC is a heterogenous disease associated with a number of genetic or somatic mutations. Diagnostic markers are used for risk stratification and early detection, which might prolong overall survival. Nowadays, the widespread use of semi-invasive endoscopic methods and feacal blood tests characterised by suboptimal accuracy of diagnostic results has led to the detection of cases at later stages. New molecular noninvasive tests based on the detection of CRC alterations seem to be more sensitive and specific then the current methods. Therefore, research aiming at identifying molecular markers, such as DNA, RNA and proteins, would improve survival rates and contribute to the development of personalized medicine. The identification of “ideal” diagnostic biomarkers, having high sensitivity and specificity, being safe, cheap and easy to measure, remains a challenge. The purpose of this review is to discuss recent advances in novel diagnostic biomarkers for tumor tissue, blood and stool samples in CRC patients.
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Beltrán-García J, Osca-Verdegal R, Mena-Mollá S, Seco-Cervera M, Peiró-Chova L, García-Giménez JL, Laurent-Puig P, Cervantes A. Translational epigenetics in precision medicine of colorectal cancer. EPIGENETICS IN PRECISION MEDICINE 2022:19-41. [DOI: 10.1016/b978-0-12-823008-4.00018-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Combined analysis of KARS mutation and p16INK4a and p14ARF methylation status in locally advanced rectal carcinoma treated with preoperative chemoradiotherapy. ARCH BIOL SCI 2022. [DOI: 10.2298/abs220222011k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Current management of locally advanced rectal carcinoma (LARC) involves
preoperative chemoradiotherapy (preCRT) before surgery. Despite improved
local control rate, the response to preCRT of individual patients is
variable and may reflect heterogeneous biological properties among tumors of
the same clinical stage. Identifying novel molecular parameters with
predictive and/or prognostic value is of great clinical importance for a
personalized therapeutic approach. In this study, KRAS mutation status was
analyzed by direct sequencing, while methylation-specific polymerase chain
reaction (MSP) was used to examine p16INK4a and p14ARF gene methylation
status in pretreatment tumor biopsies of 60 patients with LARC. The examined
molecular changes of KRAS, p16INK4a and p14ARF genes were mutually
independent (p16INK4a/KRAS, P=0.272; p14ARF/KRAS, P=0.923; p16INK4a/p14ARF,
P=0.715). However, the simultaneous presence of p14ARF methylation and KRAS
mutation was associated with a more frequent appearance of local recurrences
and distant metastasis (P=0.027). Moreover, patients with the simultaneous
presence of p16INK4a and p14ARF methylation and KRAS mutation had
significantly shorter overall survival (P=0.011). The obtained results
strongly suggest that combined analyses of examined genetic and epigenetic
molecular alterations could contribute to the identification of LARC patient
subgroups with more aggressive tumor behavior and worse disease outcome.
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Jurmeister P, Wrede N, Hoffmann I, Vollbrecht C, Heim D, Hummel M, Wolkenstein P, Koch I, Heynol V, Schmitt WD, Thieme A, Teichmann D, Sers C, von Deimling A, Thierauf JC, von Laffert M, Klauschen F, Capper D. Mucosal melanomas of different anatomic sites share a common global DNA methylation profile with cutaneous melanoma but show location-dependent patterns of genetic and epigenetic alterations. J Pathol 2022; 256:61-70. [PMID: 34564861 DOI: 10.1002/path.5808] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/30/2021] [Accepted: 09/22/2021] [Indexed: 02/03/2023]
Abstract
Cutaneous, ocular, and mucosal melanomas are histologically indistinguishable tumors that are driven by a different spectrum of genetic alterations. With current methods, identification of the site of origin of a melanoma metastasis is challenging. DNA methylation profiling has shown promise for the identification of the site of tumor origin in various settings. Here we explore the DNA methylation landscape of melanomas from different sites and analyze if different melanoma origins can be distinguished by their epigenetic profile. We performed DNA methylation analysis, next generation DNA panel sequencing, and copy number analysis of 82 non-cutaneous and 25 cutaneous melanoma samples. We further analyzed eight normal melanocyte cell culture preparations. DNA methylation analysis separated uveal melanomas from melanomas of other primary sites. Mucosal, conjunctival, and cutaneous melanomas shared a common global DNA methylation profile. Still, we observed location-dependent DNA methylation differences in cancer-related genes, such as low frequencies of RARB (7/63) and CDKN2A promoter methylation (6/63) in mucosal melanomas, or a high frequency of APC promoter methylation in conjunctival melanomas (6/9). Furthermore, all investigated melanomas of the paranasal sinus showed loss of PTEN expression (9/9), mainly caused by promoter methylation. This was less frequently seen in melanomas of other sites (24/98). Copy number analysis revealed recurrent amplifications in mucosal melanomas, including chromosomes 4q, 5p, 11q and 12q. Most melanomas of the oral cavity showed gains of chromosome 5p with TERT amplification (8/10), while 11q amplifications were enriched in melanomas of the nasal cavity (7/16). In summary, mucosal, conjunctival, and cutaneous melanomas show a surprisingly similar global DNA methylation profile and identification of the site of origin by DNA methylation testing is likely not feasible. Still, our study demonstrates tumor location-dependent differences of promoter methylation frequencies in specific cancer-related genes together with tumor site-specific enrichment for specific chromosomal changes and genetic mutations. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Philipp Jurmeister
- Institute of Pathology, Ludwig Maximilians University Hospital Munich, Munich, Germany
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Niklas Wrede
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Inga Hoffmann
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Claudia Vollbrecht
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Daniel Heim
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Michael Hummel
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Peggy Wolkenstein
- German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Berlin, Germany
| | - Ines Koch
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Verena Heynol
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Wolfgang Daniel Schmitt
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Anne Thieme
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Berlin, Germany
| | - Daniel Teichmann
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Berlin, Germany
| | - Christine Sers
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andreas von Deimling
- Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Julia Cara Thierauf
- Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Maximilian von Laffert
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Frederick Klauschen
- Institute of Pathology, Ludwig Maximilians University Hospital Munich, Munich, Germany
| | - David Capper
- German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Berlin, Germany
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Liu Z, Tang H, Zhang W, Wang J, Wan L, Li X, Ji Y, Kong N, Zhang Y, Wang J, Fan Z, Guo Q. Coupling of serum CK20 and hyper-methylated CLIP4 as promising biomarker for colorectal cancer diagnosis: from bioinformatics screening to clinical validation. Aging (Albany NY) 2021; 13:26161-26179. [PMID: 34965217 PMCID: PMC8751608 DOI: 10.18632/aging.203804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 12/13/2021] [Indexed: 11/25/2022]
Abstract
Colorectal cancer (CRC) is one of the most common and lethal malignancies. The identification of minimally invasive and precise biomarkers is an urgent need for the early diagnosis of CRC. Through bioinformatics analysis of 395 CRC tissues and 63 CRC cell lines, CK18, CK20, de-methylated HPDL and hyper-methylated CLIP4 were identified as candidate serum biomarkers. Then, a training cohort consisting of 60 CRC, 30 colorectal adenomas (CA) and 33 healthy controls and a validation cohort consisting of 60 CRC, 30 CA and 30 healthy controls were enrolled. In the training cohort, enzyme-linked immunosorbent assay (ELISA) showed that CK18 and CK20 were all significantly higher in CRC and CA. CK18 diagnosed CRC with 46.67% sensitivity and 87.3% specificity; CK20 diagnosed CRC with 28.33% sensitivity and 90.47% specificity. Methylation-specific PCR (MSP) indicated that de-methylated HPDL and hyper-methylated CLIP4 were significantly detected in CRC and CA. De-methylated HPDL diagnosed CRC with 36.67% sensitivity and 93.65% specificity and hyper-methylated CLIP4 with 73.33% sensitivity and 84.13% specificity. Random combined analysis suggested that CK20/hyper-methylated CLIP4 diagnosed CRC with 91.67% sensitivity and 82.54% specificity. In the validation cohort, CK20 diagnosed CRC with 36.7% sensitivity and 88.3% specificity and hyper-methylated CLIP4 with 80% sensitivity and 85% specificity. CK20/hyper-methylated CLIP4 diagnosed CRC with 95% sensitivity and 81.7% specificity. Compared with serum biomarkers reported before, CK20/hyper-methylated CLIP4 possessed the potential to be a new effective and precise diagnostic biomarker for CRC.
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Affiliation(s)
- Zhongjian Liu
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, Kunming, China.,The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Hui Tang
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, Kunming, China.,The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Wen Zhang
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, Kunming, China.,The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Jinli Wang
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, Kunming, China.,The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Lilan Wan
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, Kunming, China.,The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Xisha Li
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, Kunming, China.,The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Yuping Ji
- Department of Gastroenterology, The Third People's Hospital of Yunnan Province, Kunming, China
| | - Na Kong
- Department of Gastroenterology, The Third People's Hospital of Yunnan Province, Kunming, China
| | - Yanfang Zhang
- Department of Gastroenterology, The Third People's Hospital of Yunnan Province, Kunming, China
| | - Jiangang Wang
- Department of Gastroenterology, The Third People's Hospital of Yunnan Province, Kunming, China
| | - Zhang Fan
- Department of Gastroenterology, The Third People's Hospital of Yunnan Province, Kunming, China
| | - Qiang Guo
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, Kunming, China.,The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
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Alizadeh-Sedigh M, Fazeli MS, Mahmoodzadeh H, Sharif SB, Teimoori-Toolabi L. Methylation of FBN1, SPG20, ITF2, RUNX3, SNCA, MLH1, and SEPT9 genes in circulating cell-free DNA as biomarkers of colorectal cancer. Cancer Biomark 2021; 34:221-250. [PMID: 34957998 DOI: 10.3233/cbm-210315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Investigating aberrant tumor-specific methylation in plasma cell-free DNA provides a promising and noninvasive biomarker for cancer detection. OBJECTIVE We aimed to investigate methylation status of some promoter regions in the plasma and tumor tissues to find biomarkers for early detection of colorectal cancer. METHODS This case-control study on seventy colorectal cancer patients and fifty matched healthy controls used Methylation-Specific High-Resolution Melting Curve analysis to evaluate the methylation of the selected promoter regions in converted genomic tissue DNA and plasma cfDNA. RESULTS The methylation levels in selected regions of SPG20 (+24375 to +24680, +24209 to +24399, and +23625 to +23883), SNCA (+807 to +1013, +7 to +162, and -180 to +7), FBN1 (+223 to +429, +1 to +245, and -18 to -175), ITF2 (+296 to +436 and -180 to +55), SEPT9 (-914412 to -91590 and -99083 to -92264), and MLH1 (-13 to +22) were significantly higher in tumor tissues compared with normal adjacent tissues. The methylation levels of FBN1, ITF2, SNCA, and SPG20 promoters were significantly higher in the patient's plasma compared to patient's normal tissue and plasma of healthy control subjects. FBN1, SPG20, and SEPT9 promoter methylation had a good diagnostic performance for discriminating CRC tissues from normal adjacent tissues (AUC > 0.8). A panel of SPG20, FBN1, and SEPT9 methylation had a higher diagnostic value than that of any single biomarker and other panels in tissue-based assay (AUC > 0.9). The methylation of FBN1(a) and SPG20(a) regions, as the closest region to the first coding sequence (CDS), had a good diagnostic performance in plasma cfDNA (AUC > 0.8) while a panel consisted of FBN1(a) and SPG20(a) regions showed excellent diagnostic performance for CRC detection in plasma cfDNA (AUC > 0.9). CONCLUSION Methylation of FBN1(a) and SPG20(a) promoter regions in the plasma cfDNA can be an excellent simple, non-invasive blood-based test for early detection of CRC.
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Affiliation(s)
- Maryam Alizadeh-Sedigh
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Mohammad Sadegh Fazeli
- Department of Surgery, Division of Colorectal Surgery, Imam Khomeini Medical Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Habibollah Mahmoodzadeh
- Cancer Institute of Iran, Imam Khomeini Medical Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahin Behrouz Sharif
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Ladan Teimoori-Toolabi
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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49
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Saha SK, Islam SMR, Saha T, Nishat A, Biswas PK, Gil M, Nkenyereye L, El-Sappagh S, Islam MS, Cho SG. Prognostic role of EGR1 in breast cancer: a systematic review. BMB Rep 2021. [PMID: 34488929 PMCID: PMC8560464 DOI: 10.5483/bmbrep.2021.54.10.087] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
EGR1 (early growth response 1) is dysregulated in many cancers and exhibits both tumor suppressor and promoter activities, making it an appealing target for cancer therapy. Here, we used a systematic multiomics analysis to review the expression of EGR1 and its role in regulating clinical outcomes in breast cancer (BC). EGR1 expression, its promoter methylation, and protein expression pattern were assessed using various publicly available tools. COSMIC-based somatic mutations and cBioPortal-based copy number alterations were analyzed, and the prognostic roles of EGR1 in BC were determined using Prognoscan and Kaplan-Meier Plotter. We also used bc-GenEx-Miner to investigate the EGR1 co-expression profile. EGR1 was more often downregulated in BC tissues than in normal breast tissue, and its knockdown was positively correlated with poor survival. Low EGR1 expression levels were also associated with increased risk of ER+, PR+, and HER2-BCs. High positive correlations were observed among EGR1, DUSP1, FOS, FOSB, CYR61, and JUN mRNA expression in BC tissue. This systematic review suggested that EGR1 expression may serve as a prognostic marker for BC patients and that clinicopathological parameters influence its prognostic utility. In addition to EGR1, DUSP1, FOS, FOSB, CYR61, and JUN can jointly be considered prognostic indicators for BC.
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Affiliation(s)
- Subbroto Kumar Saha
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea
| | - S. M. Riazul Islam
- Department of Computer Science and Engineering, Sejong University, Seoul 05006, Korea
| | - Tripti Saha
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea
| | - Afsana Nishat
- Department of Microbiology & Cell Science, University of Florida, Gainesville, FL 32611, USA
| | - Polash Kumar Biswas
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea
| | - Minchan Gil
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea
| | - Lewis Nkenyereye
- Department of Computer and Information Security, Sejong University, Seoul 05006, Korea
| | - Shaker El-Sappagh
- Centro Singular de Investigación en Tecnoloxías Intelixentes (CiTIUS), Universidade de Santiago de Compostela, 15705 Santiago de Compostela, Spain
| | - Md. Saiful Islam
- School of Information and Communication Technology, Griffith University, QLD 4222, Australia
| | - Ssang-Goo Cho
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea
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50
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Shao X, Wang H, Yu Y, Zhou C. Combined detection of stool-based methylation indicators for early screening of colorectal neoplasm. Am J Transl Res 2021; 13:11597-11607. [PMID: 34786085 PMCID: PMC8581910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 08/13/2021] [Indexed: 06/13/2023]
Abstract
In the past two decades, several methylated DNA targets, including gene promoters and other intronic markers have been explored in tumors and benign lesions. Therefore, it can be expected that a panel of stool-based biomarkers will become a screening method for colorectal cancer (CRC) and adenoma with better sensitivity and specificity, aiming to decrease the incidence and mortality of CRC. In this study, the methylation of secreted frizzled-related protein 1 (SFRP1), hyperplastic polyposis protein 1 (HPP1), α-internexin (INA), Wnt inhibitory factor 1 (WIF1), tissue factor pathway inhibitor 2 (TFPI2), ikaros family zinc finger protein 1 (IKZF1), and spastic paraplegia 20 (SPG20) were detected in stool samples from patients with CRC, adenoma, polyps, and healthy controls, respectively, and these biomarkers were used to establish a logistic regression model for classification. Receiver operating characteristic (ROC) curves were drawn to assess the importance of each biomarker. Subsequently, a biomarker or combination of biomarkers was analyzed for early screening of high-risk neoplasm. The data showed that when a single biomarker was used for CRC screening, the sensitivity ranged from 63.9% to 76.8%, the area under the curve (AUC) ranged from 0.821 to 0.875, and the accuracy ranged from 77.0% to 84.5%. Finally, the methylation of SFRP1, HPP1, TFPI2, and IKZF1 was selected using a backward stepwise method in the multivariate logistic analysis according to the Akaike Information Criterion. These findings indicate that stool DNA biomarkers have good diagnostic power in discriminating high-risk level of neoplasm from healthy population.
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Affiliation(s)
- Xinyu Shao
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University Suzhou, Jiangsu, China
| | - Huiyu Wang
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University Suzhou, Jiangsu, China
| | - Yang Yu
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University Suzhou, Jiangsu, China
| | - Chunli Zhou
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University Suzhou, Jiangsu, China
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