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Simons RB, Karkala F, Kukk MM, Adams HHH, Kayser M, Vidaki A. Comparative performance evaluation of bisulfite- and enzyme-based DNA conversion methods. Clin Epigenetics 2025; 17:56. [PMID: 40181442 PMCID: PMC11969950 DOI: 10.1186/s13148-025-01855-7] [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] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 03/01/2025] [Indexed: 04/05/2025] Open
Abstract
BACKGROUND Bisulfite conversion (BC) has been the gold standard in DNA methylation profiling for decades. During this chemical process, non-methylated cytosines are converted into uracils, while methylated cytosines remain intact. Despite its popularity, BC has major drawbacks when used for sensitive applications with low-quality and -quantity DNA samples, such as the required large amount of DNA input, the caused DNA fragmentation and loss, and the resulting reduced sequence complexity. Lately, to account for BC-related disadvantages the first commercial enzymatic conversion (EC) kit was launched. While EC follows the same conversion principle as BC it uses two enzymatic steps instead of one chemical step with BC. In this study, we validated and compared the conversion performance of the most widely used BC and EC kits using a multiplex qPCR assay (qBiCo) we recently developed, which provides several indexes: conversion efficiency, converted DNA recovery and fragmentation. RESULTS Firstly, we implemented and standardized both DNA conversion methods. Secondly, using qBiCo, we performed a developmental validation for both conversion approaches, including testing the following parameters: repeatability, reproducibility, sensitivity and robustness. Regarding conversion efficiency, both methods performed similarly, with the limit of reproducible conversion being 5 ng and 10 ng for BC and EC, respectively. The recovery, however, is structurally overestimated for BC: 2.3 ± 0.7 and 0.7 ± 0.2 for EC. In contrast, degraded DNA input resulted in high fragmentation values after BC and low-medium values for EC (14.4 ± 1.2 and 3.3 ± 0.4, respectively). Finally, we converted 10 ng of 22 genomic DNA samples using both methods. We observed an overestimation of the BC DNA recovery (130%) and a low recovery for EC (40%). CONCLUSIONS Our findings indicate that both DNA conversion methods have strengths and weaknesses. BC shows a high recovery, whereas EC does not cause extensive fragmentation that is characteristic to BC. EC is, therefore, more robust to the analysis of degraded DNA such as forensic-type or cell-free DNA, at least for the genomic DNA inputs tested here. We believe that the low recovery of EC could be improved by further optimizing and automating the bead-based cleanup steps. Overall, our study provides the first independent benchmarking of bisulfite- and enzyme-based conversion kits.
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Affiliation(s)
- Roy B Simons
- Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Faidra Karkala
- Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Marta M Kukk
- Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Hieab H H Adams
- Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Manfred Kayser
- Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Athina Vidaki
- Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
- Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, The Netherlands.
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2
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Hajebi Khaniki S, Shokoohi F. Data-Driven Identification of Early Cancer-Associated Genes via Penalized Trans-Dimensional Hidden Markov Models. Biomolecules 2025; 15:294. [PMID: 40001597 PMCID: PMC11853217 DOI: 10.3390/biom15020294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/13/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Colorectal cancer (CRC) is a significant worldwide health problem due to its high prevalence, mortality rates, and frequent diagnosis at advanced stages. While diagnostic and therapeutic approaches have evolved, the underlying mechanisms driving CRC initiation and progression are not yet fully understood. Early detection is critical for improving patient survival, as initial cancer stages often exhibit epigenetic changes-such as DNA methylation-that regulate gene expression and tumor progression. Identifying DNA methylation patterns and key survival-related genes in CRC could thus enhance diagnostic accuracy and extend patient lifespans. In this study, we apply two of our recently developed methods for identifying differential methylation and analyzing survival using a sparse, finite mixture of accelerated failure time regression models, focusing on key genes and pathways in CRC datasets. Our approach outperforms two other leading methods, yielding robust findings and identifying novel differentially methylated cytosines. We found that CRC patient survival time follows a two-component mixture regression model, where genes CDH11, EPB41L3, and DOCK2 are active in the more aggressive form of CRC, whereas TMEM215, PPP1R14A, GPR158, and NAPSB are active in the less aggressive form.
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Affiliation(s)
- Saeedeh Hajebi Khaniki
- Department of Biostatistics, School of Health, Mashhad University of Medical Sciences, Mashhad 9137673119, Iran;
| | - Farhad Shokoohi
- Department of Mathematical Sciences, University of Nevada Las Vegas, Las Vegas, NV 89154, USA
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Bowen CM, Duzagac F, Martel-Martel A, Reyes-Uribe L, Zaheer M, Thompson J, Deng N, Sinha R, Mazumdar S, Taggart MW, Jain AK, Tosti E, Edelmann W, Sinha KM, Vilar E. Inhibition of histone methyltransferase EZH2 for immune interception of colorectal cancer in Lynch syndrome. JCI Insight 2025; 10:e177545. [PMID: 39946195 PMCID: PMC11949072 DOI: 10.1172/jci.insight.177545] [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: 11/20/2023] [Accepted: 02/12/2025] [Indexed: 03/25/2025] Open
Abstract
Colorectal precancers in Lynch syndrome (LS) exhibit a distinct immune profile, presenting unique opportunities for developing immune-interception strategies to prevent carcinogenesis. Epigenetic modulation by EZH2 of immune-related genes is implicated in the carcinogenesis of different cancer types, including colorectal cancer. This study utilizes a mouse model of LS and ex vivo colonic organoids to assess the effects of the EZH2 inhibitor GSK503 on immune regulatory pathways, tumorigenesis, and epigenetic reprogramming. Our findings revealed that GSK503 significantly increased CD4+ and CD8+ T cells in both splenocytes and colonic mucosa of treated mice compared with controls. Additionally, a preventive dose of GSK503 over 9 weeks notably reduced adenoma multiplicity, demonstrating its efficacy as a preventive modality. Single-cell RNA-Seq and molecular analyses showed activation of immune and apoptotic markers, along with a reduction in H3K27 methylation levels in colonic crypts. ChIP sequencing further revealed decreased levels of H3K27me3 and H3K4me1, while levels of the active enhancer marks H3K4me3 and H3K27Ac increased in treated mice. Collectively, these findings indicate that EZH2 inhibition enhances immune responses through epigenetic reprogramming in the genome of LS mice, establishing a promising framework for the clinical development of EZH2 inhibitors as a cancer prevention strategy for LS carriers.
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Affiliation(s)
| | | | | | | | | | | | - Nan Deng
- Department of Clinical Cancer Prevention
| | - Ria Sinha
- Department of Clinical Cancer Prevention
| | | | | | - Abhinav K. Jain
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Elena Tosti
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Winfried Edelmann
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA
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4
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Mitsuhashi R, Sato K, Kawakami H. Novel Epigenetics Control (EpC) Nanocarrier for Cancer Therapy Through Dual-Targeting Approach to DNA Methyltransferase and Ten-Eleven Translocation Enzymes. EPIGENOMES 2025; 9:6. [PMID: 39982248 PMCID: PMC11843842 DOI: 10.3390/epigenomes9010006] [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: 12/03/2024] [Revised: 01/15/2025] [Accepted: 02/04/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND/OBJECTIVES Aberrant hypermethylation in the promoter regions of tumor suppressor genes facilitates the pathogenesis and progression of cancer. Therefore, inhibitors targeting DNA methyltransferase (DNMT) have been tested in clinical studies. However, the current monotherapy of DNMT inhibitors shows limited efficacy. Furthermore, the mechanism of action of DNMT inhibitors is DNA replication-dependent. To address these limitations, we developed a novel core-shell-type "epigenetics control (EpC) nanocarrier" that encapsulated decitabine (5-aza-dC) in the PLGA core nanoparticle and hybridized TET1 gene-encoding pDNA on the lipid shell surface. This study aimed to evaluate whether the dual delivery of DNMT inhibitors and pDNA of TET1 could synergistically enhance tumor suppressor gene expression and induce cell cycle arrest and/or apoptosis in cancer cells. Herein, we demonstrate the potential of the EpC carrier in HCT116 human colon cancer cells to upregulate tumor suppressor gene expression and rapidly achieve cell cycle arrest. METHODS PLGA core nanoparticles were prepared by the W/O/W double emulsion method. The formation of core-shell nanoparticles and complexation with pDNA were investigated and optimized by dynamic light scattering, zeta potential measurement, and agarose gel electrophoresis. The cellular uptake and transfection efficiency were measured by confocal laser scanning microscopy and a luciferase assay, respectively. The expression of p53 protein was detected by Western blotting. The anti-tumor effects of the EpC nanocarrier were evaluated by cell cycle analysis and an apoptosis assay. RESULTS The EpC nanocarrier delivered the DNMT inhibitor and TET gene-encoding pDNA into HCT116 cells. It promoted the expression of the tumor suppressor protein p53 and induced rapid cell cycle arrest in the G2/M phase in HCT116 cells. CONCLUSIONS Our findings suggest that the dual-targeting of DNMT and TET enzymes effectively repairs aberrant DNA methylation and induces growth arrest in cancer cells, and the dual-targeting strategy may contribute to the advancement of epigenetic cancer therapy.
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Affiliation(s)
| | - Kiyoshi Sato
- Department of Applied Chemistry for Environment, Graduate School of Urban Environmental Sciences, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji 192-0397, Tokyo, Japan
| | - Hiroyoshi Kawakami
- Department of Applied Chemistry for Environment, Graduate School of Urban Environmental Sciences, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji 192-0397, Tokyo, Japan
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5
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Sun Y, Kong D, Zhang Q, Xiang R, Lu S, Feng L, Zhang H. DNA methylation biomarkers for predicting lymph node metastasis in colorectal cancer. Clin Transl Oncol 2025; 27:439-448. [PMID: 39026026 DOI: 10.1007/s12094-024-03601-6] [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: 05/05/2024] [Accepted: 07/06/2024] [Indexed: 07/20/2024]
Abstract
Colorectal cancer is one of the most common cancers worldwide. Lymph node metastasis is an important marker of colorectal cancer progression and plays a key role in the evaluation of patient prognosis. Accurate preoperative assessment of lymph node metastasis is crucial for devising appropriate treatment plans. However, current clinical imaging methods have limitations in many aspects. Therefore, the discovery of a method for accurately predicting lymph node metastasis is crucial clinical decision-making. DNA methylation is a common epigenetic modification that can regulate gene expression, which also has an important impact on the development of colorectal cancer. It is considered to be a promising biomarker with good specificity and stability and has promising application in predicting lymph node metastasis in patients with colorectal cancer. This article reviews the characteristics and limitations of currently available methods for predicting lymph node metastasis in patients with colorectal cancer and discusses the role of DNA methylation as a biomarker.
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Affiliation(s)
- Yu Sun
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Deyang Kong
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, 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, 100021, China
| | - Qi Zhang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, 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, 100021, China
| | - Renshen Xiang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, 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, 100021, China
| | - Shuaibing Lu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, 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, 100021, China
| | - Lin Feng
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Haizeng Zhang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, 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, 100021, China.
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Ma W, Tang W, Kwok JS, Tong AH, Lo CW, Chu AT, Chung BH. A review on trends in development and translation of omics signatures in cancer. Comput Struct Biotechnol J 2024; 23:954-971. [PMID: 38385061 PMCID: PMC10879706 DOI: 10.1016/j.csbj.2024.01.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 01/31/2024] [Accepted: 01/31/2024] [Indexed: 02/23/2024] Open
Abstract
The field of cancer genomics and transcriptomics has evolved from targeted profiling to swift sequencing of individual tumor genome and transcriptome. The steady growth in genome, epigenome, and transcriptome datasets on a genome-wide scale has significantly increased our capability in capturing signatures that represent both the intrinsic and extrinsic biological features of tumors. These biological differences can help in precise molecular subtyping of cancer, predicting tumor progression, metastatic potential, and resistance to therapeutic agents. In this review, we summarized the current development of genomic, methylomic, transcriptomic, proteomic and metabolic signatures in the field of cancer research and highlighted their potentials in clinical applications to improve diagnosis, prognosis, and treatment decision in cancer patients.
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Affiliation(s)
- Wei Ma
- Hong Kong Genome Institute, Hong Kong, China
| | - Wenshu Tang
- Hong Kong Genome Institute, Hong Kong, China
| | | | | | | | | | - Brian H.Y. Chung
- Hong Kong Genome Institute, Hong Kong, China
- Department of Pediatrics and Adolescent Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Hong Kong Genome Project
- Hong Kong Genome Institute, Hong Kong, China
- Department of Pediatrics and Adolescent Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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7
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Takenaka Y, Watanabe M. Environmental Factor Index (EFI): A Novel Approach to Measure the Strength of Environmental Influence on DNA Methylation in Identical Twins. EPIGENOMES 2024; 8:44. [PMID: 39584967 PMCID: PMC11587003 DOI: 10.3390/epigenomes8040044] [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: 09/03/2024] [Revised: 11/13/2024] [Accepted: 11/19/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND/OBJECTIVES The dynamic interaction between genomic DNA, epigenetic modifications, and phenotypic traits was examined in identical twins. Environmental perturbations can induce epigenetic changes in DNA methylation, influencing gene expression and phenotypes. Although DNA methylation mediates gene-environment correlations, the quantitative effects of external factors on DNA methylation remain underexplored. This study aimed to quantify these effects using a novel approach. METHODS A cohort study was conducted on healthy monozygotic twins to evaluate the influence of environmental stimuli on DNA methylation. We developed the Environmental Factor Index (EFI) to identify methylation sites showing statistically significant changes in response to environmental stimuli. We analyzed the identified sites for associations with disorders, DNA methylation markers, and CpG islands. RESULTS The EFI identified methylation sites that exhibited significant associations with genes linked to various disorders, particularly cancer. These sites were overrepresented on CpG islands compared to other genomic features, highlighting their regulatory importance. CONCLUSIONS The EFI is a valuable tool for understanding the molecular mechanisms underlying disease pathogenesis. It provides insights into the development of preventive and therapeutic strategies and offers a new perspective on the role of environmental factors in epigenetic regulation.
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Affiliation(s)
- Yoichi Takenaka
- Faculty of Informatics, Kansai University, Osaka 569-1052, Japan
- Center for Twin Research, Graduate School of Medicine, The University of Osaka, Osaka 565-0871, Japan (M.W.)
| | - Osaka Twin Research Group
- Center for Twin Research, Graduate School of Medicine, The University of Osaka, Osaka 565-0871, Japan (M.W.)
| | - Mikio Watanabe
- Center for Twin Research, Graduate School of Medicine, The University of Osaka, Osaka 565-0871, Japan (M.W.)
- Department of Clinical Laboratory and Biomedical Sciences, Graduate School of Medicine, The University of Osaka, Osaka 565-0871, Japan
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8
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Tian S, Chen M. The mechanisms and drug therapies of colorectal cancer and epigenetics: bibliometrics and visualized analysis. Front Pharmacol 2024; 15:1466156. [PMID: 39268463 PMCID: PMC11391208 DOI: 10.3389/fphar.2024.1466156] [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: 07/17/2024] [Accepted: 08/19/2024] [Indexed: 09/15/2024] Open
Abstract
BACKGROUND Numerous studies have demonstrated a link between epigenetics and CRC. However, there has been no systematic analysis or visualization of relevant publications using bibliometrics. METHODS 839 publications obtained from the Web of Science Core (WoSCC) were systematically analyzed using CiteSpace and VOSviewer software. RESULTS The results show that the countries, institutions, and authors with the most published articles are the United States, Harvard University, and Ogino and Shuji, respectively. SEPT9 is a blood test for the early detection of colorectal cancer. Vitamin D and gut microbiota mediate colorectal cancer and epigenetics, and probiotics may reduce colorectal cancer-related symptoms. We summarize the specific epigenetic mechanisms of CRC and the current existence and potential epigenetic drugs associated with these mechanisms. It is closely integrated with clinical practice, and the possible research directions and challenges in the future are proposed. CONCLUSION This study reviews the current research trends and hotspots in CRC and epigenetics, which can promote the development of this field and provide references for researchers in this field.
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Affiliation(s)
- Siyu Tian
- School of Clinical Medicine, Chengdu University of TCM, Chengdu, China
| | - Min Chen
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Sun Q, Tian Q, Bravo Iniguez A, Sun X, Zhang H, Deavila J, Du M, Zhu MJ. AMPK Deficiency Increases DNA Methylation and Aggravates Colorectal Tumorigenesis in AOM/DSS Mice. Genes (Basel) 2024; 15:835. [PMID: 39062614 PMCID: PMC11276171 DOI: 10.3390/genes15070835] [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: 05/26/2024] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 07/28/2024] Open
Abstract
The incidence of colorectal cancer (CRC) is closely linked to metabolic diseases. Accumulating evidence suggests the regulatory role of AMP-activated protein kinase (AMPK) in cancer metabolic reprogramming. In this study, wild-type and AMPK knockout mice were subjected to azoxymethane-induced and dextran sulfate sodium (AOM/DSS)-promoted colitis-associated CRC induction. A stable AMPK-deficient Caco-2 cell line was also established for the mechanistic studies. The data showed that AMPK deficiency accelerated CRC development, characterized by increased tumor number, tumor size, and hyperplasia in AOM/DSS-treated mice. The aggravated colorectal tumorigenesis resulting from AMPK ablation was associated with reduced α-ketoglutarate production and ten-eleven translocation hydroxylase 2 (TET2) transcription, correlated with the reduced mismatch repair protein mutL homolog 1 (MLH1) protein. Furthermore, in AMPK-deficient Caco-2 cells, the mRNA expression of mismatch repair and tumor suppressor genes, intracellular α-ketoglutarate, and the protein level of TET2 were also downregulated. AMPK deficiency also increased hypermethylation in the CpG islands of Mlh1 in both colonic tissues and Caco-2 cells. In conclusion, AMPK deficiency leads to reduced α-ketoglutarate concentration and elevates the suppressive epigenetic modifications of tumor suppressor genes in gut epithelial cells, thereby increasing the risk of colorectal tumorigenesis. Given the modifiable nature of AMPK activity, it holds promise as a prospective molecular target for the prevention and treatment of CRC.
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Affiliation(s)
- Qi Sun
- School of Food Science, Washington State University, Pullman, WA 99164, USA; (Q.S.); (Q.T.); (A.B.I.); (X.S.)
| | - Qiyu Tian
- School of Food Science, Washington State University, Pullman, WA 99164, USA; (Q.S.); (Q.T.); (A.B.I.); (X.S.)
| | - Alejandro Bravo Iniguez
- School of Food Science, Washington State University, Pullman, WA 99164, USA; (Q.S.); (Q.T.); (A.B.I.); (X.S.)
| | - Xiaofei Sun
- School of Food Science, Washington State University, Pullman, WA 99164, USA; (Q.S.); (Q.T.); (A.B.I.); (X.S.)
| | - Hui Zhang
- Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA;
| | - Jeanene Deavila
- Department of Animal Science, Washington State University, Pullman, WA 99164, USA; (J.D.); (M.D.)
| | - Min Du
- Department of Animal Science, Washington State University, Pullman, WA 99164, USA; (J.D.); (M.D.)
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman, WA 99164, USA; (Q.S.); (Q.T.); (A.B.I.); (X.S.)
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Higashi T, Hayashi H, Hanamatsu Y, Saigo C, Matsuhashi N, Takeuchi T. Expression of IZUMO2 in colorectal cancer in association with clinicopathological features. Pathol Res Pract 2024; 256:155263. [PMID: 38484656 DOI: 10.1016/j.prp.2024.155263] [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: 12/27/2023] [Accepted: 03/09/2024] [Indexed: 04/14/2024]
Abstract
IZUMO2 belongs to the testis-expressed IZUMO family of proteins, which are characterized by an N-terminal IZUMO domain. Based on integrated analysis of expression profiles and matched DNA methylation data from a public database, IZUMO2 represents a prognosis-related methylation-driven gene in colorectal cancer. However, it remains unclear whether IZUMO2 protein expression is suppressed or overexpressed in colorectal cancer cells. In this study, we aimed to elucidate the expression of the IZUMO2 protein in colorectal cancer, with a focus on the clinicopathological features. Sixty-four colorectal cancer tissue specimens were immunohistochemically stained using specific antibodies against IZUMO2. IZUMO2 immunoreactivity was detected at the invasion front in 30 of the 64 colorectal cancer samples. Kaplan-Meier analysis demonstrated that patients with IZUMO2 immunoreactivity had a relatively shorter overall and progression-free survival (log-rank test, P = 0.046 and 0.019, respectively). IZUMO2 immunoreactivity served as an independent factor predictive of poor progression-free survival in colorectal cancer (P = 0.025) as determined via the Cox proportional hazard regression model. Moreover, IZUMO2 immunoreactivity represented an independent factor for poor overall survival (P = 0.035) and progression-free survival (P = 0.013) in patients with colon cancer. The present findings suggest that IZUMO2 is expressed in many colorectal cancers, especially at the cancer invasion front, and may represent an indicator of poor prognosis in colorectal cancer.
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Affiliation(s)
- Toshiya Higashi
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hirokatsu Hayashi
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yuki Hanamatsu
- Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan; Center for One Medicine Innovative Translational Research; COMIT, Gifu University, Gifu, Japan.
| | - Chiemi Saigo
- Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan; Center for One Medicine Innovative Translational Research; COMIT, Gifu University, Gifu, Japan; The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Japan
| | - Nobuhisa Matsuhashi
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Tamotsu Takeuchi
- Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan; Center for One Medicine Innovative Translational Research; COMIT, Gifu University, Gifu, Japan
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11
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Cao Q, Tian Y, Deng Z, Yang F, Chen E. Epigenetic Alteration in Colorectal Cancer: Potential Diagnostic and Prognostic Implications. Int J Mol Sci 2024; 25:3358. [PMID: 38542332 PMCID: PMC10969857 DOI: 10.3390/ijms25063358] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/01/2024] [Accepted: 03/12/2024] [Indexed: 01/03/2025] Open
Abstract
Colorectal cancer (CRC), a prevalent malignant tumor of the digestive system, ranks as the third and second in global incidence and mortality, respectively, in 2020, with 1.93 million new cases (≈10% of all cancers). There are 940,000 deaths (≈9.4% of all cancers), and the incidence of CRC in younger patients (under 50 years of age) has become a new trend. The pathogenesis of CRC is primarily attributed to a series of genetic and epigenetic abnormalities within normal colonic epithelial cells, coupled with the reshaping of the tumor microenvironment in the surrounding stroma. This process leads to the transformation of colorectal adenomas into invasive adenocarcinomas. Although genetic changes are known to be the primary driving force in the occurrence and progression of CRC, recent research indicates that epigenetic regulation serves as a crucial molecular marker in cancer, playing a significant role in the pathological and physiological control of interactions between genetics and the environment. This review discusses the current global epidemiology of CRC, its risk factors, and preventive treatment strategies. The current study explores the latest advancements in the epigenetic regulation of CRC, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). These developments hold potential as screening tools, prognostic biomarkers, and therapeutic targets for CRC.
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Affiliation(s)
- Qing Cao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
| | - Ye Tian
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
| | - Zhiyi Deng
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
| | - Fangfang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
| | - Erfei Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
- School of Medicine, Northwest University, Xi’an 710069, China
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12
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Ghazimoradi MH, Pakravan K, Khalafizadeh A, Babashah S. TET1 regulates stem cell properties and cell cycle of Cancer stem cells in triple-negative breast cancer via DNA demethylation. Biochem Pharmacol 2024; 219:115913. [PMID: 37995981 DOI: 10.1016/j.bcp.2023.115913] [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: 10/14/2023] [Revised: 11/04/2023] [Accepted: 11/07/2023] [Indexed: 11/25/2023]
Abstract
The role of cancer stem cells in metastasis, recurrence, and resistance to conventional therapies is significant. Addressing these cells could potentially decrease cancer reoccurrences and mortality rates. TET1, a crucial gene involved in stem cell self-renewal and potency, may also play a part in cancer stem cells, which warrants further research. To explore the role of TET1 in cancer stem cells, we conducted experiments involving loss and gain. We then analyzed factors such as migration, invasion, cell cycle, cell viability, mammosphere formation, and the CD44+/CD24- subpopulation of cancer cells. We also investigate the influence of TET1 on CCNB1, CDK1, and OCT4. Our study reveals that TET1 can regulate the phenotype of cancer stem cells via OCT4. Additionally, it can control the cell cycle by increasing CDK1 and CCNB1 levels. These findings suggest that targeting DNA methylation and TET1 could be an effective strategy to overcome obstacles posed by Cancer stem cells. Our research also indicates that TET1 can influence the phenotype of cancer stem cells and the cell cycle of breast cancer cells potentially through OCT4, CCNB1, and CDK1. This highlights the importance of TET1 in breast cancer cases and suggests a potential therapeutic approach through DNA methylation and modulation of TET1.
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Affiliation(s)
- Mohammad H Ghazimoradi
- Department of Molecular Genetics, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | - Katayoon Pakravan
- Department of Molecular Genetics, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | - Ali Khalafizadeh
- Department of Molecular Genetics, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | - Sadegh Babashah
- Department of Molecular Genetics, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran.
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13
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Postwala H, Shah Y, Parekh PS, Chorawala MR. Unveiling the genetic and epigenetic landscape of colorectal cancer: new insights into pathogenic pathways. Med Oncol 2023; 40:334. [PMID: 37855910 DOI: 10.1007/s12032-023-02201-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 09/19/2023] [Indexed: 10/20/2023]
Abstract
Colorectal cancer (CRC) is a complex disease characterized by genetic and epigenetic alterations, playing a crucial role in its development and progression. This review aims to provide insights into the emerging landscape of these alterations in CRC pathogenesis to develop effective diagnostic tools and targeted therapies. Genetic alterations in signaling pathways such as Wnt/β-catenin, and PI3K/Akt/mTOR are pivotal in CRC development. Genetic profiling has identified distinct molecular subtypes, enabling personalized treatment strategies. Epigenetic modifications, including DNA methylation and histone modifications, also contribute to CRC pathogenesis by influencing critical cellular processes through gene silencing or activation. Non-coding RNAs have emerged as essential players in epigenetic regulation and CRC progression. Recent research highlights the interplay between genetic and epigenetic alterations in CRC. Genetic mutations can affect epigenetic modifications, leading to dysregulated gene expression and signaling cascades. Conversely, epigenetic changes can modulate genetic expression, amplifying or dampening the effects of genetic alterations. Advancements in understanding pathogenic pathways have potential clinical applications. Identifying genetic and epigenetic markers as diagnostic and prognostic biomarkers promises more accurate risk assessment and early detection. Challenges remain, including validating biomarkers and developing robust therapeutic strategies through extensive research and clinical trials. The dynamic nature of genetic and epigenetic alterations necessitates a comprehensive understanding of their temporal and spatial patterns during CRC progression. In conclusion, the genetic and epigenetic landscape of CRC is increasingly being unraveled, providing valuable insights into its pathogenesis. Integrating genetic and epigenetic knowledge holds great potential for improving diagnostics, prognostics, and personalized therapies in CRC. Continued research efforts are vital to translate these findings into clinical practice, ultimately improving patient outcomes.
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Affiliation(s)
- Humzah Postwala
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, 380009, Gujarat, India
| | - Yesha Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, 380009, Gujarat, India
| | - Priyajeet S Parekh
- AV Pharma LLC, 1545 University Blvd N Ste A, Jacksonville, Florida, 32211, USA
| | - Mehul R Chorawala
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, 380009, Gujarat, India.
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14
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Dong X, Zhang Y, Sun Y, Nan Q, Li M, Ma L, Zhang L, Luo J, Qi Y, Miao Y. Promoter hypermethylation and comprehensive regulation of ncRNA lead to the down-regulation of ZNF880, providing a new insight for the therapeutics and research of colorectal cancer. BMC Med Genomics 2023; 16:148. [PMID: 37370088 PMCID: PMC10294494 DOI: 10.1186/s12920-023-01571-2] [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: 06/02/2022] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
The human genome encodes more than 350 kinds of Krüppel-associated box (KRAB) domain-containing zinc-finger proteins (KZFPs), KRAB-type ZNF transcription factor family (KZNF) plays a vital role in gene regulatory networks. The KZNF family members include a large number of highly homologous genes, gene subtypes and pseudogenes, and their expression has a high degree of tissue specificity and precision. Due to the high complexity of its regulatory network, the KZNF gene family has not been researched in sufficient, and the role of its members in the occurrence of cancer is mostly unexplored. In this study, ZNF880 was significantly associated with overall survival (OS) and disease-free survival (DFS) in colorectal carcinoma (CRC) patients. Low ZNF880 expression resulted in shorter OS and DFS. Combined with Colon adenocarcinoma (COAD) and Rectum adenocarcinoma (READ) data collection in the TCGA database, we found that ZNF880 was significantly down-regulated in CRC. Further analysis of the sequence variation of ZNF880 in CRC showed that ZNF880 accumulated a large number of SNV in the C2H2 domain and KRAB domain, while promoter region of ZNF880 also showed high methylation in COAD and READ. Combined with the Cbioportal and TIMER databases, the expression of mutant ZNF880 was significantly lower in COAD compared to the wild type. Simultaneously, the lncRNA-miRNA-ZNF880 ceRNA regulatory network was constructed through co-expression and miRNAs target gene prediction, demonstrating the precision of the ZNF880 regulatory network. In addition, the decreased expression of ZNF880 caused the significant immune infiltration decreases of CD8 + cells in COAD. In contrast, the immune infiltration of CD4 + cells and macrophages in COAD is positively correlated with ZNF880. Finally, through protein-protein interaction (PPI) network analysis and transcription factor target gene prediction, we screened out the genes most likely to be related to the function of ZNF880. CENPK, IFNGR2, REC8 and ZBTB17 were identified as the most closely functioning genes with ZNF880, which may indicate that ZNF880 has important links with the formation of cell centromere, tumor immunity, cell cycle and other pathways closely related to the occurrence of CRC. These studies show that the down-regulation of ZNF880 gene is closely related to CRC, and the targeted change of the expression of its regulatory molecules (miRNA and lncRNA) may be a new perspective for CRC treatment.
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Affiliation(s)
- Xiangqian Dong
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Yinghui Zhang
- Department of Gastroenterology, Affiliated Hospital of Yunnan University, Kunming, 650021, China
| | - Yang Sun
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Qiong Nan
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Maojuan Li
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Lanqing Ma
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Lei Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Juan Luo
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Yating Qi
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Yinglei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China.
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China.
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15
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Lu Y, Cao Q, Yu Y, Sun Y, Jiang X, Li X. Pan-cancer analysis revealed H3K4me1 at bivalent promoters premarks DNA hypermethylation during tumor development and identified the regulatory role of DNA methylation in relation to histone modifications. BMC Genomics 2023; 24:235. [PMID: 37138231 PMCID: PMC10157937 DOI: 10.1186/s12864-023-09341-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 04/27/2023] [Indexed: 05/05/2023] Open
Abstract
BACKGROUND DNA hypermethylation at promoter CpG islands (CGIs) is a hallmark of cancers and could lead to dysregulation of gene expression in the development of cancers, however, its dynamics and regulatory mechanisms remain elusive. Bivalent genes, that direct development and differentiation of stem cells, are found to be frequent targets of hypermethylation in cancers. RESULTS Here we performed comprehensive analysis across multiple cancer types and identified that the decrease in H3K4me1 levels coincides with DNA hypermethylation at the bivalent promoter CGIs during tumorigenesis. Removal of DNA hypermethylation leads to increment of H3K4me1 at promoter CGIs with preference for bivalent genes. Nevertheless, the alteration of H3K4me1 by overexpressing or knockout LSD1, the demethylase of H3K4, doesn't change the level or pattern of DNA methylation. Moreover, LSD1 was found to regulate the expression of a bivalent gene OVOL2 to promote tumorigenesis. Knockdown of OVOL2 in LSD1 knockout HCT116 cells restored the cancer cell phenotype. CONCLUSION In summary, our work identified a universal indicator that can pre-mark DNA hypermethylation in cancer cells, and dissected the interplay between H3K4me1 and DNA hypermethylation in detail. Current study also reveals a novel mechanism underlying the oncogenic role of LSD1, providing clues for cancer therapies.
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Affiliation(s)
- Yang Lu
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China
| | - Qiang Cao
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China
| | - Yue Yu
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China
| | - Yazhou Sun
- The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Xuan Jiang
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China.
| | - Xin Li
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China.
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16
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Boughanem H, Kompella P, Tinahones FJ, Macias-Gonzalez M. An overview of vitamins as epidrugs for colorectal cancer prevention. Nutr Rev 2023; 81:455-479. [PMID: 36018754 DOI: 10.1093/nutrit/nuac065] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Gene expression altering epigenomic modifications such as DNA methylation, histone modification, and chromosome remodeling is crucial to regulating many biological processes. Several lifestyle factors, such as diet and natural, bioactive food compounds, such as vitamins, modify epigenetic patterns. However, epigenetic dysregulation can increase the risk of many diseases, including cancer. Various studies have provided supporting and contrasting evidence on the relationship between vitamins and cancer risk. Though there is a gap in knowledge about whether dietary vitamins can induce epigenetic modifications in the context of colorectal cancer (CRC), the possibility of using them as epidrugs for CRC treatment is being explored. This is promising because such studies might be informative about the most effective way to use vitamins in combination with DNA methyltransferase inhibitors and other approved therapies to prevent and treat CRC. This review summarizes the available epidemiological and observational studies involving dietary, circulating levels, and supplementation of vitamins and their relationship with CRC risk. Additionally, using available in vitro, in vivo, and human observational studies, the role of vitamins as potential epigenetic modifiers in CRC is discussed. This review is focused on the action of vitamins as modifiers of DNA methylation because aberrant DNA methylation, together with genetic alterations, can induce the initiation and progression of CRC. Although this review presents some studies with promising results, studies with better study designs are necessary. A thorough understanding of the underlying molecular mechanisms of vitamin-mediated epigenetic regulation of CRC genes can help identify effective therapeutic targets for CRC prevention and treatment.
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Affiliation(s)
- Hatim Boughanem
- are with the Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, Malaga, Spain.,are with the Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Pallavi Kompella
- are with the Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, Malaga, Spain.,is with the Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA
| | - Francisco J Tinahones
- are with the Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, Malaga, Spain.,are with the Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Manuel Macias-Gonzalez
- are with the Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, Malaga, Spain.,are with the Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
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17
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Baghel VS, Shinde S, Sinha V, Dixit V, Tiwari AK, Saxena S, Vishvakarma NK, Shukla D, Bhatt P. Inhibitors targeting epigenetic modifications in cancer. TRANSCRIPTION AND TRANSLATION IN HEALTH AND DISEASE 2023:287-324. [DOI: 10.1016/b978-0-323-99521-4.00007-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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18
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Chuang JP, Tsai HL, Chen PJ, Chang TK, Su WC, Yeh YS, Huang CW, Wang JY. Comprehensive Review of Biomarkers for the Treatment of Locally Advanced Colon Cancer. Cells 2022; 11:3744. [PMID: 36497002 PMCID: PMC9740797 DOI: 10.3390/cells11233744] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/16/2022] [Accepted: 11/19/2022] [Indexed: 11/25/2022] Open
Abstract
Despite the implementation of global screening programs, colorectal cancer (CRC) remains the second leading cause of cancer-related deaths worldwide. More than 10% of patients with colon cancer are diagnosed as having locally advanced disease with a relatively poor five-year survival rate. Locally advanced colon cancer (LACC) presents surgical challenges to R0 resection. The advantages and disadvantages of preoperative radiotherapy for LACC remain undetermined. Although several reliable novel biomarkers have been proposed for the prediction and prognosis of CRC, few studies have focused solely on the treatment of LACC. This comprehensive review highlights the role of predictive biomarkers for treatment and postoperative oncological outcomes for patients with LACC. Moreover, this review discusses emerging needs and approaches for the discovery of biomarkers that can facilitate the development of new therapeutic targets and surveillance of patients with LACC.
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Affiliation(s)
- Jen-Pin Chuang
- Pingtung Hospital, Ministry of Health and Welfare, Pingtung 90054, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Department of Surgery, National Cheng Kung University Hospital, Tainan 70101, Taiwan
| | - Hsiang-Lin Tsai
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Po-Jung Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Tsung-Kun Chang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Division of Trauma and Surgical Critical Care, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Wei-Chih Su
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yung-Sung Yeh
- Department of Emergency Medicine, Faculty of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Injury Prevention and Control, College of Public Health, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ching-Wen Huang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jaw-Yuan Wang
- Pingtung Hospital, Ministry of Health and Welfare, Pingtung 90054, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
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19
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Sahoo OS, Pethusamy K, Srivastava TP, Talukdar J, Alqahtani MS, Abbas M, Dhar R, Karmakar S. The metabolic addiction of cancer stem cells. Front Oncol 2022; 12:955892. [PMID: 35957877 PMCID: PMC9357939 DOI: 10.3389/fonc.2022.955892] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer stem cells (CSC) are the minor population of cancer originating cells that have the capacity of self-renewal, differentiation, and tumorigenicity (when transplanted into an immunocompromised animal). These low-copy number cell populations are believed to be resistant to conventional chemo and radiotherapy. It was reported that metabolic adaptation of these elusive cell populations is to a large extent responsible for their survival and distant metastasis. Warburg effect is a hallmark of most cancer in which the cancer cells prefer to metabolize glucose anaerobically, even under normoxic conditions. Warburg's aerobic glycolysis produces ATP efficiently promoting cell proliferation by reprogramming metabolism to increase glucose uptake and stimulating lactate production. This metabolic adaptation also seems to contribute to chemoresistance and immune evasion, a prerequisite for cancer cell survival and proliferation. Though we know a lot about metabolic fine-tuning in cancer, what is still in shadow is the identity of upstream regulators that orchestrates this process. Epigenetic modification of key metabolic enzymes seems to play a decisive role in this. By altering the metabolic flux, cancer cells polarize the biochemical reactions to selectively generate "onco-metabolites" that provide an added advantage for cell proliferation and survival. In this review, we explored the metabolic-epigenetic circuity in relation to cancer growth and proliferation and establish the fact how cancer cells may be addicted to specific metabolic pathways to meet their needs. Interestingly, even the immune system is re-calibrated to adapt to this altered scenario. Knowing the details is crucial for selective targeting of cancer stem cells by choking the rate-limiting stems and crucial branch points, preventing the formation of onco-metabolites.
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Affiliation(s)
- Om Saswat Sahoo
- Department of Biotechnology, National Institute of technology, Durgapur, India
| | - Karthikeyan Pethusamy
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | | | - Joyeeta Talukdar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Mohammed S. Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
- BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester, United Kingdom
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, Saudi Arabia
- Computers and communications Department, College of Engineering, Delta University for Science and Technology, Gamasa, Egypt
| | - Ruby Dhar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Subhradip Karmakar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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20
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Jiang HH, Xing SW, Tang X, Chen Y, Lin K, He LW, Lin MB, Tang EJ. Novel multiplex stool-based assay for the detection of early-stage colon cancer in a Chinese population. World J Gastroenterol 2022; 28:2705-2732. [PMID: 35979157 PMCID: PMC9260868 DOI: 10.3748/wjg.v28.i24.2705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 01/14/2022] [Accepted: 05/14/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Stool DNA (sDNA) methylation analysis is a promising, noninvasive approach for colorectal cancer screening; however, reliable biomarkers for detecting early-stage colon cancer (ECC) are lacking, particularly in the Chinese population.
AIM To identify a novel stool-based assay that can improve the effectiveness of ECC screening.
METHODS A blinded case-control study was performed using archived stool samples from 125 ECC patients, and 125 control subjects with normal colonoscopy. The cohort was randomly divided into training and test sets at a 1.5:1 ratio. Targeted bisulfite sequencing (TBSeq) was conducted on five pairs of preoperative and postop-erative sDNA samples from ECC patients to identify DNA methylation biomarkers, which were validated using pyrosequencing. By logistic regression analysis, a multiplex stool-based assay was developed in the training set, and the detection performance was further assessed in the test set and combined set. The χ2 test was used to investigate the association of detection sensitivity with clinico-pathological features.
RESULTS Following TBSeq, three hypermethylated cytosine-guanine sites were selected as biomarkers, including paired box 8, Ras-association domain family 1 and secreted frizzled-related protein 2, which differed between the groups and were involved in important cancer pathways. An sDNA panel containing the three biomarkers was constructed with a logistic model. Receiver operating characteristic (ROC) analysis revealed that this panel was superior to the fecal immunochemical test (FIT) or serum carcinoembryonic antigen for the detection of ECC. We further found that the combination of the sDNA panel with FIT could improve the screening effectiveness. In the combined set, the sensitivity, specificity and area under the ROC curve for this multiplex assay were 80.0%, 93.6% and 0.918, respectively, and the performance remained excellent in the subgroup analysis by tumor stage. In addition, the detection sensitivity did not differ with tumor site, tumor stage, histological differentiation, age or sex, but was significantly higher in T4 than in T1-3 stage tumors (P = 0.041).
CONCLUSION We identified a novel multiplex stool-based assay combining sDNA methylation biomarkers and FIT, which could detect ECC with high sensitivity and specificity throughout the colon, showing a promising application perspective.
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Affiliation(s)
- Hui-Hong Jiang
- Department of General Surgery, Yangpu Hospital, Tongji University, Shanghai 200090, China
- Institute of Gastrointestinal Surgery and Translational Medicine, Tongji University School of Medicine, Shanghai 200090, China
| | - Si-Wei Xing
- Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University, Shanghai 200090, China
| | - Xuan Tang
- Department of General Surgery, Yangpu Hospital, Tongji University, Shanghai 200090, China
| | - Ying Chen
- Institute of Gastrointestinal Surgery and Translational Medicine, Tongji University School of Medicine, Shanghai 200090, China
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University, Shanghai 200090, China
| | - Kang Lin
- Department of General Surgery, Yangpu Hospital, Tongji University, Shanghai 200090, China
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University, Shanghai 200090, China
| | - Lu-Wei He
- Institute of Gastrointestinal Surgery and Translational Medicine, Tongji University School of Medicine, Shanghai 200090, China
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University, Shanghai 200090, China
| | - Mou-Bin Lin
- Department of General Surgery, Yangpu Hospital, Tongji University, Shanghai 200090, China
- Institute of Gastrointestinal Surgery and Translational Medicine, Tongji University School of Medicine, Shanghai 200090, China
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University, Shanghai 200090, China
| | - Er-Jiang Tang
- Institute of Gastrointestinal Surgery and Translational Medicine, Tongji University School of Medicine, Shanghai 200090, China
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University, Shanghai 200090, China
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21
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Wang L, Liu Y, Zhang D, Xiong X, Hao T, Zhong L, Zhao Y. Diagnostic accuracy of DNA-based SDC2 methylation test in colorectal cancer screening: a meta-analysis. BMC Gastroenterol 2022; 22:314. [PMID: 35754025 PMCID: PMC9235166 DOI: 10.1186/s12876-022-02395-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Background A growing body of research suggests that methylated genes can be used as early diagnostic markers for cancer. Some studies on methylated Syndecan 2 (SDC2) have shown that it has a great diagnostic ability in colorectal cancer. This meta-analysis was aimed to estimate the diagnostic performance of methylated SDC2 as a potential novel biomarker to screen for the colorectal cancer. Methods Two independent researchers conducted a comprehensive literature search to identify all relevant studies on SDC2 methylation for the diagnosis of colorectal cancer from inception to March 1, 2021. By using STATA and Revman software, the data were analyzed using a Bivariate mixed model. The quality of each study was also evaluated. Results A total of 12 studies comprised of 1574 colorectal cancer patients and 1945 healthy people were included in our meta-analysis. Bivariate analysis showed a pooled sensitivity of 0.81 [95% confidence interval (CI) 0.74–0.86], specificity of 0.95 (95% CI 0.93–0.96), positive likelihood ratio of 15.29 (95% CI 10.83–21.60), and negative likelihood ratio of 0.21 (95% CI 0.15–0.27). The diagnostic odds ratio and the area under the summary ROC curve for diagnosing colorectal cancer were 74.42 (95% CI45.44–121.89) and 0.96 (95% CI 0.94–0.97), respectively. For adenomas, the pooled sensitivity and specificity were 0.47 (95% CI 0.34–0.61) and 0.95 (95% CI 0.92–0.97), respectively. Conclusions Our analysis revealed that methylated SDC2 could be considered as a potential novel biomarker to screen for colorectal cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02395-7.
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Affiliation(s)
- Lixing Wang
- Department of Nuclear Medicine, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Yu Liu
- Department of Nuclear Medicine, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Duohan Zhang
- Department of Nuclear Medicine, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Xiaoliang Xiong
- Department of Nuclear Medicine, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Tingting Hao
- Department of Nuclear Medicine, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Lili Zhong
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, 130041, China.
| | - Yinlong Zhao
- Department of Nuclear Medicine, The Second Hospital of Jilin University, Changchun, 130041, China.
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Epigenetic insights in the diagnosis, prognosis, and treatment selection in CRC, an updated review. Mol Biol Rep 2022; 49:10013-10022. [PMID: 35727475 DOI: 10.1007/s11033-022-07569-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 05/05/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIM The gradual accumulation of genetic and epigenetic alterations can lead to the development of colorectal cancer. In the last decade much research has been done to discover how methylation as an epigenetic alteration leads to carcinogenesis. While Methylation is a biological process, it can influence gene expression by affecting the promoter activity. This article reviews the role of methylation in critical pathways in CRC. METHODS In this study using appropriate keywords, all research and review articles related to the role of methylation on different cancers were collected and analyzed. Also, existing information on methylation detection methods and therapeutic sensitivity or resistance due to DNA methylation were reviewed. RESULTS The results of this survey revealed that while Methylation is a biological process, it can influence gene expression by affecting the promoter activity. Promoter methylation is associated with up or downregulation of genes involved in critical pathways, including cell cycle, DNA repair, and cell adherence. Hence promoter methylation can be used as a molecular tool for early diagnosis, improving treatment, and predicting treatment resistance. CONCLUSION Current knowledge on potential methylation biomarkers for diagnosis and prognoses of CRC has also been discussed. Our survey proposes that a multi-biomarker panel is more efficient than a single biomarker in the early diagnosis of CRC.
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Lucknuch T, Praihirunkit P. Evaluation of Age-associated DNA Methylation Markers in Colorectal Cancer of Thai Population. FORENSIC SCIENCE INTERNATIONAL: REPORTS 2022. [DOI: 10.1016/j.fsir.2022.100265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Ji H, Li K, Jiang W, Li J, Zhang JA, Zhu X. MRVI1 and NTRK3 Are Potential Tumor Suppressor Genes Commonly Inactivated by DNA Methylation in Cervical Cancer. Front Oncol 2022; 11:802068. [PMID: 35141152 PMCID: PMC8818726 DOI: 10.3389/fonc.2021.802068] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/24/2021] [Indexed: 11/13/2022] Open
Abstract
The abnormally methylated tumor suppressor genes (TSGs) associated with cervical cancer are unclear. DNA methylation data, RNA-seq expression profiles, and overall survival data were downloaded from TCGA CESC database. DMGs and DEGs were obtained through CHAMP and DESeq packages, respectively. TSGs were downloaded from TSGene 2.0. Candidate hypermethylated/down-regulated TSGs were further evaluated and pyrosequencing was used to confirm their difference in methylation levels of selected TSGs in cervical cancer patients. A total of 25946 differentially methylated CpGs corresponding to 2686 hypermethylated genes and 4898 hypomethylated genes between cervical cancer and adjacent normal cervical tissues were found in this study. Besides, 693 DEGs (109 up-regulated and 584 down-regulated) were discovered in cervical cancer tissues. Then, 192 hypermethylated/down-regulated genes were obtained in cervical cancer compared to adjacent tissues. Interestingly, 26 TSGs were found in hypermethylated/down-regulated genes. Among these genes, low expression of MRVI1 and NTRK3 was associated with poor overall survival in cervical cancer. Moreover, GEO data showed that MRVI1 and NTRK3 were significantly decreased in cervical cancer tissues. The expression levels of MRVI1 and NTRK3 were negatively correlated with the methylation levels of their promoter CpG sites. Additionally, elevated methylation levels of MRVI1 and NTRK3 promoter were further verified in cervical cancer tissues by pyrosequencing experiments. Finally, the ROC results showed that the promoter methylation levels of MRVI1 and NTRK3 had the ability to discriminate cervical cancer from healthy samples. The study contributes to our understanding of the roles of MRVI1 and NTRK3 in cervical cancer.
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Affiliation(s)
- Huihui Ji
- Center of Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kehan Li
- Center of Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wenxiao Jiang
- Center of Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jingwei Li
- Department of Obstetrics and Gynecology, Taizhou Woman and Children’s Hospital of Wenzhou Medical University, Taizhou, China
| | - Jian-an Zhang
- Center of Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xueqiong Zhu
- Center of Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Obstetrics and Gynecology, Taizhou Woman and Children’s Hospital of Wenzhou Medical University, Taizhou, China
- *Correspondence: Xueqiong Zhu,
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Shahi A, Koyyala VPB, Rathaur ES, Biddut MA, Hossain A, Hasan MK, Alam J, Hossain T, Khatun N. Association between Gastric Cancer with Behavioral and Dietary Factors: A Hospital Based Case-Control Study in South Asia. ASIAN JOURNAL OF ONCOLOGY 2021. [DOI: 10.1055/s-0041-1740106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
Abstract
Background Gastric cancer (GC) is one of the most common malignancies and a leading cause of mortality and morbidity worldwide. It is the fourth leading cancer in Bangladesh. Identification of risk factors, effective prevention, and early diagnosis are the most important interventions against GC.
Objectives To find an association of dietary and behavioral factors in the development of GC among the Bangladeshi population.
Methods This case–control study was conducted from January 2017 to December 2018 at the National Institute of Cancer Research and Hospital, Dhaka, Bangladesh. A total of 178 patients were studied (89 case and 89 controls). Data were collected via face-to-face interview using a standard structured questionnaire, posing questions about socio-demographic, behavioral and dietary habits, and clinical factors. A binary logistic regression method was used to calculate the odds ratio (OR).
Results Among 178 patients, the age group ranged from 30 to 80 years and most patients were between 51 to 60 years. The results showed that regular consumption of red meat, duration of smoking, smokeless tobacco, fast food and fatty food, and family history of any type of cancer were directly associated with the risk of GC. On the contrary, a habit of regular walking and playing sports has an inverse association with GC. Adjusted OR shows regular consumption of red meat has 2.6 times more risk (OR = 2.661) of developing GC compared with irregular meat consumption, and a person with a history of Helicobacter pylori infection is 53% (OR = 7.263; 95% confidence interval: 3.614–14.597) more likely to develop cancer. In contrast, people who were doing exercise regularly for at least 30 minutes/day are 62.7% (OR = 0.373) less likely to develop GC than those who did not.
Conclusion The study showed an association of some dietary and behavioral factor in the development of GC. However, more research in this field is required to understand the etiology, for the development of suitable screening test, for demarcation of high-risk population, and to develop and evaluate the effectiveness of primary prevention programs.
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Affiliation(s)
- Arun Shahi
- Medical Oncology Unit, Faculty of Internal Medicine, Patan Academy of Health Science, Lalitpur, Nepal
| | | | - Ela Singh Rathaur
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Thailand
| | - Md. Assaduzaman Biddut
- Department of Medical Oncology, National Institute of Cancer Research and Hospital, Mohakhali, Dhaka, Bangladesh
| | - Anwor Hossain
- Department of Medical Oncology, National Institute of Cancer Research and Hospital, Mohakhali, Dhaka, Bangladesh
| | - Md. Kamrul Hasan
- Department of Medical Oncology, National Institute of Cancer Research and Hospital, Mohakhali, Dhaka, Bangladesh
| | - Jahangir Alam
- Department of Medical Oncology, National Institute of Cancer Research and Hospital, Mohakhali, Dhaka, Bangladesh
| | - Tanzina Hossain
- Department of Medical Oncology, National Institute of Cancer Research and Hospital, Mohakhali, Dhaka, Bangladesh
| | - Nazrina Khatun
- Department of Medical Oncology, National Institute of Cancer Research and Hospital, Mohakhali, Dhaka, Bangladesh
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Leptin Protein Expression and Promoter Methylation in Ovarian Cancer: A Strong Prognostic Value with Theranostic Promises. Int J Mol Sci 2021; 22:ijms222312872. [PMID: 34884678 PMCID: PMC8657586 DOI: 10.3390/ijms222312872] [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: 11/04/2021] [Revised: 11/23/2021] [Accepted: 11/24/2021] [Indexed: 12/13/2022] Open
Abstract
Ovarian cancer (OC) is the deadliest among all gynecological cancers. Epidemiological studies showed that obesity might influence many cancers including OC. One of the key factors that may link obesity and OC is leptin (LEP), known as an adipokine with pleiotropic effects on body homeostasis. This study aims to investigate the expression pattern of LEP, assess the methylation profiles of LEP and their associations with clinicopathological features including survival outcomes of OC patients. The protein expression of LEP was evaluated in 208 samples using both tissue microarray and immunohistochemistry techniques. The methylation profiles of LEP were measured in 63 formalin-fixed, paraffin-embedded tumor tissues by quantitative polymerase chain reaction using a MethyLight assay. Our results showed a significant association of LEP protein overexpression with several clinicopathological variables, mainly tumor subtype, LVI, age of menarche, tumor size and stage (p < 0.04). Kaplan-Meier analysis (using low expression versus high expression as a discriminator) indicated that LEP protein overexpression is a powerful positive prognosticator of both OC recurrence (DFS) and disease-specific survival (DSS) in our OC cohort (log-rank p = 0.01 and p = 0.002, respectively). This implies that patients with high LEP expression profiles live longer with less recurrence rates. Methylation analysis results demonstrated a clear association between no/low LEP protein expression pattern (38%) and LEP promoter CpG island hypermethylation (43%). Results of this study suggest that LEP is a powerful prognosticator of OC recurrence and DSS. LEP expression in OC seems to be regulated by its promoter hypermethylation through gene partial/total silencing. Further multi-institutional studies using larger cohorts are required to demystify the intricate molecular functions of this leptin-driven effects in OC pathophysiology and to accurately assess its theranostic potential and validate its prognostic/predictive power in OC onset, progression towards more effective and personalized management of OC patients.
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Gutierrez A, Demond H, Brebi P, Ili CG. Novel Methylation Biomarkers for Colorectal Cancer Prognosis. Biomolecules 2021; 11:1722. [PMID: 34827720 PMCID: PMC8615818 DOI: 10.3390/biom11111722] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/03/2021] [Accepted: 11/09/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) comprises the third most common cancer worldwide and the second regarding number of deaths. In order to make a correct and early diagnosis to predict metastasis formation, biomarkers are an important tool. Although there are multiple signaling pathways associated with cancer progression, the most recognized are the MAPK pathway, p53 pathway, and TGF-β pathway. These pathways regulate many important functions in the cell, such as cell cycle regulation, proliferation, differentiation, and metastasis formation, among others. Changes in expression in genes belonging to these pathways are drivers of carcinogenesis. Often these expression changes are caused by mutations; however, epigenetic changes, such as DNA methylation, are increasingly acknowledged to play a role in the deregulation of oncogenic genes. This makes DNA methylation changes an interesting biomarkers in cancer. Among the newly identified biomarkers for CRC metastasis INHBB, SMOC2, BDNF, and TBRG4 are included, all of which are highly deregulated by methylation and closely associated with metastasis. The identification of such biomarkers in metastasis of CRC may allow a better treatment and early identification of cancer formation in order to perform better diagnostics and improve the life expectancy.
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Affiliation(s)
| | | | - Priscilla Brebi
- Millennium Institute on Immunology and Immunotherapy, Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (A.G.); (H.D.)
| | - Carmen Gloria Ili
- Millennium Institute on Immunology and Immunotherapy, Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (A.G.); (H.D.)
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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.
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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
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Turpín-Sevilla MDC, Pérez-Sanz F, García-Solano J, Sebastián-León P, Trujillo-Santos J, Carbonell P, Estrada E, Tuomisto A, Herruzo I, Fennell LJ, Mäkinen MJ, Rodríguez-Braun E, Whitehall VLJ, Conesa A, Conesa-Zamora P. Global Methylome Scores Correlate with Histological Subtypes of Colorectal Carcinoma and Show Different Associations with Common Clinical and Molecular Features. Cancers (Basel) 2021; 13:cancers13205165. [PMID: 34680315 PMCID: PMC8533997 DOI: 10.3390/cancers13205165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/03/2021] [Accepted: 10/11/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND The typical methylation patterns associated with cancer are hypermethylation at gene promoters and global genome hypomethylation. Aberrant CpG island hypermethylation at promoter regions and global genome hypomethylation have not been associated with histological colorectal carcinomas (CRC) subsets. Using Illumina's 450 k Infinium Human Methylation beadchip, the methylome of 82 CRCs were analyzed, comprising different histological subtypes: 40 serrated adenocarcinomas (SAC), 32 conventional carcinomas (CC) and 10 CRCs showing histological and molecular features of microsatellite instability (hmMSI-H), and, additionally, 35 normal adjacent mucosae. Scores reflecting the overall methylation at 250 bp, 1 kb and 2 kb from the transcription starting site (TSS) were studied. RESULTS SAC has an intermediate methylation pattern between CC and hmMSI-H for the three genome locations. In addition, the shift from promoter hypermethylation to genomic hypomethylation occurs at a small sequence between 250 bp and 1 Kb from the gene TSS, and an asymmetric distribution of methylation was observed between both sides of the CpG islands (N vs. S shores). CONCLUSION These findings show that different histological subtypes of CRC have a particular global methylation pattern depending on sequence distance to TSS and highlight the so far underestimated importance of CpGs aberrantly hypomethylated in the clinical phenotype of CRCs.
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Affiliation(s)
- María del Carmen Turpín-Sevilla
- Facultad de Medicina, Universidad Francisco de Vitoria, Ctra. Pozuelo-Majadahonda, Km 1800, Pozuelo de Alarcón, 28223 Madrid, Spain; (M.d.C.T.-S.); (I.H.)
| | - Fernando Pérez-Sanz
- Biomedical Informatics & Bioinformatics Platform, Institute for Biomedical Research of Murcia (IMIB)/Foundation for Healthcare Training & Research of the Region of Murcia (FFIS), Calle Luis Fontes Pagán 9, 30003 Murcia, Spain;
| | - José García-Solano
- Department of Pathology, Santa Lucía General University Hospital (HGUSL), C/Mezquita s/n, 30202 Cartagena, Spain;
- Facultad de Ciencias de la Salud, Universidad Católica de Murcia (UCAM), Campus Los Jerónimos, 30107 Guadalupe, Spain
- Group of Molecular Pathology and Pharmacogenetics, Institute for Biomedical Research from Murcia (IMIB), HGUSL, 30202 Cartagena, Spain
| | - Patricia Sebastián-León
- IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain;
| | - Javier Trujillo-Santos
- Department of Internal Medicine, Santa Lucía General University Hospital (HGUSL), C/Mezquita s/n, 30202 Cartagena, Spain;
| | - Pablo Carbonell
- Biochemistry and Clinical Genetic Center, Virgen de la Arrixaca University Hospital, 30100 Murcia, Spain;
| | - Eduardo Estrada
- Department of Social Psychology and Methodology, Universidad Autónoma de Madrid, 28049 Madrid, Spain;
| | - Anne Tuomisto
- Cancer and Translational Medicine Research Unit, Department of Pathology, University of Oulu, P.O. Box 5000, 90014 Oulu, Finland; (A.T.); (M.J.M.)
| | - Irene Herruzo
- Facultad de Medicina, Universidad Francisco de Vitoria, Ctra. Pozuelo-Majadahonda, Km 1800, Pozuelo de Alarcón, 28223 Madrid, Spain; (M.d.C.T.-S.); (I.H.)
| | - Lochlan J. Fennell
- QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; (L.J.F.); (V.L.J.W.)
- Conjoint Internal Medicine Laboratory, Pathology Queensland, Herston, QLD 4006, Australia
- Faculty of Medicine, The University of Queensland, Herston, QLD 4072, Australia
| | - Markus J. Mäkinen
- Cancer and Translational Medicine Research Unit, Department of Pathology, University of Oulu, P.O. Box 5000, 90014 Oulu, Finland; (A.T.); (M.J.M.)
| | - Edith Rodríguez-Braun
- Clinical Oncology Department, Santa Lucía General University Hospital (HGUSL). C/Mezquita s/n, 30202 Cartagena, Spain;
| | - Vicki L. J. Whitehall
- QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; (L.J.F.); (V.L.J.W.)
- Conjoint Internal Medicine Laboratory, Pathology Queensland, Herston, QLD 4006, Australia
- Faculty of Medicine, The University of Queensland, Herston, QLD 4072, Australia
| | - Ana Conesa
- Microbiology and Cell Sciences Department, Institute for Food and Agricultural Sciences, Genetics Institute, University of Florida, Gainesville, FL 32611, USA;
| | - Pablo Conesa-Zamora
- Facultad de Ciencias de la Salud, Universidad Católica de Murcia (UCAM), Campus Los Jerónimos, 30107 Guadalupe, Spain
- Group of Molecular Pathology and Pharmacogenetics, Institute for Biomedical Research from Murcia (IMIB), HGUSL, 30202 Cartagena, Spain
- Clinical Oncology Department, Santa Lucía General University Hospital (HGUSL). C/Mezquita s/n, 30202 Cartagena, Spain;
- Department of Clinical Analysis, Santa Lucía General University Hospital (HGUSL), C/Mezquita s/n, 30202 Cartagena, Spain
- Correspondence: ; Tel.: +34-968128600 (ext. 951615)
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Tan S, Gui W, Wang S, Sun C, Xu X, Liu L. A methylation-based prognostic model predicts survival in patients with colorectal cancer. J Gastrointest Oncol 2021; 12:1590-1600. [PMID: 34532113 DOI: 10.21037/jgo-21-376] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 07/29/2021] [Indexed: 12/19/2022] Open
Abstract
Background To construct a model that could effectively predict the prognosis of colorectal cancer (CRC) by searching for methylated-differentially expressed genes (MDEGs). Methods We identified MDEGs through four databases from Gene Expression Omnibus (GEO) and annotated their functions via bioinformatics analysis. Subsequently, after adjusting for gender, age, and grading, multivariate Cox hazard analysis was utilized to select MDEGs interrelated with the prognosis of CRC, and LASSO analysis was utilized to fit the prediction model in the training set. Furthermore, another independent dataset was harnessed to verify the effectiveness of the model in predicting prognosis. Results In total, 252 hypomethylated and up-regulated genes and 132 hypermethylated and down-regulated genes were identified, 27 of which were correlated with the prognosis of CRC, and a 10-gene prognostic model was established after LASSO analysis. The overall survival rate could be effectively grouped into different risks by the median score of this model in the training set [risk ratio (HR) =2.27, confidence interval (95% CI), 1.69-3.13, P=8.15×10-8], and the validity of its effect in predicting prognosis in CRC was verified in the validation dataset (HR =1.75, 95% CI, 1.15-2.70, P=9.32×10-3). Conclusions Our model could effectively predict the overall survival rate of patients with CRC and provides potential application guidelines for its clinically personalized treatment.
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Affiliation(s)
- Shanyue Tan
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Weiwei Gui
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Sumeng Wang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chongqi Sun
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xian Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lingxiang Liu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Lee CC, Kuo YC, Hu JM, Chang PK, Sun CA, Yang T, Li CW, Chen CY, Lin FH, Hsu CH, Chou YC. MTNR1B polymorphisms with CDKN2A and MGMT methylation status are associated with poor prognosis of colorectal cancer in Taiwan. World J Gastroenterol 2021; 27:5737-5752. [PMID: 34629798 PMCID: PMC8473598 DOI: 10.3748/wjg.v27.i34.5737] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/30/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Identifying novel colorectal cancer (CRC) prognostic biomarkers is crucial to helping clinicians make appropriate therapy decisions. Melatonin plays a major role in managing the circadian rhythm and exerts oncostatic effects on different kinds of tumours.
AIM To explore the relationship between MTNR1B single-nucleotide polymorphism (SNPs) combined with gene hypermethylation and CRC prognosis.
METHODS A total of 94 CRC tumour tissues were investigated. Genotyping for the four MTNR1B SNPs (rs1387153, rs2166706, rs10830963, and rs1447352) was performed using multiplex polymerase chain reaction. The relationships between the MTNR1B SNPs and CRC 5-year overall survival (OS) was assessed by calculating hazard ratios with 95%CIs.
RESULTS All SNPs (rs1387153, rs2166706, rs10830963, and rs1447352) were correlated with decreased 5-year OS. In stratified analysis, rs1387153, rs10830963, and rs1447352 risk genotype combined with CDKN2A and MGMT methylation status were associated with 5-year OS. A strong cumulative effect of the four polymorphisms on CRC prognosis was observed. Four haplotypes of MTNR1B SNPs were also associated with the 5-year OS. MTNR1B SNPs combined with CDKN2A and MGMT gene methylation status could be used to predict shorter CRC survival.
CONCLUSION The novel genetic biomarkers combined with epigenetic biomarkers may be predictive tool for CRC prognosis and thus could be used to individualise treatment for patients with CRC.
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Affiliation(s)
- Chia-Cheng Lee
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- Medical Informatics Office, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Yu-Cheng Kuo
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Je-Ming Hu
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Pi-Kai Chang
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Chien-An Sun
- Department of Public Health, College of Medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan
- Big Data Research Center, College of Medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan
| | - Tsan Yang
- Department of Health Business Administration, Meiho University, Pingtung 91202, Taiwan
| | - Chuan-Wang Li
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei 114, Taiwan
- Institute of Preventive Medicine, National Defense Medical Center, New Taipei City 237, Taiwan
| | - Chao-Yang Chen
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Fu-Huang Lin
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Chih-Hsiung Hsu
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Yu-Ching Chou
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
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Rezayi Soufiani A, Dolatkhah R, Raeisi M, Chavoshi H, Mohammadi P, Mehdinavaz Aghdam A. Hypermethylation of MIR129-2 Regulates SOX4 Transcription and Associates with Metastasis in Patients with Colorectal Cancer. J Gastrointest Cancer 2021; 53:718-724. [PMID: 34499308 DOI: 10.1007/s12029-021-00708-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND MicroRNA-129-2 (miR-129-2), targeting SOX4, has been shown to be involved in the pathogenesis of different cancers. Here in this study, we examined the methylation levels of the promoter region of MIR19-2 gene as well as transcription of miR-129-2 and mRNA expression of SOX4 in the tumoral tissues from colorectal cancer (CRC) patients and compared those in the normal marginal tissues. METHODS Fifty CRC patients with Iranian Azari ethnicity were recruited. Genomic DNAs were extracted from the tumoral and normal tissues and the methylation level of the promoter regions of the MIR129-2 gene was determined using methylation-specific PCR (MSP) by evaluating 100 CG sites. The RNA content of the samples was isolated and the transcript levels of miR-129-2 and SOX4 were measured using quantitative real-time PCR. RESULTS Methylation level of the MIR192-2 promoter was significantly higher in the tumoral tissues compared to that in the normal marginal tissues (84% vs. 28%; P = 0.0041). The expression level of miR-192-2 was significantly downregulated (fold change = 0.34, P = 0.028) but SOX4 mRNA expression was upregulated (fold change = 2.7, P = 0.019) in the tumoral tissues compared to that in the normal marginal tissues. There was a significant correlation between the methylation level of the MIR192-2 promoter and the expression levels of miR-192-2 and SOX4 in the tumoral tissues. Associations were observed between the methylation of the MIR192-2 promoter and lymph node and liver metastasis. CONCLUSIONS It seems that MIR192-2 promoter hypermethylation might regulate the expression of SOX4 and therefore modulate metastasis in CRC.
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Affiliation(s)
- Alireza Rezayi Soufiani
- Tuberculosis and Lung Disease Research Center, Daneshgah St, Tabriz University of Medical Science, Tabriz, Iran
| | - Roya Dolatkhah
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mortaza Raeisi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Chavoshi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Payam Mohammadi
- Tuberculosis and Lung Disease Research Center, Daneshgah St, Tabriz University of Medical Science, Tabriz, Iran
| | - Abdolreza Mehdinavaz Aghdam
- Tuberculosis and Lung Disease Research Center, Daneshgah St, Tabriz University of Medical Science, Tabriz, Iran.
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Sanaei M, Kavoosi F, Ghasemzadeh V. Investigation of the Effect of 5-Aza-2'-Deoxycytidine in Comparison to and in Combination with Trichostatin A on p16INK4a, p14ARF, p15INK4b Gene Expression, Cell Growth Inhibition and Apoptosis Induction in Colon Cancer Caco-2 Cell Line. Int J Prev Med 2021; 12:64. [PMID: 34447506 PMCID: PMC8357004 DOI: 10.4103/ijpvm.ijpvm_11_20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 04/22/2020] [Indexed: 11/04/2022] Open
Abstract
Background The cell cycle is divided into four phases, G1, G2, S, and M phase. The mammalian cell cycle is controlled and governed by the kinase complexes including cyclin and the cyclin-dependent kinase (CDK), cyclin-CDK complexes. The activity of the complexes is regulated by cyclin-dependent kinase inhibitors (CDKIs), the INK4, and the CDK interacting protein/kinase inhibitory protein (CIP/KIP) families. Promoter hypermethylation and histone deacetylation of CDKIs have been reported in several cancers. These changes can be reversed by DNA demethylating agents, such as decitabine, 5-Aza-2'-deoxycytidine (5-Aza-CdR), and histone deacetylase inhibitors (HDACIs), such as trichostatin A. Previously, we reported the effect of 5-Aza-CdR and trichostatin A (TSA) on hepatocellular carcinoma (HCC). The present study aimed to investigate the effect of 5-Aza-CdR in comparison to and in combination with trichostatin A on p16INK4a, p14ARF, p15INK4b genes expression, cell growth inhibition and apoptosis induction in colon cancer Caco-2 cell line. Methods The Caco-2 cells were cultured and treated with 5-Aza-CdR and TSA (alone and combined). The cell viability, apoptosis, and relative gene expression were determined by MTT assay, flow cytometry, and real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively. Results Both compounds inhibited cell growth, induced apoptosis, and up-regulated the p16INK4a, p14ARF, p15INK4b gene significantly. The TSA had a more significant effect in comparison to 5-Aza-CdR. Furthermore, maximal apoptosis and up-regulation were observed with combined treatment. Conclusions our finding indicated that 5-Aza-CdR and TSA can epigenetically re-activate the p16INK4a, p14ARF, p15INK4b gene resulting in cell growth inhibition and apoptosis induction in colon cancer.
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Affiliation(s)
- Masumeh Sanaei
- Research Center for Non-Communicable Diseases, Jahrom University of Medical Sciences, Jahrom, Fars Province, Iran
| | - Fraidoon Kavoosi
- Research Center for Non-Communicable Diseases, Jahrom University of Medical Sciences, Jahrom, Fars Province, Iran
| | - Vahid Ghasemzadeh
- Department of Student of Research Committee, Jahrom University of Medical Sciences, Jahrom, Fars Province, Iran
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Xu F, Yu S, Han J, Zong M, Tan Q, Zeng X, Fan L. Detection of Circulating Tumor DNA Methylation in Diagnosis of Colorectal Cancer. Clin Transl Gastroenterol 2021; 12:e00386. [PMID: 34382948 PMCID: PMC8367071 DOI: 10.14309/ctg.0000000000000386] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Emerging evidence has demonstrated the potential of the circulating tumor DNA (ctDNA) methylation in the application of cancer diagnosis. METHODS Three genes including Septin9, Syndecan-2 (SDC2), and branched-chain amino acid transaminase 1 (BCAT1), which have been well demonstrated to have aberrant expression in colorectal cancer (CRC) as tumor suppressors, were selected for detection. A total of 234 peripheral plasma samples from 104 patients with CRC and 130 patients with colorectal polyps, and 60 plasma samples from healthy controls, were collected before any treatment. A real-time polymerase chain reaction-based gene panel was used to detect the methylation of Septin9, SDC2, and BCAT1. The composite score (P) was calculated according to the cycle threshold values of the 3 methylated genes using the logistic regression equation. RESULTS The ctDNA methylation of the 3 genes had a significantly higher level in patients with CRC, compared with patients with colorectal polyps and healthy controls. The composite score (P) showed association with tumor stages in CRC but not with the tumor location (colon or rectum). In addition, BCAT1 and Septin9 showed better performance for CRC diagnosis, by which CRC was able to distinguish from polyps with sensitivity of 83.7%, specificity of 93.9%, and area under the curve of 0.908. The diagnostic efficiency was significantly improved by combining composite score (P), carcinoembryonic antigen, and fecal immunochemical test for hemoglobin (area under the curve = 0.962). DISCUSSION The composite score (P) derived from the ctDNA methylation levels of Septin9, SDC2, and BCAT1 can be used for CRC diagnosis with high sensitivity and high specificity. A combination of ctDNA methylation, carcinoembryonic antigen, and fecal immunochemical test for hemoglobin was proved to be the most effective approach to diagnose CRC.
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Affiliation(s)
- Fei Xu
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, P. R. China;
| | - Shanshan Yu
- Department of Clinical Laboratory, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, P. R. China;
| | - Junyi Han
- Department of Gastrointestinal and Colorectal Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, P. R. China
| | - Ming Zong
- Department of Clinical Laboratory, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, P. R. China;
| | - Qi Tan
- Department of Clinical Laboratory, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, P. R. China;
| | - Xin Zeng
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, P. R. China;
| | - Lieying Fan
- Department of Clinical Laboratory, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, P. R. China;
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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).
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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.
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Kang B, Lee HS, Jeon SW, Park SY, Choi GS, Lee WK, Heo S, Lee DH, Kim DS. Progressive alteration of DNA methylation of Alu, MGMT, MINT2, and TFPI2 genes in colonic mucosa during colorectal cancer development. Cancer Biomark 2021; 32:231-236. [PMID: 34092617 DOI: 10.3233/cbm-203259] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is characterized by different pathways of carcinogenesis and is a heterogeneous disease with diverse molecular landscapes that reflect histopathological and clinical information. Changes in the DNA methylation status of colon epithelial cells have been identified as critical components in CRC development and appear to be emerging biomarkers for the early detection and prognosis of CRC. OBJECTIVE To explore the underlying disease mechanisms and identify more effective biomarkers of CRC. METHODS We compared the levels and frequencies of DNA methylation in 11 genes (Alu, APC, DAPK, MGMT, MLH1, MINT1, MINT2, MINT3, p16, RGS6, and TFPI2) in colorectal cancer and its precursor adenomatous polyp with normal tissue of healthy subjects using pyrosequencing and then evaluated the clinical value of these genes. RESULTS Aberrant methylation of Alu, MGMT, MINT2, and TFPI2 genes was progressively accumulated during the normal-adenoma-carcinoma progression. Additionally, CGI methylation occurred either as an adenoma-associated event for APC, MLH1, MINT1, MINT31, p16, and RGS6 or a tumor-associated event for DAPK. Moreover, relatively high levels and frequencies of DAPK, MGMT, and TFPI2 methylation were detected in the peritumoral nonmalignant mucosa of cancer patients in a field-cancerization manner, as compared to normal mucosa from healthy subjects. CONCLUSION This study identified several biomarkers associated with the initiation and progression of CRC. As novel findings, they may have important clinical implications for CRC diagnostic and prognostic applications. Further large-scale studies are needed to confirm these findings.
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Affiliation(s)
- Ben Kang
- Department of Pediatrics and Bio-medical Research Institute, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Hyun Seok Lee
- Department of Internal Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Seong Woo Jeon
- Department of Internal Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Soo Yeun Park
- Department of General Surgery, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Gyu Seog Choi
- Department of General Surgery, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Won Kee Lee
- Department of Preventive Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Somi Heo
- Department of Preventive Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Duk Hee Lee
- Department of Preventive Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Dong Sun Kim
- Department of Anatomy, School of Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
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A systematic review and meta-analysis of the DNA methylation in colorectal cancer among Iranian population. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Zhang H, Xu C, Shi C, Zhang J, Qian T, Wang Z, Ma R, Wu J, Jiang F, Feng J. Hypermethylation of heparanase 2 promotes colorectal cancer proliferation and is associated with poor prognosis. J Transl Med 2021; 19:98. [PMID: 33663522 PMCID: PMC7934273 DOI: 10.1186/s12967-021-02770-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 02/25/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The epigenetic abnormality of tumor-associated genes contributes to the pathogenesis of colorectal carcinoma (CRC). However, methylation in colorectal cancer is still poorly characterized. METHOD By integration of DNA methylation data from the GEO database and gene expression data from The Cancer Genome Atlas database, the aberrantly methylated genes involved in CRC tumorigenesis were identified. Subsequent in vitro experiments further validated their role in CRC. RESULTS We performed integrative genomic analysis and identified HPSE2, a novel tumor suppressor gene that is frequently inactivated through promoter methylation in CRC. K-M survival analysis showed that hypermethylation-low expression of heparanase 2 (HPSE2) was related to poor patient prognosis. Overexpression of HPSE2 reduced cell proliferation in vivo and in vitro. HPSE2 could regulate the p53 signaling pathway to block the cell cycle in G1 phase. CONCLUSION HPSE2, a novel tumor suppressor gene that is frequently inactivated through promoter methylation in CRC. HPSE2 performs a tumor suppressive function by activating the p53/ p21 signaling cascade. The promoter hypermethylation of HPSE2 is a potential therapeutic target in patients with CRC, especially those with late-stage CRC.
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Affiliation(s)
- Hui Zhang
- Department of General Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210000, Jiangsu, People's Republic of China
| | - Chenxin Xu
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210000, Jiangsu, People's Republic of China
| | - Chen Shi
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210000, Jiangsu, People's Republic of China
| | - Junying Zhang
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210000, Jiangsu, People's Republic of China
| | - Ting Qian
- Department of Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210000, Jiangsu, People's Republic of China
| | - Zhuo Wang
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210000, Jiangsu, People's Republic of China
| | - Rong Ma
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210000, Jiangsu, People's Republic of China
| | - Jianzhong Wu
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210000, Jiangsu, People's Republic of China
| | - Feng Jiang
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210000, Jiangsu, People's Republic of China.
| | - Jifeng Feng
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210000, Jiangsu, People's Republic of China.
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Grady WM, Yu M, Markowitz SD. Epigenetic Alterations in the Gastrointestinal Tract: Current and Emerging Use for Biomarkers of Cancer. Gastroenterology 2021; 160:690-709. [PMID: 33279516 PMCID: PMC7878343 DOI: 10.1053/j.gastro.2020.09.058] [Citation(s) in RCA: 139] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023]
Abstract
Colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, and esophageal cancer are leading causes of cancer-related deaths worldwide. A fundamental trait of virtually all gastrointestinal cancers is genomic and epigenomic DNA alterations. Cancer cells acquire genetic and epigenetic alterations that drive the initiation and progression of the cancers by altering the molecular and cell biological processes of the cells. These alterations, as well as other host and microenvironment factors, ultimately mediate the clinical behavior of the precancers and cancers and can be used as biomarkers for cancer risk determination, early detection of cancer and precancer, determination of the prognosis of cancer and prediction of the response to therapy. Epigenetic alterations have emerged as one of most robust classes of biomarkers and are the basis for a growing number of clinical tests for cancer screening and surveillance.
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Affiliation(s)
- William M. Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA,Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Ming Yu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
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Afshan FU, Masood A, Nissar B, Chowdri NA, Naykoo NA, Majid M, Ganai BA. Promoter hypermethylation regulates vitamin D receptor (VDR) expression in colorectal cancer-A study from Kashmir valley. Cancer Genet 2021; 252-253:96-106. [PMID: 33486463 DOI: 10.1016/j.cancergen.2021.01.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 12/28/2020] [Accepted: 01/09/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Colorectal carcinogenesis (CRC) is a multistep process, involving both genetic and epigenetic modifications of genes involved in diverse pathways ranging from tumor suppression to DNA mismatch repair. PURPOSE This study was undertaken to assess the role of promoter methylation of vitamin D receptor (VDR) gene, a transcription factor with myriad biological functions, in relation to its expression and clinicopathological parameters. METHODS Tissue specimens were taken from a total of 75 colorectal cancer cases paired with their normal surrounding epithelium and analyzed by Real-time RT-PCR for assessing the expression profile and MS-PCR for analyzing the promoter methylation status of the VDR gene. Blood sample from the same patients was drawn for vitamin D estimation. RESULTS The frequency of promoter methylation in cancerous tissue was 37.33% against 9.33% in normal tissues (p<0.001). The hypermethylated status of VDR promoter showed significantly inverse association with its expression (p=0.008). Furthermore, when compared with the clinical parameters, methylation status of VDR promoter was significantly associated with tumor staging (p=0.008), grading (p<0.001), depth of invasion (p=0.002) and lymph node metastases (p<0.001). Univariate and multivariate analysis indicated patients with increased VDR expression (p<0.001) and decreased methylation status (p=0.012) exhibited longer overall survival. Additionally, serum 25(OH)D3 levels were not significantly associated with any of the patient characteristics. CONCLUSION Our study, first of its kind from Kashmir, indicated that VDR shows aberrant methylation pattern in CRC with consequent loss in its expression.
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Affiliation(s)
- Falaque Ul Afshan
- Department of Biochemistry, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir 190006, India.
| | - Akbar Masood
- Department of Biochemistry, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir 190006, India.
| | - Bushra Nissar
- Department of Biochemistry, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir 190006, India.
| | - Nisar Ahmad Chowdri
- Division of Colorectal Surgery, SKIMS, Soura, Srinagar, Jammu and Kashmir 190011, India.
| | - Niyaz Ahmad Naykoo
- Department of Biotechnology, Government College for Women, Srinagar, Jammu and Kashmir 190002, India.
| | - Misbah Majid
- Department of Biochemistry, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir 190006, India.
| | - Bashir Ahmad Ganai
- Centre For Research and Development, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir 190006, India.
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Laugsand EA, Brenne SS, Skorpen F. DNA methylation markers detected in blood, stool, urine, and tissue in colorectal cancer: a systematic review of paired samples. Int J Colorectal Dis 2021; 36:239-251. [PMID: 33030559 PMCID: PMC7801356 DOI: 10.1007/s00384-020-03757-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/17/2020] [Indexed: 02/04/2023]
Abstract
PURPOSE Methylated cell-free DNA in liquid biopsies are promising non-invasive biomarkers for colorectal cancer (CRC). Optimal markers would have high sensitivity and specificity for early detection of CRC and could be detected in more than one type of material from the patient. We systematically reviewed the literature on DNA methylation markers of colorectal cancer, detected in more than one type of material, regarding their potential as contributors to a panel for screening and follow-up of CRC. METHODS The databases MEDLINE, Web of Science, and Embase were systematically searched. Data extraction and review was performed by two authors independently. Agreement between methylation status in tissue and other materials (blood/stool/urine) was analyzed using the McNemar test and Cohen's kappa. RESULTS From the 51 included studies, we identified seven single markers with sensitivity ≥ 75% and specificity ≥ 90% for CRC. We also identified one promising plasma panel and two stool panels. The correspondence of methylation status was evaluated as very good for four markers, but only marginal for most of the other markers investigated (12 of 21). CONCLUSION The included studies reported only some of the variables and markers of interest and included few patients. Hence, a meta-analysis was not possible at this point. Larger, prospective studies must be designed to study the discordant detection of markers in tissue and liquid biopsies. When reporting their findings, such studies should use a standardized format.
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Affiliation(s)
- Eivor Alette Laugsand
- Department of Surgery, Levanger Hospital, Nord-Trøndelag Hospital trust, N-7600, Levanger, Norway.
- Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), N-7491, Trondheim, Norway.
| | - Siv Sellæg Brenne
- Department of Surgery, Levanger Hospital, Nord-Trøndelag Hospital trust, N-7600, Levanger, Norway
- Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), N-7491, Trondheim, Norway
| | - Frank Skorpen
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), N-7491, Trondheim, Norway
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Dhar GA, Saha S, Mitra P, Nag Chaudhuri R. DNA methylation and regulation of gene expression: Guardian of our health. THE NUCLEUS 2021; 64:259-270. [PMID: 34421129 PMCID: PMC8366481 DOI: 10.1007/s13237-021-00367-y] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 07/30/2021] [Indexed: 02/07/2023] Open
Abstract
One of the most critical epigenetic signatures present in the genome of higher eukaryotes is the methylation of DNA at the C-5 position of the cytosine ring. Based on the sites of DNA methylation in a locus, it can serve as a repressive or activation mark for gene expression. In a crosstalk with histone modifiers, DNA methylation can consequently either inhibit binding of the transcription machinery or generate a landscape conducive for transcription. During developmental phases, the DNA methylation pattern in the genome undergoes alterations as a result of regulated balance between de novo DNA methylation and demethylation. Resultantly, differentiated cells inherit a unique DNA methylation pattern that fine tunes tissue-specific gene expression. Although apparently a stable epigenetic mark, DNA methylation is actually labile and is a complex reflection of interaction between epigenome, genome and environmental factors prior to birth and during progression of life. Recent findings indicate that levels of DNA methylation in an individual is a dynamic outcome, strongly influenced by the dietary environment during germ cell formation, embryogenesis and post birth exposures. Loss of balances in DNA methylation during developmental stages may result in imprinting disorders, while at any later stage may lead to increased predisposition to various diseases and abnormalities. This review aims to provide an outline of how our epigenome is uniquely guided by our lifetime of experiences beginning in the womb and how understanding it better holds future possibilities of improvised clinical applications.
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Affiliation(s)
- Gaurab Aditya Dhar
- grid.59056.3f0000 0001 0664 9773Department of Biotechnology, St. Xavier’s College, 30 Mother Teresa Sarani, Kolkata, 700016 India
| | - Shagnik Saha
- grid.59056.3f0000 0001 0664 9773Department of Biotechnology, St. Xavier’s College, 30 Mother Teresa Sarani, Kolkata, 700016 India
| | - Parama Mitra
- grid.59056.3f0000 0001 0664 9773Department of Biotechnology, St. Xavier’s College, 30 Mother Teresa Sarani, Kolkata, 700016 India
| | - Ronita Nag Chaudhuri
- grid.59056.3f0000 0001 0664 9773Department of Biotechnology, St. Xavier’s College, 30 Mother Teresa Sarani, Kolkata, 700016 India
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Guo X, Song C, Fang L, Li M, Yue L, Sun Q. FLRT2 functions as Tumor Suppressor gene inactivated by promoter methylation in Colorectal Cancer. J Cancer 2020; 11:7329-7338. [PMID: 33193897 PMCID: PMC7646184 DOI: 10.7150/jca.47558] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 10/11/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epigenetic alterations, especially DNA methylation, contribute to the initiation and progression of CRC. To identify novel methylated tumor suppressors in CRC, MethylRAD-Seq screening was performed. As the result, FLRT2 was found to be preferentially methylated. In the present study, we aimed to elucidate the epigenetic regulations and biological functions of FLRT2 in CRC. Significant FLRT2 hypermethylation was initially confirmed in CRC samples and cell lines. Meanwhile, downregulated expression of FLRT2 was observed in CRC, which is probably attributed to promoter methylation of FLRT2. Consistently, the expression of FLRT2 was restored after treatment with DNA demethylating agent 5-AZA. FLRT2 overexpression resulted in impaired cell viability and colony formation. Additionally, FLRT2 overexpression led to a reduction in cell migration and cell invasion. Furthermore, we also observed that FLRT2 induced cell cycle arrest. Mechanistically, these effects were associated with the downregulation of phosphor-AKT, phosphor-ERK, CDK2, Cyclin A, and MMP2, and upregulation of P21. Taken together, these results define a tumor-suppressor role of FLRT2 with epigenetic silencing in the pathogenesis of CRC. Moreover, FLRT2 promoter methylation may be a useful epigenetic biomarker for the prevention and treatment of CRC.
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Affiliation(s)
- Xiaohong Guo
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Chao Song
- Department of Pathology, Zibo Central Hospital, Zibo, Shandong, China
| | - Lei Fang
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Min Li
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Longtao Yue
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Qing Sun
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
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Ili C, Buchegger K, Demond H, Castillo-Fernandez J, Kelsey G, Zanella L, Abanto M, Riquelme I, López J, Viscarra T, García P, Bellolio E, Saavedra D, Brebi P. Landscape of Genome-Wide DNA Methylation of Colorectal Cancer Metastasis. Cancers (Basel) 2020; 12:E2710. [PMID: 32971738 PMCID: PMC7564781 DOI: 10.3390/cancers12092710] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/02/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer is a heterogeneous disease caused by both genetic and epigenetics factors. Analysing DNA methylation changes occurring during colorectal cancer progression and metastasis formation is crucial for the identification of novel epigenetic markers of patient prognosis. Genome-wide methylation sequencing of paired samples of colon (normal adjacent, primary tumour and lymph node metastasis) showed global hypomethylation and CpG island (CGI) hypermethylation of primary tumours compared to normal. In metastasis we observed high global and non-CGI regions methylation, but lower CGI methylation, compared to primary tumours. Gene ontology analysis showed shared biological processes between hypermethylated CGIs in metastasis and primary tumours. After complementary analysis with The Cancer Genome Atlas (TCGA) cohort, FIGN, HTRA3, BDNF, HCN4 and STAC2 genes were found associated with poor survival. We mapped the methylation landscape of colon normal tissues, primary tumours and lymph node metastasis, being capable of identified methylation changes throughout the genome. Furthermore, we found five genes with potential for methylation biomarkers of poor prognosis in colorectal cancer patients.
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Affiliation(s)
- Carmen Ili
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (C.I.); (K.B.); (H.D.); (L.Z.); (J.L.); (T.V.)
| | - Kurt Buchegger
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (C.I.); (K.B.); (H.D.); (L.Z.); (J.L.); (T.V.)
- Departamento Ciencias Básicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Hannah Demond
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (C.I.); (K.B.); (H.D.); (L.Z.); (J.L.); (T.V.)
- Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; (J.C.-F.); (G.K.)
| | - Juan Castillo-Fernandez
- Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; (J.C.-F.); (G.K.)
| | - Gavin Kelsey
- Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; (J.C.-F.); (G.K.)
- Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1TN, UK
| | - Louise Zanella
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (C.I.); (K.B.); (H.D.); (L.Z.); (J.L.); (T.V.)
| | - Michel Abanto
- Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile;
| | - Ismael Riquelme
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Temuco 4810101, Chile;
| | - Jaime López
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (C.I.); (K.B.); (H.D.); (L.Z.); (J.L.); (T.V.)
| | - Tamara Viscarra
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (C.I.); (K.B.); (H.D.); (L.Z.); (J.L.); (T.V.)
| | - Patricia García
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330034, Chile;
| | - Enrique Bellolio
- Departamento Anatomía Patológica, Facultad de Medicina, Universidad de La Frontera, Temuco 4781180, Chile;
- Departamento de Medicina Interna, Hospital Hernán Henríquez Aravena, Temuco 4781151, Chile;
| | - David Saavedra
- Departamento de Medicina Interna, Hospital Hernán Henríquez Aravena, Temuco 4781151, Chile;
- Clínica Alemana de Temuco, Temuco 4810297, Chile
| | - Priscilla Brebi
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (C.I.); (K.B.); (H.D.); (L.Z.); (J.L.); (T.V.)
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Detect differentially methylated regions using non-homogeneous hidden Markov model for bisulfite sequencing data. Methods 2020; 189:34-43. [PMID: 32949692 DOI: 10.1016/j.ymeth.2020.09.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 06/11/2020] [Accepted: 09/11/2020] [Indexed: 11/22/2022] Open
Abstract
DNA methylation plays an important role in many biological processes and diseases. With the rise of the whole genome bisulfite sequencing technique, aberrant methylation patterns can now be detected by comparing paired normal and disease samples at the single nucleotide level. We develop a novel Bayesian method for detecting differentially methylated regions from paired bisulfite sequencing data, and implement it as a R package called BSDMR. Based on a non-homogeneous hidden Markov model, BSDMR provides a better modeling strategy for the spatial correlation between CpG sites and takes into consideration the relationship between methylation signals from normal and disease samples. Simulations show that BSDMR performs well even under low read depth and has a smaller false discovery rates than existing methods. We also apply BSDMR to the colon cancer data from Gene Expression Omnibus. The detected DMRs are well supported by existing biomedical literatures.
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Wu HY, Yang B, Geng DH. Clinical significance of expression of fibrous sheath interacting protein 1 in colon cancer. World J Gastrointest Oncol 2020; 12:677-686. [PMID: 32699582 PMCID: PMC7340994 DOI: 10.4251/wjgo.v12.i6.677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/11/2020] [Accepted: 05/05/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The occurrence and development of colon cancer are complex, involving a variety of genetic changes, such as mutation and activation of oncogenes, inactivation of tumour suppressor genes, and aberrant proliferation and apoptosis regulation mechanisms. Fibrous sheath interacting protein 1 (FSIP1) is a newly discovered oncogene that is frequently activated in a variety of tumours such as breast cancer and bladder cancer. However, the clinical significance of FSIP1 in colon cancer is unclear. In this study, we analysed the clinical significance of expression of FSIP1 in human colon cancer, aimed to clarify the biological role of FSIP1 in the development and progression of colon cancer.
AIM To investigate the clinical significance of expression of FSIP1 in colon cancer.
METHODS From March 2011 to March 2014, 302 specimens of tumour tissues and paracancerous tissues were obtained from patients pathologically diagnosed with colon cancer at Shengjing Hospital of China Medical University. Immunohistochemistry was used to detect FSIP1 expression in colon cancer tissues and adjacent normal tissues. Spearman correlation coefficient and Cox regression analyses were used to determine the relationship between FSIP1 expression and clinicopathological factors and prognosis, as well as the impact on survival.
RESULTS Compared with its expression in adjacent normal tissues, FSIP1 was expressed at higher levels in colon cancer tissues. Spearman correlation analysis showed that high expression of FSIP1 was positively correlated with clinicopathological stage, lymph node metastasis, and poor prognosis in colon cancer; it was negatively correlated with the degree of tumour differentiation. Cox regression analysis showed that high FSIP1 expression was an independent risk factor for the prognosis of colon cancer patients.
CONCLUSION High expression of FSIP1 may be one of the important factors affecting the clinical outcome of colon cancer patients and leading to poor prognosis.
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Affiliation(s)
- Hui-Ying Wu
- Department of Nursing, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Bin Yang
- Department of Nursing, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Dong-Hua Geng
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
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Liu X, Wen J, Li C, Wang H, Wang J, Zou H. High-Yield Methylation Markers for Stool-Based Detection of Colorectal Cancer. Dig Dis Sci 2020; 65:1710-1719. [PMID: 31720923 DOI: 10.1007/s10620-019-05908-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 10/15/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Many methylation markers associated with colorectal cancer have been reported, but few of them are actually used in clinical practice. AIMS This study was designed to identify promising methylation markers for stool-based detection of colorectal cancer. METHODS We first tested 324 reported methylated genes in colorectal cancer cell lines. A total of 111 heavily methylated genes were selected for further evaluation with a pilot set of colorectal cancer and adjacent normal tissues. Ten high-yield methylated markers were further studied in 319 tissue samples. Eventually, the four best markers, namely methylated COL4A1, COL4A2, TLX2, and ITGA4, were validated in 240 stool samples. Methylation-specific PCR (MSP) and real-time MSP (qMSP) were employed for methylation detection. RESULTS After hierarchical selection, ten differentially methylated genes demonstrated high sensitivity and specificity for the detection of colorectal cancer in tissue. When validated in stool samples, the four with the best performance-COL4A1, COL4A2, TLX2, and ITGA4-were able to detect 82.5-92.5% of colorectal cancers and 41.6-58.4% of adenomas (≥ 1 cm) with specificity of 88.0-96.4%. The best combination, COL4A2 and TLX2, detected 91.3% of CRCs and 51.9% of advanced adenomas in stool with 97.6% specificity. CONCLUSIONS Methylated COL4A1, COL4A2, TLX2, and ITGA4 demonstrated high accuracy for the detection of colorectal neoplasms in stool. They are potentially valuable markers for the detection of colorectal cancer.
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Affiliation(s)
- Xianglin Liu
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China
| | - Jialing Wen
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China
| | - Chujun Li
- Digestive Endoscopy Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hui Wang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jianping Wang
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China.,Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hongzhi Zou
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Yuancun Erheng Road, Guangzhou, 510655, Guangdong, China. .,Creative Biosciences (Guangzhou) CO., Ltd., Guangzhou, Guangdong, China.
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Liu L, Shao Z, Lv J, Xu F, Ren S, Jin Q, Yang J, Ma W, Xie H, Zhang D, Chen X. Identification of Early Warning Signals at the Critical Transition Point of Colorectal Cancer Based on Dynamic Network Analysis. Front Bioeng Biotechnol 2020; 8:530. [PMID: 32548109 PMCID: PMC7272579 DOI: 10.3389/fbioe.2020.00530] [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: 12/13/2019] [Accepted: 05/04/2020] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Due to the lack of early diagnosis methods and warning signals of CRC and its strong heterogeneity, the determination of accurate treatments for CRC and the identification of specific early warning signals are still urgent problems for researchers. In this study, the expression profiles of cancer tissues and the expression profiles of tumor-adjacent tissues in 28 CRC patients were combined into a human protein–protein interaction (PPI) network to construct a specific network for each patient. A network propagation method was used to obtain a mutant giant cluster (GC) containing more than 90% of the mutation information of one patient. Next, mutation selection rules were applied to the GC to mine the mutation sequence of driver genes in each CRC patient. The mutation sequences from patients with the same type CRC were integrated to obtain the mutation sequences of driver genes of different types of CRC, which provide a reference for the diagnosis of clinical CRC disease progression. Finally, dynamic network analysis was used to mine dynamic network biomarkers (DNBs) in CRC patients. These DNBs were verified by clinical staging data to identify the critical transition point between the pre-disease state and the disease state in tumor progression. Twelve known drug targets were found in the DNBs, and 6 of them have been used as targets for anticancer drugs for clinical treatment. This study provides important information for the prognosis, diagnosis and treatment of CRC, especially for pre-emptive treatments. It is of great significance for reducing the incidence and mortality of CRC.
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Affiliation(s)
- Lei Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Zhuo Shao
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Jiaxuan Lv
- School of Stomatology, Harbin Medical University, Harbin, China
| | - Fei Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Sibo Ren
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Qing Jin
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Jingbo Yang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Weifang Ma
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Hongbo Xie
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Denan Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Xiujie Chen
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
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Virtual spectral histopathology of colon cancer - biomedical applications of Raman spectroscopy and imaging. J Mol Liq 2020. [DOI: 10.1016/j.molliq.2020.112676] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Liu J, Ke F, Chen T, Zhou Q, Weng L, Tan J, Shen W, Li L, Zhou J, Xu C, Cheng H, Zhou J. MicroRNAs that regulate PTEN as potential biomarkers in colorectal cancer: a systematic review. J Cancer Res Clin Oncol 2020; 146:809-820. [PMID: 32146564 DOI: 10.1007/s00432-020-03172-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 02/27/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE MicroRNAs (miRNAs) participate in a variety of biological processes, including tumorigenesis, progression, invasion, and drug resistance to multiple cancers. Phosphatase and tensin homolog (PTEN) is a cancer suppressor gene that has been certified to be regulated by miRNAs in various tumors, including colorectal cancer (CRC). In this review, we screened articles focusing on low PTEN expression in CRC, observed the expression of related miRNAs, analyzed their correlation and relationship with clinicopathological features, and discussed the possibility of these miRNAs as prognostic molecules. METHODS We conducted a systematic search for articles published in the Web of Science, PubMed and EBSCO databases between January 1, 2002, and July 18, 2019. We identified these studies by using combinations of the following index entries and key words: 'colorectal tumor OR colorectal neoplasm OR colorectal carcinoma OR colorectal cancer OR CRC', 'protein tyrosine phosphatase OR PTEN', and 'microRNA OR MiRNA OR miRNA OR MicroRNA'. Moreover, we evaluated the underlying association between alterations in PTEN and CRC prognosis. RESULTS PTEN expression was obviously lower in CRC tissues than in normal mucosa. However, PTEN expression did not differ significantly between adenoma and normal tissues. PTEN tends to be negatively associated with tumor size and metastasis. MiR-21, miR-200a, miR-543, miR-32, miR-92a, miR-26a, miR-106a and miR-181a were correlated with the downregulation of PTEN. MiR-26a, miR-106a and miR-181a were obviously higher in CRC tissues than in normal tissues, while PTEN was downregulated in CRC tissues. Additionally, miRNAs were mainly positively correlated with distant metastasis, followed by TNM stage. The relationship between miRNAs and tumor differentiation is controversial. However, there were no significant differences between miRNAs and either sex or age. CONCLUSIONS The loss of PTEN may be a diagnostic factor for CRC patients. The above-mentioned miRNAs may function as oncogenes in CRC and represent potential targets for CRC therapy. However, further prospective clinical studies are necessary.
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Affiliation(s)
- Jianrong Liu
- School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China
| | - Fei Ke
- Pathology Department, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China
| | - Tingting Chen
- Jiangsu Collaborative Innovation Center of TCM Prevention and Treatment of Tumor, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China
| | - Qing Zhou
- Jiangsu Collaborative Innovation Center of TCM Prevention and Treatment of Tumor, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China
| | - Lingling Weng
- Imaging Department, Nanjing Hospital of Chinese Medicine, Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China
| | - Jiani Tan
- Jiangsu Collaborative Innovation Center of TCM Prevention and Treatment of Tumor, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China
| | - Weixing Shen
- Jiangsu Collaborative Innovation Center of TCM Prevention and Treatment of Tumor, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China
| | - Liu Li
- Jiangsu Collaborative Innovation Center of TCM Prevention and Treatment of Tumor, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China
| | - Jinyong Zhou
- Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China
| | - Changliang Xu
- Jiangsu Collaborative Innovation Center of TCM Prevention and Treatment of Tumor, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China
| | - Haibo Cheng
- Jiangsu Collaborative Innovation Center of TCM Prevention and Treatment of Tumor, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China.
| | - Jinrong Zhou
- School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China.
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