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Zhao Y, Zhang Z, Qiu JH, Li RY, Sun ZG. Catching cancer signals in the blood: Innovative pathways for early esophageal cancer diagnosis. World J Gastroenterol 2025; 31:101838. [PMID: 40093671 PMCID: PMC11886526 DOI: 10.3748/wjg.v31.i10.101838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 01/23/2025] [Accepted: 02/05/2025] [Indexed: 02/26/2025] Open
Abstract
In recent years, significant progress has been made in the application of DNA methylation for the early detection of esophageal cancer (EC). As an epigenetic modification, DNA methylation allows for noninvasive screening by detecting the methylation status of circulating tumor DNA. Studies have shown that the methylation of genes such as SHOX2, SEPTIN9, EPO, and RNF180 significantly improves diagnostic sensitivity and specificity. Currently, SEPTIN9 has been approved by the Food and Drug Administration for colorectal cancer screening, while SHOX2 and EPO show promising results in EC, and RNF180 has potential in gastrointestinal tumors. This editorial reviews the study by Liu et al, which demonstrated the potential of combining the methylation of these four genes for early EC screening. In addition to their roles in early diagnosis, DNA methylation markers are gaining attention because of their roles in predicting recurrence and in postoperative follow-up. By monitoring changes in methylation levels, these markers can provide valuable insights into treatment efficacy and long-term management. As research progresses, liquid biopsy technology is expected to become an essential tool in the precision diagnosis and treatment of EC, benefiting patients significantly.
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Affiliation(s)
- Yue Zhao
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan 250063, Shandong Province, China
| | - Zhan Zhang
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan 250063, Shandong Province, China
| | - Jian-Hao Qiu
- Department of Thoracic Surgery, The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Jinan 250063, Shandong Province, China
| | - Rong-Yang Li
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan 250063, Shandong Province, China
| | - Zhen-Guo Sun
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan 250063, Shandong Province, China
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Malinowska K, Tarhonska K, Foksiński M, Sicińska P, Jabłońska E, Reszka E, Zarakowska E, Gackowski D, Górecka K, Balcerczyk A, Bukowska B. Impact of Short-Term Exposure to Non-Functionalized Polystyrene Nanoparticles on DNA Methylation and Gene Expression in Human Peripheral Blood Mononuclear Cells. Int J Mol Sci 2024; 25:12786. [PMID: 39684496 DOI: 10.3390/ijms252312786] [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: 11/04/2024] [Revised: 11/25/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
The aim of the present study was to investigate the concentration- and size-dependent effects of non-functionalized polystyrene nanoparticles (PS-NPs) of varying diameters (29 nm, 44 nm, and 72 nm) on specific epigenetic modifications and gene expression profiles related to carcinogenesis in human peripheral blood mononuclear cells (PBMCs) in vitro. This in vitro human-cell-based model is used to investigate the epigenetic effect of various environmental xenobiotics. PBMCs were exposed to PS-NPs at concentrations ranging from 0.001 to 100 µg/mL for 24 h period. The analysis encompassed epigenetic DNA modifications, including levels of 5-methyl-2'-deoxycytidine (5-mdC) and 5-(hydroxymethyl)-2'-deoxycytidine (5-hmdC), as well as the levels of 2'-deoxyuridine (dU) and 5-(hydroxymethyl)-2'-deoxyuridine (5-hmdU) by mass spectrometry methods, methylation in the promoter regions of selected tumor suppressor genes TP53 (P53), CDKN2A (P16), and CDKN1A (P21) and proto-oncogenes (CCND1, BCL2, BCL6), along with the expression profile of the indicated genes by real-time PCR assays. The results obtained revealed no significant changes in global DNA methylation/demethylation levels in PBMCs after short-term exposure to non-functionalized PS-NPs. Furthermore, there were no changes observed in the level of dU, a product of cytosine deamination. However, the level of 5-hmdU, a product of both 5-hmdC deamination and thymine oxidation, was increased at the highest concentrations of larger PS-NPs (72 nm). None of the PS-NPs caused a change in the methylation pattern of the promoter regions of the TP53, CDKN2A, CDKN1A, CCND1, BCL2 and BCL6 genes. However, gene profiling indicated that PS-NPs with a diameter of 29 nm and 44 nm altered the expression of the TP53 gene. The smallest PS-NPs with a diameter of 29 nm increased the expression of the TP53 gene at a concentration of 10 µg/mL, while PS-NPs with a diameter of 44 nm did so at a concentration of 100 µg/mL. An increase in the expression of the CDKN2A gene was also observed when PBMCs were exposed to PS-NPs with 29 nm in diameter at the highest concentration. The observed effect depended on both the concentration and the size of the PS-NPs.
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Affiliation(s)
- Kinga Malinowska
- Department of Biophysics of Environmental Pollution, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska Str. 141/143, 90-236 Lodz, Poland
| | - Kateryna Tarhonska
- Department of Translational Research, Nofer Institute of Occupational Medicine, Teresy Str. 8, 91-348 Lodz, Poland
| | - Marek Foksiński
- Department of Clinical Biochemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-092 Bydgoszcz, Poland
| | - Paulina Sicińska
- Department of Biophysics of Environmental Pollution, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska Str. 141/143, 90-236 Lodz, Poland
| | - Ewa Jabłońska
- Department of Translational Research, Nofer Institute of Occupational Medicine, Teresy Str. 8, 91-348 Lodz, Poland
| | - Edyta Reszka
- Department of Biophysics of Environmental Pollution, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska Str. 141/143, 90-236 Lodz, Poland
| | - Ewelina Zarakowska
- Department of Clinical Biochemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-092 Bydgoszcz, Poland
| | - Daniel Gackowski
- Department of Clinical Biochemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-092 Bydgoszcz, Poland
| | - Karolina Górecka
- The Bio-Med-Chem Doctoral School, University of Lodz, 90-237 Lodz, Poland
- Lodz Institutes of the Polish Academy of Sciences, University of Lodz, 90-237 Lodz, Poland
| | - Aneta Balcerczyk
- Department of Oncobiology and Epigenetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
| | - Bożena Bukowska
- Department of Biophysics of Environmental Pollution, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska Str. 141/143, 90-236 Lodz, Poland
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Liu XJ, Pi GL, Wang S, Kai JD, Yu HF, Shi HW, Yu J, Zeng H. Plasma DNA methylation detection for early screening, diagnosis, and monitoring of esophageal adenocarcinoma and squamous cell carcinoma. World J Gastroenterol 2024; 30:4609-4619. [PMID: 39575407 PMCID: PMC11572633 DOI: 10.3748/wjg.v30.i43.4609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 09/06/2024] [Accepted: 09/13/2024] [Indexed: 10/31/2024] Open
Abstract
BACKGROUND The early diagnosis rate of esophageal cancer (EC), one of the most prevalent digestive tract cancers worldwide, remains low. AIM To investigate the utility of plasma SHOX2, SEPTIN9, EPO, and RNF180 methylation in the clinical diagnosis and monitoring of EC. METHODS Plasma samples were collected from 210 patients at Hubei Cancer Hospital, and TaqMan polymerase chain reaction was employed to detect plasma SHOX2, SEPTIN9, RNF180, and EPO methylation. The area under the curve was used to estimate their diagnostic value for EC. Cox and logistic regression analyses were used to estimate the independent screening risk factors for patients with EC. RESULTS The sensitivity and specificity of combined assessment of plasma SHOX2, SEPTIN9, RNF180, and EPO methylation for adenocarcinoma, squamous cell carcinoma (SCC), and EC detection were 66.67% and 86.27%, 77.40% and 85.29%, and 76.19% and 86.27%, respectively; the area under the curve values for diagnosing adenocarcinoma, SCC, and EC were 0.737 [95% confidence interval (CI): 0.584-0.89], 0.824 (95%CI: 0.775-0.891), and 0.864 (95%CI: 0.809-0.92), respectively. CONCLUSION According to our findings, plasma SHOX2, SEPTIN9, RNF180, and EPO methylation exhibits appreciated sensitivity for diagnosing EC. The precise measurement of plasma SHOX2, SEPTIN9, RNF180, and EPO methylation can improve EC diagnosis and therapy efficacy monitoring.
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Affiliation(s)
- Xu-Ji Liu
- Department of Radiotherapy and Oncology, Wuhan Sixth Hospital and Affiliated Hospital of Jianghan University, Wuhan 430015, Hubei Province, China
- Department of Radiotherapy and Oncology, Jianghan University, School of Medicine, Wuhan 430015, Hubei Province, China
| | - Guo-Liang Pi
- Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, Hubei Province, China
| | - Sheng Wang
- Department of Thoracic Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, Hubei Province, China
| | - Jin-Dan Kai
- Department of Thoracic Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, Hubei Province, China
| | - Hui-Fang Yu
- Department of Thoracic Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, Hubei Province, China
| | - Hong-Wei Shi
- Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, Hubei Province, China
| | - Jing Yu
- Department of Laboratory Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Hui Zeng
- Department of Radiotherapy and Oncology, Wuhan Sixth Hospital and Affiliated Hospital of Jianghan University, Wuhan 430015, Hubei Province, China
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Chatterjee K, Mal S, Ghosh M, Chattopadhyay NR, Roy SD, Chakraborty K, Mukherjee S, Aier M, Choudhuri T. Blood-based DNA methylation in advanced Nasopharyngeal Carcinoma exhibited distinct CpG methylation signature. Sci Rep 2023; 13:22086. [PMID: 38086861 PMCID: PMC10716134 DOI: 10.1038/s41598-023-45001-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 10/14/2023] [Indexed: 12/18/2023] Open
Abstract
The TNM staging system is currently used to detect cancer stages. Regardless, a small proportion of cancer patients recur even after therapy, suggesting more specific molecular tools are required to justify the stage-specific detection and prompt cancer diagnosis. Thus, we aimed to explore the blood-based DNA methylation signature of metastatic nasopharyngeal carcinoma (NPC) to establish a holistic methylation biomarker panel. For the identification of methylation signature, the EPIC BeadChip-based array was performed. Comparative analysis for identifying unique probes, validation, and functional studies was investigated by analyzing GEO and TCGA datasets. We observed 4093 differentially methylated probes (DMPs), 1232 hydroxymethylated probes, and 25 CpG islands. Gene expression study revealed both upregulated and downregulated genes. Correlation analysis suggested a positive (with a positive r, p ≤ 0.05) and negative (with a negative r, p ≤ 0.05) association with different cancers. TFBS analysis exhibited the binding site for many TFs. Furthermore, gene enrichment analysis indicated the involvement of those identified genes in biological pathways. However, blood-based DNA methylation data uncovered a distinct DNA methylation pattern, which might have an additive role in NPC progression by altering the TFs binding. Moreover, based on tissue-specificity, a variation of correlation between methylation and gene expression was noted in different cancers.
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Affiliation(s)
- Koustav Chatterjee
- Department of Biotechnology, Visva-Bharati, Santiniketan, Birbhum, West Bengal, India, 731235
| | - Sudipa Mal
- Department of Biotechnology, Visva-Bharati, Santiniketan, Birbhum, West Bengal, India, 731235
| | - Monalisha Ghosh
- Department of Biotechnology, Visva-Bharati, Santiniketan, Birbhum, West Bengal, India, 731235
| | | | - Sankar Deb Roy
- Department of Radiation Oncology, Eden Medical Center, Dimapur, Nagaland, India
| | - Koushik Chakraborty
- Department of Biotechnology, Visva-Bharati, Santiniketan, Birbhum, West Bengal, India, 731235
| | - Syamantak Mukherjee
- Department of Biotechnology, Visva-Bharati, Santiniketan, Birbhum, West Bengal, India, 731235
| | - Moatoshi Aier
- Department of Pathology, Eden Medical Center, Dimapur, Nagaland, India
| | - Tathagata Choudhuri
- Department of Biotechnology, Visva-Bharati, Santiniketan, Birbhum, West Bengal, India, 731235.
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Xia Y, Wang Y, Shan M, Hao Y, Liu H, Chen Q, Liang Z. Advances in the pathogenesis and clinical application prospects of tumor biomolecules in keloid. BURNS & TRAUMA 2022; 10:tkac025. [PMID: 35769828 PMCID: PMC9233200 DOI: 10.1093/burnst/tkac025] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 02/13/2022] [Indexed: 12/29/2022]
Abstract
Keloid scarring is a kind of pathological healing manifestation after skin injury and possesses various tumor properties, such as the Warburg effect, epithelial-mesenchymal transition (EMT), expression imbalances of apoptosis-related genes and the presence of stem cells. Abnormal expression of tumor signatures is critical to the initiation and operation of these effects. Although previous experimental studies have recognized the potential value of a single or several tumor biomolecules in keloids, a comprehensive evaluation system for multiple tumor signatures in keloid scarring is still lacking. This paper aims to summarize tumor biomolecules in keloids from the perspectives of liquid biopsy, genetics, proteomics and epigenetics and to investigate their mechanisms of action and feasibility from bench to bedside. Liquid biopsy is suitable for the early screening of people with keloids due to its noninvasive and accurate performance. Epigenetic biomarkers do not require changes in the gene sequence and their reversibility and tissue specificity make them ideal therapeutic targets. Nonetheless, given the ethnic specificity and genetic predisposition of keloids, more large-sample multicenter studies are indispensable for determining the prevalence of these signatures and for establishing diagnostic criteria and therapeutic efficacy estimations based on these molecules.
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Affiliation(s)
- Yijun Xia
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
| | - Youbin Wang
- Department of Plastic Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Mengjie Shan
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
| | - Yan Hao
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
| | - Hao Liu
- Department of Plastic Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Qiao Chen
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
| | - Zhengyun Liang
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
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Piper TB, Nielsen HJ, Christensen IJ. Serological cancer-associated protein biomarker levels at bowel endoscopy: Increased risk of subsequent primary malignancy. Tumour Biol 2022; 44:1-16. [PMID: 35180141 DOI: 10.3233/tub-211501] [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: 11/15/2022] Open
Abstract
BACKGROUND It was previously shown in three subpopulations that subjects not identified with colorectal cancer (CRC) at bowel endoscopy, but with increased serological cancer-associated protein biomarker levels had an increased risk of being diagnosed with subsequent malignant diseases. OBJECTIVE The aim of the present study was to perform a pooled analysis of subjects from the three subpopulations and subsequently validate the results in an independent study. The study population denoted the training set includes N = 4,076 subjects with symptoms attributable to CRC and the independent validation set N = 3,774 similar subjects. METHODS Levels of CEA, CA19-9, TIMP-1 and YKL-40 were determined in blood samples collected prior to diagnostic bowel endoscopy. Follow-up of subjects not diagnosed with CRC at endoscopy, was ten years and identified subjects diagnosed with primary intra- or extra-colonic malignant diseases. The primary analysis was time to a newly diagnosed malignant disease and was analyzed with death as a competing risk in the training set. Subjects with HNPCC or FAP were excluded. The cumulated incidence was estimated for each biomarker and in a multivariate model. The resulting model was then validated on the second study population. RESULTS In the training set primary malignancies were identified in 515 (12.6%) of the 4,076 subjects, who had a colorectal endoscopy with non-malignant findings. In detail, 33 subjects were subsequently diagnosed with CRC and 482 subjects with various extra-colonic cancers. Multivariate additive analysis of the dichotomized biomarkers demonstrated that CEA (HR = 1.50, 95% CI:1.21-1.86, p < 0.001), CA19-9 (HR = 1.41, 95% CI:1.10-1.81, p = 0.007) and TIMP-1 (HR = 1.25 95% CI: 1.01-1.54, p = 0.041) were significant predictors of subsequent malignancy. The cumulated incidence at 5 years landmark time was 17% for those subjects with elevated CEA, CA19-9 and TIMP-1 versus 6.7% for those with low levels of all. When the model was applied to the validation set the cumulated 5-year incidence was 10.5% for subjects with elevated CEA, CA19-9 and TIMP-1 and 5.6% for subjects with low levels of all biomarkers. Further analysis demonstrated a significant interaction between TIMP-1 and age in the training set. The age dependency of TIMP-1 indicated a greater risk of malignancy in younger subjects if the biomarker was elevated. This observation was validated in the second set. CONCLUSION Elevated cancer-associated protein biomarker levels in subjects with non-malignant findings at large bowel endoscopy identifies subjects at increased risk of being diagnosed with subsequent primary malignancy. CEA, CA19-9 and TIMP-1 were significant predictors of malignant disease in this analysis. TIMP-1 was found dependent on age. The results were validated in an independent symptomatic population.
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Affiliation(s)
- Thomas B Piper
- Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark
| | - Hans J Nielsen
- Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark.,Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Caramujo-Balseiro S, Faro C, Carvalho L. Metabolic pathways in sporadic colorectal carcinogenesis: A new proposal. Med Hypotheses 2021; 148:110512. [PMID: 33548761 DOI: 10.1016/j.mehy.2021.110512] [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] [Received: 10/25/2020] [Revised: 01/09/2021] [Accepted: 01/22/2021] [Indexed: 02/07/2023]
Abstract
Given the reports made about geographical differences in Colorectal Cancer (CRC) occurrence, suggesting a link between dietary habits, genes and cancer risk, we hypothesise that there are four fundamental metabolic pathways involved in diet-genes interactions, directly implicated in colorectal carcinogenesis: folate metabolism; lipid metabolism; oxidative stress response; and inflammatory response. Supporting this hypothesis are the evidence given by the significant associations between several diet-genes polymorphisms and CRC, namely: MTHFR, MTR, MTRR and TS (involved in folate metabolism); NPY, APOA1, APOB, APOC3, APOE, CETP, LPL and PON1 (involved in lipid metabolism); MNSOD, SOD3, CAT, GSTP1, GSTT1 and GSTM1 (involved in oxidative stress response); and IL-1, IL-6, TNF-α, and TGF-β (involved in inflammatory response). We also highlight the association between some foods/nutrients/nutraceuticals that are important in CRC prevention or treatment and the four metabolic pathways proposed, and the recent results of genome-wide association studies, both assisting our hypothesis. Finally, we propose a new line of investigation with larger studies, using accurate dietary biomarkers and investigating the four metabolic pathways genes simultaneously. This line of investigation will be essential to understand the full complexity of the association between nature and nurture in CRC and perhaps in other types of cancers. Only with this in-depth knowledge will it be possible to make personalised nutrition recommendations for disease prevention and management.
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Affiliation(s)
- Sandra Caramujo-Balseiro
- Institute of Anatomical and Molecular Pathology, Faculty of Medicine - University of Coimbra, Coimbra, Portugal; Department of Life Sciences - University of Coimbra, Coimbra, Portugal.
| | - Carlos Faro
- Department of Life Sciences - University of Coimbra, Coimbra, Portugal; UC Biotech, Cantanhede, Portugal
| | - Lina Carvalho
- Institute of Anatomical and Molecular Pathology, Faculty of Medicine - University of Coimbra, Coimbra, Portugal
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Xing F, Zhao D, Wu SY, Tyagi A, Wu K, Sharma S, Liu Y, Deshpande R, Wang Y, Cleary J, Miller LD, Chittiboyina AG, Yalamanchili C, Mo YY, Watabe K. Epigenetic and Posttranscriptional Modulation of SOS1 Can Promote Breast Cancer Metastasis through Obesity-Activated c-Met Signaling in African-American Women. Cancer Res 2021; 81:3008-3021. [PMID: 33446575 DOI: 10.1158/0008-5472.can-19-4031] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 07/28/2020] [Accepted: 01/07/2021] [Indexed: 11/16/2022]
Abstract
Ethnicity is considered to be one of the major risk factors in certain subtypes of breast cancer. However, the mechanism of this racial disparity remains poorly understood. Here, we demonstrate that SOS1, a key regulator of Ras pathway, is highly expressed in African-American (AA) patients with breast cancer compared with Caucasian-American patients. Because of the higher obesity rate in AA women, increased levels of SOS1 facilitated signal transduction of the c-Met pathway, which was highly activated in AA patients with breast cancer via hepatocyte growth factor secreted from adipocytes. Elevated expression of SOS1 also enhanced cancer stemness through upregulation of PTTG1 and promoted M2 polarization of macrophages by CCL2 in metastatic sites. SOS1 was epigenetically regulated by a super-enhancer identified by H3K27ac in AA patients. Knockout of the super-enhancer by CRISPR in AA cell lines significantly reduced SOS1 expression. Furthermore, SOS1 was posttranscriptionally regulated by miR-483 whose expression is reduced in AA patients through histone trimethylation (H3K27me3) on its promoter. The natural compound, taxifolin, suppressed signaling transduction of SOS1 by blocking the interaction between SOS1 and Grb2, suggesting a potential utility of this compound as a therapeutic agent for AA patients with breast cancer. SIGNIFICANCE: These findings elucidate the signaling network of SOS1-mediated metastasis in African-American patients, from the epigenetic upregulation of SOS1 to the identification of taxifolin as a potential therapeutic strategy against SOS1-driven tumor progression.
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Affiliation(s)
- Fei Xing
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
| | - Dan Zhao
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Shih-Ying Wu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Abhishek Tyagi
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Kerui Wu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Sambad Sharma
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Yin Liu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Ravindra Deshpande
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Yuezhu Wang
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Jacob Cleary
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Lance D Miller
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Amar G Chittiboyina
- National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, Oxford, Mississippi
| | - Chinni Yalamanchili
- National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, Oxford, Mississippi
| | - Yin-Yuan Mo
- Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi
| | - Kounosuke Watabe
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
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Wang L, Zhang MX, Zhang MF, Tu ZW. ZBTB7A functioned as an oncogene in colorectal cancer. BMC Gastroenterol 2020; 20:370. [PMID: 33167891 PMCID: PMC7650168 DOI: 10.1186/s12876-020-01456-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 09/16/2020] [Indexed: 12/22/2022] Open
Abstract
Background Despite zinc finger and BTB domain-containing 7A (ZBTB7A) documented importance in multiple tumors, the function and clinical value in Colorectal cancer (CRC) remain elusive. The aim of this study was to evaluate the functional roles and the clinical value of ZBTB7A in CRC progression. Methods The level of ZBTB7A was detected in a large cohort of CRC patients (n = 189) by immunohistochemistry (IHC), and we analyzed the diagnostic and prognostic value of the protein. In addition, the functional roles of ZBTB7A on CRC were explored in vitro and in vivo. Results Survival analyses indicated that patients with high ZBTB7A expression made the prognosis worse (P = 0.024). Functionally, knockdown of ZBTB7A could markedly inhibit tumor proliferation in vitro and in vivo, whereas ZBTB7A overexpression displayed the opposite results. Conclusions ZBTB7A was associated with poor survival outcomes and functioned as an oncogene in CRC patients, indicating that it is a potential prognostic biomarker and therapeutic target for CRC patients.
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Affiliation(s)
- Li Wang
- Department of Radiotherapy, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, 200000, China
| | - Meng-Xia Zhang
- Department of Nasopharyngeal Carcinoma, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China
| | - Mei-Fang Zhang
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, China.
| | - Zi-Wei Tu
- Department of Radiotherapy, Jiangxi Cancer Hospital, Medical College, Nanchang University, No. 519, Beijing East Road, Qingshan Lake District, Nanchang, 330029, Jiangxi, China.
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Petersen MM, Ferm L, Kleif J, Piper TB, Rømer E, Christensen IJ, Nielsen HJ. Triage May Improve Selection to Colonoscopy and Reduce the Number of Unnecessary Colonoscopies. Cancers (Basel) 2020; 12:E2610. [PMID: 32932734 PMCID: PMC7563245 DOI: 10.3390/cancers12092610] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 09/11/2020] [Accepted: 09/11/2020] [Indexed: 12/18/2022] Open
Abstract
Implementation of population screening for colorectal cancer by direct colonoscopy or follow-up colonoscopy after a positive fecal blood test has challenged the overall capacity of bowel examinations. Certain countries are facing serious colonoscopy capacity constraints, which have led to waiting lists and long time latency of follow-up examinations. Various options for improvement are considered, including increased cut-off values of the fecal blood tests. Results from major clinical studies of blood-based, cancer-associated biomarkers have, however, led to focus on a Triage concept for improved selection to colonoscopy. The Triage test may include subject age, concentration of hemoglobin in a feces test and a combination of certain blood-based cancer-associated biomarkers. Recent results have indicated that Triage may reduce the requirements for colonoscopy by around 30%. Such results may be advantageous for the capacity, the healthcare budgets and in particular, the subjects, who do not need an unnecessary, unpleasant and risk-associated bowel examination.
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Affiliation(s)
- Mathias M. Petersen
- Department of Surgical Gastroenterology, Hvidovre Hospital, 2650 Hvidovre, Denmark; (M.M.P.); (L.F.); (J.K.); (T.B.P.); (E.R.); (I.J.C.)
| | - Linnea Ferm
- Department of Surgical Gastroenterology, Hvidovre Hospital, 2650 Hvidovre, Denmark; (M.M.P.); (L.F.); (J.K.); (T.B.P.); (E.R.); (I.J.C.)
| | - Jakob Kleif
- Department of Surgical Gastroenterology, Hvidovre Hospital, 2650 Hvidovre, Denmark; (M.M.P.); (L.F.); (J.K.); (T.B.P.); (E.R.); (I.J.C.)
| | - Thomas B. Piper
- Department of Surgical Gastroenterology, Hvidovre Hospital, 2650 Hvidovre, Denmark; (M.M.P.); (L.F.); (J.K.); (T.B.P.); (E.R.); (I.J.C.)
| | - Eva Rømer
- Department of Surgical Gastroenterology, Hvidovre Hospital, 2650 Hvidovre, Denmark; (M.M.P.); (L.F.); (J.K.); (T.B.P.); (E.R.); (I.J.C.)
| | - Ib J. Christensen
- Department of Surgical Gastroenterology, Hvidovre Hospital, 2650 Hvidovre, Denmark; (M.M.P.); (L.F.); (J.K.); (T.B.P.); (E.R.); (I.J.C.)
| | - Hans J. Nielsen
- Department of Surgical Gastroenterology, Hvidovre Hospital, 2650 Hvidovre, Denmark; (M.M.P.); (L.F.); (J.K.); (T.B.P.); (E.R.); (I.J.C.)
- Institute of Clinical Medicine, University of Copenhagen, 2100 Copenhagen, Denmark
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11
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Raut JR, Guan Z, Schrotz-King P, Brenner H. Fecal DNA methylation markers for detecting stages of colorectal cancer and its precursors: a systematic review. Clin Epigenetics 2020; 12:122. [PMID: 32778176 PMCID: PMC7418412 DOI: 10.1186/s13148-020-00904-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 07/09/2020] [Indexed: 02/06/2023] Open
Abstract
Background DNA methylation biomarkers in stool may have applications in early colorectal cancer (CRC) detection; however, their association with stages of CRC carcinogenesis or their performance in detecting various stages is unclear. We aimed to systematically review the evidence for DNA methylation markers in stool for risk stratification or detection of specific CRC stages, as well as precursors of CRC. Methods We conducted a systematic search in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed and ISI Web of Knowledge to identify relevant studies published until 14th January 2020. Two reviewers independently extracted data on study population characteristics, candidate genes, methylation measurement methods, odds ratios (ORs), overall and stage-specific sensitivities, specificities, areas under the receiver operating characteristics curve, and p-values for statistical significance for OR and for association of methylation levels with stage. Results Twenty-seven studies that reported stage-specific associations or performances of fecal DNA methylation markers for detecting colorectal neoplasms were identified. All studies used methylation-specific polymerase chain reaction for assessing methylation levels in the promoter or exon 1 regions of targeted genes. However, most studies were underpowered and limited by their case-control design. Furthermore, the stage-specific associations or sensitivities were validated for two markers (hypermethylation of GATA4 and VIM) only. Conclusion Methylation markers in stool may be useful for detection of CRC precursors or CRC staging, but promising candidate markers need to be validated in longitudinal studies on large screening populations, performing epigenome-wide analyses. Identification of stage-specific DNA methylation biomarkers in stool could boost current strategies towards early detection and enable different approaches to precision medicine for CRC.
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Affiliation(s)
- Janhavi R Raut
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.,Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany
| | - Zhong Guan
- Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany.,Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Petra Schrotz-King
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Hermann Brenner
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. .,Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. .,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
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12
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DNA methylation patterns of LINE-1 and Alu for pre-symptomatic dementia in type 2 diabetes. PLoS One 2020; 15:e0234578. [PMID: 32525932 PMCID: PMC7289438 DOI: 10.1371/journal.pone.0234578] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 05/28/2020] [Indexed: 12/13/2022] Open
Abstract
The identification of early markers of dementia is important for higher-risk populations such as those with type 2 diabetes (T2D). Retrotransposons, including long interspersed nuclear element 1 (LINE-1) and Alu, comprise ~40% of the human genome. Although dysregulation of these retrotransposons can induce aberrant gene regulation and genomic instability, their role in the development of pre-symptomatic dementia (PSD) among T2D patients is unknown. Here, we examined locus-specific changes in LINE-1 and Alu methylation in PSD and the potential to offset these changes via supplementation with folate and vitamin B12. We interrogated DNA methylation patterns corresponding to 22,352 probes for LINE-1 and Alu elements using publicly-available Illumina Infinium 450K methylation datasets from i) an 18-month prospective study in 28 T2D patients (GSE62003) and ii) an intervention study in which 44 individuals were supplemented with folic acid (400 μg/day) and vitamin B12 (500 μg/day) over two years (GSE74548). We identified 714 differentially methylated positions (DMP) mapping to retrotransposons in T2D patients who developed PSD in comparison to those who did not (PFDR < 0.05), comprised of 2.4% (228 probes) of all LINE-1 probes and 3.8% (486 probes) of all Alu probes. These loci were enriched in genes with functions related to Alzheimer's disease and cognitive decline, including GNB5, GNG7 and PKN3 (p < 0.05). In older individuals supplemented with folate/vitamin B12, 85 (11.9%) PSD retrotransposon loci showed significant changes in methylation (p < 0.05): participants with the MTHFR CC genotype predominantly showed hypermethylation at these loci, while hypomethylation was observed more frequently in those with the TT genotype. In T2D patients, LINE-1 and Alu elements are differentially methylated in PSD in a locus-specific manner and may offer clinical utility in monitoring risk of dementia. Further work is required to examine the potential for dietary supplementation in lowering the risk of PSD.
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