|
1
|
Heydari Z, Moeinvaziri F, Mirazimi SMA, Dashti F, Smirnova O, Shpichka A, Mirzaei H, Timashev P, Vosough M. Alteration in DNA methylation patterns: Epigenetic signatures in gastrointestinal cancers. Eur J Pharmacol 2024; 973:176563. [PMID: 38593929 DOI: 10.1016/j.ejphar.2024.176563] [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: 01/22/2024] [Revised: 03/20/2024] [Accepted: 04/03/2024] [Indexed: 04/11/2024]
Abstract
Abnormalities in epigenetic modifications can cause malignant transformations in cells, leading to cancers of the gastrointestinal (GI) tract, which accounts for 20% of all cancers worldwide. Among the epigenetic alterations, DNA hypomethylation is associated with genomic instability. In addition, CpG methylation and promoter hypermethylation have been recognized as biomarkers for different malignancies. In GI cancers, epigenetic alterations affect genes responsible for cell cycle control, DNA repair, apoptosis, and tumorigenic-specific signaling pathways. Understanding the pattern of alterations in DNA methylation in GI cancers could help scientists discover new molecular-based pharmaceutical treatments. This study highlights alterations in DNA methylation in GI cancers. Understanding epigenetic differences among GI cancers may improve targeted therapies and lead to the discovery of new diagnostic biomarkers.
Collapse
Affiliation(s)
- Zahra Heydari
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
| | - Farideh Moeinvaziri
- Department of Regenerative Medicine, Cell Science Research Centre, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Kashan University of Medical Sciences, Kashan, Iran
| | - Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Kashan University of Medical Sciences, Kashan, Iran
| | - Olga Smirnova
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
| | - Anastasia Shpichka
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Peter Timashev
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia; World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov University, Moscow, Russia; Chemistry Department, Lomonosov Moscow State University, Moscow, Russia.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Centre, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| |
Collapse
|
|
2
|
Xu Y, Wang Z, Pei B, Wang J, Xue Y, Zhao G. DNA methylation markers in esophageal cancer. Front Genet 2024; 15:1354195. [PMID: 38774285 PMCID: PMC11106492 DOI: 10.3389/fgene.2024.1354195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 04/19/2024] [Indexed: 05/24/2024] Open
Abstract
Background Esophageal cancer (EC) is a prevalent malignancy characterized by a low 5-year survival rate, primarily attributed to delayed diagnosis and limited therapeutic options. Currently, early detection of EC heavily relies on endoscopy and pathological examination, which pose challenges due to their invasiveness and high costs, leading to low patient compliance. The detection of DNA methylation offers a non-endoscopic, cost-effective, and secure approach that holds promising prospects for early EC detection. Methods To identify improved methylation markers for early EC detection, we conducted a comprehensive review of relevant literature, summarized the performance of DNA methylation markers based on different input samples and analytical methods in EC early detection and screening. Findings This review reveals that blood cell free DNA methylation-based method is an effective non-invasive method for early detection of EC, although there is still a need to improve its sensitivity and specificity. Another highly sensitive and specific non-endoscopic approach for early detection of EC is the esophageal exfoliated cells based-DNA methylation analysis. However, while there are substantial studies in esophageal adenocarcinoma, further more validation is required in esophageal squamous cell carcinoma. Conclusion In conclusion, DNA methylation detection holds significant potential as an early detection and screening technology for EC.
Collapse
Affiliation(s)
- Yongle Xu
- Suzhou Municipal Hospital, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing Medical University, Suzhou, China
| | - Zhenzhen Wang
- Department of Laboratory Medicine, Affiliated Xuzhou Maternity and Child Healthcare Hospital of Xuzhou Medical University, Xuzhou, China
| | - Bing Pei
- Department of Clinical Laboratory, The Affiliated Suqian First People’s Hospital of Nanjing Medical University, Suqian, China
| | - Jie Wang
- Department of Spleen and Stomach Diseases, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, China
| | - Ying Xue
- Suzhou Municipal Hospital, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing Medical University, Suzhou, China
| | - Guodong Zhao
- Department of Spleen and Stomach Diseases, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, China
- Zhejiang University of Technology, Hangzhou, China
- ZJUT Yinhu Research Institute of Innovation and Entrepreneurship, Hangzhou, China
| |
Collapse
|
|
3
|
Li D, Yuan Y, Meng C, Lin Z, Zhao M, Shi L, Li M, Ye D, Cai Y, He X, Ye H, Zhou S, Zhou H, Gao S. Low expression of miR-182 caused by DNA hypermethylation accelerates acute lymphocyte leukemia development by targeting PBX3 and BCL2: miR-182 promoter methylation is a predictive marker for hypomethylation agents + BCL2 inhibitor venetoclax. Clin Epigenetics 2024; 16:48. [PMID: 38528641 PMCID: PMC10964616 DOI: 10.1186/s13148-024-01658-2] [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: 01/13/2024] [Accepted: 03/14/2024] [Indexed: 03/27/2024] Open
Abstract
BACKGROUND miR-182 promoter hypermethylation frequently occurs in various tumors, including acute myeloid leukemia, and leads to low expression of miR-182. However, whether adult acute lymphocyte leukemia (ALL) cells have high miR-182 promoter methylation has not been determined. METHODS To assess the methylation status of the miR-182 promoter, methylation and unmethylation-specific PCR analysis, bisulfite-sequencing analysis, and MethylTarget™ assays were performed to measure the frequency of methylation at the miR-182 promoter. Bone marrow cells were isolated from miR-182 knockout (182KO) and 182 wild type (182WT) mice to construct BCR-ABL (P190) and Notch-induced murine B-ALL and T-ALL models, respectively. Primary ALL samples were performed to investigate synergistic effects of the hypomethylation agents (HMAs) and the BCL2 inhibitor venetoclax (Ven) in vitro. RESULTS miR-182 (miR-182-5P) expression was substantially lower in ALL blasts than in normal controls (NCs) because of DNA hypermethylation at the miR-182 promoter in ALL blasts but not in normal controls (NCs). Knockout of miR-182 (182KO) markedly accelerated ALL development, facilitated the infiltration, and shortened the OS in a BCR-ABL (P190)-induced murine B-ALL model. Furthermore, the 182KO ALL cell population was enriched with more leukemia-initiating cells (CD43+B220+ cells, LICs) and presented higher leukemogenic activity than the 182WT ALL population. Furthermore, depletion of miR-182 reduced the OS in a Notch-induced murine T-ALL model, suggesting that miR-182 knockout accelerates ALL development. Mechanistically, overexpression of miR-182 inhibited proliferation and induced apoptosis by directly targeting PBX3 and BCL2, two well-known oncogenes, that are key targets of miR-182. Most importantly, DAC in combination with Ven had synergistic effects on ALL cells with miR-182 promoter hypermethylation, but not on ALL cells with miR-182 promoter hypomethylation. CONCLUSIONS Collectively, we identified miR-182 as a tumor suppressor gene in ALL cells and low expression of miR-182 because of hypermethylation facilitates the malignant phenotype of ALL cells. DAC + Ven cotreatment might has been applied in the clinical try for ALL patients with miR-182 promoter hypermethylation. Furthermore, the methylation frequency at the miR-182 promoter should be a potential biomarker for DAC + Ven treatment in ALL patients.
Collapse
Affiliation(s)
- Danyang Li
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, 1 Xuefubei Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Yigang Yuan
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, 1 Xuefubei Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Chen Meng
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, 1 Xuefubei Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Zihan Lin
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, 1 Xuefubei Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Min Zhao
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, 1 Xuefubei Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Liuzhi Shi
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, 1 Xuefubei Street, Ouhai District, Wenzhou, Zhejiang Province, China
| | - Min Li
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, 1 Xuefubei Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Daijiao Ye
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, 1 Xuefubei Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Yue Cai
- Department of Clinical Medicine, Wenzhou Medical University, Chashan District, Wenzhou, Zhejiang Province, China
| | - Xiaofei He
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, 1 Xuefubei Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
- The Key Laboratory of Pediatric Hematology and Oncology Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 Xuanyuanxi Road, Wenzhou, Zhejiang Province, China
| | - Haige Ye
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, 1 Xuefubei Street, Ouhai District, Wenzhou, Zhejiang Province, China
| | - Shujuan Zhou
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, 1 Xuefubei Street, Ouhai District, Wenzhou, Zhejiang Province, China
| | - Haixia Zhou
- The Key Laboratory of Pediatric Hematology and Oncology Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 Xuanyuanxi Road, Wenzhou, Zhejiang Province, China.
- Department of Hematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 Xuanyuanxi Road, Wenzhou, Zhejiang Province, China.
| | - Shenmeng Gao
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, 1 Xuefubei Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China.
- The Key Laboratory of Pediatric Hematology and Oncology Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 Xuanyuanxi Road, Wenzhou, Zhejiang Province, China.
| |
Collapse
|
|
4
|
Jiang Y, Huang H, Liu J, Luo D, Mu R, Yuan J, Lin J, Chen Q, Tao W, Yang L, Zhang M, Zhang P, Fang F, Xu J, Gong Q, Xie Z, Zhang Y. Hippo cooperates with p53 to maintain foregut homeostasis and suppress the malignant transformation of foregut basal progenitor cells. Proc Natl Acad Sci U S A 2024; 121:e2320559121. [PMID: 38408237 PMCID: PMC10927585 DOI: 10.1073/pnas.2320559121] [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: 11/28/2023] [Accepted: 01/23/2024] [Indexed: 02/28/2024] Open
Abstract
Basal progenitor cells serve as a stem cell pool to maintain the homeostasis of the epithelium of the foregut, including the esophagus and the forestomach. Aberrant genetic regulation in these cells can lead to carcinogenesis, such as squamous cell carcinoma (SCC). However, the underlying molecular mechanisms regulating the function of basal progenitor cells remain largely unknown. Here, we use mouse models to reveal that Hippo signaling is required for maintaining the homeostasis of the foregut epithelium and cooperates with p53 to repress the initiation of foregut SCC. Deletion of Mst1/2 in mice leads to epithelial overgrowth in both the esophagus and forestomach. Further molecular studies find that Mst1/2-deficiency promotes epithelial growth by enhancing basal cell proliferation in a Yes-associated protein (Yap)-dependent manner. Moreover, Mst1/2 deficiency accelerates the onset of foregut SCC in a carcinogen-induced foregut SCC mouse model, depending on Yap. Significantly, a combined deletion of Mst1/2 and p53 in basal progenitor cells sufficiently drives the initiation of foregut SCC. Therefore, our studies shed light on the collaborative role of Hippo signaling and p53 in maintaining squamous epithelial homeostasis while suppressing malignant transformation of basal stem cells within the foregut.
Collapse
Affiliation(s)
- Yu Jiang
- State Key Laboratory of Microbial Metabolism and Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai200240, China
| | - Haidi Huang
- State Key Laboratory of Microbial Metabolism and Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai200240, China
| | - Jiangying Liu
- State Key Laboratory of Microbial Metabolism and Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai200240, China
| | - Dan Luo
- State Key Laboratory of Microbial Metabolism and Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai200240, China
| | - Rongzi Mu
- State Key Laboratory of Microbial Metabolism and Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai200240, China
| | - Jianghong Yuan
- State Key Laboratory of Microbial Metabolism and Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai200240, China
| | - Jihong Lin
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou350001, China
| | - Qiyue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou350001, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou350001, China
| | - Wufan Tao
- State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai200433, China
| | - Ling Yang
- Clinical Medical Research Center of The Affiliated Hospital and Inner Mongolia Key Laboratory of Medical Cellular Biology, Inner Mongolia Medical University, Hohhot010050, China
| | - Man Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou510120, China
| | - Pingping Zhang
- State Key Laboratory of Microbial Metabolism and Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai200240, China
| | - Fengqin Fang
- Department of Laboratory Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200336, China
| | - Jianming Xu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX77030
| | - Qingqiu Gong
- State Key Laboratory of Microbial Metabolism and Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai200240, China
| | - Zhiping Xie
- State Key Laboratory of Microbial Metabolism and Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai200240, China
| | - Yongchun Zhang
- State Key Laboratory of Microbial Metabolism and Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai200240, China
| |
Collapse
|
|
5
|
Fang Q, Yuan Z, Hu H, Zhang W, Wang G, Wang X. Genome-wide discovery of circulating cell-free DNA methylation biomarkers for colorectal cancer detection. Clin Epigenetics 2023; 15:119. [PMID: 37501075 PMCID: PMC10375686 DOI: 10.1186/s13148-023-01518-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 06/12/2023] [Indexed: 07/29/2023] Open
Abstract
BACKGROUND Colorectal polyp is known a precursor of colorectal cancer (CRC) that holds an increased risk for progression to CRC. Circulating cell-free DNA (cfDNA) methylation has shown favorable performance in the detection and monitoring the malignant progression in a variety of cancers. RESULTS To discover cfDNA methylation markers for the diagnosis of CRC, we first performed a genome-wide analysis between eight CRC and eight polyp tissues using the Infinium HumanMethylationEPIC BeadChip. We identified 7008 DMCs, and after filtering, we validated 39 DMCs by MethylTarget sequencing in 62 CRC and 56 polyp tissues. A panel of four CpGs (cg04486886, cg06712559, cg13539460, and cg27541454) was selected as the methylation marker in tissue by LASSO and random forest models. A diagnosis prediction model was built based on the four CpGs, and the methylation diagnosis score (md-score) can effectively discriminate tissues with CRC from polyp patients (AUROC > 0.9). Finally, the cg27541454 was confirmed hypermethylated in CRC (AUC = 0.85) in the plasma validation cohort. CONCLUSIONS Our findings suggest that the md-score could robustly detect CRC from polyp tissues, and cg27541454 may be a promising candidate noninvasive biomarker for CRC early diagnosis.
Collapse
Affiliation(s)
- Qingxiao Fang
- Colorectal Cancer Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ziming Yuan
- Colorectal Cancer Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Hanqing Hu
- Colorectal Cancer Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Weiyuan Zhang
- Colorectal Cancer Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Guiyu Wang
- Colorectal Cancer Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
| | - Xishan Wang
- Colorectal Cancer Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| |
Collapse
|
|
6
|
Shi J, Wu L, Chen Y, Zhang M, Yu J, Ren L, He Y, Li J, Ma S, Hu W, Peng H. Association between CORIN methylation and hypertension in Chinese adults. Postgrad Med J 2023; 99:753-762. [DOI: https:/doi.org/10.1136/pmj-2022-141802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2024]
Abstract
Abstract
Background
Corin, a physical activator of atrial natriuretic peptide, has been associated with hypertension with unclear mechanisms. Here, we aimed to examine whether CORIN gene methylation was involved in the underlying molecular mechanisms.
Methods
DNA methylation levels of CORIN were measured by target bisulfite sequencing using genomic DNA isolated from peripheral blood mononuclear cells in 2498 participants in the Gusu cohort (discovery sample) and 1771 independent participants (replication sample). We constructed a mediation model with DNA methylation as the predictor, serum corin as the mediator, and hypertension as the outcome, adjusting for covariates. Multiple testing was controlled by false discovery rate (FDR) approach.
Results
Of the 9 CpGs assayed, hypermethylation at all CpGs were significantly associated with a lower level of blood pressure in the discovery sample and eight associations were also significant in the replication sample (all FDR-adjusted p<0.05). Serum corin mediated approximately 3.07% (p=0.004), 6.25% (p=0.002) and 10.11% (p=0.034) of the associations of hypermethylation at one CpG (Chr4:47840096) with systolic and diastolic blood pressure, and hypertension, respectively. All these mediations passed the causal inference test.
Conclusions
These results suggest that hypermethylation in the CORIN gene is associated with a lower odds of prevalent hypertension and may be involved in the role of corin in blood pressure regulation.
Collapse
Affiliation(s)
- Jijun Shi
- Department of Neurology , , Suzhou , China
- Second Affiliated Hospital of Soochow University , , Suzhou , China
| | - Lei Wu
- Department of Maternal and Child Health , , Suzhou, Jiangsu , China
- Suzhou Industrial Park Center for Disease Control and Prevention , , Suzhou, Jiangsu , China
| | - Yan Chen
- Department of Nephrology , , Jiangyin, Jiangsu , China
- The Affiliated Jiangyin Hospital of Southeast University Medical College , , Jiangyin, Jiangsu , China
| | - Mingzhi Zhang
- Department of Epidemiology , , Suzhou , China
- Soochow University Medical College , , Suzhou , China
| | - Jia Yu
- Department of Epidemiology , , Suzhou, Jiangsu , China
- School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases of Soochow University , , Suzhou, Jiangsu , China
| | - Liyun Ren
- Department of Epidemiology , , Suzhou , China
- Soochow University Medical College , , Suzhou , China
| | - Yan He
- Department of Epidemiology , , Suzhou , China
- Soochow University Medical College , , Suzhou , China
| | - Jing Li
- Department of Epidemiology , , Suzhou, Jiangsu , China
- School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases of Soochow University , , Suzhou, Jiangsu , China
| | - Shengqi Ma
- Department of Epidemiology , , Suzhou, Jiangsu , China
- School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases of Soochow University , , Suzhou, Jiangsu , China
| | - Weidong Hu
- Department of Neurology , , Suzhou , China
- Second Affiliated Hospital of Soochow University , , Suzhou , China
| | - Hao Peng
- Department of Epidemiology , , Suzhou, Jiangsu , China
- School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases of Soochow University , , Suzhou, Jiangsu , China
| |
Collapse
|
|
7
|
Peng H, Palma-Gudiel H, Soriano-Tarraga C, Jimenez-Conde J, Zhang M, Zhang Y, Zhao J. Epigenome-wide association study identifies novel genes associated with ischemic stroke. Clin Epigenetics 2023; 15:106. [PMID: 37370144 DOI: 10.1186/s13148-023-01520-x] [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: 04/24/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND DNA methylation has previously been associated with ischemic stroke, but the specific genes and their functional roles in ischemic stroke remain to be determined. Here we aimed to identify differentially methylated genes that play a functional role in ischemic stroke in a Chinese population. RESULTS Genome-wide DNA methylation assessed with the Illumina Methylation EPIC Array in a discovery sample including 80 Chinese adults (40 cases vs. 40 controls) found that patients with ischemic stroke were characterized by increased DNA methylation at six CpG loci (individually located at TRIM6, FLRT2, SOX1, SOX17, AGBL4, and FAM84A, respectively) and decreased DNA methylation at one additional locus (located at TLN2). Targeted bisulfite sequencing confirmed six of these differentially methylated probes in an independent Chinese population (853 cases vs. 918 controls), and one probe (located at TRIM6) was further verified in an external European cohort (207 cases vs. 83 controls). Experimental manipulation of DNA methylation in engineered human umbilical vein endothelial cells indicated that the identified differentially methylated probes located at TRIM6, TLN2, and FLRT2 genes may play a role in endothelial cell adhesion and atherosclerosis. CONCLUSIONS Altered DNA methylation of the TRIM6, TLN2, and FLRT2 genes may play a functional role in ischemic stroke in Chinese populations.
Collapse
Affiliation(s)
- Hao Peng
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, China
| | - Helena Palma-Gudiel
- Department of Epidemiology, College of Public Health and Health Professions and College of Medicine, University of Florida, 2004 Mowry Road, Gainesville, FL, 32610, USA
| | - Carolina Soriano-Tarraga
- Neurovascular Research Group, Department of Neurology of Hospital del Mar-IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS, Universitat Pompeu Fabra, Barcelona, Spain
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
- NeuroGenomics and Informatics, Department of Psychiatry, Washington University in St. Louis, St. Louis, USA
| | - Jordi Jimenez-Conde
- Neurovascular Research Group, Department of Neurology of Hospital del Mar-IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS, Universitat Pompeu Fabra, Barcelona, Spain
| | - Mingzhi Zhang
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, China
| | - Yonghong Zhang
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, China.
| | - Jinying Zhao
- Department of Epidemiology, College of Public Health and Health Professions and College of Medicine, University of Florida, 2004 Mowry Road, Gainesville, FL, 32610, USA.
| |
Collapse
|
|
8
|
Shi Y, Chang C, Xu L, Jiang P, Wei K, Zhao J, Xu L, Jin Y, Zhang R, Wang H, Qian Y, Qin Y, Ding Q, Jiang T, Guo S, Wang R, He D. Circulating DNA methylation level of CXCR5 correlates with inflammation in patients with rheumatoid arthritis. Immun Inflamm Dis 2023; 11:e902. [PMID: 37382265 PMCID: PMC10288483 DOI: 10.1002/iid3.902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 03/14/2023] [Accepted: 05/22/2023] [Indexed: 06/30/2023] Open
Abstract
OBJECTIVES To assess the differences in circulating DNA methylation levels of CXCR5 between rheumatoid arthritis (RA) and osteoarthritis (OA) and healthy controls (HC), and the correlation of methylation changes with clinical characteristics of RA patients. METHODS Peripheral blood samples were collected from 239 RA patients, 30 patients with OA, and 29 HC. Target region methylation sequencing to the promoter region of CXCR5 was achieved using MethylTarget. The methylation level of cg04537602 and methylation haplotype were compared among the three groups, and the correlation between methylation levels and clinical characteristics of RA patients was performed by Spearman's rank correlation analysis. RESULTS The methylation level of cg04537602 was significantly higher in the peripheral blood of RA patients compared with OA patients (p = 1.3 × 10-3 ) and in the HC group (p = 5.5 × 10- 4 ). The sensitivity was enhanced when CXCR5 methylation level combined with rheumatoid factor and anti-cyclic citrullinated peptide with area under curve (AUC) of 0.982 (95% confidence interval 0.970-0.995). The methylation level of cg04537602 in RA was positively correlated with C-reactive protein (CRP) (r = .16, p = .01), and in RA patients aged 60 years and above, cg04537602 methylation levels were positively correlated with CRP (r = .31, p = 4.7 × 10- 4 ), tender joint count (r = .21, p = .02), visual analog scales score (r = .21, p = .02), Disease Activity Score in 28 joints (DAS28) using the CRP level DAS28-CRP (r = .27, p = 2.1 × 10- 3 ), and DAS28-ESR (r = .22, p = .01). We also observed significant differences of DNA methylation haplotypes in RA patients compared with OA patients and HC, which was consistent with single-loci-based CpG methylation measurement. CONCLUSION The methylation level of CXCR5 was significantly higher in RA patients than in OA and HC, and correlated with the level of inflammation in RA patients, our study establishes a link between CXCR5 DNA methylation and clinical features that may help in the diagnosis and disease management of RA patients.
Collapse
Affiliation(s)
- Yiming Shi
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Cen Chang
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Lingxia Xu
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Ping Jiang
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Kai Wei
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Jianan Zhao
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Linshuai Xu
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Yehua Jin
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Runrun Zhang
- Department of RheumatologyThe Second Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhouChina
| | - Huijuan Wang
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Yi Qian
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Yingying Qin
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Qin Ding
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Ting Jiang
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Shicheng Guo
- Computation and Informatics in Biology and MedicineUniversity of Wisconsin‐MadisonMadisonWisconsinUSA
- Department of Medical Genetics, School of Medicine and Public HealthUniversity of Wisconsin‐ MadisonMadisonWisconsinUSA
| | - Rongsheng Wang
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Dongyi He
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| |
Collapse
|
|
9
|
Chen L, Jiang J, Yao J, Lu Y, Zhang X, Zhang M, Zhang Q, Peng H. Association between CORIN promoter methylation and stroke: Results from two independent samples of Chinese adults. Front Neurol 2023; 14:1103374. [PMID: 37064175 PMCID: PMC10102360 DOI: 10.3389/fneur.2023.1103374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 03/13/2023] [Indexed: 04/03/2023] Open
Abstract
ObjectiveAs the physical activator of natriuretic peptides, corin has been associated with stroke, but the underlying mechanism is not very clear. Here, we examined whether the CORIN promoter’s methylation, an epigenetic DNA modification, was associated with the risk of stroke in two independent samples.MethodsA total of 1771 participants including 853 stroke cases and 918 healthy controls were included as a discovery sample and 2,498 community members with 10 years of follow-up were included as a replication sample. DNA methylation of the CORIN promoter was quantified by target bisulfite sequencing in both samples. We first examined the single CpG association, followed by a gene-based analysis of the joint association between multiple CpG methylation and stroke, adjusting for conventional risk factors.ResultsThe single CpG association analysis found that hypermethylation at all of the 9 CpG sites assayed was significantly associated with lower odds of prevalent stroke in the discovery sample (all p < 0.05), and three of them located at Chr4:47840038 (HR = 0.74, p = 0.015), Chr4:47839941 (HR = 0.80, p = 0.047), and Chr4:47839933 (HR = 0.82, p = 0.050) were also significantly associated with incident stroke in the replication sample. The gene-based association analysis found that DNA methylation of the 9 CpG sites at the CORIN promoter was jointly associated with stroke in both samples (all p < 0.05).ConclusionDNA methylation levels of the CORIN gene promoter were lower in stroke patients and predicted a higher risk of incident stroke in Chinese adults. The underlying causality warranted further investigation.
Collapse
Affiliation(s)
- Linan Chen
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Jun Jiang
- Department of Tuberculosis Control, Suzhou Center for Disease Control and Prevention, Suzhou, China
| | - Jialing Yao
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Ying Lu
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Xiaolong Zhang
- Department of Tuberculosis Control, Suzhou Center for Disease Control and Prevention, Suzhou, China
| | - Mingzhi Zhang
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Qiu Zhang
- Department of Chronic Disease, Gusu Center for Disease Control and Prevention, Suzhou, China
- *Correspondence: Hao Peng, ; Qiu Zhang,
| | - Hao Peng
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou, China
- *Correspondence: Hao Peng, ; Qiu Zhang,
| |
Collapse
|
|
10
|
Tang Z, Yang Y, Zhang Q, Liang T. Epigenetic dysregulation-mediated COL12A1 upregulation predicts worse outcome in intrahepatic cholangiocarcinoma patients. Clin Epigenetics 2023; 15:13. [PMID: 36694230 PMCID: PMC9875497 DOI: 10.1186/s13148-022-01413-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 12/18/2022] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Collagen type XII alpha 1 chain (COL12A1) is associated with human cancer progression. Nevertheless, the expression pattern and the function of COL12A1 in intrahepatic cholangiocarcinoma (iCCA) remain unknown. The present study was performed to assess the role of COL12A1 in iCCA. RESULTS A total of 1669 genes, differentially expressed between iCCA and nontumor liver tissue samples, were identified as potential tumor-specific biomarkers for iCCA patients. Of these, COL12A1 was significantly upregulated in clinical iCCA tissue samples and correlated with epithelial-mesenchymal transition gene set enrichment score and advanced tumor stage in clinical iCCA. COL12A1-high expression was associated with the poor prognoses of iCCA patients (n = 421) from four independent cohorts. Promoter hypermethylation-induced downregulation of miR-424-5p resulted in COL12A1 upregulation in clinical iCCA. Experimental knockout of COL12A1 inhibited the proliferation, invasiveness and growth of iCCA cells. MiR-424-5p had a therapeutic potential in iCCA via directly targeting COL12A1. CONCLUSIONS Promoter hypermethylation-induced miR-424-5p downregulation contributes to COL12A1 upregulation in iCCA. COL12A1 is a promising druggable target for epigenetic therapy of iCCA.
Collapse
Affiliation(s)
- Zengwei Tang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, Zhejiang, China
- Zhejiang University Cancer Center, Hangzhou, 310058, Zhejiang, China
| | - Yuan Yang
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, Zhejiang, China
- Zhejiang University Cancer Center, Hangzhou, 310058, Zhejiang, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China.
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China.
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, Zhejiang, China.
- Zhejiang University Cancer Center, Hangzhou, 310058, Zhejiang, China.
| |
Collapse
|
|
11
|
Zhang Y, Zhang Y, Peng L, Zhang L. Research Progress on the Predicting Factors and Coping Strategies for Postoperative Recurrence of Esophageal Cancer. Cells 2022; 12:cells12010114. [PMID: 36611908 PMCID: PMC9818463 DOI: 10.3390/cells12010114] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 12/01/2022] [Accepted: 12/20/2022] [Indexed: 12/29/2022] Open
Abstract
Esophageal cancer is one of the malignant tumors with poor prognosis in China. Currently, the treatment of esophageal cancer is still based on surgery, especially in early and mid-stage patients, to achieve the goal of radical cure. However, esophageal cancer is a kind of tumor with a high risk of recurrence and metastasis, and locoregional recurrence and distant metastasis are the leading causes of death after surgery. Although multimodal comprehensive treatment has advanced in recent years, the prediction, prevention and treatment of postoperative recurrence and metastasis of esophageal cancer are still unsatisfactory. How to reduce recurrence and metastasis in patients after surgery remains an urgent problem to be solved. Given the clinical demand for early detection of postoperative recurrence of esophageal cancer, clinical and basic research aiming to meet this demand has been a hot topic, and progress has been observed in recent years. Therefore, this article reviews the research progress on the factors that influence and predict postoperative recurrence of esophageal cancer, hoping to provide new research directions and treatment strategies for clinical practice.
Collapse
Affiliation(s)
- Yujie Zhang
- Department of Oncology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China
| | - Yuxin Zhang
- Department of Pediatric Surgery, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China
| | - Lin Peng
- Department of Oncology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China
| | - Li Zhang
- Department of Oncology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China
- Correspondence:
| |
Collapse
|
|
12
|
Yu Q, Xia N, Zhao Y, Jin H, Chen R, Ye F, Chen L, Xie Y, Wan K, Zhou J, Zhou D, Lv X. Genome-wide methylation profiling identify hypermethylated HOXL subclass genes as potential markers for esophageal squamous cell carcinoma detection. BMC Med Genomics 2022; 15:247. [PMID: 36447287 PMCID: PMC9706897 DOI: 10.1186/s12920-022-01401-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 11/22/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND Numerous studies have revealed aberrant DNA methylation in esophageal squamous cell carcinoma (ESCC). However, they often focused on the partial genome, which resulted in an inadequate understanding of the shaped methylation features and the lack of available methylation markers for this disease. METHODS The current study investigated the methylation profiles between ESCC and paired normal samples using whole-genome bisulfite sequencing (WGBS) data and obtained a group of differentially methylated CpGs (DMC), differentially methylated regions (DMR), and differentially methylated genes (DMG). The DMGs were then verified in independent datasets and Sanger sequencing in our custom samples. Finally, we attempted to evaluate the performance of these genes as methylation markers for the classification of ESCC. RESULTS We obtained 438,558 DMCs, 15,462 DMRs, and 1568 DMGs. The four significantly enriched gene families of DMGs were CD molecules, NKL subclass, HOXL subclass, and Zinc finger C2H2-type. The HOXL subclass homeobox genes were observed extensively hypermethylated in ESCC. The HOXL-score estimated by HOXC10 and HOXD1 methylation, whose methylation status were then confirmed by sanger sequencing in our custom ESCC samples, showed good ability in discriminating ESCC from normal samples. CONCLUSIONS We observed widespread hypomethylation events in ESCC, and the hypermethylated HOXL subclass homeobox genes presented promising applications for the early detection of esophageal squamous cell carcinoma.
Collapse
Affiliation(s)
- Qiuning Yu
- grid.412633.10000 0004 1799 0733Otorhinolaryngology Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Namei Xia
- grid.412633.10000 0004 1799 0733Department of Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Yanteng Zhao
- grid.412633.10000 0004 1799 0733Department of Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Huifang Jin
- grid.412633.10000 0004 1799 0733Department of Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Renyin Chen
- grid.412633.10000 0004 1799 0733Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Fanglei Ye
- grid.412633.10000 0004 1799 0733Otorhinolaryngology Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Liyinghui Chen
- grid.412633.10000 0004 1799 0733Department of Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Ying Xie
- grid.412633.10000 0004 1799 0733Department of Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Kangkang Wan
- Wuhan Ammunition Life-tech Company, Ltd., Wuhan, Hubei China
| | - Jun Zhou
- Wuhan Ammunition Life-tech Company, Ltd., Wuhan, Hubei China
| | - Dihan Zhou
- Wuhan Ammunition Life-tech Company, Ltd., Wuhan, Hubei China
| | - Xianping Lv
- grid.412633.10000 0004 1799 0733Department of Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| |
Collapse
|
|
13
|
Shi J, Wu L, Chen Y, Zhang M, Yu J, Ren L, He Y, Li J, Ma S, Hu W, Peng H. Association between CORIN methylation and hypertension in Chinese adults. Postgrad Med J 2022; 99:pmj-2022-141802. [PMID: 37117043 DOI: 10.1136/pmj-2022-141802] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 07/22/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND Corin, a physical activator of atrial natriuretic peptide, has been associated with hypertension with unclear mechanisms. Here, we aimed to examine whether CORIN gene methylation was involved in the underlying molecular mechanisms. METHODS DNA methylation levels of CORIN were measured by target bisulfite sequencing using genomic DNA isolated from peripheral blood mononuclear cells in 2498 participants in the Gusu cohort (discovery sample) and 1771 independent participants (replication sample). We constructed a mediation model with DNA methylation as the predictor, serum corin as the mediator, and hypertension as the outcome, adjusting for covariates. Multiple testing was controlled by false discovery rate (FDR) approach. RESULTS Of the 9 CpGs assayed, hypermethylation at all CpGs were significantly associated with a lower level of blood pressure in the discovery sample and eight associations were also significant in the replication sample (all FDR-adjusted p<0.05). Serum corin mediated approximately 3.07% (p=0.004), 6.25% (p=0.002) and 10.11% (p=0.034) of the associations of hypermethylation at one CpG (Chr4:47840096) with systolic and diastolic blood pressure, and hypertension, respectively. All these mediations passed the causal inference test. CONCLUSIONS These results suggest that hypermethylation in the CORIN gene is associated with a lower odds of prevalent hypertension and may be involved in the role of corin in blood pressure regulation.
Collapse
Affiliation(s)
- Jijun Shi
- Department of Neurology, Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Lei Wu
- Department of Maternal and Child Health, Suzhou Industrial Park Center for Disease Control and Prevention, Suzhou, Jiangsu, China
| | - Yan Chen
- Department of Nephrology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu, China
| | - Mingzhi Zhang
- Department of Epidemiology, Soochow University Medical College, Suzhou, China
| | - Jia Yu
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases of Soochow University, Suzhou, Jiangsu, China
| | - Liyun Ren
- Department of Epidemiology, Soochow University Medical College, Suzhou, China
| | - Yan He
- Department of Epidemiology, Soochow University Medical College, Suzhou, China
| | - Jing Li
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases of Soochow University, Suzhou, Jiangsu, China
| | - Shengqi Ma
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases of Soochow University, Suzhou, Jiangsu, China
| | - Weidong Hu
- Department of Neurology, Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Hao Peng
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases of Soochow University, Suzhou, Jiangsu, China
| |
Collapse
|
|
14
|
Peng H, Fan Y, Li J, Zheng X, Zhong C, Zhu Z, He Y, Zhang M, Zhang Y. DNA Methylation of the Natriuretic Peptide System Genes and Ischemic Stroke: Gene-Based and Gene Set Analyses. Neurol Genet 2022; 8:e679. [PMID: 35620136 PMCID: PMC9128040 DOI: 10.1212/nxg.0000000000000679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/18/2022] [Indexed: 11/15/2022]
Abstract
Background and Objectives The natriuretic peptide (NP) system has been considered an important regulator for ischemic stroke (IS) with a limited clinical implication. A better understanding of the underlying molecular mechanisms is urgent. Here, we aimed to examine the role of DNA methylation of NP system genes in IS. Methods DNA methylation at promoter regions of 4 core NP system genes, e.g., CORIN, FURIN, NPPA, and NPPB, was measured by targeted bisulfite sequencing in 853 patients with IS and 918 controls. We first examined the association between DNA methylation at each single CpG and IS, followed by gene-based and gene set analyses to examine the joint associations of DNA methylation at multiple CpGs in a gene or all 4 genes as a pathway with IS. Results After control of covariates and multiple testing, DNA methylation at 19 of the 36 assayed CpGs was individually associated with IS at q < 0.05. Higher average methylation levels at the targeted regions of CORIN (odds ratio [OR] = 0.64, 95% confidence interval [CI]: 0.56–0.73), FURIN (OR = 0.78, 95% CI: 0.69–0.88), and NPPA (OR = 0.78, 95% CI: 0.69–0.88) were associated with a lower odds of IS (all q < 0.05). The truncated product method revealed the same gene-based associations (all q < 0.05) and found that DNA methylation at all 4 NP system genes together was jointly associated with IS (p = 0.0001). Discussion DNA methylation at NP system genes was downregulated in patients with IS. Our results may unravel a molecular mechanism underlying the regulating effect of the NP system on IS and highlight the relevance of testing the joint effect of multiple CpGs in the epigenetic analysis.
Collapse
Affiliation(s)
- Hao Peng
- Department of Epidemiology (H.P., J.L., X.Z., C.Z., Z.Z., Y.H., M.Z., Y.Z.), School of Public Health, Medical College of Soochow University; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (H.P.); and Medical College of Soochow University (Y.F.), Suzhou, China
| | - Yiming Fan
- Department of Epidemiology (H.P., J.L., X.Z., C.Z., Z.Z., Y.H., M.Z., Y.Z.), School of Public Health, Medical College of Soochow University; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (H.P.); and Medical College of Soochow University (Y.F.), Suzhou, China
| | - Jing Li
- Department of Epidemiology (H.P., J.L., X.Z., C.Z., Z.Z., Y.H., M.Z., Y.Z.), School of Public Health, Medical College of Soochow University; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (H.P.); and Medical College of Soochow University (Y.F.), Suzhou, China
| | - Xiaowei Zheng
- Department of Epidemiology (H.P., J.L., X.Z., C.Z., Z.Z., Y.H., M.Z., Y.Z.), School of Public Health, Medical College of Soochow University; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (H.P.); and Medical College of Soochow University (Y.F.), Suzhou, China
| | - Chongke Zhong
- Department of Epidemiology (H.P., J.L., X.Z., C.Z., Z.Z., Y.H., M.Z., Y.Z.), School of Public Health, Medical College of Soochow University; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (H.P.); and Medical College of Soochow University (Y.F.), Suzhou, China
| | - Zhengbao Zhu
- Department of Epidemiology (H.P., J.L., X.Z., C.Z., Z.Z., Y.H., M.Z., Y.Z.), School of Public Health, Medical College of Soochow University; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (H.P.); and Medical College of Soochow University (Y.F.), Suzhou, China
| | - Yan He
- Department of Epidemiology (H.P., J.L., X.Z., C.Z., Z.Z., Y.H., M.Z., Y.Z.), School of Public Health, Medical College of Soochow University; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (H.P.); and Medical College of Soochow University (Y.F.), Suzhou, China
| | - Mingzhi Zhang
- Department of Epidemiology (H.P., J.L., X.Z., C.Z., Z.Z., Y.H., M.Z., Y.Z.), School of Public Health, Medical College of Soochow University; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (H.P.); and Medical College of Soochow University (Y.F.), Suzhou, China
| | - Yonghong Zhang
- Department of Epidemiology (H.P., J.L., X.Z., C.Z., Z.Z., Y.H., M.Z., Y.Z.), School of Public Health, Medical College of Soochow University; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (H.P.); and Medical College of Soochow University (Y.F.), Suzhou, China
| |
Collapse
|
|
15
|
Fu J, Zhang L, Li D, Tian T, Wang X, Sun H, Ge A, Liu Y, Zhang X, Huang H, Meng S, Zhang D, Zhao L, Sun S, Zheng T, Jia C, Zhao Y, Pang D. DNA Methylation of Imprinted Genes KCNQ1, KCNQ1OT1, and PHLDA2 in Peripheral Blood Is Associated with the Risk of Breast Cancer. Cancers (Basel) 2022; 14:cancers14112652. [PMID: 35681632 PMCID: PMC9179312 DOI: 10.3390/cancers14112652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/23/2022] [Accepted: 05/25/2022] [Indexed: 02/01/2023] Open
Abstract
Methylation alterations of imprinted genes lead to loss of imprinting (LOI). Although studies have explored the mechanism of LOI in breast cancer (BC) development, the association between imprinted gene methylation in peripheral blood and BC risk is largely unknown. We utilized HumanMethylation450 data from TCGA and GEO (n = 1461) to identify the CpG sites of imprinted genes associated with BC risk. Furthermore, we conducted an independent case-control study (n = 1048) to validate DNA methylation of these CpG sites in peripheral blood and BC susceptibility. cg26709929, cg08446215, cg25306939, and cg16057921, which are located at KCNQ1, KCNQ1OT1, and PHLDA2, were discovered to be associated with BC risk. Subsequently, the association between cg26709929, cg26057921, and cg25306939 methylation and BC risk was validated in our inhouse dataset. All 22 CpG sites in the KCNQ1OT1 region were associated with BC risk. Individuals with a hypermethylated KCNQ1OT1 region (>0.474) had a lower BC risk (OR: 0.553, 95% CI: 0.397−0.769). Additionally, the methylation of the KCNQ1OT1 region was not significantly different among B cells, monocytes, and T cells, which was also observed at CpG sites in PHLDA2. In summary, the methylation of KCNQ1, KCNQ1OT1, and PHLDA2 was associated with BC risk, and KCNQ1OT1 methylation could be a potential biomarker for BC risk assessment.
Collapse
Affiliation(s)
- Jinming Fu
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
- Department of Biostatistics, School of Public Health, Xuzhou Medical University, Xuzhou 221004, China
| | - Lei Zhang
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
| | - Dapeng Li
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
| | - Tian Tian
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
| | - Xuan Wang
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
| | - Hongru Sun
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
| | - Anqi Ge
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
| | - Yupeng Liu
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
| | - Xianyu Zhang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150081, China;
| | - Hao Huang
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
| | - Shuhan Meng
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
| | - Ding Zhang
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
| | - Liyuan Zhao
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
| | - Simin Sun
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
| | - Ting Zheng
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
| | - Chenyang Jia
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
| | - Yashuang Zhao
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, China; (J.F.); (L.Z.); (D.L.); (T.T.); (X.W.); (H.S.); (A.G.); (Y.L.); (H.H.); (S.M.); (D.Z.); (L.Z.); (S.S.); (T.Z.); (C.J.)
- Correspondence: (Y.Z.); (D.P.); Tel.: +86-451-8750-2823 (Y.Z.); +86-451-8750-2885 (D.P.)
| | - Da Pang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150081, China;
- Correspondence: (Y.Z.); (D.P.); Tel.: +86-451-8750-2823 (Y.Z.); +86-451-8750-2885 (D.P.)
| |
Collapse
|
|
16
|
Serum Atrial Natriuretic Peptide, NPPA Promoter Methylation, and Cardiovascular Disease: A 10-year Follow-Up Study in Chinese Adults. Glob Heart 2022; 17:27. [PMID: 35586748 PMCID: PMC8992767 DOI: 10.5334/gh.1116] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 03/16/2022] [Indexed: 11/20/2022] Open
|
|
17
|
He Y, Li Y, Zhang J, Chen L, Li J, Zhang M, Zhang Q, Lu Y, Jiang J, Zhang X, Hu J, Ding Y, Zhang M, Peng H. FURIN Promoter Methylation Predicts the Risk of Incident Diabetes: A Prospective Analysis in the Gusu Cohort. Front Endocrinol (Lausanne) 2022; 13:873012. [PMID: 35399937 PMCID: PMC8990793 DOI: 10.3389/fendo.2022.873012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 02/25/2022] [Indexed: 12/02/2022] Open
Abstract
Background Furin has been associated with diabetes but the underlying mechanisms are unclear. As a mediator linking fixed genome and dynamic environment, DNA methylation of its coding gene FURIN may be involved. Here, we aimed to examine the prospective association between DNA methylation in FURIN promoter and incident diabetes during 4 years of follow-up in Chinese adults. Methods DNA methylation levels in FURIN promoter were quantified by target bisulfite sequencing using peripheral blood from 1836 participants in the Gusu cohort who were free of diabetes at baseline. To examine the association between DNA methylation levels in FURIN promoter and incident diabetes, we constructed a logistic regression model adjusting for the conventional factors. Multiple testing was controlled by adjusting for the total number of CpG sites assayed using the false-discovery rate approach. Results Among the 1836 participants free of diabetes at baseline, 109 (5.94%) participants developed diabetes during the average of 4 years of follow-up. Hypermethylation at two of the eight CpG sites assayed in the FURIN promoter was associated with an increased risk of diabetes, after multivariable adjustment and multiple testing correction. Every 5% increment in methylation levels at CpG1 and CpG2 were associated with a 22% (OR=1.22, 95%CI: 1.05-1.43, P=0.009, q=0.038) and 39% (OR=1.39, 95%CI: 1.08-1.77, P=0.009, q=0.038) higher risk of incident diabetes, respectively. The gene-based association analysis revealed that DNA methylation at multiple CpG loci was jointly associated with incident diabetes (P<0.001). Using the average methylation level of the 8 CpG loci in FURIN promoter revealed a similar association (OR=1.28, 95% CI: 1.02-1.62, P=0.037). Conclusions These results suggested that the hypermethylation levels in FURIN promoter were associated with an increased risk for incident diabetes in Chinese adults.
Collapse
Affiliation(s)
- Yan He
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| | - Yinan Li
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Jianan Zhang
- Department of Chronic Disease, Taicang Center for Disease Control and Prevention, Suzhou, China
| | - Linan Chen
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Jing Li
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Min Zhang
- Department of Central Office, Suzhou National New and Hi-Tech Industrial Development Zone Center for Disease Control and Prevention, Suzhou, China
| | - Qiu Zhang
- Department of Chronic Disease, Gusu Center for Disease Control and Prevention, Suzhou, China
| | - Ying Lu
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Jun Jiang
- Department of Tuberculosis Control, Suzhou Center for Disease Control and Prevention, Suzhou, China
| | - Xiaolong Zhang
- Department of Tuberculosis Control, Suzhou Center for Disease Control and Prevention, Suzhou, China
| | - Jianwei Hu
- Department of Central Office, Maternal and Child Health Bureau of Kunshan, Suzhou, China
| | - Yi Ding
- Department of Preventive Medicine, College of Clinical Medicine, Suzhou Vocational Health College, Suzhou, China
| | - Mingzhi Zhang
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Hao Peng
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| |
Collapse
|
|
18
|
Multi-omic characterization of genome-wide abnormal DNA methylation reveals diagnostic and prognostic markers for esophageal squamous-cell carcinoma. Signal Transduct Target Ther 2022; 7:53. [PMID: 35210398 PMCID: PMC8873499 DOI: 10.1038/s41392-022-00873-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 11/23/2021] [Accepted: 12/30/2021] [Indexed: 02/07/2023] Open
Abstract
This study investigates aberrant DNA methylations as potential diagnosis and prognosis markers for esophageal squamous-cell carcinoma (ESCC), which if diagnosed at advanced stages has <30% five-year survival rate. Comparing genome-wide methylation sites of 91 ESCC and matched adjacent normal tissues, we identified 35,577 differentially methylated CpG sites (DMCs) and characterized their distribution patterns. Integrating whole-genome DNA and RNA-sequencing data of the same samples, we found multiple dysregulated transcription factors and ESCC-specific genomic correlates of identified DMCs. Using featured DMCs, we developed a 12-marker diagnostic panel with high accuracy in our dataset and the TCGA ESCC dataset, and a 4-marker prognostic panel distinguishing high-risk patients. In-vitro experiments validated the functions of 4 marker host genes. Together these results provide additional evidence for the important roles of aberrant DNA methylations in ESCC development and progression. Our DMC-based diagnostic and prognostic panels have potential values for clinical care of ESCC, laying foundations for developing targeted methylation assays for future non-invasive cancer detection methods.
Collapse
|
|
19
|
Lu Z, Su K, Wang X, Zhang M, Ma S, Li H, Qiu Y. Expression Profiles of tRNA-Derived Small RNAs and Their Potential Roles in Primary Nasopharyngeal Carcinoma. Front Mol Biosci 2022; 8:780621. [PMID: 34988117 PMCID: PMC8722782 DOI: 10.3389/fmolb.2021.780621] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 11/17/2021] [Indexed: 11/13/2022] Open
Abstract
Introduction: tRNA-derived small RNAs (tsRNAs), a class of small non-coding RNAs, are divided into two categories: tRNA-related fragments (tRFs) and tRNA halves (tiRNAs). Abnormal expression of tsRNAs has been found in diverse cancers, which indicates that further understanding of the function of tsRNAs will help identify new biomarkers and potential therapeutic targets. Until now, the underlying roles of tsRNAs in primary nasopharyngeal carcinoma (NPC) are still unknown. Methods: tRF and tiRNA sequencing was performed on four pairs of NPC tissues and healthy controls. Thirty pairs of NPC samples were used for quantitative real-time polymerase chain reaction (qRT-PCR) verification, and the ROC analysis was used to evaluate the diagnostic efficiency initially. Target prediction and bioinformatics analysis of validated tRFs and tiRNAs were conducted to explore the mechanisms of tsRNAs in NPC’s pathogenesis. Results: A total of 158 differentially expressed tRFs and tiRNAs were identified, of which 88 are upregulated and 70 are downregulated in NPC. Three validated tRFs in the results of qRT-PCR were consistent with the sequencing data: two upregulations (tRF-1:28-Val-CAC-2 and tRF-1:24-Ser-CGA-1-M3) and one downregulation (tRF-55:76-Arg-ACG-1-M2). The GO and KEGG pathway enrichment analysis showed that the potential target genes of validated tRFs are widely enriched in cancer pathways. The related modules may play an essential role in the pathogenesis of NPC. Conclusions: The tsRNAs may become a novel class of biological diagnostic indicators and possible targets for NPC.
Collapse
Affiliation(s)
- Zhaoyi Lu
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.,Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Kai Su
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xiaomin Wang
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Mingjie Zhang
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Shiyin Ma
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Hui Li
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yuanzheng Qiu
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China
| |
Collapse
|
|
20
|
Li J, Zhu J, Zhang Q, Chen L, Ma S, Lu Y, Shen B, Zhang R, Zhang M, He Y, Wu L, Peng H. NPPA Promoter Hypomethylation Predicts Central Obesity Development: A Prospective Longitudinal Study in Chinese Adults. Obes Facts 2022; 15:257-270. [PMID: 34875662 PMCID: PMC9021652 DOI: 10.1159/000521295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 11/26/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Atrial natriuretic peptide plays a potential role in obesity with unclear molecular mechanisms. The objective of this study was to examine the association between its coding gene (natriuretic peptide A [NPPA]) methylation and obesity. METHODS Peripheral blood DNA methylation of NPPA promoter was quantified at baseline by targeted bisulfite sequencing for 2,497 community members (mean aged 53 years, 38% men) in the Gusu cohort. Obesity was repeatedly assessed by body mass index (BMI) and waist circumference (WC) at baseline and follow-up examinations. The cross-sectional, longitudinal, and prospective associations between NPPA promoter methylation and obesity were examined. RESULTS Of the 9 CpG loci assayed, DNA methylation levels at 6 CpGs were significantly lower in participants with central obesity than those without (all p < 0.05 for permutation test). These CpG methylation levels at baseline were also inversely associated with dynamic changes in BMI or WC during follow-up (all p < 0.05 for permutation test). After an average 4 years of follow-up, hypermethylation at the 6 CpGs (CpG2 located at Chr1:11908348, CpG3 located at Chr1:11908299, CpG4 located at Chr1:11908200, CpG5 located at Chr1:11908182, CpG6 located at Chr1:11908178, and CpG8 located at Chr1:11908165) was significantly associated with a lower risk of incident central obesity (all p < 0.05 for permutation test). CONCLUSIONS Hypomethylation at NPPA promoter was associated with increased future risk of central obesity in Chinese adults. Aberrant DNA methylation of the NPPA gene may participate in the mechanisms of central obesity.
Collapse
Affiliation(s)
- Jing Li
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Jinhua Zhu
- Department of Chronic Disease Management, Center for Disease Prevention and Control of Wujiang District, Suzhou, China
| | - Qiu Zhang
- Department of Chronic Disease Management, Center for Disease Prevention and Control of Gusu District, Suzhou, China
| | - Linan Chen
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Shengqi Ma
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Ying Lu
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Bin Shen
- Department of Chronic Disease Management, Center for Disease Prevention and Control of Wujiang District, Suzhou, China
| | - Rongyan Zhang
- Department of Chronic Disease Management, Center for Disease Prevention and Control of Wujiang District, Suzhou, China
| | - Mingzhi Zhang
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Yan He
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou, China
| | - Lei Wu
- Department of Maternal and Child Health, Suzhou Industrial Park Center for Disease Control and Prevention, Suzhou, China
- *Lei Wu,
| | - Hao Peng
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou, China
- ** Hao Peng,
| |
Collapse
|
|
21
|
Wang H, DeFina SM, Bajpai M, Yan Q, Yang L, Zhou Z. DNA methylation markers in esophageal cancer: an emerging tool for cancer surveillance and treatment. Am J Cancer Res 2021; 11:5644-5658. [PMID: 34873485 PMCID: PMC8640794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 09/30/2021] [Indexed: 06/13/2023] Open
Abstract
Esophageal carcinoma (EC) is one of the most pervasive cancers in the world, with upwards of 500,000 new diagnoses, annually. Despite its prominence, advancements in the detection and treatment of EC have been marginal over the past 30 years and the survival rate continues to stay below 20%. This is due to the uncommonly heterogeneous presentation of EC which presents unprecedented challenges in improving patient survival and quality of care. However, distinct epigenetic alterations to the DNA methylome may provide an avenue to drastically improve the detection and treatment of EC. Specifically, the creation of novel biomarker panels that consist of EC-specific methylation markers have shown promise as a potential alternative to the more invasive, contemporary diagnostic methods. Additionally, growing insight into the biological and clinical properties of EC-specific methylation patterns have opened a window of opportunity for enhanced treatment; of growing interest is the application of "DNMT inhibitors" - a class of drugs which inhibit excessive methylation and have been shown to re-sensitize chemoresistant tumors. Here we provide a comprehensive review of the current advancements in EC DNA methylation to underscore a potential approach to its detection and treatment.
Collapse
Affiliation(s)
- He Wang
- Department of Pathology, Yale School of Medicine, Yale UniversityNew Haven, Connecticut, United States
| | - Samuel M DeFina
- Department of Pathology, Yale School of Medicine, Yale UniversityNew Haven, Connecticut, United States
| | - Manisha Bajpai
- Department of Medicine-Gastroenterology and Hepatology, Rutgers-Robert Wood Johnson Medical School, Rutgers The State University of New JerseyNew Brunswick, NJ, United States
| | - Qin Yan
- Department of Pathology, Yale School of Medicine, Yale UniversityNew Haven, Connecticut, United States
| | - Lei Yang
- Department of Pathology, Yale School of Medicine, Yale UniversityNew Haven, Connecticut, United States
| | - Zhongren Zhou
- Department of Pathology & Laboratory Medicine, Rutgers-Robert Wood Johnson Medical School, Rutgers The State University of New JerseyNew Brunswick, NJ, United States
| |
Collapse
|
|
22
|
Pu W, Qian F, Liu J, Shao K, Xiao F, Jin Q, Liu Q, Jiang S, Zhang R, Zhang J, Guo S, Zhang J, Ma Y, Ju S, Ding W. Targeted Bisulfite Sequencing Reveals DNA Methylation Changes in Zinc Finger Family Genes Associated With KRAS Mutated Colorectal Cancer. Front Cell Dev Biol 2021; 9:759813. [PMID: 34778269 PMCID: PMC8581662 DOI: 10.3389/fcell.2021.759813] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/11/2021] [Indexed: 11/24/2022] Open
Abstract
Background: Colorectal cancer (CRC) is a leading cause of cancer death, and early diagnosis of CRC could significantly reduce its mortality rate. Previous studies suggest that the DNA methylation status of zinc finger genes (ZFGs) could be of potential in CRC early diagnosis. However, the comprehensive evaluation of ZFGs in CRC is still lacking. Methods: We first collected 1,426 public samples on genome-wide DNA methylation, including 1,104 cases of CRC tumors, 54 adenomas, and 268 para-tumors. Next, the most differentially methylated ZFGs were identified and validated in two replication cohorts comprising 218 CRC patients. Finally, we compared the prediction capabilities between the ZFGs and the SEPT9 in all CRC patients and the KRAS + and KRAS- subgroup. Results: Five candidate ZFGs were selected: ESR1, ZNF132, ZNF229, ZNF542, and ZNF677. In particular, ESR1 [area under the curve (AUC) = 0.91] and ZNF132 (AUC = 0.93) showed equivalent or better diagnostic capability for CRC than SEPT9 (AUC = 0.91) in the validation dataset, suggesting that these two ZFGs might be of potential for CRC diagnosis in the future. Furthermore, we performed subgroup analysis and found a significantly higher diagnostic capability in KRAS + (AUC ranged from 0.97 to 1) than that in KRAS- patients (AUC ranged from 0.74 to 0.86) for all these five ZFGs, suggesting that these ZFGs could be ideal diagnostic markers for KRAS mutated CRC patients. Conclusion: The methylation profiles of the candidate ZFGs could be potential biomarkers for the early diagnosis of CRC, especially for patients carrying KRAS mutations.
Collapse
Affiliation(s)
- Weilin Pu
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Human Phenome Institute, Fudan University, Shanghai, China
| | - Fei Qian
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Jing Liu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Keke Shao
- Department of Laboratory Medicine, The First People’s Hospital of Yancheng City, Yancheng, China
| | - Feng Xiao
- Department of Pathology, The Third People’s Hospital of Nantong City, Nantong, China
| | - Qin Jin
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Qingmei Liu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Shuai Jiang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Rui Zhang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Jun Zhang
- Department of Gastroenterology, Huashan Hospital, Fudan University, Shanghai, China
| | - Shicheng Guo
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI, United States
| | - Jianfeng Zhang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Yanyun Ma
- Human Phenome Institute, Fudan University, Shanghai, China
- Six Industrial Research Institute, Fudan University, Shanghai, China
| | - Shaoqing Ju
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Weifeng Ding
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| |
Collapse
|
|
23
|
Xu J, Pan HW, Wang XQ, Chen KP. Status of diagnosis and treatment of esophageal cancer and non-coding RNA correlation research: a narrative review. Transl Cancer Res 2021; 10:4532-4552. [PMID: 35116309 PMCID: PMC8798506 DOI: 10.21037/tcr-21-687] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 08/20/2021] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To describe and discuss the progression of the non-coding RNA as biomarkers in early esophageal cancer. BACKGROUND Esophageal cancer without obvious symptoms during early stages is one of the most common cancers, the current clinical treatments offer possibilities of a cure, but the survival rates and the prognoses remain poor, it is a serious threat to human life and health. Most patients are usually diagnosed during terminal stages due to low sensitivity of esophageal cancer's early detection techniques. With the development of molecular biology, an increasing number of non-coding RNAs are found to be associated with the occurrence, development, and prognosis of esophageal cancer. Some of these have begun to be used in clinics and laboratories for diagnosis, treatment, and prognosis, with the goal of reducing mortality. METHODS The information for this paper was collected from a variety of sources, including a search of the keynote's references, a search for texts in college libraries, and discussions with experts in the field of esophageal cancer clinical treatment. CONCLUSIONS Non-coding RNA does play a regulatory role in the development of esophageal cancer, which can predict the occurrence or prognosis of tumors, and become a new class of tumor markers and therapeutic targets in clinical applications. In this review, we survey the recent developments in the incidence, diagnosis, and treatment of esophageal cancer, especially with new research progresses on non-coding RNA biomarkers in detail, and discuss its potential clinical applications.
Collapse
Affiliation(s)
- Jia Xu
- School of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Hui-Wen Pan
- Department of Cardiothoracic Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
| | - Xue-Qi Wang
- School of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Ke-Ping Chen
- School of Life Sciences, Jiangsu University, Zhenjiang, China
| |
Collapse
|
|
24
|
Min Q, Wang Y, Wu Q, Li X, Teng H, Fan J, Cao Y, Fan P, Zhan Q. Genomic and epigenomic evolution of acquired resistance to combination therapy in esophageal squamous cell carcinoma. JCI Insight 2021; 6:150203. [PMID: 34494553 PMCID: PMC8492345 DOI: 10.1172/jci.insight.150203] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 07/21/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUNDTargeted arterial infusion of verapamil combined with chemotherapy (TVCC) is an effective clinical interventional therapy for esophageal squamous cell carcinoma (ESCC), but multidrug resistance (MDR) remains the major cause of relapse or poor prognosis, and the underlying molecular mechanisms of MDR, temporal intratumoral heterogeneity, and clonal evolutionary processes of resistance have not been determined.METHODSTo elucidate the roles of genetic and epigenetic alterations in the evolution of acquired resistance during therapies, we performed whole-exome sequencing on 16 serial specimens from 7 patients with ESCC at every cycle of therapeutic intervention from 3 groups, complete response, partial response, and progressive disease, and we performed whole-genome bisulfite sequencing for 3 of these 7 patients, 1 patient from each group.RESULTSPatients with progressive disease exhibited a substantially higher genomic and epigenomic temporal heterogeneity. Subclonal expansions driven by the beneficial new mutations were observed during combined therapies, which explained the emergence of MDR. Notably, SLC7A8 was identified as a potentially novel MDR gene, and functional assays demonstrated that mutant SLC7A8 promoted the resistance phenotypes of ESCC cell lines. Promoter methylation dynamics during treatments revealed 8 drug resistance protein-coding genes characterized by hypomethylation in promoter regions. Intriguingly, promoter hypomethylation of SLC8A3 and mutant SLC7A8 were enriched in an identical pathway, protein digestion and absorption, indicating a potentially novel MDR mechanism during treatments.CONCLUSIONOur integrated multiomics investigations revealed the dynamics of temporal genetic and epigenetic inter- and intratumoral heterogeneity, clonal evolutionary processes, and epigenomic changes, providing potential MDR therapeutic targets in treatment-resistant patients with ESCC during combined therapies.FUNDINGNational Natural Science Foundation of China, Science Foundation of Peking University Cancer Hospital, CAMS Innovation Fund for Medical Sciences, Major Program of Shenzhen Bay Laboratory, Guangdong Basic and Applied Basic Research Foundation, and the third round of public welfare development and reform pilot projects of Beijing Municipal Medical Research Institutes.
Collapse
Affiliation(s)
- Qingjie Min
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yan Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Qingnan Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xianfeng Li
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Huajing Teng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Jiawen Fan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yiren Cao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Pingsheng Fan
- Department of Medical Oncology, Anhui Provincial Cancer Hospital, Hefei, China
| | - Qimin Zhan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, China
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China
- Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| |
Collapse
|
|
25
|
Qin Y, Zhou J, Fan Z, Gu J, Li X, Lin D, Deng D, Wei W. Evaluation of the Impact of Intratumoral Heterogeneity of Esophageal Cancer on Pathological Diagnosis and P16 Methylation and the Representativity of Endoscopic Biopsy. Front Oncol 2021; 11:683876. [PMID: 34485122 PMCID: PMC8416173 DOI: 10.3389/fonc.2021.683876] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 07/27/2021] [Indexed: 01/22/2023] Open
Abstract
Background P16 methylation is expected to be potential diagnostic and therapeutic targets for esophageal cancer (EC). The intratumoral heterogeneity (ITH) of EC has been mentioned but has not been quantitatively measured yet. We aimed to clarify the impact of ITH on pathological diagnosis and P16 methylation, and the concordance between endoscopic biopsy and the corresponding surgically resected tissue. Methods We designed a systematic sampling method (SSM) compared with a general sampling method (GSM) to obtain EC tumor tissue, tumor biopsy, and normal squamous epithelium biopsy. MethyLight assay was utilized to test P16 methylation. All specimens obtained by the SSM were pathologically diagnosed. Results A total of 81 cases were collected by the GSM, and 91.4% and 8.6% of them were esophageal squamous cell carcinomas (ESCCs) and esophageal adenocarcinomas (EADs), respectively. Nine SSM cases were 100.0% ESCCs. The positive rates of P16 methylation of the GSM tumor and normal tissues were 63.0% (51/81) and 32.1% (26/81), respectively. For SSM samples, tumor tissues were 100.0% (40/40) EC and 85.0% (34/40) P16 methylated; tumor biopsy was 64.4% (29/45) diagnosed of EC and 68.9% P16 methylated; the corresponding normal biopsies were 15.7% (8/51) dysplasia and 54.9% (28/51) P16 methylated. The concordance of pathological diagnosis and P16 methylation between tumor biopsy and the corresponding tumor tissue was 75.0% and 62.5%, respectively. Conclusion The SSM we designed was efficient in measuring the ITH of EC. We found inadequate concordance between tumor biopsy and tissue in pathological diagnosis and P16 methylation.
Collapse
Affiliation(s)
- Yu Qin
- National Cancer Registry Office, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Zhou
- Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, Beijing, China
| | - Zhiyuan Fan
- National Cancer Registry Office, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianhua Gu
- National Cancer Registry Office, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinqing Li
- National Cancer Registry Office, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dongmei Lin
- Department of Pathology, Peking University Cancer Hospital, Beijing, China
| | - Dajun Deng
- Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, Beijing, China
| | - Wenqiang Wei
- National Cancer Registry Office, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| |
Collapse
|
|
26
|
Zhang L, Li D, Du F, Huang H, Yuan C, Fu J, Sun S, Tian T, Liu X, Sun H, Zhu L, Xu J, Liu Y, Cui B, Zhao Y. A panel of differentially methylated regions enable prognosis prediction for colorectal cancer. Genomics 2021; 113:3285-3293. [PMID: 34302946 DOI: 10.1016/j.ygeno.2021.07.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/17/2021] [Accepted: 07/07/2021] [Indexed: 01/22/2023]
Abstract
We aim to identify a panel of differentially methylated regions (DMRs) for predicting survival outcomes for patients with CRC from the TCGA (n = 393). Four DMRs (MUC12, TBX20, CHN2, and B3GNT7) were selected as candidate prognostic markers for CRC. The prediction potential of selected DMRs was validated by the targeted bisulfite sequencing method in an independent cohort with 251 Chinese CRC patients. DMR methylation scores (DMSs) were constructed to evaluate the prognosis of CRC. Results of the validation cohort confirmed that higher DMSs were associated with poor overall survival (OS) of CRC, with hazard ratio (HR) value ranged from 1.445 to 2.698 in multivariable Cox models. Patients in the high prognostic index (high-PI) group showed a markedly unfavorable prognosis compared to the low-PI group in both TCGA discovery cohort (HR = 3.508, 95%CI: 2.196-5.604, P < 0.001) and independent validation cohort (HR = 1.912, 95%CI: 1.258-2.907, P = 0.002).
Collapse
Affiliation(s)
- Lei Zhang
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China
| | - Dapeng Li
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China
| | - Fenqi Du
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China
| | - Hao Huang
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China
| | - Chao Yuan
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China
| | - Jinming Fu
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China
| | - Simin Sun
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China
| | - Tian Tian
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China
| | - Xinyan Liu
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China
| | - Hongru Sun
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China
| | - Lin Zhu
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China
| | - Jing Xu
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China
| | - Yanlong Liu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China
| | - Binbin Cui
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China.
| | - Yashuang Zhao
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin 150081, Heilongjiang Province, PR China.
| |
Collapse
|
|
27
|
Bioinformatics-based analysis of the lncRNA-miRNA-mRNA and TF regulatory networks reveals functional genes in esophageal squamous cell carcinoma. Biosci Rep 2021; 40:225786. [PMID: 32662828 PMCID: PMC7441485 DOI: 10.1042/bsr20201727] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/12/2020] [Accepted: 07/13/2020] [Indexed: 02/08/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a 5-year survival rate unsatisfied malignancies. The study aimed to identify the novel diagnostic and prognostic targets for ESCC. Expression profiling (GSE89102, GSE97051, and GSE59973) data were downloaded from the GEO database. Then, differentially expressed (DE) lncRNAs, DEmiRNAs, and genes (DEGs) with P-values < 0.05, and |log2FC| ≥ 2, were identified using GEO2R. Functional enrichment analysis of miRNA-related mRNAs and lncRNA co-expressed mRNA was performed. LncRNA–miRNA–mRNA, protein–protein interaction of miRNA-related mRNAs and DEGs, co-expression, and transcription factors-hub genes network were constructed. The transcriptional data, the diagnostic and prognostic value of hub genes were estimated with ONCOMINE, receiver operating characteristic (ROC) analyses, and Kaplan–Meier plotter, respectively. Also, the expressions of hub genes were assessed through qPCR and Western blot assays. The CDK1, VEGFA, PRDM10, RUNX1, CDK6, HSP90AA1, MYC, EGR1, and SOX2 used as hub genes. And among them, PRDM10, RUNX1, and CDK6 predicted worse overall survival (OS) in ESCC patients. Our results showed that the hub genes were significantly up-regulated in ESCA primary tumor tissues and cell lines, and exhibited excellent diagnostic efficiency. These results suggest that the hub genes may server as potential targets for the diagnosis and treatment of ESCC.
Collapse
|
|
28
|
Ye H, Li T, Wang H, Wu J, Yi C, Shi J, Wang P, Song C, Dai L, Jiang G, Huang Y, Yu Y, Li J. TSPAN1, TMPRSS4, SDR16C5, and CTSE as Novel Panel for Pancreatic Cancer: A Bioinformatics Analysis and Experiments Validation. Front Immunol 2021; 12:649551. [PMID: 33815409 PMCID: PMC8015801 DOI: 10.3389/fimmu.2021.649551] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 02/23/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is a lethal malignancy with a poor prognosis. This study aims to identify pancreatic cancer-related genes and develop a robust diagnostic model to detect this disease. Weighted gene co-expression network analysis (WGCNA) was used to determine potential hub genes for pancreatic cancer. Their mRNA and protein expression levels were validated through reverse transcription PCR (RT-PCR) and immunohistochemical (IHC). Diagnostic models were developed by eight machine learning algorithms and ten-fold cross-validation. Four hub genes (TSPAN1, TMPRSS4, SDR16C5, and CTSE) were identified based on bioinformatics. RT-PCR showed that the four hub genes were expressed at medium to high levels, IHC revealed that their protein expression levels were higher in pancreatic cancer tissues. For the panel of these four genes, eight models performed with 0.87-0.92 area under the curve value (AUC), 0.91-0.94 sensitivity, and 0.84-0.86 specificity in the validation cohort. In the external validation set, these models also showed good performance (0.86-0.98 AUC, 0.84-1.00 sensitivity, and 0.86-1.00 specificity). In conclusion, this study has identified four hub genes that might be closely related to pancreatic cancer: TSPAN1, TMPRSS4, SDR16C5, and CTSE. Four-gene panels might provide a theoretical basis for the diagnosis of pancreatic cancer.
Collapse
Affiliation(s)
- Hua Ye
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Tiandong Li
- College of Public Health, Zhengzhou University, Zhengzhou, China
- Laboratory of Molecular Biology, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou, China
| | - Hua Wang
- College of Public Health, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou, China
| | - Jinyu Wu
- College of Public Health, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou, China
| | - Chuncheng Yi
- College of Public Health, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou, China
| | - Jianxiang Shi
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou, China
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Peng Wang
- College of Public Health, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou, China
| | - Chunhua Song
- College of Public Health, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou, China
| | - Liping Dai
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou, China
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Guozhong Jiang
- Deparment of Pathology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuxin Huang
- Program in Public Health, University of California, Irvine, Irvine, CA, United States
| | - Yongwei Yu
- Department of Pathology, Second Military Medical University, Shanghai, China
| | - Jitian Li
- Laboratory of Molecular Biology, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou, China
| |
Collapse
|
|
29
|
Bian Y, Bi G, Wei T, Yao G, Chen Z, Zhan C, Fan H. Integrative genome-scale analysis of immune infiltration in esophageal carcinoma. Int Immunopharmacol 2021; 93:107371. [PMID: 33535118 DOI: 10.1016/j.intimp.2021.107371] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/29/2020] [Accepted: 01/04/2021] [Indexed: 12/19/2022]
Abstract
To explore the molecular mechanism in the esophageal squamous carcinoma (ESCC) environment, we selected datasets of ESCC patients from The Cancer Genome Atlas (TCGA) (n = 78) and explored the infiltration condition of 24 immune cells in each sample. We assorted the microenvironment of ESCC into two Infiltration groups (I and II) and built a random forest classifier model. We showed traits of gene and clinicopathology in the tumor microenvironment (TME) phenotypes systematically. Infiltration I had low infiltration of immune cells and immunomodulators but relatively higher mutation load, while Infiltration II was enriched with cytotoxic T cells and immunosuppressive cells. The upregulation of several immune cytokines like IFN-γ, TNF-β, and PD-L1 was seen in Infiltration II. The infiltration group was an independent predictor of prognosis showed by Multivariable Cox analysis (Infiltration II vs. I, hazard ratio = 2.73, 95% confidence interval = 1.08-6.91, p = 0.03). All the results can be verified in datasets from the Gene Expression Omnibus database (GEO) and our institution (n = 98). Our results demonstrate a synthesis of the infiltration pattern of the immune in ESCC. We reveal the mechanism of TME, which may contribute to the progress of immunotherapy for patients with ESCC.
Collapse
Affiliation(s)
- Yunyi Bian
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Guoshu Bi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Tengteng Wei
- Department of Thoracic Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Guangyu Yao
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhencong Chen
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng Zhan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Hong Fan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
| |
Collapse
|
|
30
|
Cui J, Wang L, Zhong W, Chen Z, Chen J, Yang H, Liu G. Development and Validation of Epigenetic Signature Predict Survival for Patients with Laryngeal Squamous Cell Carcinoma. DNA Cell Biol 2021; 40:247-264. [PMID: 33481663 DOI: 10.1089/dna.2020.5789] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Establishing epigenetic signature to improve the accuracy of survival prediction and optimize therapeutic strategies for laryngeal squamous cell carcinoma (LSCC) by a genome-wide integrated analysis of methylation and the transcriptome. LSCC DNA methylation datasets and RNA sequencing datasets were acquired from the Cancer Genome Atlas (TCGA). MethylMix was applied to detect DNA methylation-driven genes (MDGs), which developed an epigenetic signature. The predictive accuracy and clinical value of the epigenetic signature were evaluated by receiver operating characteristic and decision curve analysis, and compared with tumor-node-metastasis (TNM) stage system. In addition, prognostic value of the epigenetic signature was validated by external Gene Expression Omnibus (GEO) database. According to five MDGs of epigenetic signature, the candidate small molecules for LSCC were screen out by the CMap database. A total of 88 DNA MDGs were identified, five of which (MAGEB2, SUSD1, ZNF382, ZNF418, and ZNF732) were chosen to construct an epigenetic signature. The epigenetic signature can effectively divide patients into high-risk and low-risk group, with the area under curve (AUC) of 0.8 (5-year overall survival [OS]) and AUC of 0.745 (3-year OS). Stratification analysis affirmed that the epigenetic signature was still a significant statistical prognostic model in subsets of patients with different clinical variables. Multivariate Cox regression analysis indicated that the efficacy of epigenetic signature appears independent of other clinicopathological characteristics. In terms of predictive capacity and clinical usefulness, the epigenetic signature was superior to traditional TNM stage. In addition, the epigenetic signature was confirmed in external LSCC cohorts from GEO. Finally, CMap matched the 10 most significant small molecules as promising therapeutic drugs to reverse the LSCC gene expression. An epigenetic signature, with five DNA MDGs, was identified and validated in LSCC patients by integrating multidimensional genomic data, which may offer novel research directions and prospects for individualized treatment of patients with LSCC.
Collapse
Affiliation(s)
- Jie Cui
- Department of Head and Neck Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, PR China
| | - Liping Wang
- Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Hainan Medical University, Haikou, PR China
| | - Waisheng Zhong
- Department of Head Neck Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China
| | - Zhen Chen
- Department of Intensive Care Unit, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, PR China
| | - Jie Chen
- Department of Head Neck Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China
| | - Hong Yang
- Department of Head and Neck Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, PR China
| | - Genglong Liu
- Department of Pathology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, PR China
| |
Collapse
|
|
31
|
Li Y, Zhang Q, Di Zhang, Cai Q, Fan J, Venners SA, Jiang S, Li J, Xu X. The effect of ABCA1 gene DNA methylation on blood pressure levels in a Chinese hyperlipidemic population. J Hum Hypertens 2021; 35:1139-1148. [PMID: 33462393 DOI: 10.1038/s41371-020-00479-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 06/08/2020] [Accepted: 12/11/2020] [Indexed: 11/09/2022]
Abstract
Hypertension is an important public health challenge worldwide. Epigenetic studies are providing novel insight into the underlying mechanisms of hypertension. We investigated the effect of DNA methylation in ATP-binding cassette transporter 1 (ABCA1) gene on blood pressure levels in a Chinese hyperlipidemic population. We randomly selected 211 individuals with hyperlipidemia who had not received any lipid-lowering treatment at baseline from our previous statin pharmacogenetics study (n = 734). DNA methylation loci at the ABCA1 gene were measured by MethylTarget, a next generation bisulfite sequencing-based multiple targeted cytosine-guanine dinucleotide methylation analysis method. Mean DNA methylation level was used in statistical analysis. In all subjects, higher mean ABCA1_B methylation was positively associated with systolic blood pressure (SBP) (β = 8.27, P = 0.008; β = 8.78, P = 0.005) and explained 2.7% and 5.8% of SBP variation before and after adjustment for lipids, respectively. We further divided all patients into three groups based on the tertile of body mass index (BMI) distribution. In the middle tertile of BMI, there was a significantly positive relationship between mean ABCA1_A methylation and SBP (β = 0.89, P = 0.003) and DBP (β = 0.32, P = 0.030). Mean ABCA1_A methylation explained 11.0% of SBP variation and 5.3% of DBP variation, respectively. Furthermore, mean ABCA1_A methylation (β = 0.79; P = 0.007) together with age and gender explained up to 24.1% of SBP variation. Our study provides new evidence that the ABCA1 DNA methylation profile is associated with blood pressure levels, which highlights that DNA methylation might be a significant molecular mechanism involved in the pathophysiological process of hypertension.
Collapse
Affiliation(s)
- Yajie Li
- School of Life Sciences, Anhui University, Hefei, China
| | - Qian Zhang
- School of Life Sciences, Anhui University, Hefei, China
| | - Di Zhang
- School of Life Sciences, Anhui University, Hefei, China
| | - Qianru Cai
- School of Life Sciences, Anhui University, Hefei, China
| | - Juanlin Fan
- School of Life Sciences, Anhui University, Hefei, China
| | - Scott A Venners
- Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada
| | - Shanqun Jiang
- School of Life Sciences, Anhui University, Hefei, China. .,Institute of Biomedicine, Anhui Medical University, Hefei, China.
| | - Jianping Li
- Department of Cardiology, Peking University First Hospital, Beijing, China.
| | - Xiping Xu
- Institute of Biomedicine, Anhui Medical University, Hefei, China.,National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
32
|
Chen X, Huang L, Yang T, Xu J, Zhang C, Deng Z, Yang X, Liu N, Chen S, Lin S. METTL3 Promotes Esophageal Squamous Cell Carcinoma Metastasis Through Enhancing GLS2 Expression. Front Oncol 2021; 11:667451. [PMID: 34094960 PMCID: PMC8170325 DOI: 10.3389/fonc.2021.667451] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 04/26/2021] [Indexed: 12/27/2022] Open
Abstract
Recent studies have identified pleiotropic roles of methyltransferase-like 3 (METTL3) in tumor progression. However, the roles of METTL3 in esophageal squamous cell carcinoma (ESCC) are still unclear. Here, we investigated the function and mechanism of METTL3 in ESCC tumorigenesis. We reported that higher METTL3 expression was found in ESCC tissues and was markedly associated with depth of invasion and poor prognosis. Loss- and gain-of function studies showed that METTL3 promoted the migration and invasion of ESCC cells in vitro. Integrated methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-Seq) analysis first demonstrated that glutaminase 2 (GLS2) was regulated by METTL3 via m6A modification. Our findings identified METTL3/GLS2 signaling as a potential therapeutic target in antimetastatic strategies against ESCC.
Collapse
Affiliation(s)
- Xiaoting Chen
- Clinical Department of Guangdong Metabolic Disease Research Centre of Integrated Chinese and Western Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Lanlan Huang
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
- Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Tingting Yang
- Clinical Department of Guangdong Metabolic Disease Research Centre of Integrated Chinese and Western Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiexuan Xu
- Clinical Department of Guangdong Metabolic Disease Research Centre of Integrated Chinese and Western Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Chengyong Zhang
- Clinical Department of Guangdong Metabolic Disease Research Centre of Integrated Chinese and Western Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhendong Deng
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiaorong Yang
- Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Naihua Liu
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Size Chen
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precise Therapy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- *Correspondence: Shaoqiang Lin, ; Size Chen,
| | - Shaoqiang Lin
- Clinical Department of Guangdong Metabolic Disease Research Centre of Integrated Chinese and Western Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precise Therapy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- *Correspondence: Shaoqiang Lin, ; Size Chen,
| |
Collapse
|
|
33
|
Zheng L, Li L, Xie J, Jin H, Zhu N. Six Novel Biomarkers for Diagnosis and Prognosis of Esophageal squamous cell carcinoma: validated by scRNA-seq and qPCR. J Cancer 2021; 12:899-911. [PMID: 33403046 PMCID: PMC7778544 DOI: 10.7150/jca.50443] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 11/16/2020] [Indexed: 12/24/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide. ESCC has a generally poor prognosis and there is a lack of available biomarkers for diagnosis and prognosis. The aim of the study was to identify novel biomarkers for ESCC. We screened the overlapping differentially expressed genes (DEGs) acquired from six Gene Expression Omnibus (GEO) ESCC datasets and The Cancer Genome Atlas (TCGA) ESCC datasets. Subsequently, protein-protein interaction network analysis was performed to identify the key hub genes. Then, Kaplan Meier survival and receiver operating curve (ROC) analysis were utilized to clarify the diagnostic and prognostic role of these hub genes. The UALCAN database, single cell RNA sequencing (scRNA-seq) and real-time quantitative PCR (qPCR) were performed to confirm the expression levels of identified hub genes. Finally, immune infiltration analysis was conducted to investigate the role of these genes in the pathogenesis of ESCC. The results showed that PBK, KIF2C, NUF2, KIF20A, RAD51AP1, and DEPDC1 effectively distinguish ESCC tissues from normal samples, and all of them were significantly correlated with overall survival. The results of scRNA-seq and qPCR indicated that the expression levels of hub genes in ESCC were significantly higher than in normal cells or tissues. Further immune infiltration analysis showed that infiltration of dendritic cells was significantly negatively correlated with PBK, KIF2C, NUF2, RAD51AP1, and DEPDC1 expression levels. In conclusion, our results suggest that PBK, KIF2C, NUF2, KIF20A, RAD51AP1 and DEPDC1 are all potential biomarkers for ESCC diagnosis and prognosis may also be potential therapeutic targets for ESCC.
Collapse
Affiliation(s)
- Liuhai Zheng
- Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Linzhi Li
- Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Jun Xie
- Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Hai Jin
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Naishuo Zhu
- Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| |
Collapse
|
|
34
|
Abstract
Pseudogenes are commonly labeled as "junk DNA" given their perceived nonfunctional status. However, the advent of large-scale genomics projects prompted a revisit of pseudogene biology, highlighting their key functional and regulatory roles in numerous diseases, including cancers. Integrative analyses of cancer data have shown that pseudogenes can be transcribed and even translated, and that pseudogenic DNA, RNA, and proteins can interfere with the activity and function of key protein coding genes, acting as regulators of oncogenes and tumor suppressors. Capitalizing on the available clinical research, we are able to get an insight into the spread and variety of pseudogene biomarker and therapeutic potential. In this chapter, we describe pseudogenes that fulfill their role as diagnostic or prognostic biomarkers, both as unique elements and in collaboration with other genes or pseudogenes. We also report that the majority of prognostic pseudogenes are overexpressed and exert an oncogenic role in colorectal, liver, lung, and gastric cancers. Finally, we highlight a number of pseudogenes that can establish future therapeutic avenues.
Collapse
|
|
35
|
Singh SR, Meyer-Jens M, Alizoti E, Bacon WC, Davis G, Osinska H, Gulick J, Reischmann-Düsener S, Orthey E, McLendon PM, Molkentin JD, Schlossarek S, Robbins J, Carrier L. A high-throughput screening identifies ZNF418 as a novel regulator of the ubiquitin-proteasome system and autophagy-lysosomal pathway. Autophagy 2020; 17:3124-3139. [PMID: 33249983 PMCID: PMC8526018 DOI: 10.1080/15548627.2020.1856493] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway (ALP) are two major protein degradation pathways in eukaryotic cells. Initially considered as two independent pathways, there is emerging evidence that they can work in concert. As alterations of UPS and ALP function can contribute to neurodegenerative disorders, cancer and cardiac disease, there is great interest in finding targets that modulate these catabolic processes. We undertook an unbiased, total genome high-throughput screen to identify novel effectors that regulate both the UPS and ALP. We generated a stable HEK293 cell line expressing a UPS reporter (UbG76V-mCherry) and an ALP reporter (GFP-LC3) and screened for genes for which knockdown increased both UbG76V-mCherry intensity and GFP-LC3 puncta. With stringent selection, we isolated 80 candidates, including the transcription factor ZNF418 (ZFP418 in rodents). After screen validation with Zfp418 overexpression in HEK293 cells, we evaluated Zfp418 knockdown and overexpression in neonatal rat ventricular myocytes (NRVMs). Endogenous and overexpressed ZFP418 were localized in the nucleus. Subsequent experiments showed that ZFP418 negatively regulates UPS and positively regulates ALP activity in NRVMs. RNA-seq from Zfp418 knockdown revealed altered gene expression of numerous ubiquitinating and deubiquitinating enzymes, decreased expression of autophagy activators and initiators and increased expression of autophagy inhibitors. We found that ZPF418 activated the promoters of Dapk2 and Fyco1, which are involved in autophagy. RNA-seq from Zfp418 knockdown revealed accumulation of several genes involved in cardiac development and/or hypertrophy. In conclusion, our study provides evidence that ZNF418 activates the ALP, inhibits the UPS and regulates genes associated with cardiomyocyte structure/function. Abbreviations: ACTN2, actinin alpha 2; ALP, autophagy-lysosomal pathway; COPB1, COPI coat complex subunit beta 1; DAPK2, death associated protein kinase 2; FYCO1, FYVE and coiled-coil domain autophagy adaptor 1; HEK293, human embryonic kidney cells 293; HTS, high-throughput screen; LC3, microtubule associated protein 1 light chain 3; NRVMs, neonatal rat ventricular myocytes; RNA-seq, RNA sequencing; RPS6, ribosomal protein S6; TNNI3, troponin I, cardiac 3; UPS, ubiquitin-proteasome system; shRNA, short hairpin RNA; SQSTM1/p62, sequestosome 1; VPS28, VPS28 subunit of ESCRT-I; ZNF418/ZFP418, zinc finger protein 418.
Collapse
Affiliation(s)
- Sonia R Singh
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.,Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH, USA
| | - Moritz Meyer-Jens
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Erda Alizoti
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - W Clark Bacon
- Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH, USA
| | - Gregory Davis
- Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH, USA
| | - Hanna Osinska
- Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH, USA
| | - James Gulick
- Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH, USA
| | - Silke Reischmann-Düsener
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Ellen Orthey
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Patrick M McLendon
- Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH, USA
| | - Jeffery D Molkentin
- Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH, USA
| | - Saskia Schlossarek
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Jeffrey Robbins
- Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH, USA
| | - Lucie Carrier
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| |
Collapse
|
|
36
|
Jiang S, Cai Q, Zhang D, Fan J, Hu S, Venners SA. Effect of ABCG1 gene DNA methylations on the lipid-lowering efficacy of simvastatin. Pharmacogenomics 2020; 22:27-39. [PMID: 33356546 DOI: 10.2217/pgs-2020-0068] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: We investigated the effect of ABCG1 gene DNA methylation in the lipid-lowering efficacy of simvastatin. Materials & methods: An extreme sampling approach was used to select 211 individuals from the top and bottom 15% of adjusted lipid-lowering response residuals to simvastatin after eight consecutive weeks. DNA methylation was measured before treatment by the MethylTarget bisulfite sequencing method. Results: ABCG1_A DNA methylations were negatively associated with baseline high-density lipoprotein cholesterol (HDL-C) and the change in HDL-C after treatment. ABCG1_C methylations were also related to the change in triglyceride and HDL-C. Moreover, mean ABCG1_A and ABCG1_C methylations explain 7.2% of the ΔTC (total cholesterol) and 17.5% of the ΔHDL-C level variability, respectively. Conclusion: DNA methylations at the ABCG1 gene play significant inhibitory effects in the lipid-lowering therapy of simvastatin.
Collapse
Affiliation(s)
- Shanqun Jiang
- School of Life Sciences, Anhui University, Hefei, 230601, China.,Institute of Physical Science & Information Technology, Anhui University, Hefei, 230601, China.,Institute of Biomedicine, Anhui Medical University, Hefei, 230032, China
| | - Qianru Cai
- School of Life Sciences, Anhui University, Hefei, 230601, China
| | - Di Zhang
- School of Life Sciences, Anhui University, Hefei, 230601, China
| | - Juanlin Fan
- School of Life Sciences, Anhui University, Hefei, 230601, China
| | - Shengnan Hu
- School of Life Sciences, Anhui University, Hefei, 230601, China
| | - Scott A Venners
- Faculty of Health Sciences, Simon Fraser University, Burnaby, BC V5A1S6, Canada
| |
Collapse
|
|
37
|
Li N, Liu K, Dong S, Ou L, Li J, Lai M, Wang Y, Bao Y, Shi H, Wang X, Wang S. Identification of CHRNB4 as a Diagnostic/Prognostic Indicator and Therapeutic Target in Human Esophageal Squamous Cell Carcinoma. Front Oncol 2020; 10:571167. [PMID: 33304845 PMCID: PMC7701245 DOI: 10.3389/fonc.2020.571167] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 10/20/2020] [Indexed: 12/20/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumors and there is a lack of biomarkers for ESCC diagnosis and prognosis. Family subunits of cholinergic nicotinic receptor genes (CHRNs) are involved in smoking behavior and tumor cell proliferation. Previous researches have shown similar molecular features and pathogenic mechanisms among ESCC, head and neck squamous cell carcinoma (HNSC), and lung squamous cell carcinoma (LUSC). Using edgeR, three mutual differentially expressed genes of CHRNs were found to be significantly upregulated at the mRNA level in ESCC, LUSC, and HNSC compared to matched normal tissues. Kaplan–Meier survival analysis showed that high expression of CHRNB4 was associated with unfavorable prognosis in ESCC and HNSC. The specific expression analysis revealed that CHRNB4 is highly expressed selectively in squamous cell carcinomas compared to adenocarcinoma. Cox proportional hazards regression analysis was performed to find that just the single gene CHRNB4 has enough independent prognostic ability, with the area under curve surpassing the tumor-node-metastasis (TNM) staging-based model, the most commonly used model in clinical application in ESCC. In addition, an effective prognostic nomogram was established combining the TNM stage, gender of patients, and expression of CHRNB4 for ESCC patients, revealing an excellent prognostic ability when compared to the model of CHRNB4 alone or TNM. Gene Set Enrichment Analysis results suggested that the expression of CHRNB4 was associated with cancer-related pathways, such as the mTOR pathway. Cell Counting Kit-8, cloning formation assay, and western blot proved that CHRNB4 knockdown can inhibit the proliferation of ESCC cells via the Akt/mTOR and ERK1/2/mTOR pathways, which might facilitate the prolonged survival of patients. Furthermore, we conducted structure-based molecular docking, and potential modulators against CHRNB4 were screened from FDA approved drugs. These findings suggested that CHRNB4 specifically expressed in SCCs, and may serve as a promising biomarker for diagnosis and prognosis prediction, and it can even become a therapeutic target of ESCC patients.
Collapse
Affiliation(s)
- Nan Li
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, China
| | - Kaisheng Liu
- Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Shaowei Dong
- Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Ling Ou
- Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Jieling Li
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, China
| | - Minshan Lai
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, China
| | - Yue Wang
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, China
| | - Yucheng Bao
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, China
| | - Huijie Shi
- Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Xiao Wang
- Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Shaoxiang Wang
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, China
| |
Collapse
|
|
38
|
Salta S, Macedo-Silva C, Miranda-Gonçalves V, Lopes N, Gigliano D, Guimarães R, Farinha M, Sousa O, Henrique R, Jerónimo C. A DNA methylation-based test for esophageal cancer detection. Biomark Res 2020; 8:68. [PMID: 33292587 PMCID: PMC7691099 DOI: 10.1186/s40364-020-00248-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 11/16/2020] [Indexed: 12/14/2022] Open
Abstract
Background Esophageal cancer (ECa) is the 7th most incident cancer and the 6th leading cause of cancer-related death. Most patients are diagnosed with locally advanced or metastatic disease, enduring poor survival. Biomarkers enabling early cancer detection may improve patient management, treatment effectiveness, and survival, are urgently needed. In this context, epigenetic-based biomarkers such as DNA methylation are potential candidates. Methods Herein, we sought to identify and validate DNA methylation-based biomarkers for early detection and prediction of response to therapy in ECa patients. Promoter methylation levels were assessed in a series of treatment-naïve ECa, post-neoadjuvant treatment ECa, and normal esophagus tissues, using quantitative methylation-specific PCR for COL14A1, GPX3, and ZNF569. Results ZNF569 methylation (ZNF569me) levels significantly differed between ECa and normal samples (p < 0.001). Moreover, COL14A1 methylation (COL14A1me) and GPX3 methylation (GPX3me) levels discriminated adenocarcinomas and squamous cell carcinomas, respectively, from normal samples (p = 0.002 and p = 0.009, respectively). COL14A1me & ZNF569me accurately identified adenocarcinomas (82.29%) whereas GPX3me & ZNF569me identified squamous cell carcinomas with 81.73% accuracy. Furthermore, ZNF569me and GPX3me levels significantly differed between normal and pre-treated ECa. Conclusion The biomarker potential of a specific panel of methylated genes for ECa was confirmed. These might prove useful for early detection and might allow for the identification of minimal residual disease after adjuvant therapy.
Collapse
Affiliation(s)
- Sofia Salta
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Catarina Macedo-Silva
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Vera Miranda-Gonçalves
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Nair Lopes
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Davide Gigliano
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, Porto, 4200-072, Portugal
| | - Rita Guimarães
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, Porto, 4200-072, Portugal
| | - Mónica Farinha
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, Porto, 4200-072, Portugal
| | - Olga Sousa
- Department of Radiation Oncology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, Porto, 4200-072, Portugal
| | - Rui Henrique
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, Porto, 4200-072, Portugal.,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar- University of Porto , Rua de Jorge Viterbo Ferreira, 228, Porto, 4050-313, Portugal
| | - Carmen Jerónimo
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal. .,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar- University of Porto , Rua de Jorge Viterbo Ferreira, 228, Porto, 4050-313, Portugal.
| |
Collapse
|
|
39
|
Li D, Zhang L, Fu J, Huang H, Sun S, Zhang D, Zhao L, Ucheojor Onwuka J, Zhao Y, Cui B. SCTR hypermethylation is a diagnostic biomarker in colorectal cancer. Cancer Sci 2020; 111:4558-4566. [PMID: 32970347 PMCID: PMC7734158 DOI: 10.1111/cas.14661] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 07/12/2020] [Accepted: 09/12/2020] [Indexed: 12/12/2022] Open
Abstract
Diagnostic markers for both colorectal cancer (CRC) and its precursor lesions are lacking. Although aberrant methylation of the secretin receptor (SCTR) gene was observed in CRC, the diagnostic performance has not been evaluated. Therefore, this study aimed to assess and verify the diagnostic value of SCTR methylation of CRC and its precursor lesions through integrating the largest methylation data. The diagnostic performance of SCTR methylation was analyzed in the discovery set from The Cancer Genome Atlas (TCGA) CRC methylation data (N = 440), and verified in a large-scale test set (N = 938) from the Gene Expression Omnibus (GEO). Targeted bisulfite sequencing analysis was developed and applied to detect the methylation status of SCTR in our independent validation set (N = 374). Our findings revealed that the SCTR gene was frequently hypermethylated at its CpG islands in CRC. In the TCGA discovery set, the diagnostic score was constructed using 4 CpG sites (cg01013590, cg20505223, cg07176264, and cg26009192) and achieved high diagnostic performance (area under the ROC curve [AUC] = 0.964). In the GEO test set, the diagnostic score had robust diagnostic ability to distinguish CRC (AUC = 0.948) and its precursor lesions (AUC = 0.954) from normal samples. Moreover, hypermethylation of the SCTR gene was also found in cell-free DNA samples collected from CRC patients, but not in those from healthy controls. In the validation set, consistent results were observed using the targeted bisulfite sequencing array. Our study highlights that hypermethylation at CpG islands of the SCTR gene is a potential diagnostic biomarker in CRCs and its precursor lesions.
Collapse
Affiliation(s)
- DaPeng Li
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Lei Zhang
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - JinMing Fu
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Hao Huang
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - SiMin Sun
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Ding Zhang
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - LiYuan Zhao
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Justina Ucheojor Onwuka
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - YaShuang Zhao
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - BinBin Cui
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
| |
Collapse
|
|
40
|
Wang A, Zhang M, Ding Y, Mo X, Zhong C, Zhu Z, Guo D, Zheng X, Xu T, Liu Y, Zhang Y, Peng H. Associations of B-Type Natriuretic Peptide and Its Coding Gene Promoter Methylation With Functional Outcome of Acute Ischemic Stroke: A Mediation Analysis. J Am Heart Assoc 2020; 9:e017499. [PMID: 32875935 PMCID: PMC7727007 DOI: 10.1161/jaha.120.017499] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background The prognostic role of B‐type natriuretic peptide (BNP) in stroke has been suggested, but limited studies have shown mixed results and unknown underlying mechanisms. DNA methylation, a molecular modification that alters gene expression, may represent a candidate mechanism for this purpose. We aimed to examine the associations of BNP and methylation of its coding gene (natriuretic peptide B [NPPB]) with the functional outcome in a large sample of patients with acute ischemic stroke from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). Methods and Results Leveraging participants from CATIS with available specimens, serum proBNP (equimolarly produced with BNP) was measured in 3216 patients (mean age, 62 years; 64% men), and peripheral blood DNA methylation of the NPPB promoter was quantified by targeted bisulfite sequencing in 806 patients (mean age, 62 years; 54% men). The functional outcome was defined as an ordered modified Rankin Scale score assessed at 14 days or hospital discharge after stroke onset. Mediation analysis was conducted to test the potential mediating effect of proBNP on the relationship between NPPB methylation and functional outcome. The results showed that a higher level of proBNP was significantly associated with a higher risk of having a poorer functional outcome (odds ratio [OR], 1.14; P=0.006). Every 5% of hypermethylation at 2 (Chr1:11919160 [OR, 0.93; P=0.022] and Chr1:11918989 [OR, 0.92; P=0.032]) of 11 CpG loci assayed was associated with 7% and 8% lower risk, respectively, of having a poor functional outcome. In addition, proBNP was negatively correlated to hypermethylation at 1 CpG (Chr1:11918989 [β=−0.029; P=0.009]) and mediated approximately 7.69% (95% CI, 2.50%–13.82%) of the association between this CpG methylation and the functional outcome. Conclusions Hypermethylation at the NPPB promoter is associated with the functional outcome after ischemic stroke, at least partially by suppressing BNP expression or excretion.
Collapse
Affiliation(s)
- Aili Wang
- Department of Epidemiology School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Medical College of Soochow University Suzhou China
| | - Mingzhi Zhang
- Department of Epidemiology School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Medical College of Soochow University Suzhou China
| | - Yi Ding
- Department of Epidemiology School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Medical College of Soochow University Suzhou China
| | - Xingbo Mo
- Department of Epidemiology School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Medical College of Soochow University Suzhou China
| | - Chongke Zhong
- Department of Epidemiology School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Medical College of Soochow University Suzhou China
| | - Zhengbao Zhu
- Department of Epidemiology School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Medical College of Soochow University Suzhou China
| | - Daoxia Guo
- Department of Epidemiology School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Medical College of Soochow University Suzhou China
| | - Xiaowei Zheng
- Department of Epidemiology School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Medical College of Soochow University Suzhou China
| | - Tan Xu
- Department of Epidemiology School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Medical College of Soochow University Suzhou China
| | - Yan Liu
- Genesky Biotechnologies Inc Shanghai China
| | - Yonghong Zhang
- Department of Epidemiology School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Medical College of Soochow University Suzhou China
| | - Hao Peng
- Department of Epidemiology School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Medical College of Soochow University Suzhou China
| |
Collapse
|
|
41
|
Li J, Zhu J, Ren L, Ma S, Shen B, Yu J, Zhang R, Zhang M, He Y, Peng H. Association between NPPA promoter methylation and hypertension: results from Gusu cohort and replication in an independent sample. Clin Epigenetics 2020; 12:133. [PMID: 32883357 PMCID: PMC7469321 DOI: 10.1186/s13148-020-00927-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/25/2020] [Indexed: 12/14/2022] Open
Abstract
Background Atrial natriuretic peptide (ANP), one of the main members of the natriuretic peptides system, has been associated with hypertension and related complications, but the underlying molecular mechanisms are not very clear. Here, we aimed to examine whether DNA methylation, a molecular modification to the genome, of the natriuretic peptide A gene (NPPA), the coding gene of ANP, was associated with hypertension. Methods Peripheral blood DNA methylation of NPPA promoter was quantified by target bisulfite sequencing in 2498 community members (mean aged 53 years, 38% men) as a discovery sample and 1771 independent participants (mean aged 62 years, 54% men) as a replication sample. In both samples, we conducted a single CpG association analysis, followed by a gene-based association analysis, to examine the association between NPPA promoter methylation and hypertension, adjusting for age, sex, education level, cigarette smoking, alcohol consumption, obesity, fasting glucose, and lipids. Multiple testing was controlled by the false discovery rate approach. Results Of the 9 CpG loci assayed, hypermethylation at 5 CpGs (CpG1, CpG3, CpG6, CpG8, and CpG9) was significantly associated with a lower odds of prevalent hypertension in the discovery sample, and one CpG methylation (CpG1 located at Chr1:11908353) was successfully replicated in the replication sample (OR = 0.82, 95%CI 0.74–0.91, q = 0.002) after adjusting for covariates and multiple testing. The gene-based analysis found that DNA methylation of the 9 CpGs at NPPA promoter as a whole was significantly associated with blood pressure and prevalent hypertension in both samples (all P < 0.05). Conclusions DNA methylation levels at NPPA promoter were decreased in Chinese adults with hypertension. Aberrant DNA methylation of the NPPA gene may participate in the mechanisms of hypertension.
Collapse
Affiliation(s)
- Jing Li
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, 199 Renai Road, Industrial Park District, Suzhou, 215123, China
| | - Jinhua Zhu
- Department of Chronic Disease Management, Center for Disease Prevention and Control of Wujiang District, Suzhou, China
| | - Liyun Ren
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, 199 Renai Road, Industrial Park District, Suzhou, 215123, China
| | - Shengqi Ma
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, 199 Renai Road, Industrial Park District, Suzhou, 215123, China
| | - Bin Shen
- Department of Chronic Disease Management, Center for Disease Prevention and Control of Wujiang District, Suzhou, China
| | - Jia Yu
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, 199 Renai Road, Industrial Park District, Suzhou, 215123, China
| | - Rongyan Zhang
- Department of Chronic Disease Management, Center for Disease Prevention and Control of Wujiang District, Suzhou, China
| | - Mingzhi Zhang
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, 199 Renai Road, Industrial Park District, Suzhou, 215123, China
| | - Yan He
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, 199 Renai Road, Industrial Park District, Suzhou, 215123, China.,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| | - Hao Peng
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, 199 Renai Road, Industrial Park District, Suzhou, 215123, China. .,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
| |
Collapse
|
|
42
|
Sang L, Yu Z, Wang A, Li H, Dai X, Sun L, Liu H, Yuan Y. Identification of methylated-differentially expressed genes and pathways in esophageal squamous cell carcinoma. Pathol Res Pract 2020; 216:153050. [PMID: 32825936 PMCID: PMC7283077 DOI: 10.1016/j.prp.2020.153050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/26/2020] [Accepted: 06/07/2020] [Indexed: 12/19/2022]
Abstract
Methylation, as an epigenetic modification, can affect gene expression and play a role in the occurrence and development of cancer. This research is devoted to discover methylated-differentially expressed genes (MDEGs) in esophageal squamous cell carcinoma (ESCC) and explore special associated pathways. We downloaded GSE51287 methylation profiles and GSE26886 expression profiles from GEO DataSets, and performed a comprehensive bioinformatics analysis. Totally, 19 hypermethylated, lowly expressed genes (Hyper-LGs) were identified, and involved in regulation of cell proliferation, phosphorus metabolic process and protein kinase activity. Meanwhile, 17 hypomethylated, highly expressed genes (Hypo-HGs) were participated in collagen catabolic process, metallopeptidase and cytokine activity. Pathway analysis determined that Hyper-LGs were enriched in arachidonic acid metabolism pathway, while Hypo-HGs were primarily associated with the cytokine-cytokine receptor interaction pathway. IL 6, MMP3, MMP9, SPP1 were identified as hub genes based on the PPI network that combined 7 ranked methods included in cytoHubba, and verification was performed in human tissues. Our integrated analysis identified many novel genetic lesions in ESCC and provides a crucial molecular foundation to improve our understanding of ESCC. Hub genes, including IL 6, MMP3, MMP9 and SPP1, could be considered for use as aberrant methylation-based biomarkers to facilitate the accurate diagnosis and therapy of ESCC.
Collapse
Affiliation(s)
- Liang Sang
- Cancer Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Ultrasound Department, the First Hospital of China Medical University, Shenyang 110001, China
| | - Zhanwu Yu
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No. 44 Xiaoheyan Road, Shenyang, Liaoning 110042, China
| | - Ang Wang
- Cancer Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China
| | - Hao Li
- Cancer Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China
| | - Xiantong Dai
- Cancer Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China
| | - Liping Sun
- Cancer Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China
| | - Hongxu Liu
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No. 44 Xiaoheyan Road, Shenyang, Liaoning 110042, China.
| | - Yuan Yuan
- Cancer Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
| |
Collapse
|
|
43
|
Ma Y, Yao Y, Zhong N, Angwa LM, Pei J. The dose-time effects of fluoride on the expression and DNA methylation level of the promoter region of BMP-2 and BMP-7 in rats. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2020; 75:103331. [PMID: 32004919 DOI: 10.1016/j.etap.2020.103331] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 10/21/2019] [Accepted: 01/22/2020] [Indexed: 06/10/2023]
Abstract
Skeletal fluorosis is a chronic metabolic bone disease caused by excessive exposed to fluoride. Recent studies have shown that fluoride causes abnormal bone metabolism through disrupting the expression of Bone Morphogenetic Proteins (BMPs). However, the relationship between fluoride and BMPs is not fully understood, and the mechanism of fluoride on BMPs expression is still unclear. This study investigated the dose-time effects of fluoride on BMP-2 and BMP-7 levels and DNA methylation status of the promoter regions of these two genes in peripheral blood of rats. Eighty Wistar male rats were randomly divided into four groups and treated for 1 month and 3 months with distilled water (control), 25 mg/L, 50 mg/L or 100 mg/L of sodium fluoride (NaF). Rats exposed to fluoride had higher protein expression of BMP-2 and BMP-7 in plasma at 1 month and 3 months. An increase in BMP-2 expression was also observed with an increase of fluoride exposure time. Significant hypomethylation was observed in 2 CpG sites (CpGs) of BMP-2 and 1 CpG site of BMP-7 promoter regions in the fluoride treatment groups. It concludes that fluoride has a dose-response effect on BMP-2 in fluorosis rats, and fluoride-induced hypomethylation of specific CpGs may play an essential role in the regulation of BMP-2 and BMP-7 expression in rats.
Collapse
Affiliation(s)
- Yongzheng Ma
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, People's Republic of China
| | - Yingjie Yao
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, People's Republic of China
| | - Nan Zhong
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, People's Republic of China
| | - Linet Musungu Angwa
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, People's Republic of China
| | - Junrui Pei
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, People's Republic of China.
| |
Collapse
|
|
44
|
Chen J, Wang X, Wang X, Li W, Shang C, Chen T, Chen Y. A FITM1-Related Methylation Signature Predicts the Prognosis of Patients With Non-Viral Hepatocellular Carcinoma. Front Genet 2020; 11:99. [PMID: 32174969 PMCID: PMC7056874 DOI: 10.3389/fgene.2020.00099] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 01/29/2020] [Indexed: 12/11/2022] Open
Abstract
Although great progress has been made in treatment against hepatitis virus infection, the prognosis of hepatocellular carcinoma (HCC) remains unsatisfied. Therefore, there is an unmet need to explore biomarkers or prognostic models for monitoring non-viral hepatocellular carcinoma. Accumulating evidence indicates that DNA methylation participates in carcinogenesis of malignancies. In the present study, we analyzed 101 non-viral HCC patients from TCGA database to figure out methylation-driven genes (MDGs) that might get involved in non-viral HCC pathogenesis using MethyMix algorithm. Then we picked out 8 key genes out of 137 MDGs that could affect the overall survival (OS) of both methylation and expression level. Using PCA, Uni-variate, Multi-variate, and LASSO cox regression analyses, we confirmed the potential prognostic value of these eight epigenetic genes. Ultimately, combined with immunohistochemistry (IHC), ROC, OS, and GSEA analyses, fat storage-inducing transmembrane protein1 (FITM1) was identified as a novel tumor suppressor gene in non-viral HCC and an applicable FITM1-methylation-based signature was built in a training set and validated in a testing set. Briefly, our work provides several potential biomarkers, especially FITM1, as well as a new method for disease surveillance and treatment strategy development.
Collapse
Affiliation(s)
- Jie Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xicheng Wang
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xining Wang
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wenxin Li
- Department of Cardiology, The Eight Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Changzhen Shang
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tao Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yajin Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
45
|
Specific DNA methylation markers in the diagnosis and prognosis of esophageal cancer. Aging (Albany NY) 2019; 11:11640-11658. [PMID: 31834866 PMCID: PMC6932928 DOI: 10.18632/aging.102569] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 11/23/2019] [Indexed: 12/14/2022]
Abstract
The early diagnosis and accurate prognosis prediction of esophageal cancer is an essential part of improving survival. However, these diseases lack effective and specific markers. A total of 1,744 samples of HumanMethylation450 data were integrated to identify and validate specific methylation markers for esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) as well as for Barrett's esophagus (BE) using The Cancer Genome Atlas and the Gene Expression Omnibus. The diagnostic and prognostic methylation classifiers were constructed by moderated t-statistics and the least absolute shrinkage and selection operator method. The diagnostic methylation classifier using 12 CpG sites was constructed in training set (377 samples) that could effectively discriminate samples of BE, EAC, and ESCC from normal tissue (AUC = 0.992), which achieved highly predictive ability in both internal (187 samples, AUC = 0.990) and external validation (184 samples, AUC = 0.978). The prognostic methylation classifier with 3 CpG and 2 CpG sites for EAC and ESCC respectively, could accurately estimate the prognosis of an individual patient and improved the predictive ability of the tumor node metastasis staging system. Overall, our study systematically analyzed large-scale methylation data and provided promising markers for the diagnosis and prognosis of esophageal cancer.
Collapse
|
|
46
|
Tang L, Liou YL, Wan ZR, Tang J, Zhou Y, Zhuang W, Wang G. Aberrant DNA methylation of PAX1, SOX1 and ZNF582 genes as potential biomarkers for esophageal squamous cell carcinoma. Biomed Pharmacother 2019; 120:109488. [DOI: 10.1016/j.biopha.2019.109488] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 09/08/2019] [Accepted: 09/22/2019] [Indexed: 12/23/2022] Open
|
|
47
|
Wang J, Zhang Q, Zhu Q, Liu C, Nan X, Wang F, Fang L, Liu J, Xie C, Fu S, Song B. Identification of methylation-driven genes related to prognosis in clear-cell renal cell carcinoma. J Cell Physiol 2019; 235:1296-1308. [PMID: 31273792 PMCID: PMC6899764 DOI: 10.1002/jcp.29046] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 06/13/2019] [Indexed: 12/16/2022]
Abstract
With the participation of the existing treatment methods, the prognosis of advanced clear‐cell renal cell carcinoma (ccRCC) is poor. More evidence indicates the presence of methylation in ccRCC cancer cells, but there is a lack of studies on methylation‐driven genes in ccRCC. We analyzed the open data of ccRCC in The Cancer Genome Atlas database to obtain ccRCC‐related methylation‐driven genes, and then carried out pathway enrichment, survival, and joint survival analyses. More important, we deeply explored the correlation between differential methylation sites and the expression of these driving genes. Finally, we screened 29 methylation‐driven genes via MethylMix, of which six were significantly associated with the survival of ccRCC patients. This study demonstrated that the effect of hypermethylation or hypomethylation on prognosis is different, and the level of methylation of key methylation sites is associated with gene expression. We identified methylation‐driven genes independently predicting prognosis in ccRCC, which offers theoretical support in bioinformatics for the study of methylation in ccRCC and a new perspective for the epigenetic study of ccRCC.
Collapse
Affiliation(s)
- Jia Wang
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China.,Department of Oncology, Zibo Maternal and Child Health Hospital, Zibo, China.,Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Qiujing Zhang
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China.,Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Qingqing Zhu
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China.,Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Chengxiang Liu
- Department of Oncology, Jinan Jigang Hospital, Jinan, China
| | - Xueli Nan
- Department of Oncology, Wu Di People Hospital, Binzhou, China
| | - Fuxia Wang
- Department of Oncology, YunCheng Conuntry People's Hospital, YunCheng, China
| | - Lihua Fang
- Department of Oncology, Chang Qing District People's Hospital, Jinan, China
| | - Jie Liu
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Chao Xie
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Shuai Fu
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Bao Song
- Basic Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| |
Collapse
|
|
48
|
Wang L, Sun L, Wang Y, Yao B, Liu R, Chen T, Tu K, Liu Q, Liu Z. miR-1204 promotes hepatocellular carcinoma progression through activating MAPK and c-Jun/AP1 signaling by targeting ZNF418. Int J Biol Sci 2019; 15:1514-1522. [PMID: 31337980 PMCID: PMC6643133 DOI: 10.7150/ijbs.33658] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 04/04/2019] [Indexed: 12/11/2022] Open
Abstract
Emerging evidence has indicated that abnormal microRNAs (miRNAs) participated in carcinogenesis and tumor progression in hepatocellular carcinoma (HCC). Better understanding the association between miRNAs and HCC may contribute to discover novel therapeutic approaches for diagnosis and treatments. In the current study, we have shown that miR-1204 level was elevated in HCC tissues and cell lines, which was associated with malignant clinical features, including large tumor size and advanced TNM stage. Furthermore, gain-or loss-of function assays demonstrated that miR-1204 promoted cell proliferation in vitro and tumor growth in vivo as well as inhibited apoptosis in vitro. Luciferase reporter gene assays confirmed that ZNF418 was a direct downstream target of miR-1204. Recuse assays showed that ZNF418 mediates the biological function of miR-1204 on HCC cells through regulating MAPK and c-Jun signaling. In conclusion, our results suggest that miR-1204 functions as an oncogene to promote proliferation and inhibit apoptosis through regulating MAPK and c-Jun signaling by targeting ZNF418, and potentially serves as a novel prognostic biomarker and therapeutic target for HCC.
Collapse
Affiliation(s)
- Liang Wang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China, 710061
| | - Liankang Sun
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China, 710061
| | - Yufeng Wang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China, 710061
| | - Bowen Yao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China, 710061
| | - Runkun Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China, 710061
| | - Tianxiang Chen
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China, 710061
| | - Kangsheng Tu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China, 710061
| | - Qingguang Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China, 710061
| | - Zhikui Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China, 710061
| |
Collapse
|
|
49
|
Li D, Bai Y, Feng Z, Li W, Yang C, Guo Y, Lin C, Zhang Y, He Q, Hu G, Li X. Study of Promoter Methylation Patterns of HOXA2, HOXA5, and HOXA6 and Its Clinicopathological Characteristics in Colorectal Cancer. Front Oncol 2019; 9:394. [PMID: 31165042 PMCID: PMC6536611 DOI: 10.3389/fonc.2019.00394] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 04/26/2019] [Indexed: 01/30/2023] Open
Abstract
Research on DNA methylation offers great potential for the identification of biomarkers that can be applied for accurately assessing an individual's risk for cancer. In this article, we try to find the ideal epigenetic genes involved in colorectal cancer (CRC) based on a CRC database and our CRC cohort. The top 20 genes with an extremely high frequency of hypermethylation in CRC were identified in the latest database. Remarkably, 3 HOXA genes were included in this list and ranked at the top. The percentage of methylation in the HOXA5, HOXA2, and HOXA6 genes in CRC were up to 67.62, 58.36, and 31.32%, respectively, and ranked first in CRC among all human tumor tissues. Paired colorectal tumor samples and adjacent non-tumor colorectal tissue samples and four CRC cell lines were selected for MethylTarget™ assays. The results demonstrated that CRC tissues and cells had a stronger methylation status around the 3 HOXA gene promoter regions compared with adjacent non-tumor colonic tissue samples. The Receiver operator characteristic curve (ROC) curves for HOXA genes show excellent diagnostic ability in distinguishing tissue from healthy individuals and CRC patients, especially for Stage I patients (AUC = 0.9979 in HOXA2, 0.9309 in HOXA5, and 0.8025 in HOXA6). An association analysis between the methylation pattern of HOXA genes and clinical indicators was performed and found that HOXA2 methylation was significantly associated with age, N, stage, M, lymphovascular invasion, perineural invasion, lymph node number. HOXA5 methylation was associated with age, T, M, stage, and tumor status, and HOXA6 methylation was associated with age and KRAS mutation. Notably, we found that the highest methylation of HOXA5 and HOXA2 occurs in the early stages of colorectal cancer tissues such as stage I, N0, MO, and non-invasive tissues. The methylation levels declined as tumors progressed. However, methylation level at any stage of the tumor was still significantly higher than in normal tissues (p < 0.0001). The mRNA of the 3 HOXA genes was downregulated in early tumor stages due to hypermethylation of CpG islands adjacent to the promoters of the genes. In addition, hypermethylation of HOXA5 and HOXA6 mainly occurred in patients < 60 years old and with MSI-L, MSS, CIMP.L and non-CIMP tumors. Together, this suggests that epigenetic silencing of 3 adjacent HOXA genes may be an important event in the progression of colorectal cancer.
Collapse
Affiliation(s)
- Daojiang Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yang Bai
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Zhicai Feng
- Department of Burns and Plastic Surgery of the Third Xiangya Hospital of Central South University, Changsha, China
| | - Wanwan Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Chunxing Yang
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yihang Guo
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Changwei Lin
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yi Zhang
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Quanyong He
- Department of Burns and Plastic Surgery of the Third Xiangya Hospital of Central South University, Changsha, China
| | - Gui Hu
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Xiaorong Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| |
Collapse
|
|
50
|
Cai G, Huang Z, Yu L, Li L. A preliminary study showing no association between methylation levels of C3 gene promoter and the risk of CAD. Lipids Health Dis 2019; 18:5. [PMID: 30611277 PMCID: PMC6320636 DOI: 10.1186/s12944-018-0949-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 12/17/2018] [Indexed: 01/16/2023] Open
Abstract
OBJECTIVE Coronary artery disease (CAD) is a multi-factor disease. Complement component 3 (C3) plays an important role in the development of CAD. The present study investigated the association between DNA methylation status of C3 gene promoter and the risk of CAD. METHODS One hundred CAD patients and 1 hundred age-and gender- matched controls were recruited in current study. Methylation levels in CpG island in C3 promoter were determined by the method of bisulfite amplicon sequencing. RESULTS Methylation levels of four CpG sites in C3 promoter were measured. There were no significant difference in methylation level of each CpG site between CAD patients and controls. Average methylation rate was also calculated. No significant difference in average methylation rate was observed between CAD and control groups. Stratified analyses based on EH, DM and smoking status were carried out, no significant association between C3 promoter methylation levels and the susceptibility of CAD was observed. Furthermore, seven haplotypes were established and no significant difference in haplotypes was observed between CAD and control groups. However, our study showed that C3 DNA methylation levels were positively associated with LDL-C levels. CONCLUSION The present study showed no association between methylation levels of C3 promoter and the risk of CAD. However, the methylation levels might be related to LDL-C levels.
Collapse
Affiliation(s)
- Gaojun Cai
- Department of Cardiology, Wujin Hospital affiliated with Jiangsu University, Changzhou, Jiangsu Province, 213017 China
| | - Zhiying Huang
- Department of Pediatrics, No. 2 Hospital of Changzhou, Changzhou, 213001 Jiangsu China
| | - Lei Yu
- Department of Cardiology, Wujin Hospital affiliated with Jiangsu University, Changzhou, Jiangsu Province, 213017 China
| | - Li Li
- Department of Cardiology, Wujin Hospital affiliated with Jiangsu University, Changzhou, Jiangsu Province, 213017 China
| |
Collapse
|