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Ye M, Xu G, Zhang L, Kong Z, Qiu Z. Meta Analysis of Methylenetetrahydrofolate Reductase (MTHFR) C677T polymorphism and its association with folate and colorectal cancer. BMC Cancer 2025; 25:169. [PMID: 39875876 PMCID: PMC11776141 DOI: 10.1186/s12885-025-13546-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 01/16/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND DNA hypomethylation and uracil misincorporation into DNA, both of which have a very important correlation with colorectal carcinogenesis. Folate plays a crucial role in DNA synthesis, acting as a coenzyme in one-carbon metabolism, which involves the synthesis of purines, pyrimidines, and methyl groups. MTHFR, a key enzyme in folate metabolism, has been widely studied in relation to neural tube defects and hypertension, but its role in colorectal cancer remains underexplored. Therefore, understanding the role of folate and MTHFR genes in colorectal cancer may be helpful for potential preventive or therapeutic interventions. In this meta-analysis, the effects of MTHFR genotype and folate intake on colorectal cancer incidence were analyzed. METHODS We searched PubMed,Embase, Web of Science, and CNKI database to identify relevant studies up to January 2024. We included a series of studies on the association of MTHFR C677T genotype and folate intake with colorectal cancer incidence. The meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P). It included 100 studies (39702 cases and 55718 controls),that investigated the association between the MTHFR C677T polymorphism and colorectal cancer (CRC). Additionally, the analysis incorporated further stratification by ethnic population and geographical region. Furthermore, Six of the studies which clarified high amount of folate might be a protective factor for CRC in all three MTHFR C677T genotype, especially in TT genotype. RESULTS MTHFR 677TT genotype was negatively associated with CRC incidence compared with CC genotype (OR = 0.89; 95% CI: 0.85-0.93; P < 0.00001; Z = 5.17). MTHFR 677CT genotype was not significantly associated with colorectal cancer incidence (OR = 1.00; 95% CI: 0.98,1.03). A negative correlation between TT genotype and CRC was observed in ethnics of Asians (OR = 0.83, 95% CI: 0.76, 0.91), Caucasians (OR = 0.93, 95% CI: 0.88, 0.99) and the region of USA (OR = 0.77, 95% CI: 0.71, 0.85), Asia (OR = 0.93, 95% CI: 0.86, 1.00) and Europe (OR = 0.93, 95% CI:0.87, 1.00),but not in Indian (TT: OR = 1.67, 95% CI: 1.06, 2.63; CT: OR = 1.31, 95% CI: 1.00, 1.73)). Amount folate intakes might reduce the morbidity of CRC for people in MTHFR 677TT genotype (OR = 0.68; 95% CI: 0.48,0.96; P = 0.03). CONCLUSION The analysis showed that the incidence of colorectal cancer was reduced among individuals with TT genotype. The individuals with TT genotype and amount folate intake may collectively improve the incidence of colorectal cancer. While the MTHFR 677TT genotype is associated with a reduced risk of CRC, especially in certain populations, these findings should be interpreted with caution due to the limitations of retrospective studies.
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Affiliation(s)
- Meng Ye
- The First Clinical Medical College, Guangdong Medical University, Zhanjiang, 524023, P.R. China
| | - Guojie Xu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, P.R. China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, P.R. China
| | - Liming Zhang
- The First Clinical Medical College, Guangdong Medical University, Zhanjiang, 524023, P.R. China
| | - Zhihui Kong
- Department of Laboratory Medicine, Jingshan People's Hospital, Jingshan, 431800, P.R. China.
| | - Zhenhua Qiu
- Department of Laboratory Medicine, Affiliated Gaozhou People's Hospital, Guangdong Medical University, Maoming, 525200, P.R. China.
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Gomes-Fernandes B, Trindade LM, de Castro Bastos Rodrigues M, Cardoso JPD, Lima FT, Rogerio L, de Vasconcelos Generoso S, Carneiro JG, da Silva RG, de Souza RP, De Marco L, Bastos-Rodrigues L. Association between KRAS mutation and alcohol consumption in Brazilian patients with colorectal cancer. Sci Rep 2024; 14:26445. [PMID: 39488539 PMCID: PMC11531595 DOI: 10.1038/s41598-024-75048-2] [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: 06/14/2024] [Accepted: 10/01/2024] [Indexed: 11/04/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of morbidity and mortality worldwide. Detection before metastasis and efficient treatment of disease significantly improve patient survival and quality of life. However, limitations in diagnosis and postoperative surveillance are associated with low CRC detection and survival rates. Thus, this project aimed to evaluate the molecular profile of patients diagnosed with CRC, as molecular biomarkers constitute a new frontier for diagnosis, treatment and prognosis. Methods and Results: 42 patients were included in the study, predominantly male (59.5%), with a median age of 63 years (SD: 10.0; min: 41; max: 83). The majority of primary tumors were located in the rectum (38.1%), in the sigmoid (33.3%) and in the ascending (21.4%) colon. We evaluated the genes KRAS, NRAS, BRAF, EGFR and TP53 using Sanger sequencing. Somatic and germline mutations were found in the KRAS, EGFR and TP53 genes, with the most common somatic alteration being rs121913529 in KRAS. This variant was also strongly associated with alcoholism (p = 0.002). Furthermore, patients with somatic mutations in TP53 had significantly higher mortality compared to those with wild-type alleles (OR: 11.2; 95% CI 1.25-2.45). Conclusions: Our findings support a relationship between alcohol consumption and the rs121913529 mutation, which is classified as pathogenic for colorectal cancer. Thus, further studies investigating the link between alcohol consumption, colorectal carcinogenesis and tumor progression ought to be conducted.
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Affiliation(s)
- Bianca Gomes-Fernandes
- Centro de Tecnologia em Medicina Molecular - Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Luísa Martins Trindade
- Departamento de Nutrição, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 35010-177, Brazil
| | | | - João Pedro Duarte Cardoso
- Centro de Tecnologia em Medicina Molecular - Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Frederico Temponi Lima
- Centro de Tecnologia em Medicina Molecular - Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Luíza Rogerio
- Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | | | - Juliana Garcia Carneiro
- Laboratório Personal - Diagnósticos de Precisão, Clínica Personal, Belo Horizonte, Minas Gerais, Brazil
| | - Rodrigo Gomes da Silva
- Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Renan Pedra de Souza
- Laboratório de Biologia Integrativa - Grupo de Pesquisa em Bioestatística e Epidemiologia Molecular, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Luiz De Marco
- Centro de Tecnologia em Medicina Molecular - Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- Departamento de Cirurgia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Luciana Bastos-Rodrigues
- Centro de Tecnologia em Medicina Molecular - Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
- Departamento de Nutrição, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 35010-177, Brazil.
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Aslanov H, Bayramov B, Reissfelder C, Abdullayeva S, Mammadova Z, Aliyev F, Keese M, Hajibabazade J, Yagublu V. MTHFR Gene C677T Polymorphism (rs1801133) and Susceptibility to Colorectal Polyps in an Azerbaijani Population. J Clin Med 2023; 13:219. [PMID: 38202226 PMCID: PMC10779477 DOI: 10.3390/jcm13010219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/26/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND Understanding the relationships between the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, colorectal polyps, and CRC risk can aid in advancing personalized medicine approaches in CRC prevention. The aim of the current study is to identify the association of C677T polymorphism of the MTHFR gene with the risk of colorectal polyps in the Azerbaijani population. METHODS This study included 125 patients with colon polyps and 155 healthy individuals as a control group. DNA was extracted from venous blood samples obtained from patients and healthy individuals, and the results were analyzed through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and agarose gel electrophoresis. RESULTS Wild-type, heterozygote, and homozygous mutant were revealed within 69 (55.2%), 49 (39.2%), and 7 (5.6%) patients and within 100 (64.5%), 45 (29%), and 10 (6.5%) healthy controls, respectively. However, no significant statistical associations were observed between CT and TT genotypes, dominant (CC vs. CT + TT) and recessive (CC + CT vs. TT) models, and the mutant T allele and disease risk. There were also no significant differences between patients and controls regarding age, sex, smoking and alcohol use. CONCLUSION Our research did not reveal any significant association between the MTHFR C677T polymorphism and susceptibility to colorectal polyps in the Azerbaijan population.
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Affiliation(s)
- Hazi Aslanov
- Department of Surgery, Scientific Center of Surgery after academician M.A.Topchubashov, Baku AZ1122, Azerbaijan;
| | - Bayram Bayramov
- Laboratory of Human Genetics, Genetic Resources Institute of Ministry of Science and Education, Baku AZ1106, Azerbaijan; (B.B.); (Z.M.)
- Department of Natural Sciences, Western Caspian University, Baku AZ1001, Azerbaijan
| | - Christoph Reissfelder
- Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany;
| | - Shams Abdullayeva
- Department of Neurology, Westpfalz-Klinikum, 67655 Kaiserslautern, Germany;
| | - Zeynab Mammadova
- Laboratory of Human Genetics, Genetic Resources Institute of Ministry of Science and Education, Baku AZ1106, Azerbaijan; (B.B.); (Z.M.)
| | - Fikrat Aliyev
- Department of Pathomorphology, Scientific Center of Surgery after academician M.A.Topchubashov, Baku AZ1122, Azerbaijan;
| | - Michael Keese
- Department of Vascular Surgery, Theresienkrankenhaus, 68165 Mannheim, Germany;
| | - Javahir Hajibabazade
- Carver College of Medicine, University of Iowa, Bowen Science Building, 51 Newton, Road, Iowa City, IA 52242-1009, USA
| | - Vugar Yagublu
- Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany;
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Huang Y, Hu Q, Wei Z, Chen L, Luo Y, Li X, Li C. Influence of MTHFR polymorphism, alone or in combination with smoking and alcohol consumption, on cancer susceptibility. Open Life Sci 2023; 18:20220680. [PMID: 37772262 PMCID: PMC10523282 DOI: 10.1515/biol-2022-0680] [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: 02/27/2023] [Revised: 05/17/2023] [Accepted: 07/18/2023] [Indexed: 09/30/2023] Open
Abstract
5,10-methylenetetrahydrofolate reductase (MTHFR) mutations play a significant role in various types of cancers, serving as crucial regulators of folate levels in this process. Several studies have examined the effects of smoking and drinking on MTHFR-related cancers, yielding inconsistent results. Therefore, the objective of this study was to evaluate the magnitude of the effects of gene-smoking or gene-drinking interactions on cancer development. We conducted a comprehensive literature search in PubMed, Web of Science, CNKI, and Wan Fang databases up until May 10th, 2022, to identify relevant articles that met our inclusion criteria. The extracted data from these studies were used to calculate the overall odds ratio (OR) and corresponding 95% confidence interval (95% CI) using either a fixed-effect or random-effect model in Stata version 11.2. Stratified analyses were performed based on ethnicity, control group origin, and cancer classification to assess the risk of cancers associated with gene-smoking or gene-drinking interactions. Sensitivity analyses were conducted to investigate potential sources of heterogeneity, and publication bias was assessed using the Begg's test and Egger's test. Additionally, regression analysis was employed to explore the influence of relevant variables on heterogeneity. To evaluate the statistical correlations, analytical methods such as the false-positive report probability and the Bayesian false discovery probability were applied to assess the reliability of the findings. In our meta-analysis, a total of 47 articles were included, comprising 13,701 cases and 21,995 controls for the C677T polymorphism and 5,149 cases and 8,450 controls for the A1298C polymorphism. The results indicated a significant association between C677T polymorphism and cancer risks when combined with smoking (CT + TT vs CC, OR [95% CI] = 1.225 [1.009-1.487], p = 0.041). Stratified analysis further revealed a significant increase in liver cancer risk for individuals with the C677T when combined with smoking (liver cancer: CT + TT vs CC, OR [95% CI] = 1.564 [1.014-2.413], p = 0.043), particularly among Asian smokers (CT + TT vs CC, OR [95% CI] = 1.292 [1.007-1.658], p = 0.044). Regarding the A1298C polymorphism, an elevated risk of cancer was observed in mixed populations alone (CC + AC vs AA, OR [95% CI] = 1.609 [1.087-2.381], p = 0.018), as well as when combined with smoking (CC + AC vs AA, OR [95% CI] = 1.531 [1.127-2.080], p = 0.006). In non-drinkers, C677T polymorphism was found to be associated with esophageal cancer risk (C677T: CT + TT vs CC, OR [95% CI] = 1.544 [1.011-2.359], p = 0.044) and colon cancer risk (CC + AC vs AA, OR [95% CI] = 1.877 [1.166-3.054], p = 0.010), but there was no clear link between this polymorphism and cancer risk among drinkers. The association between the C677T polymorphism and cancer risk among smokers was found to be significant, suggesting that the combination of tobacco and the C677T polymorphism may enhance the carcinogenic process, particularly in liver cancer. However, no similar relationship was observed for the A1298C polymorphism. Interestingly, significantly increased cancer risk was observed in individuals with C677T genetic variants who were nondrinkers, but not among drinkers. These findings highlight the potential role of the C677T polymorphism in modifying cancer risk in specific contexts, such as smoking and alcohol consumption.
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Affiliation(s)
- Yonghui Huang
- Department of Prosthodontics, The Affiliated Stomatology Hospital of Guangxi Medical University, Nanning530021, P. R. China
| | - Qiurui Hu
- Department of Prosthodontics, The Affiliated Stomatology Hospital of Guangxi Medical University, Nanning530021, P. R. China
| | - Zhenxia Wei
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of Guangxi Medical University, Nanning530021, P. R. China
| | - Li Chen
- Department of Prosthodontics, The Affiliated Stomatology Hospital of Guangxi Medical University, Nanning530021, P. R. China
| | - Ying Luo
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Nanning 530021, P. R. China
| | - Xiaojie Li
- Department of Prosthodontics, The Affiliated Stomatology Hospital of Guangxi Medical University, Nanning530021, P. R. China
- Medical Scientific Research Center, College of Stomatology, Guangxi Medical University, Nanning530021, P. R. China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Nanning 530021, P. R. China
| | - Cuiping Li
- Medical Scientific Research Center, College of Stomatology, Guangxi Medical University, Nanning530021, P. R. China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Nanning 530021, P. R. China
- Department of Experiment, The Affiliated Stomatology Hospital of Guangxi Medical University, Nanning530021, P. R. China
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Rodriguez FD, Coveñas R. Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers. Cancers (Basel) 2021; 13:cancers13143548. [PMID: 34298760 PMCID: PMC8306032 DOI: 10.3390/cancers13143548] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/01/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Of all yearly deaths attributable to alcohol consumption globally, approximately 12% are due to cancers, representing approximately 0.4 million deceased individuals. Ethanol metabolism disturbs cell biochemistry by targeting the structure and function of essential biomolecules (proteins, nucleic acids, and lipids) and by provoking alterations in cell programming that lead to cancer development and cancer malignancy. A better understanding of the metabolic and cell signaling realm affected by ethanol is paramount to designing effective treatments and preventive actions tailored to specific neoplasias. Abstract The World Health Organization identifies alcohol as a cause of several neoplasias of the oropharynx cavity, esophagus, gastrointestinal tract, larynx, liver, or female breast. We review ethanol’s nonoxidative and oxidative metabolism and one-carbon metabolism that encompasses both redox and transfer reactions that influence crucial cell proliferation machinery. Ethanol favors the uncontrolled production and action of free radicals, which interfere with the maintenance of essential cellular functions. We focus on the generation of protein, DNA, and lipid adducts that interfere with the cellular processes related to growth and differentiation. Ethanol’s effects on stem cells, which are responsible for building and repairing tissues, are reviewed. Cancer stem cells (CSCs) of different origins suffer disturbances related to the expression of cell surface markers, enzymes, and transcription factors after ethanol exposure with the consequent dysregulation of mechanisms related to cancer metastasis or resistance to treatments. Our analysis aims to underline and discuss potential targets that show more sensitivity to ethanol’s action and identify specific metabolic routes and metabolic realms that may be corrected to recover metabolic homeostasis after pharmacological intervention. Specifically, research should pay attention to re-establishing metabolic fluxes by fine-tuning the functioning of specific pathways related to one-carbon metabolism and antioxidant processes.
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Affiliation(s)
- Francisco D. Rodriguez
- Department of Biochemistry and Molecular Biology, Faculty of Chemistry, University of Salamanca, 37007 Salamanca, Spain
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), 37007 Salamanca, Spain;
- Correspondence: ; Tel.: +34-677-510-030
| | - Rafael Coveñas
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), 37007 Salamanca, Spain;
- Institute of Neurosciences of Castilla y León (INCYL), Laboratory of Neuroanatomy of the Peptidergic Systems, University of Salamanca, 37007 Salamanca, Spain
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Sharma J, Krupenko SA. Folate pathways mediating the effects of ethanol in tumorigenesis. Chem Biol Interact 2020; 324:109091. [PMID: 32283069 DOI: 10.1016/j.cbi.2020.109091] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 04/02/2020] [Indexed: 02/08/2023]
Abstract
Folate and alcohol are dietary factors affecting the risk of cancer development in humans. The interaction between folate status and alcohol consumption in carcinogenesis involves multiple mechanisms. Alcoholism is typically associated with folate deficiency due to reduced dietary folate intake. Heavy alcohol consumption also decreases folate absorption, enhances urinary folate excretion and inhibits enzymes pivotal for one-carbon metabolism. While folate metabolism is involved in several key biochemical pathways, aberrant DNA methylation, due to the deficiency of methyl donors, is considered as a common downstream target of the folate-mediated effects of ethanol. The negative effects of low intakes of nutrients that provide dietary methyl groups, with high intakes of alcohol are additive in general. For example, low methionine, low-folate diets coupled with alcohol consumption could increase the risk for colorectal cancer in men. To counteract the negative effects of alcohol consumption, increased intake of nutrients, such as folate, providing dietary methyl groups is generally recommended. Here mechanisms involving dietary folate and folate metabolism in cancer disease, as well as links between these mechanisms and alcohol effects, are discussed. These mechanisms include direct effects on folate pathways and indirect mediation by oxidative stress, hypoxia, and microRNAs.
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Affiliation(s)
- Jaspreet Sharma
- Nutrition Research Institute and Department of Nutrition, University of North Carolina, Chapel Hill, USA
| | - Sergey A Krupenko
- Nutrition Research Institute and Department of Nutrition, University of North Carolina, Chapel Hill, USA; Department of Nutrition, University of North Carolina, Chapel Hill, USA.
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Liu H, Ma L, Wang L, Yang Y. MicroRNA-937 is overexpressed and predicts poor prognosis in patients with colon cancer. Diagn Pathol 2019; 14:136. [PMID: 31856857 PMCID: PMC6923914 DOI: 10.1186/s13000-019-0920-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 12/11/2019] [Indexed: 12/17/2022] Open
Abstract
Background Colon cancer is a heterogeneous tumor and a leading cause of cancer-related mortality. MicroRNA (miRNA) has been proposed as the biomarker in cancers. The aim of this study was to investigate the clinical significance and potential functional role of miR-937 in colon cancer. Methods In the present study, reverse transcription-quantitative polymerase chain reaction (qRT-PCR) was conducted to examine the expression levels of miR-937 in colon cancer tissues and cell lines. Kaplan-Meier curve and Cox regression analyses were used to determine the prognostic impact of miR-937 on survival. Cell Counting Kit-8 and Transwell assays were performed to examine cell proliferation, migration, and invasion, respectively. Results miR-937 was significantly upregulated in colon cancer tissues and cell lines. Clinical analysis results showed that miR-937 expression was associated with lymph node metastasis and TNM stage. Patients with high miR-937 expression predicted a shorter overall survival rate. Functionally, overexpression of miR-937 promoted cell proliferation, migration, and invasion, while inhibition of miR-937 inhibited these cellular behaviors in vitro. Conclusions These results suggested that miR-937 may act as a prognostic biomarker and a potential target for therapeutic strategy, as well as promote proliferation, migration, and invasion of colon cancer.
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Affiliation(s)
- Huiya Liu
- Department of Gastroenterology, Heze Municipal Hospital, Heze, 274400, Shandong, China
| | - Lin Ma
- Department of Laboratory Medicine, Heze Municipal Hospital, Heze, 274400, Shandong, China
| | - Ling Wang
- Department of Cardiac Intervention, Heze Municipal Hospital, Heze, 274400, Shandong, China
| | - Yizuo Yang
- Department of Geriatrics, Heze Municipal Hospital, No. 2888, Caozhou Road, Heze, 274400, Shandong, China.
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Zheng K, Yu J, Chen Z, Zhou R, Lin C, Zhang Y, Huang Z, Yu L, Zhao L, Wang Q. Ethanol promotes alcohol-related colorectal cancer metastasis via the TGF-β/RUNX3/Snail axis by inducing TGF-β1 upregulation and RUNX3 cytoplasmic mislocalization. EBioMedicine 2019; 50:224-237. [PMID: 31757777 PMCID: PMC6921366 DOI: 10.1016/j.ebiom.2019.11.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 10/04/2019] [Accepted: 11/07/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Alcohol intake is a well-known lifestyle risk factor for CRC, and an increasing number of studies have revealed that alcohol intake is also tightly associated with CRC metastasis. However, the effect of alcohol on CRC metastasis and its underlying mechanism remain unclear. METHODS A retrospective cohort study was performed to investigate the characteristics of patients with alcohol-related CRC. The effects of ethanol on the biological behaviours of CRC cells were assessed through in vivo and in vitro assays using the Lieber-DeCarli ethanol liquid diet and ethanol, respectively. The ethanol-mediated signalling pathway and downstream factors were screened through ELISA, western blot, immunofluorescence and co-immunoprecipitation. FINDINGS Most patients with alcohol-related CRC, particularly those with tumour metastasis, were characterized by a notably higher circulating ethanol level and a lower systemic acetaldehyde level. Moreover, CRC cells accumulated in ethanol, but not acetaldehyde, to notably higher levels compared with adjacent normal cells. Alcohol intake significantly promoted CRC metastasis via the ethanol-mediated TGF-β/Smad/Snail axis, and ethanol induced the cytoplasmic mislocalization of RUNX3 and further promoted the aggressiveness of CRC by targeting Snail. Pirfenidone (PFD) significantly eliminated the effects of ethanol on CRC metastasis by specifically blocking TGF-β signalling. INTERPRETATION Alcohol intake plays a vital role in CRC metastasis via the ethanol-mediated TGF-β/RUNX3/Snail axis, and PFD might be a novel therapeutic management strategy for CRC.
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Affiliation(s)
- Kehong Zheng
- Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong province, China; Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
| | - Jinlong Yu
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zetao Chen
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Rui Zhou
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Chuang Lin
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuxuan Zhang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zonghai Huang
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lina Yu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
| | - Liang Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
| | - Qian Wang
- Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong province, China.
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Falzone L, Scola L, Zanghì A, Biondi A, Di Cataldo A, Libra M, Candido S. Integrated analysis of colorectal cancer microRNA datasets: identification of microRNAs associated with tumor development. Aging (Albany NY) 2018; 10:1000-1014. [PMID: 29779016 PMCID: PMC5990389 DOI: 10.18632/aging.101444] [Citation(s) in RCA: 127] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 05/07/2018] [Indexed: 12/15/2022]
Abstract
Colorectal cancer (CRC) is one of the leading cause of cancer death worldwide. Currently, no effective early diagnostic biomarkers are available for colorectal carcinoma. Therefore, there is a need to discover new molecules able to identify pre-cancerous lesions. Recently, microRNAs (miRNAs) have been associated with the onset of specific pathologies, thus the identification of miRNAs associated to colorectal cancer may be used to detect this pathology at early stages. On these bases, the expression levels of miRNAs were analyzed to compare the miRNAs expression levels of colorectal cancer samples and normal tissues in several miRNA datasets. This analysis revealed a group of 19 differentially expressed miRNAs. To establish the interaction between miRNAs and the most altered genes in CRC, the mirDIP gene target analysis was performed in such group of 19 differentially expressed miRNAs. To recognize miRNAs able to activate or inhibit genes and pathways involved in colorectal cancer development DIANA-mirPath prediction analysis was applied. Overall, these analyses showed that the up-regulated hsa-miR-183-5p and hsa-miR-21-5p, and the down-regulated hsa-miR-195-5p and hsa-miR-497-5p were directly related to colorectal cancer through the interaction with the Mismatch Repair pathway and Wnt, RAS, MAPK, PI3K, TGF-β and p53 signaling pathways involved in cancer development.
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Affiliation(s)
- Luca Falzone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy
| | - Letizia Scola
- Department of Pathobiology and Medical Biotechnologies, University of Palermo, Palermo 90127, Italy
| | - Antonino Zanghì
- Department of Medical and Surgical Sciences and Advanced Technology "G.F. Ingrassia", University of Catania, Catania 95125, Italy
| | - Antonio Biondi
- Department of General Surgery, Vittorio Emanuele Hospital, University of Catania, Catania 95124, Italy
- Research Center for Prevention, Diagnosis and Treatment of Cancer (PreDiCT), University of Catania, Catania 95123, Italy
| | - Antonio Di Cataldo
- Department of Medical and Surgical Sciences and Advanced Technology "G.F. Ingrassia", University of Catania, Catania 95125, Italy
- Research Center for Prevention, Diagnosis and Treatment of Cancer (PreDiCT), University of Catania, Catania 95123, Italy
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy
- Research Center for Prevention, Diagnosis and Treatment of Cancer (PreDiCT), University of Catania, Catania 95123, Italy
| | - Saverio Candido
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy
- Research Center for Prevention, Diagnosis and Treatment of Cancer (PreDiCT), University of Catania, Catania 95123, Italy
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10
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Blumberg JB, Bailey RL, Sesso HD, Ulrich CM. The Evolving Role of Multivitamin/Multimineral Supplement Use among Adults in the Age of Personalized Nutrition. Nutrients 2018; 10:nu10020248. [PMID: 29470410 PMCID: PMC5852824 DOI: 10.3390/nu10020248] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 02/08/2018] [Accepted: 02/19/2018] [Indexed: 12/31/2022] Open
Abstract
Micronutrient deficiencies occur in segments of the adult population in the United States. Multivitamin/multimineral supplements (MVMS) are widely used by this population, which reduces inadequacies in micronutrient intake, but the potential for exceeding tolerable upper intake levels in others should be considered. There are concerns associated with the excessive intake of certain nutrients, particularly folic acid, and potential untoward consequences. The advent of nutrigenomics and the enhanced ability to directly study the interactions between nutrition and genetic variants and expression will allow for the conduct of more targeted studies with specific endpoints and may ultimately lead to progress in the field of personalized nutrition. The role of MVMS in health maintenance and chronic disease prevention remains controversial. Conducting studies in this area has been hampered by, among other factors, inconsistent definitions of MVMS, ranging from as few as three vitamins to broad-spectrum products containing more than two dozen vitamins and minerals. Results from some observational studies and large-scale, randomized, controlled trials suggest that MVMS may reduce the risk of some forms of cancer and, potentially, cardiovascular disease. The ongoing COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is expected to build on this research and provide additional insights into these areas.
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Affiliation(s)
- Jeffrey B Blumberg
- Friedman School of Nutrition Science and Policy, Tufts University, 711 Washington Street, Boston, MA 02111, USA.
| | - Regan L Bailey
- Department of Nutrition Science, Purdue University, 700 West State Street, West Lafayette, IN 47907, USA.
| | - Howard D Sesso
- Brigham and Women's Hospital and Harvard Medical School, 900 Commonwealth Avenue East, 3rd Floor, Boston, MA 02215, USA.
| | - Cornelia M Ulrich
- Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA.
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11
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Krupenko SA, Krupenko NI. ALDH1L1 and ALDH1L2 Folate Regulatory Enzymes in Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1032:127-143. [PMID: 30362096 DOI: 10.1007/978-3-319-98788-0_10] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Epidemiological studies implicate excess ethanol ingestion as a risk factor for several cancers and support the concept of a synergistic effect of chronic alcohol consumption and folate deficiency on carcinogenesis. Alcohol consumption affects folate-related genes and enzymes including two major folate-metabolizing enzymes, ALDH1L1 and ALDH1L2. ALDH1L1 (cytosolic 10-formyltetrahydrofolate dehydrogenase) is a regulatory enzyme in folate metabolism that controls the overall flux of one-carbon groups in folate-dependent biosynthetic pathways. It is strongly and ubiquitously down-regulated in malignant tumors via promoter methylation, and recent studies underscored this enzyme as a candidate tumor suppressor and potential marker of aggressive cancers. A related enzyme, ALDH1L2, is the mitochondrial homolog of ALDH1L1 encoded by a separate gene. In contrast to its cytosolic counterpart, ALDH1L2 is expressed in malignant tumors and cancer cell lines and was implicated in metastasis regulation. This review discusses the link between folate and cancer, modifying effects of alcohol consumption on folate-associated carcinogenesis, and putative roles of ALDH1L1 and ALDH1L2 in this process.
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Affiliation(s)
- Sergey A Krupenko
- Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA. .,UNC Nutrition Research Institute, Chapel Hill, NC, USA.
| | - Natalia I Krupenko
- Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA.,UNC Nutrition Research Institute, Chapel Hill, NC, USA
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12
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Research progression of blood and fecal metabolites in colorectal
cancer. INTERNATIONAL JOURNAL OF SURGERY: ONCOLOGY 2017. [DOI: 10.1097/ij9.0000000000000051] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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13
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Rattray NJW, Charkoftaki G, Rattray Z, Hansen JE, Vasiliou V, Johnson CH. Environmental influences in the etiology of colorectal cancer: the premise of metabolomics. CURRENT PHARMACOLOGY REPORTS 2017; 3:114-125. [PMID: 28642837 PMCID: PMC5475285 DOI: 10.1007/s40495-017-0088-z] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW In this review we discuss how environmental exposures predominate the etiology of colorectal cancer (CRC). With CRC being a personalized disease influenced by genes and environment, our goal was to explore the role metabolomics can play in identifying exposures, assessing the interplay between co-exposures, and the development of personalized therapeutic interventions. RECENT FINDINGS Approximately 10 % of CRC cases can be explained by germ-line mutations, whereas the prevailing majority are caused by an initiating exposure event occurring decades prior to diagnosis. Recent research has shown that dietary metabolites are linked to a procarcinogenic or protective environment in the colon which is modulated by the microbiome. In addition, excessive alcohol has been shown to increase the risk of CRC and is dependent on diet (folate), the response of microbiome, and genetic polymorphisms within the folate and alcohol metabolic pathways. Metabolomics can not only be used to identify this modulation of host metabolism, which could affect the progression of the tumors but also response to targeted therapeutics. SUMMARY This review highlights the current understanding of the multifaceted etiology and mechanisms of CRC development but also highlights where the field of metabolomics can contribute to a greater understanding of environmental exposure in CRC.
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Affiliation(s)
- Nicholas J. W. Rattray
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA, 06520
| | - Georgia Charkoftaki
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA, 06520
| | - Zahra Rattray
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Yale University, CT, USA 06520
| | - James E. Hansen
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Yale University, CT, USA 06520
- Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA 06520
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA, 06520
| | - Caroline H. Johnson
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA, 06520
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