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Morovati S, Mohammadi A, Masoudi R, Heidari AA, Asad Sangabi M. The power of mumps virus: Matrix protein activates apoptotic pathways in human colorectal cell lines. PLoS One 2023; 18:e0295819. [PMID: 38091318 PMCID: PMC10718445 DOI: 10.1371/journal.pone.0295819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 11/30/2023] [Indexed: 12/18/2023] Open
Abstract
New therapeutic approaches can significantly impact the control of colorectal cancer (CRC), which is increasing worldwide. In this study, we investigated the potential of targeting viral proteins to combat cancer cells. Specifically, we examined the anticancer potential of the matrix (M) protein of the mumps virus Hoshino strain in SW480 CRC cell lines. To begin, we individually transfected SW480 cells with pcDNA3 plasmids containing the mumps virus M gene. We then investigated the percentage of cell death, caspase activity, and the expression levels of genes involved in apoptosis pathways. Following this, we performed bioinformatics analysis on the M protein to identify any similarities with Bcl-2 family members and their viral homologs. Our diagnostic methods showed that treatment with the mumps M protein induced apoptosis and upregulated the expression and activity of pro-apoptotic proteins in SW480 CRC cells compared to the control and vector groups. Based on our bioinformatics studies, we proposed that the BH3 motif in the M protein may trigger apoptosis in CRC cells by interacting with cellular Bax. Overall, our study showed for the first time that the mumps virus M protein could be considered as a targeted treatment for CRC by inducing apoptotic pathways.
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Affiliation(s)
- Solmaz Morovati
- Department of Pathobiology, Division of Biotechnology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Ali Mohammadi
- Department of Pathobiology, Division of Virology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Ramin Masoudi
- Department of Pathobiology, Division of Biotechnology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Amir Ali Heidari
- Department of Clinical Sciences, Division of Aquatic Animal Health and Diseases, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Mehdi Asad Sangabi
- Department of Pathobiology, Division of Virology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
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Al Hargan A, Daghestani MH, Harrath AH. Alterations in APC, BECN1, and TP53 gene expression levels in colon cancer cells caused by monosodium glutamate. BRAZ J BIOL 2021; 83:e246970. [PMID: 34909835 DOI: 10.1590/1519-6984.246970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 03/04/2021] [Indexed: 11/21/2022] Open
Abstract
Colorectal cancer (CRC) is a disease with high incidence worldwide. As of 2018, it is the second leading cause of cancer deaths in the world. In Saudi Arabia, the incidence of this disease has been increasing in the younger population. Both genetic and lifestyle factors may have contributed to its increased incidence and pathogenesis. Monosodium glutamate (MSG) is a food flavor enhancer that can be found in many commercial foods, and it can sometimes be used as a substitute to table salt. MSG has been investigated for its possible genotoxicity, yielding controversial results. In the present study, the effect of MSG on cell viability and its effect on expression of APC, BECN1, and TP53 genes in SW620 and SW480 colon cancer cell lines were studied. TP53 is a tumor suppressor gene that functions in modifying DNA errors and/or inducing apoptosis of damaged cells, and both APC and BECN1 genes are involved in CRC and are of importance in cellular growth and metastasis. Cancer cell viability was analyzed using MTT assay, and the results showed a significant increase in the number of viable cells after 24 h of treatment with MSG with different concentrations (0.5, 1.0, 10, 50, and 100mM). Moreover, gene expression results showed a significant increase in the expression levels of APC and BECN1 under specified conditions in both cell lines; conversely, TP53 showed a significant decrease in expression in SW620 cells. Thus, it can be concluded that MSG possibly confers a pro-proliferative effect on CRC cells.
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Affiliation(s)
- A Al Hargan
- King Saud University, Department of Zoology, College of Science, Centre for Scientific and Medical Female Colleges, Riyadh, Saudi Arabia
| | - M H Daghestani
- King Saud University, Department of Zoology, College of Science, Centre for Scientific and Medical Female Colleges, Riyadh, Saudi Arabia
| | - A H Harrath
- King Saud University, Department of Zoology, College of Science, Centre for Scientific and Medical Female Colleges, Riyadh, Saudi Arabia
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Pérez‐Ortiz JM, Alguacil LF, Salas E, Hermosín‐Gutiérrez I, Gómez‐Alonso S, González‐Martín C. Antiproliferative and cytotoxic effects of grape pomace and grape seed extracts on colorectal cancer cell lines. Food Sci Nutr 2019; 7:2948-2957. [PMID: 31572588 PMCID: PMC6766557 DOI: 10.1002/fsn3.1150] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 06/05/2019] [Accepted: 06/11/2019] [Indexed: 12/17/2022] Open
Abstract
Grape pomace is the source of bioactive compounds (anthocyanins, flavonols, flavan-3-ols, and stilbenes) which exhibit antiproliferative actions on cell cultures. We have investigated the antitumoral effects of grape pomace and grape seed extracts on colon cancer cells (Caco-2, HT-29) and fibroblasts. Crude extracts prepared from white and red pomace, and grape seeds, reduced the viability and proliferation of Caco-2. HT-29 cells were resistant to these actions. Purified extracts were then prepared from the same sources and compared with the LDH test; again, all three extracts were active and purified extract from grape seed was the most potent and specific on Caco-2 cells. HT-29 cells were more sensitive to these purified extracts. The biological activity resided almost exclusively in the flavonol and flavan-3-ols subfractions, rather than the anthocyanin subfraction. Preliminary results on the mechanisms involved in these effects revealed downregulation of Myc gene expression in HT-29 and upregulation of Ptg2 in Caco-2 cells.
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Affiliation(s)
- José M. Pérez‐Ortiz
- Unidad de Investigación TraslacionalHospital General Universitario de Ciudad RealCiudad RealSpain
| | - Luis F. Alguacil
- Unidad de Investigación TraslacionalHospital General Universitario de Ciudad RealCiudad RealSpain
- Present address:
Facultad de FarmaciaUniversidad CEU San PabloMadridSpain
| | - Elisabet Salas
- Unidad de Investigación TraslacionalHospital General Universitario de Ciudad RealCiudad RealSpain
- Present address:
European Commission, Research Executive AgencyBrusselsBelgium
| | - Isidro Hermosín‐Gutiérrez
- Instituto Regional de Investigación Científica Aplicada (IRICA)Universidad de Castilla‐La ManchaCiudad RealSpain
| | - Sergio Gómez‐Alonso
- Department of food science and technologyUniversidad de Castilla‐La ManchaCiudad RealSpain
| | - Carmen González‐Martín
- Unidad de Investigación TraslacionalHospital General Universitario de Ciudad RealCiudad RealSpain
- Department of food science and technologyUniversidad de Castilla‐La ManchaCiudad RealSpain
- Present address:
Facultad de FarmaciaUniversidad CEU San PabloMadridSpain
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Zheng R, Gao D, He T, Zhang M, Zhang X, Linghu E, Wei L, Guo M. Methylation of DIRAS1 promotes colorectal cancer progression and may serve as a marker for poor prognosis. Clin Epigenetics 2017; 9:50. [PMID: 28491151 PMCID: PMC5424295 DOI: 10.1186/s13148-017-0348-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 04/26/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND DIRAS1 is a new member of the Ras gene family. It was described as a potential tumor suppressor in human glioblastomas and esophageal cancer. The role of DIRAS1 in colorectal cancer remains unclear. METHODS To explore the epigenetic changes and function of DIRAS1 in human colorectal cancer, we studied ten colorectal cancer cell lines and 146 primary colorectal cancer samples and 50 matched adjacent samples using semi-quantitative reverse transcription PCR, immunohistochemistry, methylation-specific PCR and bisulfite sequencing, western blot, flow cytometry, and transwell assays. RESULTS DIRAS1 expression was found in DKO and HCT116 cells, while reduced expression was detected in LoVo, SW48, LS180, and SW620 cells, and there was no expression detected in DLD1, HT29, RKO, and SW480 cells. Complete methylation was found in the promoter region of DLD1, HT29, RKO, and SW480 cells. Partial methylation was detected in LoVo, LS180, SW48, and SW620 cells, and unmethylation was found in DKO and HCT116 cells. These results indicate that promoter region methylation correlated with loss of/reduced expression of DIRAS1. Re-expression of DIRAS1 was induced by 5-aza-2'-deoxycytidine, suggesting that the expression of DIRAS1 is regulated by promoter region methylation. DIRAS1 was methylated in 47.3% (69/146) of primary colorectal cancer samples, no methylation was found in non-cancerous colonic tissue samples. Methylation of DIRAS1 was significantly associated with TNM stage (P < 0.05) and short survival time (P = 0.0121). DIRAS1 induced apoptosis and inhibited cell proliferation, migration, and invasion in colorectal cancer. Finally, DIRAS1 suppressed colorectal cancer cell xenograft growth in nude mice. CONCLUSIONS DIRAS1 is frequently methylated in human colorectal cancer and the expression of DIRAS1 is regulated by promoter region methylation. Methylation of DIRAS1 is a marker of poor prognosis in human colorectal cancer.
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Affiliation(s)
- Ruipan Zheng
- Department of Gastroenterology and Hepatology, Chinese People’s Liberation Army General Hospital, #28 Fuxing Road, Beijing, 100853 China
- Department of Pathology, Chinese People’s Liberation Army General Hospital, 28 Fu-Xing Road, Beijing, 100853 China
- School of Medicine, Nankai University, #94 Weijin Road, Tianjin, 300071 China
| | - Dan Gao
- Department of Gastroenterology and Hepatology, Chinese People’s Liberation Army General Hospital, #28 Fuxing Road, Beijing, 100853 China
- School of Medicine, Nankai University, #94 Weijin Road, Tianjin, 300071 China
| | - Tao He
- Department of Gastroenterology and Hepatology, Chinese People’s Liberation Army General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - Meiying Zhang
- Department of Gastroenterology and Hepatology, Chinese People’s Liberation Army General Hospital, #28 Fuxing Road, Beijing, 100853 China
- School of Medicine, Nankai University, #94 Weijin Road, Tianjin, 300071 China
| | - Xiaomei Zhang
- Department of Gastroenterology and Hepatology, Chinese People’s Liberation Army General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - Enqiang Linghu
- Department of Gastroenterology and Hepatology, Chinese People’s Liberation Army General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - Lixin Wei
- Department of Pathology, Chinese People’s Liberation Army General Hospital, 28 Fu-Xing Road, Beijing, 100853 China
| | - Mingzhou Guo
- Department of Gastroenterology and Hepatology, Chinese People’s Liberation Army General Hospital, #28 Fuxing Road, Beijing, 100853 China
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Najafzadeh M, Normington C, Jacob BK, Isreb M, Gopalan RC, Anderson D. DNA Damage in Healthy Individuals and Respiratory Patients after Treating Whole Blood In vitro with the Bulk and Nano Forms of NSAIDs. Front Mol Biosci 2016; 3:50. [PMID: 27734017 PMCID: PMC5039187 DOI: 10.3389/fmolb.2016.00050] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 08/23/2016] [Indexed: 01/09/2023] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX enzyme activity which affects the inflammatory response. Inflammation is associated with increasing cancer incidence. Pre-clinical and clinical studies have shown that NSAID treatment could cause an anti-tumor effect in cancers. In the present study, blood was taken from healthy individuals (n = 17) and patients with respiratory diseases or lung cancer (n = 36). White blood cells (WBC) were treated with either a micro-suspension, i.e., bulk (B) or nano-suspension (N) of aspirin (ASP) or ibuprofen (IBU) up to 500 μg/ml in the comet assay and up to 125 μg/ml in the micronucleus assay. In this study results were compared against untreated lymphocytes and their corresponding treated groups. The results showed, that NSAIDs in their nano form significantly reduced the DNA damage in WBCs from lung cancer patients in bulk and nano compared to untreated lymphocytes. Also, there was a decrease in the level of DNA damage in the comet assay after treating WBCs from healthy individuals, asthma and COPD groups with aspirin N (ASP N) but not with IBU N. In addition, the number of micronuclei decreased after treatment with NSAIDs in their nano form (ASP N and IBU N) in the healthy as well as in the lung cancer group. However, this was not the case for micronucleus frequency in asthma and COPD patients. These data show that lymphocytes from different groups respond differently to treatment with ASP and IBU as measured by comet assay and micronucleus assay, and that the size of the suspended particles of the drugs affects responses.
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Affiliation(s)
- Mojgan Najafzadeh
- Division of Medical Sciences, School of Life Sciences, University of Bradford Bradford, UK
| | - Charmaine Normington
- Division of Medical Sciences, School of Life Sciences, University of Bradford Bradford, UK
| | - Badie K Jacob
- Bradford Royal InfirmaryBradford, UK; St Luke's HospitalBradford, UK
| | | | | | - Diana Anderson
- Division of Medical Sciences, School of Life Sciences, University of Bradford Bradford, UK
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Veldwijk J, Essers BAB, Lambooij MS, Dirksen CD, Smit HA, de Wit GA. Survival or Mortality: Does Risk Attribute Framing Influence Decision-Making Behavior in a Discrete Choice Experiment? VALUE IN HEALTH : THE JOURNAL OF THE INTERNATIONAL SOCIETY FOR PHARMACOECONOMICS AND OUTCOMES RESEARCH 2016; 19:202-9. [PMID: 27021754 DOI: 10.1016/j.jval.2015.11.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 08/31/2015] [Accepted: 11/04/2015] [Indexed: 05/09/2023]
Abstract
OBJECTIVE To test how attribute framing in a discrete choice experiment (DCE) affects respondents' decision-making behavior and their preferences. METHODS Two versions of a DCE questionnaire containing nine choice tasks were distributed among a representative sample of the Dutch population aged 55 to 65 years. The DCE consisted of four attributes related to the decision regarding participation in genetic screening for colorectal cancer (CRC). The risk attribute included was framed positively as the probability of surviving CRC and negatively as the probability of dying from CRC. Panel mixed-logit models were used to estimate the relative importance of the attributes. The data of the positively and negatively framed DCE were compared on the basis of direct attribute ranking, dominant decision-making behavior, preferences, and importance scores. RESULTS The majority (56%) of the respondents ranked survival as the most important attribute in the positively framed DCE, whereas only a minority (8%) of the respondents ranked mortality as the most important attribute in the negatively framed DCE. Respondents made dominant choices based on survival significantly more often than based on mortality. The framing of the risk attribute significantly influenced all attribute-level estimates and resulted in different preference structures among respondents in the positively and negatively framed data set. CONCLUSIONS Risk framing affects how respondents value the presented risk. Positive risk framing led to increased dominant decision-making behavior, whereas negative risk framing led to risk-seeking behavior. Attribute framing should have a prominent part in the expert and focus group interviews, and different types of framing should be used in the pilot version of DCEs as well as in actual DCEs to estimate the magnitude of the effect of choosing different types of framing.
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Affiliation(s)
- Jorien Veldwijk
- Centre for Prevention and Health Services Research, National Institute for Public Health and the Environment, Bilthoven, The Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
| | - Brigitte A B Essers
- Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre, Maastricht, The Netherlands; CAPHRI School of Public Health and Primary Care, Maastricht University, Maastricht, The Netherlands
| | - Mattijs S Lambooij
- Centre for Prevention and Health Services Research, National Institute for Public Health and the Environment, Bilthoven, The Netherlands
| | - Carmen D Dirksen
- Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre, Maastricht, The Netherlands; CAPHRI School of Public Health and Primary Care, Maastricht University, Maastricht, The Netherlands
| | - Henriette A Smit
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - G Ardine de Wit
- Centre for Prevention and Health Services Research, National Institute for Public Health and the Environment, Bilthoven, The Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
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7
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Wang L, Wang Y, Lu Y, Zhang Q, Qu X. Heterozygous deletion of ATG5 in Apc(Min/+) mice promotes intestinal adenoma growth and enhances the antitumor efficacy of interferon-gamma. Cancer Biol Ther 2016; 16:383-91. [PMID: 25695667 DOI: 10.1080/15384047.2014.1002331] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
Autophagy related gene 5 (ATG5) was lost in 23% of the patients with colorectal cancer (CRC) and the role of loss of ATG5 in the pathogenesis of CRC remains unclear. Knockdown of ATG5 in cancer cells enhances the antitumor efficacy of lots of chemotherapeutic agents. However, there is still no animal model to validate these in vitro observations in vivo. In this study, we found that heterozygous deletion of ATG5 in Apc(Min/+) mice increased the number and size of adenomas as compared with those in Apc(Min/+)ATG5(+/+) mice. To investigate whether ATG5 deficiency could sensitize tumors to chemotherapies, we compared the antitumor effects of Interferon-gamma (IFN-γ) between Apc(Min/+)ATG5(+/+) and Apc(Min/+)ATG5(+/-) mice, as IFN-γ is a potential tumor suppressor for CRC and has been used clinically as an efficient adjuvant to chemotherapy of cancer. We revealed that heterozygous deletion of ATG5 significantly enhanced the antitumor efficacy of IFN-γ. Early treatment of Apc(Min/+)ATG5(+/-) mice with IFN-γ decreased tumor incidence rate to 16.7% and reduced the number of adenomas by 95.5% and late treatment led to regression of tumor. Moreover, IFN-γ treatment did not cause any evident toxic reaction. Mechanistic analysis revealed that heterozygous deletion of ATG5 activated EGFR/ERK1/2 and Wnt/β-catenin pathways in adenomas of Apc(Min/+) mice and enhanced the effects of IFN-γ-dependent inhibition of these 2 pathways. Our results demonstrate that ATG5 plays important roles in intestinal tumor growth and combination of IFN-γ and ATG5 deficiency or ATG5-targeted inhibition is a promising strategy for prevention and treatment of CRC.
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Key Words
- 5-FU, 5-fluorouracil
- ATG5
- ATG5, autophagy related gene 5
- Apc, adenomatous polyposis coli
- ApcMin/+ mouse
- CRC, colorectal cancer
- EGFR, epidermal growth factor receptor
- Erk, extracellular signal-regulated kinase
- IFN-γ
- IFN-γ, Interferon-gamma
- LC3, microtubule-associated protein 1 light chain 3
- PCNA, proliferating cell nuclear antigen
- colorectal cancer
- heterozygous deletion
- intestinal adenoma
- siRNAs, small interfering RNAs
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Affiliation(s)
- Lu Wang
- a Department of Pharmacology; School of Pharmaceutical Sciences ; Shandong University ; Jinan , Shandong , China
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Chen P, Wang BL, Pan BS, Guo W. MiR-1297 regulates the growth, migration and invasion of colorectal cancer cells by targeting cyclo-oxygenase-2. Asian Pac J Cancer Prev 2015; 15:9185-90. [PMID: 25422199 DOI: 10.7314/apjcp.2014.15.21.9185] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Cyclo-oxygenase-2(Cox-2), a key regulator of inflammation-producing prostaglandins, promotes cell proliferation and growth. Therefore, a better understanding of the regulatory mechanisms of Cox-2 could lead to novel targeted cancer therapies. MicroRNAs are strongly implicated in colorectal cancer but their specific roles and functions have yet to be fully elucidated. MiR-1297 plays an important role in lung adenocarcinoma and laryngeal squamous cell carcinoma, but its significance in colorectal cancer (CRC) has yet to be reported. In our present study, we found miR-1297 to be down regulated in both CRC-derived cell lines and clinical CRC samples, when compared with normal tissues. Furthermore, miR-1297 could inhibit human colorectal cancer LOVO and HCT116 cell proliferation, migration, and invasion in vitro and tumorigenesis in vivo by targeting Cox-2. Moreover, miR-1297 directly binds to the 3`-UTR of Cox-2, and the expression level was drastically decreased in LOVO and HCT116 cells following overexpression of miR-1297. Additionally, Cox-2 expression levels are inversely correlated with miR-1297 expression in human colorectal cancer xenograft tissues. These results imply that miR-1297 has the potential to provide a new approach to colorectal cancer therapy by directly inhibiting Cox-2 expression.
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Affiliation(s)
- Pu Chen
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China E-mail :
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Hui M, Yan X, Jiang Y. The tumor necrosis factor-α-238 polymorphism and digestive system cancer risk: a meta-analysis. Clin Exp Med 2015; 16:367-74. [PMID: 26047868 DOI: 10.1007/s10238-015-0363-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 05/26/2015] [Indexed: 12/12/2022]
Abstract
Many studies have reported the association between tumor necrosis factor-α (TNF-α)-238 polymorphism and digestive system cancer susceptibility, but the results were inconclusive. We performed a meta-analysis to derive a more precise estimation of the relationship between TNF-α-238 G/A polymorphism and digestive system cancer risk. Pooled analysis for the TNF-α-238 G/A polymorphism contained 26 studies with a total of 4849 cases and 8567 controls. The meta-analysis observed a significant association between TNF-α-238 G/A polymorphism and digestive system cancer risk in the overall population (GA vs GG: OR 1.19, 95 % CI 1.00-1.40, P heterpgeneity = 0.016; A vs G: OR 1.19, 95 % CI 1.03-1.39, P heterpgeneity = 0.015; dominant model: OR 1.20, 95 % CI 1.02-1.41, P heterpgeneity = 0.012). In the analysis of the ethnic subgroups, however, similar results were observed only in the Asian population, but not in the Caucasian population. Therefore, this meta-analysis suggests that TNF-α-238 G/A polymorphism is associated with a significantly increased risk of digestive system cancer. Further large and well-designed studies are needed to confirm these findings.
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Affiliation(s)
- Ming Hui
- Department of Gastroenterology, The Second Affiliated Hospital of Xinjiang Medical University, Urumchi, 830011, China
| | - Xiaojuan Yan
- Department of Emergency, Urumchi First People's Hospital, Urumchi, 830000, China
| | - Ying Jiang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xinjiang Medical University, Urumchi, 830011, China. .,Department of Infectious Diseases, The Second Affiliated Hospital of Xinjiang Medical University, No. 38, Lane 2, Nanhu East Road, Urumchi, 830000, China.
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Wang L, Wang Y, Song Z, Chu J, Qu X. Deficiency of interferon-gamma or its receptor promotes colorectal cancer development. J Interferon Cytokine Res 2015; 35:273-80. [PMID: 25383957 DOI: 10.1089/jir.2014.0132] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Genetic variations in interferon-gamma (IFN-γ) and its receptor (IFNγR) subunits are closely associated with the risk of colorectal cancer (CRC) and survival after diagnosis. However, the role of loss of IFN-γ or IFNγR function in the pathogenesis of CRC remains unclear. Here, we investigated the role of endogenous IFN-γ deficiency in adenomatous polyposis coli (Apc)-mediated intestinal tumor by developing a variant of Apc(Min/+) mice. The Apc(Min/+)IFN-γ(+/-) mice presented with increased number and size of adenomas, and 41.7% of these mice developed adenocarcinoma. Molecular analyses of the adenomas suggested that heterozygous deletion of IFN-γ promoted EGFR/Erk1/2 and Wnt/β-catenin signaling. In vitro, IFN-γ administration inhibited Apc-mutated HT-29 colon cancer cell proliferation and had no effect on the proliferation of HCT-116 colon cancer cells that express wild-type Apc. Besides, we challenged HT-29 cells with small interfering RNA targeting one of its receptor subunits IFNγR1. We found that knockdown of IFNγR1 in HT-29 cells stimulated cell proliferation and colony formation, which was also related to the regulation of EGFR/Erk1/2 and Wnt/β-catenin signaling. Thus, our results strongly support the notion that IFN-γ and IFNγR1 act as a rate-limiting factor in the development of CRC, uncovering a novel role for them in cancer biology.
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Affiliation(s)
- Lu Wang
- 1 Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University , Jinan, China
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Muc-Wierzgoń M, Nowakowska-Zajdel E, Dzięgielewska-Gęsiak S, Kokot T, Klakla K, Fatyga E, Grochowska-Niedworok E, Waniczek D, Wierzgoń J. Specific metabolic biomarkers as risk and prognostic factors in colorectal cancer. World J Gastroenterol 2014; 20:9759-9774. [PMID: 25110413 PMCID: PMC4123364 DOI: 10.3748/wjg.v20.i29.9759] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/05/2013] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
Advances in genomics, molecular pathology and metabolism have generated many candidate biomarkers of colorectal cancer with potential clinical value. Epidemiological and biological studies suggest a role for adiposity, dyslipidaemia, hyperinsulinemia, altered glucose homeostasis, and elevated expression of insulin-like growth factor (IGF) axis members in the risk and prognosis of cancer. This review discusses some recent past and current approaches being taken by researches in obesity and metabolic disorders. The authors describe three main systems as the most studied metabolic candidates of carcinogenesis: dyslipidemias, adipokines and insulin/IGF axis. However, each of these components is unsuccessful in defining the diseases risk and progression, while their co-occurrence increases cancer incidence and mortality in both men and women.
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Abstract
More than 1·2 million patients are diagnosed with colorectal cancer every year, and more than 600,000 die from the disease. Incidence strongly varies globally and is closely linked to elements of a so-called western lifestyle. Incidence is higher in men than women and strongly increases with age; median age at diagnosis is about 70 years in developed countries. Despite strong hereditary components, most cases of colorectal cancer are sporadic and develop slowly over several years through the adenoma-carcinoma sequence. The cornerstones of therapy are surgery, neoadjuvant radiotherapy (for patients with rectal cancer), and adjuvant chemotherapy (for patients with stage III/IV and high-risk stage II colon cancer). 5-year relative survival ranges from greater than 90% in patients with stage I disease to slightly greater than 10% in patients with stage IV disease. Screening has been shown to reduce colorectal cancer incidence and mortality, but organised screening programmes are still to be implemented in most countries.
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Affiliation(s)
- Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
| | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
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13
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Peng Q, Yang S, Lao X, Tang W, Chen Z, Lai H, Wang J, Sui J, Qin X, Li S. Meta-analysis of the association between COX-2 polymorphisms and risk of colorectal cancer based on case-control studies. PLoS One 2014; 9:e94790. [PMID: 24733273 PMCID: PMC3986224 DOI: 10.1371/journal.pone.0094790] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2013] [Accepted: 03/20/2014] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE Cyclooxygenase-2 (COX-2) is an inducible enzyme converting arachidonic acid to prostaglandins and playing important roles in inflammatory diseases as well as tumor development. Previous studies investigating the association between COX-2 polymorphisms and colorectal cancer (CRC) risk reported conflicting results. We performed a meta-analysis of all available studies to explore this association. METHODS All studies published up to October 2013 on the association between COX-2 polymorphisms and CRC risk were identified by searching electronic databases PubMed, EMBASE, and Cochrane library. The association between COX-2 polymorphisms and CRC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). RESULTS Ten studies with 6,774 cases and 9,772 controls were included for -1195A>G polymorphism, 13 studies including 6,807 cases and 10,052 controls were available for -765G>C polymorphism, and 8 studies containing 5,121 cases and 7,487 controls were included for 8473T>C polymorphism. With respect to -765G>C polymorphism, we did not find a significant association with CRC risk when all eligible studies were pooled into the meta-analysis. However, in subgroup analyses by ethnicity and cancer location, with a Bonferroni corrected alpha of 0.05/2, statistical significant increased CRC risk was found in the Asian populations (dominant model CC+CG vs. GG: OR = 1.399, 95%CI: 1.113-1.760, P = 0.004) and rectum cancer patients (CC vs. GG: OR = 2.270, 95%CI: 1.295-3.980, P = 0.004; Recessive model CC vs. CG+GG: OR = 2.269, 95%CI: 1.297-3.970, P = 0.004). In subgroup analysis according to source of control, no significant association was detected. With respect to -1195A>G and 8473T>C polymorphisms, no significant association with CRC risk was demonstrated in the overall and subgroup analyses. CONCLUSIONS The present meta-analysis suggests that the COX-2 -765G>C polymorphism may be a risk factor for CRC in Asians and rectum cancer patients. Further large and well-designed studies are needed to confirm this association.
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Affiliation(s)
- Qiliu Peng
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Shi Yang
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xianjun Lao
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Weizhong Tang
- Department of Anal and Colorectal Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhiping Chen
- Department of Occupational Health and Environmental Health, School of Public Health at Guangxi Medical University, Nanning, Guangxi, China
| | - Hao Lai
- Department of Gastrointestinal Surgery, Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jian Wang
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jingzhe Sui
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xue Qin
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- * E-mail: (XQ); (SL)
| | - Shan Li
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- * E-mail: (XQ); (SL)
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Battaglia V, Shields CD, Murray-Stewart T, Casero RA. Polyamine catabolism in carcinogenesis: potential targets for chemotherapy and chemoprevention. Amino Acids 2014; 46:511-9. [PMID: 23771789 PMCID: PMC3795954 DOI: 10.1007/s00726-013-1529-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Accepted: 05/30/2013] [Indexed: 01/01/2023]
Abstract
Polyamines, including spermine, spermidine, and the precursor diamine, putrescine, are naturally occurring polycationic alkylamines that are required for eukaryotic cell growth, differentiation, and survival. This absolute requirement for polyamines and the need to maintain intracellular levels within specific ranges require a highly regulated metabolic pathway primed for rapid changes in response to cellular growth signals, environmental changes, and stress. Although the polyamine metabolic pathway is strictly regulated in normal cells, dysregulation of polyamine metabolism is a frequent event in cancer. Recent studies suggest that the polyamine catabolic pathway may be involved in the etiology of some epithelial cancers. The catabolism of spermine to spermidine utilizes either the one-step enzymatic reaction of spermine oxidase (SMO) or the two-step process of spermidine/spermine N (1)-acetyltransferase (SSAT) coupled with the peroxisomal enzyme N (1)-acetylpolyamine oxidase. Both catabolic pathways produce hydrogen peroxide and a reactive aldehyde that are capable of damaging DNA and other critical cellular components. The catabolic pathway also depletes the intracellular concentrations of spermidine and spermine, which are free radical scavengers. Consequently, the polyamine catabolic pathway in general and specifically SMO and SSAT provide exciting new targets for chemoprevention and/or chemotherapy.
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Affiliation(s)
- Valentina Battaglia
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy
| | - Christina DeStefano Shields
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Program in Molecular and Translational Toxicology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21231, USA
| | - Tracy Murray-Stewart
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Robert A. Casero
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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Chan V, Blazey W, Tegay D, Harper B, Koehler S, Laurent B, Lipka S, Cohn J, Jung MK, Krishnamachari B. Impact of academic affiliation and training on knowledge of hereditary colorectal cancer. Public Health Genomics 2014; 17:76-83. [PMID: 24458016 DOI: 10.1159/000356938] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 10/31/2013] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Knowledge about hereditary colorectal cancer (CRC) can aid cancer screening and prevention in high-risk patients. Genetic testing, once conducted primarily at academic centers, is now routinely performed in a variety of clinics. Nonacademic physicians may not be aware of hereditary CRC standards of care. METHODS From August to November 2012, a survey was administered to predominantly primary care physicians evaluating academic center affiliation, past training in genetics and knowledge regarding hereditary CRC. RESULTS One hundred forty physicians completed the survey. Knowledge of hereditary CRC was neither associated with academic affiliation nor with training during medical school or residency, but with continuing medical education (CME) training. Those with CME training were more likely to know that screening could be enhanced for patients with a hereditary cancer risk (OR = 4.49, 95% CI = 1.40-14.38) and that an individual with hereditary CRC would have different screening recommendations (OR = 7.49, 95% CI = 1.37-40.81). Residency training and CME training were associated with more frequent hereditary risk assessment. CONCLUSION Genetics training may be associated with physicians' knowledge and assessment of hereditary CRC. Training at the CME level in particular may be integral to the delivery of genetic services in clinical practice.
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Affiliation(s)
- V Chan
- Department of Medicine, NYIT College of Osteopathic Medicine, Old Westbury, N.Y., USA
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Abstract
INTRODUCTION Cancers of the gastrointestinal tract account for 25 % of all cancers and for 9 % of all causes of cancer death in the world, so gastrointestinal cancers represent a major health problem. In the past decades, an emerging role has been attributed to the interactions between the gastrointestinal content and the onset of neoplasia. METHODS Thus, exogenous microbial administration of peculiar bacterial strains (probiotics) has been suggested as having a profound influence on multiple processes associated with a change in cancer risk. Probiotics are mono or mixed cultures of live microorganisms that might beneficially affect the host by improving the characteristics of indigenous microflora. Although the effects of probiotic administration has been intensively investigated in vitro, in animal models, in healthy volunteers, and in some human gastrointestinal diseases, very little is still known about the possible cross-interactions among probiotic administration, changes of intestinal flora, and the neoplastic transformation of gastrointestinal mucosa. RESULTS Theoretically, probiotics are able to reduce cancer risk by a number of mechanisms: (a) binding and degradation of potential carcinogens; (b) quantitative, qualitative and metabolic alterations of the intestinal microflora; (c) production of anti-tumorigenic or anti-mutagenic compounds; (d) competitive action towards pathogenic bacteria; (e) enhancement of the host's immune response; (f) direct effects on cell proliferation. CONCLUSION This review will attempt to highlight the literature on the most widely recognized effects of probiotics against neoplastic transformation of gastrointestinal mucosa and in particular on their effects on cell proliferation.
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Affiliation(s)
- Antonella Orlando
- Laboratory of Experimental Biochemistry, National Institute for Digestive Diseases, IRCCS S de Bellis, Via Turi 27, 70013 Castellana Grotte, Bari, Italy
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Kamat N, Khidhir MA, Alashari MM, Rannug U. Microsatellite instability and loss of heterozygosity detected in middle-aged patients with sporadic colon cancer: A retrospective study. Oncol Lett 2013; 6:1413-1420. [PMID: 24179534 PMCID: PMC3813818 DOI: 10.3892/ol.2013.1573] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Accepted: 08/05/2013] [Indexed: 02/01/2023] Open
Abstract
Microsatellite instability (MSI) is a mutator phenotype that results from a defective mismatch repair (MMR) pathway. The present study examined the incidence of MSI and loss of heterozygosity (LOH) according to five markers from the panel of the National Cancer Institute (NCI) in 38 colorectal cancer (CRC) patients from the United Arab Emirates (UAE). MSI and LOH were analyzed using fragment analyses in a multiplex PCR setting on a capillary array electrophoresis platform. The expression of the MMR proteins, hMLH1 and hMSH2, was analyzed using immunohistochemistry. The cohort consisted of 17 females (44.7%) and 21 males (55.3%) with mean ages of 59.9 and 63.3 years, respectively. The overall MSI incidence was 31.3% (95% CI, 16.1–50.0), and included three patients with high MSI (MSI-H; 9.4%; 95% CI, 2.0–25.0) and seven patients with low MSI (MSI-L; 21.9%; 95% CI, 10.7–39). LOH was detected in three patients, while the remaining 25 patients (65.8%) showed no instability and were therefore classified as microsatellite stable (MSS). MSI was detected in the following screened markers: Bat25 in seven patients, Bat26 in three patients, adenomatous polyposis coli (APC; D5S346) in five patients, AFM093xh3 (D2S123) in two patients and Mfd15 (D17S250) in three patients. Of the five MSI-positive patients, four (80%) were evidently younger, aged 38, 48, 49 and 59 years, respectively. The MSI-H incidence (9.4%) was lower compared with that of other ethnic groups. In terms of the MMR proteins, hMLH1 expression was deficient in seven patients, of whom three were MSI-H patients, and hMSH2 was deficient in three patients. Fisher’s exact test showed significant associations between hMLH1 and MSI when classified as MSS, MSI-L or MSI-H (P=0.0003). No such association was observed with abnormal MMR protein expression, age, cancer stage or gender.
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Affiliation(s)
- Nasir Kamat
- Department of Molecular Biosciences, The Wenner-Gren Institute (MBW), Stockholm University, Stockholm, Sweden
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Li X, Qu L, Zhong Y, Zhao Y, Chen H, Daru L. Association between promoters polymorphisms of matrix metalloproteinases and risk of digestive cancers: a meta-analysis. J Cancer Res Clin Oncol 2013; 139:1433-47. [PMID: 23644699 DOI: 10.1007/s00432-013-1446-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Accepted: 02/21/2013] [Indexed: 12/11/2022]
Abstract
PURPOSE A variety of studies have been performed to elucidate the polymorphisms in promoter regions of matrix metalloproteinases (MMPs) associated with the risk of digestive cancers, and yet, results remain conflicting and heterogeneous. Thus, we undertook a systematic meta-analysis to determine the genetic susceptibility of MMPs to digestive cancers. METHODS A computerized literature search was conducted in databases of PubMed, Embase, and ISI Web of Knowledge till October 2012 for any MMP genetic association study in oral squamous, gastric, esophageal, and colorectal carcinomas. Odds ratios (OR) and 95 % confidence interval (CI) were estimated for each gene under dominant and recessive models, and the heterogeneity between studies was assessed using Q test and I (2) value. Overall and subgroup analysis according to anatomical sites and ethnicity was carried out. Statistical analysis was performed with Review Manager 5.0. RESULTS A total of 40 eligible publications with 68 comparisons were included in this study. For MMP1 nt-1607, individuals with 2G state could increase risk of digestive cancers in total analysis (dominant: OR = 1.31, 95 % CI = 1.16-1.48, P < 0.00001; recessive: OR = 1.29, 95 % CI = 1.11-1.50, P = 0.0009). In the subgroup of tumor sites, significant associations were also observed in esophageal cancer and colorectal cancer under both genetic models. For MMP2 nt-1306, CT or TT carriers performed significant protection against digestive cancer in the dominant model (OR = 0.69, 95 % CI = 0.55-0.85, P = 0.0007) of the overall. In the subgroup analysis, significant association was found in esophageal cancer, with borderline effects in gastric cancer and oral squamous cell carcinoma. For MMP7 -181 A/G, significant association was observed under two genetic models in the overall (dominant: OR = 1.26, 95 % CI = 1.10-1.43, P = 0.0009; recessive: OR = 1.33, 95 % CI = 1.11-1.60, P = 0.002) and in the individual cancer subgroup of esophageal cancer and gastric cancer. For MMP9 -1,562 C/T, a borderline effect was found with digestive cancers in the total and stratified analysis of the colorectal cancer under dominant model. No association was observed in either the overall or subgroup analysis for MMP3 -1,171 5A/6A. CONCLUSIONS Our meta-analysis demonstrated the fact that polymorphisms in promoter regions of MMP genes might be related to the susceptibility of digestive cancers, with cancer development for MMP1 and MMP7, and a protection against cancer for MMP2 and MMP9. Further evidences with adequate sample sizes need to be conducted.
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Affiliation(s)
- Xiaoying Li
- State Key Laboratory of Genetic Engineering, Fudan-VARI Genetic Epidemiology Center and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, 200433, People's Republic of China
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Peng H, Xie SK, Huang MJ, Ren DL. Associations of CYP2E1 rs2031920 and rs3813867 polymorphisms with colorectal cancer risk: a systemic review and meta-analysis. Tumour Biol 2013; 34:2389-95. [PMID: 23595220 DOI: 10.1007/s13277-013-0788-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Accepted: 04/01/2013] [Indexed: 02/07/2023] Open
Abstract
Cytochrome P450 2E1 (CYP2E1) is a natural enzyme involved in the metabolic activation of many carcinogens, and the functional polymorphisms in the CYP2E1 gene might have impacts on colorectal cancer risk. Many studies were published to assess the associations of CYP2E1 rs2031920 and rs3813867 polymorphisms with colorectal cancer risk, but no consistent findings were reported. A systemic review and meta-analysis of eligible studies was performed to comprehensively assess the associations above. Odds ratios (ORs) with 95 % confidence interval (95 % CIs) were used to assess the strength of the associations. Seventeen studies from 15 publications with 17,082 individuals were finally included into this meta-analysis. Meta-analysis of the 13 studies on CYP2E1 rs2031920 polymorphism showed that there was a significant association between CYP2E1 rs2031920 polymorphism and colorectal cancer risk under two genetic models (c2 versus c1: OR = 1.19, 95 % CI 1.03-1.37, P = 0.022; c2c2/c2c1 versus c1c1: OR = 1.16, 95 % CI 1.00-1.35, P = 0.046). Meta-analysis of those four case-control studies on CYP2E1 rs3813867 polymorphism showed that there was no significant association between CYP2E1 rs3813867 polymorphism and colorectal cancer risk under all contrast models (c2 versus c1: OR = 0.96, 95 % CI 0.80-1.16, P = 0.672; c2c2 versus c1c1: OR = 1.26, 95 % CI 0.43-3.67, P = 0.672; c2c2/c1c2 versus c1c1: OR = 0.95, 95 % CI 0.78-1.16, P = 0.114; and c2c2 versus c1c2/c1c1: OR = 1.17, 95 % CI 0.41-3.36, P = 0.775). Therefore, the findings from this meta-analysis suggest that CYP2E1 rs2031920 polymorphism is associated with colorectal cancer risk, but CYP2E1 rs3813867 polymorphism is not associated with colorectal cancer risk. In addition, more well-designed studies with large sample size are needed to provide a more precise evaluation on the associations above.
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Affiliation(s)
- Hui Peng
- Department of Colorectal and Anal Surgery, The Sixth Affiliated Hospital, SunYat-sen University, 26 Yuancun Heng 2 Road, Guangzhou, 510655, Guangdong, China
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Aspirin use is associated with lower prostate cancer risk in male carriers of BRCA mutations. J Genet Couns 2013; 23:187-91. [PMID: 23881471 DOI: 10.1007/s10897-013-9629-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2012] [Accepted: 07/02/2013] [Indexed: 12/17/2022]
Abstract
Previous studies have shown that male BRCA mutation carriers stand at increased risk of developing prostate cancer and have concerns about developing cancer. Genetic counseling practitioners often discuss strategies for reducing the risk of cancer for patients at high risk due to their genetic background. Addressing modifiable health habits is one such strategy. Unfortunately, modifiable risk factors for prostate cancer have only been documented in the general population and have not yet been studied in the BRCA carrier subpopulation. Therefore, this study aimed to identify modifiable risk factors for prostate cancer in BRCA carriers. We examined prostate cancer risk factors in 74 men who were part of families with a BRCA mutation. This study examined nine dichotomous variables including: exercise, history of vasectomy, smoking history, alcohol use, finasteride use, statin use, aspirin use, coffee use, and vitamin use. The survey was sent to all cases of prostate cancer in the Hereditary Cancer Center Database at Creighton University with a known BRCA status. This study confirmed the protective benefits of daily aspirin use, which have been observed in previous studies of the general population, and suggests its benefit in BRCA carriers. Protective benefits from regular vigorous exercise and daily coffee use trended towards significance, but neither factor withstood the Bonferroni Correction for multiple comparisons.
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Kawasaki H, Igawa E, Kohosozawa R, Kobayashi M, Nishiko R, Abe H. Detection of aberrant methylation of tumor suppressor genes in plasma from cancer patients. ACTA ACUST UNITED AC 2013. [DOI: 10.1016/j.pmu.2013.04.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Colorectal carcinogenesis: a cellular response to sustained risk environment. Int J Mol Sci 2013; 14:13525-41. [PMID: 23807509 PMCID: PMC3742201 DOI: 10.3390/ijms140713525] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Revised: 06/07/2013] [Accepted: 06/14/2013] [Indexed: 12/13/2022] Open
Abstract
The current models for colorectal cancer (CRC) are essentially linear in nature with a sequential progression from adenoma through to carcinoma. However, these views of CRC development do not explain the full body of published knowledge and tend to discount environmental influences. This paper proposes that CRC is a cellular response to prolonged exposure to cytotoxic agents (e.g., free ammonia) as key events within a sustained high-risk colonic luminal environment. This environment is low in substrate for the colonocytes (short chain fatty acids, SCFA) and consequently of higher pH with higher levels of free ammonia and decreased mucosal oxygen supply as a result of lower visceral blood flow. All of these lead to greater and prolonged exposure of the colonic epithelium to a cytotoxic agent with diminished aerobic energy availability. Normal colonocytes faced with this unfavourable environment can transform into CRC cells for survival through epigenetic reprogramming to express genes which increase mobility to allow migration and proliferation. Recent data with high protein diets confirm that genetic damage can be increased, consistent with greater CRC risk. However, this damage can be reversed by increasing SCFA supply by feeding fermentable fibre as resistant starch or arabinoxylan. High protein, low carbohydrate diets have been shown to alter the colonic environment with lower butyrate levels and apparently greater mucosal exposure to ammonia, consistent with our hypothesis. Evidence is drawn from in vivo and in vitro genomic and biochemical studies to frame experiments to test this proposition.
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Mishra J, Drummond J, Quazi SH, Karanki SS, Shaw JJ, Chen B, Kumar N. Prospective of colon cancer treatments and scope for combinatorial approach to enhanced cancer cell apoptosis. Crit Rev Oncol Hematol 2012; 86:232-50. [PMID: 23098684 DOI: 10.1016/j.critrevonc.2012.09.014] [Citation(s) in RCA: 133] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Revised: 09/03/2012] [Accepted: 09/26/2012] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer is the leading cause of cancer-related mortality in the western world. It is also the third most common cancer diagnosed in both men and women in the United States with a recent estimate for new cases of colorectal cancer in the year 2012 being around 103,170. Various risk factors for colorectal cancer include life-style, diet, age, personal and family history, and racial and ethnic background. While a few cancers are certainly preventable but this does not hold true for colon cancer as it is often detected in its advanced stage and generally not diagnosed until symptoms become apparent. Despite the fact that several options are available for treating this cancer through surgery, chemotherapy, radiation therapy, immunotherapy, and nutritional-supplement therapy, but the success rates are not very encouraging when used alone where secondary complications appear in almost all these therapies. To maximize the therapeutic-effects in patients, combinatorial approaches are essential. In this review we have discussed the therapies previously and currently available to patients diagnosed with colorectal-cancer, focus on some recent developments in basic research that has shaded lights on new therapeutic-concepts utilizing macrophages/dendritic cells, natural killer cells, gene delivery, siRNA-, and microRNA-technology, and specific-targeting of tyrosine kinases that are either mutated or over-expressed in the cancerous cell to treat these cancer. Potential strategies are discussed where these concepts could be applied to the existing therapies under a comprehensive approach to enhance the therapeutic effects.
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Affiliation(s)
- Jayshree Mishra
- Department of Pharmaceutical Sciences, College of Pharmacy, Texas A&M Health Science Center, Kingsville, TX 78363, USA
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