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Sun Q, Long L. Diagnostic performances of methylated septin9 gene, CEA, CA19-9 and platelet-to-lymphocyte ratio in colorectal cancer. BMC Cancer 2024; 24:906. [PMID: 39068425 PMCID: PMC11283703 DOI: 10.1186/s12885-024-12670-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 07/22/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND This study was designed to compare the diagnostic efficacy of mSEPT9 to four blood markers (CEA, CA19-9, platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR)). In addition, we aimed to determine the combined diagnostic efficacy of mSEPT9, CEA, CA19-9, PLR and NLR in colorectal cancer. METHODS A total of 567 participants were enrolled in the study, including 308 CRC patients, 61 colorectal polyp patients and 198 healthy subjects confirmed by colonoscopy and/or tissue biopsy. Plasma samples were collected for tests. RESULTS The positive rate of mSEPT9 in CRC (71.8%) was markedly higher than that in either the colorectal polyps group (27.9%) or the healthy controls (6.1%) (P < 0.001). The levels of CEA, CA19-9, NLR and PLR in the CRC group were significantly higher than those in the non-CRC groups (P < 0.05). ROC curves comparison analyses showed that the diagnostic efficacy of mSEPT9 alone in CRC was significantly higher than CEA, CA19-9, NLR and PLR alone. The combination of mSEPT9 with CEA, CA19-9 and PLR showed superior diagnostic value. In addition, binary logistic regression was also used to build a better model for clinical diagnosis of CRC. On univariable analyses, age, mSEPT9, CEA, CA 19-9, PLR and NLR were independent predictors of CRC. When these covariates were fitted in multivariable models, the ones with positive detection of mSEPT9, CEA, CA 19-9 and PLR were more likely to have CRC. CONCLUSIONS This research revealed a significant association between mSEPT9 status and the clinicopathological characteristics of CRC patients, and the combination of mSEPT9, CEA, CA19-9 and PLR could significantly improve diagnostic efficacy in CRC.
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Affiliation(s)
- Qian Sun
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China
| | - Lu Long
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China.
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Long L, Sun Q, Yang F, Zhou H, Wang Y, Xiao C, He Q, Yi B. Significance of SDC2 and NDRG4 methylation in stool for colorectal cancer diagnosis. Clin Biochem 2024; 124:110717. [PMID: 38224931 DOI: 10.1016/j.clinbiochem.2024.110717] [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: 11/05/2023] [Revised: 12/24/2023] [Accepted: 01/10/2024] [Indexed: 01/17/2024]
Abstract
BACKGROUND Recent studies have identified methylated SDC2 and NDRG4 in colorectal cancer (CRC), however, the diagnostic value of the combined two genes remains undefined. This study aims to investigate the methylation of SDC2 and NDRG4 in stool samples and their application in diagnosis of CRC. METHODS Five groups were enrolled in our study which consisted of CRC (n = 138), advanced adenomas (n = 27), polyp (n = 35), intestinal disease control (n = 150), and healthy individuals (n = 28). Methylation status of SDC2 and NDRG4 in fecal samples were tested with appropriate commercial kits. Primary data were collected and statistical analyses were performed. RESULTS The positive rates of both SDC2 and NDRG4 methylation in stool samples of CRC group were significantly higher (P < 0.001) than those of either group of advanced adenomas, or polyp, or intestinal disease or the healthy control. It was suggested that both methylated SDC2,NDRG4, SDC2/NDRG4 and age were independent risk factors for CRC. The sensitivity of SDC2 and NDRG4 for CRC diagnosis were 73.9 % and 63.0 %, respectively, while SDC2 combined with NDRG4 had a higher sensitivity of 85.5 %. The specificity of SDC2, NDRG4 and SDC2 combined with NDRG4 achieved 91.6 %, 88.3 % and 84.6 %, respectively. The AUC for methylated SDC2 and NDRG4 were 0.828 (95 % CI: 0.780-0.876) and 0.757 (95 % CI: 0.703-0.811), respectively. In contrast, SDC2 combined with NDRG4 improved the AUC to 0.850 (95 % CI: 0.807-0.893). CONCLUSIONS This research confirmed the significance of detection of SDC2 and NDRG4 methylation by using noninvasive samples of stool. More importantly, attributing to their high level and frequency of methylation in stool, SDC2 and NDRG4 could be promising biomarkers for stool-based method for screening and early diagnosis of CRC, especially when combined.
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Affiliation(s)
- Lu Long
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China.
| | - Qian Sun
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
| | - Fang Yang
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China.
| | - Hui Zhou
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
| | - Yu Wang
- GeneTalks Biotech Co., Ltd. Changsha, Hunan Province 410000, China.
| | - Changhe Xiao
- GeneTalks Biotech Co., Ltd. Changsha, Hunan Province 410000, China.
| | - Qing He
- GeneTalks Biotech Co., Ltd. Changsha, Hunan Province 410000, China.
| | - Bin Yi
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China.
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Choudhury H, Pandey M, Saravanan V, Mun ATY, Bhattamisra SK, Parikh A, Garg S, Gorain B. Recent progress of targeted nanocarriers in diagnostic, therapeutic, and theranostic applications in colorectal cancer. BIOMATERIALS ADVANCES 2023; 153:213556. [PMID: 37478770 DOI: 10.1016/j.bioadv.2023.213556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 06/28/2023] [Accepted: 07/06/2023] [Indexed: 07/23/2023]
Abstract
Cancer at the lower end of the digestive tract, colorectal cancer (CRC), starts with asymptomatic polyps, which can be diagnosed as cancer at a later stage. It is the fourth leading cause of malignancy-associated mortality worldwide. Despite progress in conventional treatment strategies, the possibility to overcome the mortality and morbidity issues with the enhancement of the lifespan of CRC patients is limited. With the advent of nanocarrier-based drug delivery systems, a promising revolution has been made in diagnosis, treatment, and theranostic purposes for cancer management. Herein, we reviewed the progress of miniaturized nanocarriers, such as liposomes, niosomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles, employed in passive and active targeting and their role in theranostic applications in CRC. With this novel scope, the diagnosis and treatment of CRC have proceeded to the forefront of innovation, where specific characteristics of the nanocarriers, such as processability, flexibility in developing precise architecture, improved circulation, site-specific delivery, and rapid response, facilitate the management of cancer patients. Furthermore, surface-engineered technologies for the nanocarriers could involve receptor-mediated deliveries towards the overexpressed receptors on the CRC microenvironment. Moreover, the potential of clinical translation of these targeted miniaturized formulations as well as the possible limitations and barriers that could impact this translation into clinical practice were highlighted. The advancement of these newest developments in clinical research and progress into the commercialization stage gives hope for a better tomorrow.
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Affiliation(s)
- Hira Choudhury
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Manisha Pandey
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia.
| | - Vilashini Saravanan
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Amanda Tan Yee Mun
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Subrat Kumar Bhattamisra
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Ankit Parikh
- Centre for Pharmaceutical Innovation (CPI), Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Sanjay Garg
- Centre for Pharmaceutical Innovation (CPI), Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Bapi Gorain
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India.
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Yan XX, Guo N, Ru SW, Wang ZY, Sui HJ, Xu YS, Yao ZD. The deficiency of 5-methylcytosine (5mC) and its ramification in the occurrence and prognosis of colon cancer. Medicine (Baltimore) 2023; 102:e34860. [PMID: 37653838 PMCID: PMC10470721 DOI: 10.1097/md.0000000000034860] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/27/2023] [Accepted: 07/31/2023] [Indexed: 09/02/2023] Open
Abstract
The incidence and mortality of colon cancer are increasing, and effective biomarkers for its diagnosis are limited. 5-methylcytosine (5mC), a vital DNA methylation marker, plays important roles in gene expression, genomic imprinting, and transposon inhibition. This study aimed to identify the predictors of colon cancer prognosis and lay the foundation for research on therapeutic targets by detecting the levels of 5mC, 5-hydroxymethylcytosine (5hmC), 5-formyl cytosine (5fC), and 5-carboxylcytosine (5caC) in colon cancer and adjacent non-tumor tissues. A tissue microarray including 100 colon cancer tissue samples and 60 adjacent non-tumor tissue samples was used. The expression levels of 5mC and its ramifications were assessed by immunohistochemistry. According to the expression levels, patients were divided into moderately positive and strongly positive groups, and the correlation between clinicopathological characteristics and methylation marks was assessed using 2-sided chi-square tests. The prognostic values of 5mC, 5hmC, 5fC, and 5caC were tested using Kaplan-Meier analyses. Compared with adjacent non-tumor tissues, the overall levels of DNA methylation were lower in colon carcinoma lesions. However, the clinical parameters were not significantly associated with these methylation markers, except for 5hmC, which was associated with the age of cancer patients (P value = .043). Kaplan-Meier analysis disclosed that moderate positive group had a significantly shorter disease specific survival than strong positive group for patients with different levels of 5mC (65.2 vs 95.2 months, P = .014) and 5hmC (71.2 vs 97.5 months, P = .045). 5mC and its ramifications (5hmC, 5fC, and 5caC) can serve as biomarkers for colon cancer. 5mC and 5hmC are stable predictors and therapeutic targets in colon cancer. However, further understanding of its function will help to reveal the complex tumorigenic process and identify new therapeutic strategies.
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Affiliation(s)
- Xin-Xin Yan
- Department of Geriatric, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, P. R. China
| | - Na Guo
- Department of Geriatric, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, P. R. China
| | - Song-Wei Ru
- Department of Geriatric, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, P. R. China
| | - Zhi-Yuan Wang
- Department of Thoracic Surgery, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, P. R. China
| | - Hai-Juan Sui
- Department of Pharmacology, Jinzhou Medical University, Liaoning, P. R. China
| | - Yin-Shi Xu
- Outpatient Department, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, P. R. China
| | - Zhen-Dan Yao
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital and Institute, Beijing, P. R. China
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Kang X, Li X, Li Y. Sevoflurane Suppresses the Proliferation, Migration and Invasion of Colorectal Cancer Through Regulating Circ_0000423/miR-525-5p/SGPP1 Network. Cell Mol Bioeng 2022; 15:219-230. [PMID: 35401845 PMCID: PMC8938590 DOI: 10.1007/s12195-021-00717-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 12/20/2021] [Indexed: 01/24/2023] Open
Abstract
Introduction Sevoflurane (SEV) has been shown to inhibit the malignant progression in many cancers, including colorectal cancer (CRC). However, it is not clear whether SEV regulates the progression of CRC by mediating the circular RNA (circRNA) axis. Methods Different concentrations of SEV were used to treat CRC cells. Cell proliferation, migration and invasion were determined by cell counting kit 8 assay, colony formation assay and transwell assay. The expression of circ_0000423, microRNA (miR)-525-5p and sphingosine-1-phosphate phosphatase 1 (SGPP1) mRNA was measured by quantitative real-time PCR. Cell apoptosis was assessed using flow cytometry, and protein expression was measured by western blot analysis. Dual-luciferase reporter assay and RIP assay were performed to confirm the interactions among circ_0000423, miR-525-5p and SGPP1. Animal experiments were performed to explore the effect of SEV and circ_0000423 on CRC tumorigenesis. Results SEV could inhibit CRC cell proliferation, migration and invasion. Circ_0000423 was upregulated in CRC and its expression could be reduced by SEV. Overexpressed circ_0000423 reversed the inhibitory effect of SEV on CRC cell proliferation, migration and invasion and the promotion effect on cell apoptosis. MiR-525-5p could be sponged by circ_0000423, and its overexpression also abolished the regulation of circ_0000423 on the progression of SEV-treated CRC cells. In addition, SGPP1 was confirmed to be a target of miR-525-5p, and its expression was positively regulated by circ_0000423. MiR-525-5p inhibitor promoted CRC cell progression under the treatment of SEV, while these effects could be overturned by SGPP1 silencing. Furthermore, the inhibition effect of SEV on CRC tumorigenesis also could be abolished by overexpressing circ_0000423. Conclusion Our results showed that SEV inhibited CRC progression through the regulation of circ_0000423/miR-525-5p/SGPP1 axis. Supplementary Information The online version contains supplementary material available at 10.1007/s12195-021-00717-5.
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Affiliation(s)
- Xiaofang Kang
- grid.488137.10000 0001 2267 2324Department of Anesthesiology, The 980 Hospital of the Joint Logistics Support Force of the Chinese People’s Liberation Army, No. 398, Zhongshan West Road, Shijiazhuang City, 050000 Hebei Province China
| | - Xiaocong Li
- grid.488137.10000 0001 2267 2324Department of Anesthesiology, The 980 Hospital of the Joint Logistics Support Force of the Chinese People’s Liberation Army, No. 398, Zhongshan West Road, Shijiazhuang City, 050000 Hebei Province China
| | - Yanli Li
- grid.488137.10000 0001 2267 2324Department of Anesthesiology, The 980 Hospital of the Joint Logistics Support Force of the Chinese People’s Liberation Army, No. 398, Zhongshan West Road, Shijiazhuang City, 050000 Hebei Province China
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Yasuda Y, Sakai A, Ito S, Sasai K, Ishizaki A, Okano Y, Kawahara S, Jitsumori Y, Yamamoto H, Matsubara N, Shimizu K, Katayama H. Human NINEIN polymorphism at codon 1111 is associated with the risk of colorectal cancer. Biomed Rep 2020; 13:45. [PMID: 32934817 DOI: 10.3892/br.2020.1352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/07/2020] [Indexed: 01/11/2023] Open
Abstract
NINEIN serves an essential role in centrosome function as a microtubule organizing center, and in the reformation of the interphase centrosome architecture following mitosis. In the present study, the association between NINEIN Pro1111Ala (rs2236316), a missense single nucleotide polymorphism, and the risk of colorectal cancer (CRC), related to smoking and alcohol consumption habits in 200 patients with CRC and 1,141 cancer-free control participants were assessed in a case-control study performed in Japan. The results showed that the NINEIN Ala/Ala genotype compared with the Pro/Pro genotype was significantly more associated with an increased risk of CRC, and the males with the Ala/Ala genotype exhibited a significantly increased risk of CRC compared with those with Pro/Pro and Pro/Ala genotypes. Stratified analyses of the Ala/Ala genotype with CRC risk further showed an increased association in never/light drinkers (<23 g of ethanol/day), in male never/light drinkers and in male patients with rectal cancer. These findings suggest that the genetic variant of the NINEIN Pro1111Ala polymorphism has a significant effect on CRC susceptibility in the Japanese population.
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Affiliation(s)
- Yukiko Yasuda
- Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Akiko Sakai
- Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Sachio Ito
- Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Kaori Sasai
- Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Akisada Ishizaki
- Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Yoshiya Okano
- Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Seito Kawahara
- Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Yoshimi Jitsumori
- Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hiromasa Yamamoto
- Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Nagahide Matsubara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Kenji Shimizu
- Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hiroshi Katayama
- Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
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Eshghifar N, Badrlou E, Pouresmaeili F. The roles of miRNAs' clinical efficiencies in the colorectal cancer pathobiology: A review article. Hum Antibodies 2020; 28:273-285. [PMID: 32623393 DOI: 10.3233/hab-200417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
MiRNAs (microRNAs) are defined as micro directors and regulators of gene expression. Since altered miRNA expression is signified in the pathobiology of diverse cancers such as colorectal cancers (CRCs), these molecules are described as therapeutic targets, either. Manipulation of miRNAs could lead to further therapy for chemo and radio-resistant CRCs. The usage of microRNAs has indicated prominent promise in the prognosis and diagnosis of CRC, because of their unique expression pattern associated with cancer types and malignancies. Nowadays, many researchers are analyzing the correlation between miRNA polymorphisms and cancer risk. With continuous incompatibility in colorectal cancer (CRC) miRNAs expression data, it is critical to move toward the content of a "pre-laboratory" analysis to speed up efficient accuracy medicine and translational study. Pathway study for the highest expressed miRNAs- regulated target genes resulted in the identification of a considerable number of genes associated with CRC pathway including PI3K, TGFβ, and APC. In this review, we aimed to collect fruitful information about miRNAs and their potential roles in CRC, and provide a meta-analysis of the most frequently studied miRNAs in association with the disease.
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Affiliation(s)
- Nahal Eshghifar
- Department of Molecular and Cellular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elham Badrlou
- Medical Genetics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farkhondeh Pouresmaeili
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Akay S, Urkan M, Balyemez U, Erşen M, Taşar M. Is visceral obesity associated with colorectal cancer? The first volumetric study using all CT slices. ACTA ACUST UNITED AC 2020; 25:338-345. [PMID: 31287430 DOI: 10.5152/dir.2019.18350] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE We aimed to examine the possible relationship between abdominal adiposity parameters and the presence of colorectal cancer (CRC) and between these adiposity parameters and various histopathologic findings of the tumor. METHODS A total of 60 control subjects and 111 CRC patients, 63 with early-stage and 48 with advanced-stage disease, were enrolled. Medical data and abdominopelvic computed tomography (CT) examinations of each study group were retrospectively reviewed. Abdominal adiposity parameters, including visceral adipose tissue (VAT) volume, subcutaneous adipose tissue (SAT) volume, and total adipose tissue (TAT) volume, were calculated on all slices of the CT examinations with specialized software, and results for each study group were compared. Adiposity parameters were also compared with tumor histopathologic findings. RESULTS We found lower VAT and higher SAT volumes in advanced-stage CRC patients, compared with the early-stage group. However, this relationship was not statistically significant (P = 0.721 for VAT and P = 0.432 for SAT volumes). We detected significantly lower VAT and SAT volumes in the early-stage CRC group compared with the control group (P = 0.014 for both). There was no significant relationship between TAT volumes and the study groups (P = 0.06). No statistically significant relationship was detected between adipose tissue parameters and histopathologic features of the CRC group (P > 0.05). CONCLUSION We found statistically significant lower VAT and SAT volumes in patients with early-stage CRC compared with the control group. Volumetric adipose tissue measurements may be more accurate than area measurements and can easily be performed on abdominopelvic CT examination, which is the routine imaging modality for CRC patients.
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Affiliation(s)
- Sinan Akay
- Department of Radiology, University of Health Sciences, Gülhane Training and Research Hospital, Ankara, Turkey
| | - Murat Urkan
- Department of General Surgery, University of Health Sciences, Gülhane Training and Research Hospital, Ankara, Turkey
| | - Uğurcan Balyemez
- Department of Radiology, University of Health Sciences, Gülhane Training and Research Hospital, Ankara, Turkey
| | - Mehmet Erşen
- Department of Radiology, University of Health Sciences, Gülhane Training and Research Hospital, Ankara, Turkey
| | - Mustafa Taşar
- Department of Radiology, University of Health Sciences, Gülhane Training and Research Hospital, Ankara, Turkey
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Ta TV, Nguyen QN, Chu HH, Truong VL, Vuong LD. RAS/RAF mutations and their associations with epigenetic alterations for distinct pathways in Vietnamese colorectal cancer. Pathol Res Pract 2020; 216:152898. [PMID: 32089414 DOI: 10.1016/j.prp.2020.152898] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/27/2020] [Accepted: 02/16/2020] [Indexed: 02/07/2023]
Abstract
KRAS, NRAS, and BRAF are potential tumor-driven genes that are involved in the RAS/RAF/MAPK signaling pathway. RAS/RAF mutations importantly contribute to colorectal tumorigenesis since they remain the activated status of downstream pathways without regulation of the upstream EGFR signal. However, it has not been unclear how epigenetic alterations involved in colorectal tumorigenesis mediated by KRAS, NRAS, or BRAF mutations. Therefore, in this study, we investigated the frequency and distribution of KRAS/NRAS/BRAF mutations in Vietnamese colorectal cancer (CRC) and explored the relationship between genetic and epigenetic abnormalities in 156 tumors of CRC. Somatic mutations of KRAS (exon 2, codon 12/13; exon 3, codon 61), NRAS (exon 2, codon 12/13; exon 3, codon 61), and BRAF (exon 15, codon 600) was determined by Cobas® KRAS Mutation Test, Therascreen NRAS Pyro Kit and Cobas® 4800 BRAF V600 Mutation Test, respectively. Methylation status of BRCA1, MLH1, MGMT, p16, RASSF1A, and APC was detected by methylation-specific PCR. Distribution of each abnormality in clinicopathological features was also analyzed. Results showed the mutation rates of KRAS, NRAS, and BRAF were 41.0 %, 9.6 %, 8.3 % respectively, while the methylation rates of BRCA1, MLH1, MGMT, p16, RASSF1A, and APC were 16.7 %, 16.7 %, 32.7 %, 30.1 %, 30.1 %, and 37.2 % respectively. The distribution of KRAS mutation was mutually exclusive against that of NRAS (p < 0.001) and BRAF (p < 0.001) mutations in CRC. RAS/RAF mutations were more common in adenocarcinoma subtype (p = 0.020), whereas RASSF1A methylation was more frequent in mucinous adenocarcinoma subtype (p = 0.007). In addition, the frequency of having KRAS mutations was significantly higher in MGMT (p = 0.035) or RASSF1A (p = 0.043) methylated cases than in those without methylation. BRAF mutations were positively associated with MLH1 hypermethylation (p = 0.028) but were inversely associated with APC hypermethylation (p = 0.032). Overall, our results show specific interactions of genetic and epigenetic alterations and suggest the presence of independent oncogenic pathways in tumorigenesis of CRC.
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Affiliation(s)
- To Van Ta
- Pathology and Molecular Biology Center, National Cancer Hospital K, 30 Cau Buou Street, Thanh Tri, Hanoi, Viet Nam
| | - Quang Ngoc Nguyen
- Pathology and Molecular Biology Center, National Cancer Hospital K, 30 Cau Buou Street, Thanh Tri, Hanoi, Viet Nam
| | - Ha Hoang Chu
- National Key Laboratory of Gene Technology, Institute of Biotechnology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Street, Cau Giay, Hanoi, Viet Nam
| | - Van-Long Truong
- Department of Smart Food and Drug, College of BNIT, Inje University, Gimhae 50834, South Korea.
| | - Linh Dieu Vuong
- Pathology and Molecular Biology Center, National Cancer Hospital K, 30 Cau Buou Street, Thanh Tri, Hanoi, Viet Nam.
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Kobayashi M, Matsubara N, Nakachi Y, Okazaki Y, Uchino M, Ikeuchi H, Song J, Kimura K, Yasuhara M, Babaya A, Yamano T, Ikeda M, Nishikawa H, Matsuda I, Hirota S, Tomita N. Hypermethylation of Corticotropin Releasing Hormone Receptor-2 Gene in Ulcerative Colitis Associated Colorectal Cancer. In Vivo 2020; 34:57-63. [PMID: 31882463 PMCID: PMC6984071 DOI: 10.21873/invivo.11745] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 09/25/2019] [Accepted: 09/27/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIM The difficulty of early diagnosis of colitis associated colorectal cancer (CACRC) due to colonic mucosal changes in long-standing ulcerative colitis (UC) patients is often experienced in daily clinical practice. Noninvasive objective monitoring for cancer development is advantageous for optimizing treatment strategies in UC patients. We aimed to examine the epigenetic alterations occurring in CACRC, focusing on DNA hypermethylation of CpG islands. MATERIALS AND METHODS The level of DNA methylation in CpG cites was compared between CACRC and the counterpart non-tumorous mucosa using Infinium HumanMethylation 450K BeadChip. RESULTS Our subjects included 3 males and 3 females (median age, 49.5 years). The 450K CpG site DNA methylation microarray revealed that the difference in β value (level of hypermethylation) was the highest for corcicotropin releasing hormone receptor 2 (CRHR2) between CACRC and counterpart non-tumorous mucosa. CONCLUSION Detection of hypermethylation of CRHR2 may be promising for cancer screening in UC patients.
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Affiliation(s)
- Masayoshi Kobayashi
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Nagahide Matsubara
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yutaka Nakachi
- Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Japan
| | - Yasushi Okazaki
- Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Japan
| | - Motoi Uchino
- Department of Inflammatory Bowel Disease, Division of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroki Ikeuchi
- Department of Inflammatory Bowel Disease, Division of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Jihyng Song
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Kei Kimura
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Michiko Yasuhara
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Akihito Babaya
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tomoki Yamano
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Masataka Ikeda
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroki Nishikawa
- Center for Clinical Research and Education, Hyogo College of Medicine, Nishinomiya, Japan
| | - Ikuo Matsuda
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Seiichi Hirota
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Naohiro Tomita
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
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Sun X, Chen D, Jin Z, Chen T, Lin A, Jin H, Zhu Y, Lai M. Genome-wide methylation and expression profiling identify methylation-associated genes in colorectal cancer. Epigenomics 2019; 12:19-36. [PMID: 31833403 DOI: 10.2217/epi-2019-0133] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Aim: To identify methylation-associated genes in the carcinogenesis of colorectal cancer (CRC). Materials & methods: Genome-wide patterns of DNA methylation and gene expression in CRC tissues and adjacent normal tissues were determined and further validated in The Cancer Genome Atlas data and Chinese CRC patients, respectively. Gene overexpression and knockdown cells were constructed to investigate their biological roles in CRC. Results: After validations, hypermethylation of eight genes were found to be correlated with their reduced transcription, and hypomethyaltion of three genes were associated with their upregulation. CADM3, CNRIP1, GRHL2, GRIA4, GSTM2 and NRXN1 were associated with the overall survival of CRC patients. CNRIP1 and GSTM2 were mainly responsible for the proliferation in CRC cells. Conclusion: A total of 11 genes may be promising biomarkers for CRC.
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Affiliation(s)
- Xiaohui Sun
- Department of Epidemiology & Biostatistics, School of Public Health, Zhejiang University, Hangzhou 310058, Zhejiang, PR China
| | - Diyu Chen
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, PR China
| | - Ziqi Jin
- Department of Epidemiology & Biostatistics, School of Public Health, Zhejiang University, Hangzhou 310058, Zhejiang, PR China
| | - Tianhui Chen
- Group of Molecular Epidemiology & Cancer Precision Prevention, Zhejiang Academy of Medical Sciences, Hangzhou 310013, PR China
| | - Aifen Lin
- Human Tissue Bank/Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, 317000, PR China
| | - Hongchuan Jin
- Laboratory of Cancer Biology, Provincial Key Lab of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou 310020, PR China
| | - Yimin Zhu
- Department of Epidemiology & Biostatistics, School of Public Health, Zhejiang University, Hangzhou 310058, Zhejiang, PR China.,Department of Respiratory Diseases, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310020, PR China
| | - Maode Lai
- Department of Pathology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China
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12
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Chen J, Sun H, Tang W, Zhou L, Xie X, Qu Z, Chen M, Wang S, Yang T, Dai Y, Wang Y, Gao T, Zhou Q, Song Z, Liao M, Liu W. DNA methylation biomarkers in stool for early screening of colorectal cancer. J Cancer 2019; 10:5264-5271. [PMID: 31602277 PMCID: PMC6775613 DOI: 10.7150/jca.34944] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 07/09/2019] [Indexed: 12/17/2022] Open
Abstract
Objective: Detection of aberrant methylated genes in feces has been developed as an early screening method for colorectal cancer. The aim of this study was to probe the methylation status of SEPT9, BMP3, NDRG4, and SDC2 in stool and study whether methylation of these genes is associated with colorectal cancer. Materials and Methods: DNAs were isolated and purified from cancerous and non-cancerous stool samples and colorectal cancer tissue. Gene methylation levels were quantified by methylation-specific PCR on SEPT9, BMP3, NDRG4, and SDC2 and analyzed by a diagnostic model. Results: DNA methylation of SEPT9, NDRG4 and SDC2, but not BMP3, had diagnostic potential for detecting colorectal cancer. Moreover, integration of SEPT9, NDRG4, and SDC2 methylation demonstrated high feasibility for detecting colorectal cancer and adenoma, with better performance on colorectal cancer than adenoma. Conclusion: The methylation of SEPT9, NDRG4, and SDC2 in stool may be a potential biomarker for early screening of colorectal cancer.
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Affiliation(s)
- Jie Chen
- Department of Essential Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Haipeng Sun
- GeneTalks Biotech Co., Ltd. Changsha, Hunan, 410000, P. R. China
| | - Weisen Tang
- Department of Essential Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Lin Zhou
- Department of Essential Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Xi Xie
- Department of Essential Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Zhan Qu
- Department of Essential Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Mengfei Chen
- Department of Essential Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Shunyao Wang
- GeneTalks Biotech Co., Ltd. Changsha, Hunan, 410000, P. R. China
| | - Ting Yang
- GeneTalks Biotech Co., Ltd. Changsha, Hunan, 410000, P. R. China
| | - Ying Dai
- GeneTalks Biotech Co., Ltd. Changsha, Hunan, 410000, P. R. China
| | - Yongli Wang
- GeneTalks Biotech Co., Ltd. Changsha, Hunan, 410000, P. R. China
| | - Tangjie Gao
- GeneTalks Biotech Co., Ltd. Changsha, Hunan, 410000, P. R. China
| | - Qiao Zhou
- GeneTalks Biotech Co., Ltd. Changsha, Hunan, 410000, P. R. China
| | - Zhuo Song
- GeneTalks Biotech Co., Ltd. Changsha, Hunan, 410000, P. R. China
| | - Mingmei Liao
- Key Laboratory of Nanobiological Technology of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P.R. China
| | - Weidong Liu
- Department of Essential Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
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Patnaik S, Anupriya. Drugs Targeting Epigenetic Modifications and Plausible Therapeutic Strategies Against Colorectal Cancer. Front Pharmacol 2019; 10:588. [PMID: 31244652 PMCID: PMC6563763 DOI: 10.3389/fphar.2019.00588] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 05/08/2019] [Indexed: 12/14/2022] Open
Abstract
Genetic variations along with epigenetic modifications of DNA are involved in colorectal cancer (CRC) development and progression. CRC is the fourth leading cause of cancer-related deaths worldwide. Initiation and progression of CRC is the cumulation of a variety of genetic and epigenetic changes in colonic epithelial cells. Colorectal carcinogenesis is associated with epigenetic aberrations including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs. Recently, epigenetic modifications have been identified like association of hypermethylated gene Claudin11 (CLDN11) with metastasis and prognosis of poor survival of CRC. DNA methylation of genes CMTM3, SSTR2, MDF1, NDRG4 and TGFB2 are potential epigenetic biomarkers for the early detection of CRC. Tumor suppressor candidate 3 (TUSC3) mRNA expression is silenced by promoter methylation, which promotes epidermal growth factor receptor (EGFR) signaling and rescues the CRC cells from apoptosis and hence leading to poor survival rate. Previous scientific evidences strongly suggest epigenetic modifications that contribute to anticancer drug resistance. Recent research studies emphasize development of drugs targeting histone deacetylases (HDACs) and DNA methyltransferase inhibitors as an emerging anticancer strategy. This review covers potential epigenetic modification targeting chemotherapeutic drugs and probable implementation for the treatment of CRC, which offers a strong rationale to explore therapeutic strategies and provides a basis to develop potent antitumor drugs.
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14
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Wei Y, Sun Z, Wang Y, Xie Z, Xu S, Xu Y, Zhou X, Bi J, Zhu Z. Methylation in the TP53 promoter is associated with ischemic stroke. Mol Med Rep 2019; 20:1404-1410. [PMID: 31173230 DOI: 10.3892/mmr.2019.10348] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Accepted: 03/06/2019] [Indexed: 11/05/2022] Open
Abstract
Cerebral ischemic stroke (IS) is a disease presenting high morbidity and mortality rates worldwide. Understanding of the pathogenesis underlying IS may facilitate the development of effective clinical therapeutic strategies and improve the prevention of this disease, decreasing its occurrence rate. Epigenetic alterations have recently attracted attention as possible mechanisms underlying IS. Additionally, tumor protein p53 (TP53) was identified to be involved in the pathophysiology of cerebral stroke. In the present study, the methylation status of the TP53 promoter was investigated in patients with IS and in age‑matched healthy controls. The methylation status of the promoter of TP53 was significantly increased in patients with IS compared with healthy subjects. Additionally, the methylation level of the TP53 promoter was identified to be associated with carotid intima‑media thickness, the degree of carotid atherosclerosis and the circulating levels of homocysteine in peripheral blood. The present findings may improve the understanding of the role of the epigenetic modifications of the TP53 promoter in IS pathogenesis.
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Affiliation(s)
- Yan Wei
- Department of Neurology Medicine, Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Zhongzheng Sun
- Department of Neurosurgery, Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Yun Wang
- Department of Neurology Medicine, Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Zhaohong Xie
- Department of Neurology Medicine, Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Shunliang Xu
- Department of Neurology Medicine, Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Yingying Xu
- Department of Neurology Medicine, Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Xiaoyan Zhou
- Department of Neurology Medicine, Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Jianzhong Bi
- Department of Neurology Medicine, Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Zhengyu Zhu
- Department of Neurology Medicine, Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
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15
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Pan R, Yu H, Dai J, Zhou C, Ying X, Zhong J, Zhao J, Zhang Y, Wu B, Mao Y, Wu D, Ying J, Duan S. Significant association of PRMT6 hypomethylation with colorectal cancer. J Clin Lab Anal 2018; 32:e22590. [PMID: 29927001 DOI: 10.1002/jcla.22590] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 05/24/2018] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Protein arginine N-methyltransferase 6 (PRMT6) was deemed to be indispensable in the variety of biological processes. Upregulated PRMT6 was found in various human diseases including cancer. Herein, we investigated the performance of PRMT6 methylation in the diagnosis for CRC. METHODS A quantitative methylation-specific polymerase chain reaction (qMSP) method was used to measure PRMT6 promoter methylation. The percentage of methylated reference (PMR) was applied to represent gene methylation level. RESULTS Our data indicated that PRMT6 promoter methylation levels were significantly lower in CRC tissues than those in paired nontumor tissues (median PMR: 36.93% vs 63.12%, P = 1E-6) and normal intestinal tissues (median PMR: 36.93% vs 506.55%, P = 8E-12). We further examined the potential role of PRMT6 hypomethylation by the receiver operating characteristic (ROC) curve. Our results showed that the area under the curve (AUC) was 0.644 (95% CI = 0.596-0.733) between CRC tissues and paired nontumor tissues, 0.958 (95% CI = 0.919-0.998) between CRC tissues and normal intestinal tissues, and 0.899 (95% CI = 0.825-0.972) between paired nontumor tissues and normal intestinal tissues. CONCLUSION Our study firstly indicated that the hypomethylation of PRMT6 promoter could be a novel diagnostic biomarker for CRC.
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Affiliation(s)
- Ranran Pan
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Hang Yu
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Jie Dai
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Cong Zhou
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Xiuru Ying
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Jie Zhong
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Jun Zhao
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Yihan Zhang
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Boyi Wu
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Yiyi Mao
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Dongping Wu
- Department of Medical Oncology, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Ningbo, Zhejiang, China
| | - Jieer Ying
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Shiwei Duan
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
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17
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Falco M, Palma G, Rea D, De Biase D, Scala S, D'Aiuto M, Facchini G, Perdonà S, Barbieri A, Arra C. Tumour biomarkers: homeostasis as a novel prognostic indicator. Open Biol 2016; 6:160254. [PMID: 27927793 PMCID: PMC5204124 DOI: 10.1098/rsob.160254] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 11/10/2016] [Indexed: 12/15/2022] Open
Abstract
The term 'personalized medicine' refers to a medical procedure that consists in the grouping of patients based on their predicted individual response to therapy or risk of disease. In oncologic patients, a 'tailored' therapeutic approach may potentially improve their survival and well-being by not only reducing the tumour, but also enhancing therapeutic response and minimizing the adverse effects. Diagnostic tests are often used to select appropriate and optimal therapies that rely both on patient genome and other molecular/cellular analysis. Several studies have shown that lifestyle and environmental factors can influence the epigenome and that epigenetic events may be involved in carcinogenesis. Thus, in addition to traditional biomarkers, epigenetic factors are raising considerable interest, because they could potentially be used as an excellent tool for cancer diagnosis and prognosis. In this review, we summarize the role of conventional cancer genetic biomarkers and their association with epigenomics. Furthermore, we will focus on the so-called 'homeostatic biomarkers' that result from the physiological response to cancer, emphasizing the concept that an altered 'new' homeostasis influence not only tumour environment, but also the whole organism.
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Affiliation(s)
- Michela Falco
- Struttura Semplice Dipartimentale Sperimentazione Animale, Istituto Nazionale Tumori 'Fondazione G. Pascale', IRCCS, Via Mariano Semmola, 80131 Naples, Italy
| | - Giuseppe Palma
- Struttura Semplice Dipartimentale Sperimentazione Animale, Istituto Nazionale Tumori 'Fondazione G. Pascale', IRCCS, Via Mariano Semmola, 80131 Naples, Italy
| | - Domenica Rea
- Struttura Semplice Dipartimentale Sperimentazione Animale, Istituto Nazionale Tumori 'Fondazione G. Pascale', IRCCS, Via Mariano Semmola, 80131 Naples, Italy
| | - Davide De Biase
- Department of Veterinary Medicine and Animal Production, University of Naples 'Federico II', Via Delpino 1, 80137 Naples, Italy
| | - Stefania Scala
- Molecular lmmunology and Immuneregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori, IRCCS Naples 'Fondazione G. Pascale', Naples, italy, Istituto Nazionale Tumori 'Fondazione G. Pascale', IRCCS, Via Mariano Semmola, 80131 Naples, Italy
| | - Massimiliano D'Aiuto
- Division of Breast Surgery, Department of Breast Disease, National Cancer Institute, IRCCS, 'Fondazione Pascale', Naples, Italy
| | - Gaetano Facchini
- Division of Medical Oncology, Department of Uro-Gynaecological Oncology, , Istituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione G. Pascale', IRCCS, 80131 Naples, Italy
| | - Sisto Perdonà
- Department of Urology, Istituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione G. Pascale', IRCCS, 80131 Naples, Italy
| | - Antonio Barbieri
- Struttura Semplice Dipartimentale Sperimentazione Animale, Istituto Nazionale Tumori 'Fondazione G. Pascale', IRCCS, Via Mariano Semmola, 80131 Naples, Italy
| | - Claudio Arra
- Struttura Semplice Dipartimentale Sperimentazione Animale, Istituto Nazionale Tumori 'Fondazione G. Pascale', IRCCS, Via Mariano Semmola, 80131 Naples, Italy
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18
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Huang C, Liu H, Gong XL, Wu L, Wen B. Expression of DNA methyltransferases and target microRNAs in human tissue samples related to sporadic colorectal cancer. Oncol Rep 2016; 36:2705-2714. [PMID: 27666771 DOI: 10.3892/or.2016.5104] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Accepted: 07/19/2016] [Indexed: 11/06/2022] Open
Abstract
Tissue microenvironment functions as a pivotal mediator in colorectal carcinogenesis, and its alteration can cause some important cellular responses including epigenetic events. The present study examined histologically altered tissue structure, DNA methyltransferases (DNMTs) and their corresponding expression of target microRNAs (miRNA). Tissues resected by surgery were from primary colorectal carcinoma. These samples were from three locations: and were ≥10, 5 and ≤2 cm away from the proximal lesion of colon cancer, and marked as no. 1, no. 2 and no. 3, respectively. Histological alteration was assessed by H&E staining, expression of DNMT1, DNMT3A, and DNMT3B was detected by immunohistochemistry and western blotting, microarray chip was used to screen distinguishable miRNAs and miRNAs targeting DNMTs whose validation assay was performed by quantitative real-time polymerase chain reaction (qRT-PCR). Our results revealed that normal crypt structure was shown in no. 1, while many aberrant crypt foci appeared in no. 3. Significant upregulation of DNMT1, DNMT3A, and DNMT3B expression was found in para-carcinoma tissues, compared with the histopathologically unchanged tissues (P<0.05), furthermore, distinguishable expression profiling was observed of target miRNAs in tissues with different distance. Our results provide additional insights for future research of colorectal carcinogenesis by introducing the tissue microenvironment.
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Affiliation(s)
- Chao Huang
- PI‑WEI Institute of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510000, P.R. China
| | - Hong Liu
- PI‑WEI Institute of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510000, P.R. China
| | - Xiu-Li Gong
- PI‑WEI Institute of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510000, P.R. China
| | - Liyun Wu
- PI‑WEI Institute of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510000, P.R. China
| | - Bin Wen
- PI‑WEI Institute of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510000, P.R. China
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Morley-Bunker A, Walker LC, Currie MJ, Pearson J, Eglinton T. Translating colorectal cancer genetics into clinically useful biomarkers. Colorectal Dis 2016; 18:749-62. [PMID: 26990814 DOI: 10.1111/codi.13334] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 01/22/2016] [Indexed: 12/23/2022]
Abstract
Colorectal cancer (CRC) is a major health problem worldwide accounting for over a million deaths annually. While many patients with Stage II and III CRC can be cured with combinations of surgery, radiotherapy and chemotherapy, this is morbid costly treatment and a significant proportion will suffer recurrence and eventually die of CRC. Increased understanding of the molecular pathogenesis of CRC has the potential to identify high risk patients and target therapy more appropriately. Despite increased understanding of the molecular events underlying CRC development, established molecular techniques have only produced a limited number of biomarkers suitable for use in routine clinical practice to predict risk, prognosis and response to treatment. Recent rapid technological developments, however, have made genomic sequencing of CRC more economical and efficient, creating potential for the discovery of genetic biomarkers that have greater diagnostic, prognostic and therapeutic capabilities for the management of CRC. This paper reviews the current understanding of the molecular pathogenesis of CRC, and summarizes molecular biomarkers that surgeons will encounter in current clinical use as well as those under development in clinical and preclinical trials. New molecular technologies are reviewed together with their potential impact on the understanding of the molecular pathogenesis of CRC and their potential clinical utility in classification, diagnosis, prognosis and targeting of therapy.
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Affiliation(s)
- A Morley-Bunker
- Mackenzie Cancer Research Group, Department of Pathology, University of Otago, Christchurch, New Zealand
| | - L C Walker
- Mackenzie Cancer Research Group, Department of Pathology, University of Otago, Christchurch, New Zealand
| | - M J Currie
- Mackenzie Cancer Research Group, Department of Pathology, University of Otago, Christchurch, New Zealand
| | - J Pearson
- Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand
| | - T Eglinton
- Department of Surgery, University of Otago, Christchurch, New Zealand.
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20
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Qasim BJ, Al-Wasiti EA, Azzal HS. Association of global DNA hypomethylation with clinicopathological variables in colonic tumors of Iraqi patients. Saudi J Gastroenterol 2016; 22:139-47. [PMID: 26997221 PMCID: PMC4817298 DOI: 10.4103/1319-3767.178525] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND/AIM Colorectal cancer (CRC) ranks sixth among the most common 10 cancers in Iraq. It is a foremost public health dilemma and there is improved interest in understanding the fundamental principles of its molecular biology. DNA methylation in cancer has become the issue of passionate investigation. As compared with normal cells, the malignant cells show major disruptions in their DNA methylation patterns. We aimed to assess the association of global DNA hypomethylation in colonic adenomas and carcinomas of Iraqi patients, measured by immunohistochemistry of 5-methylcytosin, with different clinicopathological variables. PATIENTS AND METHODS Thirty tissue paraffin blocks from patients with colorectal adenomas, 30 tissue paraffin blocks from patients with colorectal adenocarcinomas, and 30 samples of apparently normal colonic tissue taken from autopsy cases as a control group were included in the present study. From each block, two sections of 5 μm thickness were taken, one section was stained with Hematoxylin and Eosin for revision of histopathological diagnosis and one section was immunohistochemically stained for 5-methylcytosine (5mC) and digitally analyzed by AperioImageScope software. RESULTS The mean digital value of 5mC immunohistochemical expression was sequentially decreased during neoplastic progression from normal colonic tissue into adenoma and then to carcinoma. The mean digital value of 5mC expression was significantly lower in large size adenomas (≥1 cm), and those with severe dysplasia. Concerning carcinoma cases, 5mC expression was significantly lower in stage C2. CONCLUSIONS The immunohistochemical evaluation of 5mC yields refined information on colorectal tumor biology in adenoma and carcinoma. Global DNA hypomethylation reflected by low immunohistochemical expression of 5-mC is associated with advanced colorectal adenomatous polyps suggesting that it is an early event in colorectal carcinogenesis. Also this hypomethylation can reflect bad prognosis of patients with colorectal cancer by its correlation to higher tumor stage.
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Affiliation(s)
- Ban J. Qasim
- Department of Pathology and Forensic Medicine, College of Medicine, Al-Nahrain University, Baghdad, Iraq,Address for correspondence: Dr. Ban J. Qasim, Department of Pathology and Forensic Medicine, College of Medicine, Al-Nahrain University, Baghdad, Iraq. E-mail:
| | - Estabraq A. Al-Wasiti
- Department of Chemistry and Biochemistry, College of Medicine, Al-Nahrain University, Baghdad, Iraq
| | - Hayder S. Azzal
- Department of Chemistry, Chemist in the Ministry of Health, Baghdad, Iraq
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Gao J, Wen S, Zhou H, Feng S. De-methylation of displacement loop of mitochondrial DNA is associated with increased mitochondrial copy number and nicotinamide adenine dinucleotide subunit 2 expression in colorectal cancer. Mol Med Rep 2015; 12:7033-8. [PMID: 26323487 DOI: 10.3892/mmr.2015.4256] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 07/28/2015] [Indexed: 11/06/2022] Open
Abstract
DNA methylation occurs in the displacement loop (D-loop) region of mammals; however, D-loop regions of certain tumor tissue types were found to be de‑methylated. Whether hypomethylation of the D‑loop region is involved in the regulation of the mitochondrial DNA (mtDNA) copy number and nicotinamide adenine dinucleotide subunit 2 (ND‑2) expressions in colorectal cancer has remained elusive. In the present study, the association between methylation status of the D‑loop region, mtDNA copy number and ND‑2 expression was investigated in 65 colorectal cancer specimens and their corresponding non‑cancerous tissues. In addition, a de‑methylation experiment was performed on the Caco‑2 colorectal cancer cell line by using 5‑aza-2'-deoxycytidine (5‑Aza). The methylation rate of the D‑loop region in all 65 colorectal cancer tissues was markedly reduced when compared with that of their corresponding non‑cancerous tissues (13.8 vs. 81.5%; P<0.05). Furthermore, the methylation rate of the D‑loop region in colorectal cancer tissues was markedly decreased in clinicopathological stages III and IV compared with that in clinicopathological stages I and II (7.1 and 0% vs. 25 and 16%; P<0.05). In addition, the mean relative mtDNA copy number and ND‑2 expression in colorectal cancer tissues were increased compared with those in the corresponding non‑cancerous tissues. De‑methylation of the D‑loop region was associated with an elevated mtDNA copy number and an increased ND‑2 expression. Furthermore, the mtDNA copy number and ND‑2 expression in Caco‑2 cells were significantly increased after 5‑Aza treatment. In conclusion, de‑methylation of the D‑loop region is likely to be involved in the regulation of the mtDNA copy number and ND-2 expression.
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Affiliation(s)
- Jinhang Gao
- Department of Human Anatomy, Academy of Preclinical and Forensic Medicine, West China Medicine College, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Shilei Wen
- Department of Human Anatomy, Academy of Preclinical and Forensic Medicine, West China Medicine College, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hongying Zhou
- Department of Human Anatomy, Academy of Preclinical and Forensic Medicine, West China Medicine College, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Shi Feng
- Department of Human Anatomy, Academy of Preclinical and Forensic Medicine, West China Medicine College, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Vaiopoulos AG, Athanasoula KC, Papavassiliou AG. Epigenetic modifications in colorectal cancer: Molecular insights and therapeutic challenges. Biochim Biophys Acta Mol Basis Dis 2014; 1842:971-80. [DOI: 10.1016/j.bbadis.2014.02.006] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 02/12/2014] [Accepted: 02/15/2014] [Indexed: 12/11/2022]
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Xiao Z, Li B, Wang G, Zhu W, Wang Z, Lin J, Xu A, Wang X. Validation of methylation-sensitive high-resolution melting (MS-HRM) for the detection of stool DNA methylation in colorectal neoplasms. Clin Chim Acta 2014; 431:154-63. [PMID: 24518356 DOI: 10.1016/j.cca.2014.01.044] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Revised: 01/18/2014] [Accepted: 01/26/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND Methylation-sensitive high-resolution melting (MS-HRM) is a new technique for assaying DNA methylation, but its feasibility for assaying stool in patients with colorectal cancer (CRC) is unknown. METHODS First, the MS-HRM and methylation-specific PCR (MSP) detection limits were tested. Second, the methylation statuses of SFRP2 and VIM were analyzed in stool samples by MS-HRM, and in matching tumor and normal colon tissues via bisulfite sequencing PCR (BSP). Third, a case-control study evaluated the diagnostic sensitivity and specificity of MS-HRM relative to results obtained with MSP and the fecal immunochemical test (FIT). Finally, the linearity and reproducibility of MS-HRM were assessed. RESULTS The detection limits of MS-HRM and MSP were 1% and 5%, respectively. The diagnostic sensitivities of MS-HRM (87.3%, 55/63) in stool and BSP in matching tumor tissue (92.1%, 58/63) were highly consistent (κ=0.744). The MS-HRM assay detected 92.5% (37/40) methylation in CRCs, 94.4% (34/36) in advanced adenomas, and 8.8% (5/57) in normal controls. The results of MS-HRM analysis were stable and reliable and showed fairly good linearity for both SFRP2 (P<0.001, R(2)=0.957) and VIM (P<0.001, R(2)=0.954). CONCLUSIONS MS-HRM shows potential for CRC screening.
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Affiliation(s)
- Zhujun Xiao
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Gastroenterology, Guangzhou 510515, China
| | - Bingsheng Li
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Gastroenterology, Huizhou First Hospital, Huizhou 516003, China
| | - Guozhen Wang
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Gastroenterology, Guangzhou 510515, China
| | - Weisi Zhu
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Gastroenterology, Guangzhou 510515, China
| | - Zhongqiu Wang
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Gastroenterology, Guangzhou 510515, China
| | - Jinfeng Lin
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Gastroenterology, Guangzhou 510515, China
| | - Angao Xu
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Huizhou Medicine Institute, Huizhou 516003, China.
| | - Xinying Wang
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Gastroenterology, Guangzhou 510515, China.
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Wu C, Qiu S, Lu L, Zou J, Li WF, Wang O, Zhao H, Wang H, Tang J, Chen L, Xu T, Sun Z, Liao W, Luo G, Lu X. RSPO2-LGR5 signaling has tumour-suppressive activity in colorectal cancer. Nat Commun 2014; 5:3149. [PMID: 24476626 DOI: 10.1038/ncomms4149] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 12/19/2013] [Indexed: 12/23/2022] Open
Abstract
R-spondins are a family of secreted Wnt agonists. One of the family members, R-spondin 2 (RSPO2), has an important role in embryonic development, bone formation and myogenic differentiation; however, its role in human cancers remains largely unknown. Here we show that RSPO2 expression is downregulated in human colorectal cancers (CRCs) due to promoter hypermethylation, and that the RSPO2 reduction correlates with tumour differentiation, size and metastasis. Overexpression of RSPO2 suppresses CRC cell proliferation and tumorigenicity, whereas the depletion of RSPO2 enhances tumour cell growth. RSPO2 has an inhibitory effect on Wnt/β-catenin signaling in the CRC cells that show suppressed cell proliferation. In human CRC cells, the RSPO2-induced inhibition of Wnt signaling depends on leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5); RSPO2 interacts with LGR5 to stabilize the membrane-associated zinc and ring finger 3 (ZNRF3). Our data suggest that RSPO2 functions as a tumour suppressor in human CRCs, and these data reveal a RSPO2-induced, LGR5-dependent Wnt signaling-negative feedback loop that exerts a net growth-suppressive effect on CRC cells.
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Affiliation(s)
- Changjie Wu
- 1] Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China [2]
| | - Sunquan Qiu
- 1] Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China [2]
| | - Liting Lu
- 1] Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China [2]
| | - Jiawei Zou
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Wen-feng Li
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Ouchen Wang
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Haina Zhao
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Hongxiao Wang
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Jiajia Tang
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Lin Chen
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Tao Xu
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Zhongsheng Sun
- 1] Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China [2] Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
| | - Wanqin Liao
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Guangbin Luo
- Departments of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA
| | - Xincheng Lu
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China
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Bolfi F, Miot HA, Resende M, Mazeto GMSF, Romeiro FG, Yamashiro FDS, Nunes VDS. Frequency of various types of neoplasia in a group of acromegalic patients. ARQUIVOS BRASILEIROS DE ENDOCRINOLOGIA E METABOLOGIA 2013; 57:612-6. [PMID: 24343629 DOI: 10.1590/s0004-27302013000800005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Accepted: 05/23/2013] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To determine the frequency of colon cancer, primary hyperparathyroidism, thyroid tumor, and skin cancer in all acromegalic patients in follow-up at the Clinics Hospital - Botucatu Medical School, from 2005 to 2011. SUBJECTS AND METHODS These patients were evaluated retrospectively for colon cancer, primary hyperparathyroidism, dermatological, and thyroid tumors. RESULTS Of 29 patients included at the beginning of the study, two were excluded. Among 19 patients submitted to colonoscopy, one presented colon adenocarcinoma (5%). Thyroid nodules were present in 63% of patients, and papilliferous carcinoma was confirmed in two patients (7,7%). Four patients were confirmed as having primary hyperparathyroidism (15%). The most common dermatologic lesions were thickened skin (100%), acrochordons (64%), epidermal cysts (50%), and pseudo-acanthosis nigricans (50%). Only one patient presented basal cell carcinoma. CONCLUSION Although a small number of acromegalic patients was studied, our findings confirm the high frequency of thyroid neoplasias and primary hyperparathyroidism in this group of patients.
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Choe EK, Kim D, Kim HJ, Park KJ. Association of visceral obesity and early colorectal neoplasia. World J Gastroenterol 2013; 19:8349-8356. [PMID: 24363527 PMCID: PMC3857459 DOI: 10.3748/wjg.v19.i45.8349] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 09/03/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine whether visceral adipose tissue (VAT) serves as a risk factor for colorectal adenoma-early colorectal cancer (CRC) sequence.
METHODS: A retrospective case-control study was conducted with 153 patients with stage I CRC, age/sex-matched 554 patients with colorectal adenoma and 557 normal controls. All subjects underwent various laboratory tests, abdominal fat computed tomography (CT), and colonoscopy. VAT was defined as an intra-abdominal adipose tissue area measured by CT scan. Adipose tissue area was measured at the level of the umbilicus from CT scan. We used the lowest quartile of VAT and subcutaneous adipose tissue area as a reference group.
RESULTS: The body mass index (BMI), total cholesterol, fasting glucose and VAT areas were significantly different among normal, adenoma and CRC groups. The VAT area was 120.6 ± 49.0 cm2 in normal controls, 130.6 ± 58.4 cm2 in adenoma group and 117.6 ± 51.6 cm2 in CRC group (P = 0.002). In univariate analysis, increased BMI was a risk factor for CRC compared to control (P = 0.025). However, VAT area was not a risk factor for CRC compared to control. In multivariate analysis that adjusted for smoking, alcohol consumption and subcutaneous adipose tissue area, VAT area was inversely related to CRC, compared to the adenoma (OR = 0.53, 95%CI: 0.31-0.92, highest quartile vs lowest quartile).
CONCLUSION: Our study shows that visceral obesity is not a risk factor for early CRC. Visceral obesity might influence the normal-adenoma sequence but not the adenoma-early carcinoma sequence.
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Lv Z, Zou H, Peng K, Wang J, Ding Y, Li Y, Ren X, Wang F, Chang R, Liang L, Ding Y. The suppressive role and aberrent promoter methylation of BTG3 in the progression of hepatocellular carcinoma. PLoS One 2013; 8:e77473. [PMID: 24147003 PMCID: PMC3798399 DOI: 10.1371/journal.pone.0077473] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 09/02/2013] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND BTG3 (B-cell translocation gene 3) has been identified as a tumor suppressor and hypermethylation contributes to its down-regulation in some tumors, but its role in hepatocellular carcinoma (HCC) remain unknown. This study aimed to detect the expression and methylation status of BTG3 in HCC cell lines or tissues, and determine its function in HCC progression. METHODOLOGY The expression of BTG3 was detected in HCC cell lines and HCC tissue by real-time RT-PCR, Western blot or immunohistochemistry. The promoter methylation status of BTG3 was measured by using methylation-specific PCR in HCC cell lines. A series of assays were performed to evaluate the effect of BTG3 on proliferation, invasion and cell cycle transition in vitro. RESULTS BTG3 expression was lower in HCC cell lines than in hepatocyte cell line LO2 (P<0.05). BTG3 was also down-regulated in HCC tissues. Its expression was positively correlated with differentiation and distant metastasis (P<0.05). Patients with lower BTG3 expression had shorter overall survival time (P=0.029). DNA methylation directed repression of BTG3 mRNA expression in HCC cell lines. BTG3 suppressed proliferation, invasion and induces G1/S cycle arrest of HCC cells in vitro. CONCLUSION Down-regulation of BTG3 due to the promoter hypermethylation is closely associated with proliferation, invasion and cell cycle arrest of HCC cells. It may be a novel prognostic biomarker for HCC patients.
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Affiliation(s)
- Zhenbing Lv
- Department of Pathology, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China
- Department of General Surgery, Nanchong Central Hospital, Nanchong City, Sichuan Province, People’s Republic of China
| | - Huichun Zou
- Graduate School, Southern Medical University, Guangzhou City, Guangdong Province, People’s Republic of China
| | - Kaiwen Peng
- Graduate School, Southern Medical University, Guangzhou City, Guangdong Province, People’s Republic of China
| | - Jianmei Wang
- Department of Pathology, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China
| | - Yi Ding
- Department of Radiotherapy, Nanfang Hospital, Southern Medical University, Guangzhou City, Guangdong, People’s Republic of China
| | - Yuling Li
- Department of Pathology, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China
| | - Xiaoli Ren
- Department of Pathology, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China
| | - Feifei Wang
- Department of Pathology, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China
| | - Rui Chang
- Second School of Clinical Medicine, Southern Medical University, Guangzhou City, Guangdong Province, People’s Republic of China
| | - Li Liang
- Department of Pathology, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China
- * E-mail: (YD); (LL)
| | - Yanqing Ding
- Department of Pathology, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China
- * E-mail: (YD); (LL)
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Orosz E, Ember I, Gombos K, Tóth L, Tarpay Á, Pap Á, Ottó S. Alternatives for the intensive follow-up after curative resection of colorectal cancer. Potential novel biomarkers for the recommendations. Pathol Oncol Res 2013; 19:619-29. [PMID: 23868031 DOI: 10.1007/s12253-013-9672-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 06/26/2013] [Indexed: 12/17/2022]
Abstract
Early diagnosis of recurrence and metastasis of colorectal cancer following surgery of curative intent is of vital importance in terms of survival and quality of life. The consistent implementation of appropriate patient follow-up strategy is therefore essential. Debates over the methodology, evaluation and strategy of follow-up have been known for many years, and continue today. By introducing several follow-up models, the present paper offers different options featuring certain individual, national and international, conceptual and financial aspects. Colorectal cancer is an important public health concern due to its destructive nature and frequency, it is therefore essential to develop new monitoring strategies, involving new biomarkers and extensive clinical validation. Since the recurrence rate is very high in high-risk patients, the improvement of individual patient risk estimates and the utilization of a corresponding follow-up model require broad international co-operation and common practice, along with the determination of optimal levels of evidence.
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Affiliation(s)
- Enikő Orosz
- National Institute of Oncology, Ráth György utca 7-9, 1122, Budapest, Hungary
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Ohigashi S, Sudo K, Kobayashi D, Takahashi O, Takahashi T, Asahara T, Nomoto K, Onodera H. Changes of the intestinal microbiota, short chain fatty acids, and fecal pH in patients with colorectal cancer. Dig Dis Sci 2013; 58:1717-26. [PMID: 23306850 DOI: 10.1007/s10620-012-2526-4] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Accepted: 12/03/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND New molecular biology-based methods of bacterial identification are expected to help elucidate the relationship between colorectal cancer (CRC) and intestinal microbiota. Although there is increasing evidence revealing the potential role of microbiota in CRC, it remains unclear whether microbial dysbiosis is the cause or the result of CRC onset. AIM We investigated the changes of intestinal environments in CRC or adenoma. METHODS We analyzed 13 groups of microbiota, 8 types of organic acids, and pH in feces obtained from the following 3 groups: individuals with CRC, adenoma, and non-adenoma. Ninety-three patients with CRC and 49 healthy individuals (22 with adenoma and 27 without adenoma) were enrolled. RESULTS The counts of total bacteria (10.3 ± 0.7 vs. 10.8 ± 0.3 log10 cells/g of feces; p < 0.001), 5 groups of obligate anaerobe, and 2 groups of facultative anaerobes were significantly lower in the CRC group than in the healthy individuals. While the concentrations of short chain fatty acids (SCFAs) were significantly decreased in the CRC group, the pH was increased in the CRC group (7.4 ± 0.8 vs. 6.9 ± 0.6; p < 0.001). Comparison among the CRC, adenoma, and non-adenoma groups revealed that fecal SCFAs and pH in the adenoma group were intermediate to the CRC group and the non-adenoma group. Within the CRC group, no differences in microbiota or organic acids were observed among Dukes stages. CONCLUSIONS CRC patients showed significant differences in the intestinal environment, including alterations of microbiota, decreased SCFAs, and elevated pH. These changes are not a result of CRC progression but are involved in CRC onset.
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Affiliation(s)
- Seiji Ohigashi
- Department of Gastroenterological Surgery, St. Luke's International Hospital, 9-1 Akashi-cho Chuo-ku, Tokyo, 104-8560, Japan.
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Carmona FJ, Azuara D, Berenguer-Llergo A, Fernández AF, Biondo S, de Oca J, Rodriguez-Moranta F, Salazar R, Villanueva A, Fraga MF, Guardiola J, Capellá G, Esteller M, Moreno V. DNA methylation biomarkers for noninvasive diagnosis of colorectal cancer. Cancer Prev Res (Phila) 2013; 6:656-65. [PMID: 23694962 DOI: 10.1158/1940-6207.capr-12-0501] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
DNA methylation biomarkers for noninvasive diagnosis of colorectal cancer (CRC) and precursor lesions have been extensively studied. Different panels have been reported attempting to improve current protocols in clinical practice, although no definite biomarkers have been established. In the present study, we have examined patient biopsies starting from a comprehensive analysis of DNA methylation differences between paired normal and tumor samples in known cancer-related genes aiming to select the best performing candidates informative for CRC diagnosis in stool samples. Five selected markers were considered for subsequent analyses in independent biologic cohorts and in silico data sets. Among the five selected genes, three of them (AGTR1, WNT2 and SLIT2) were validated in stool DNA of affected patients with a detection sensitivity of 78% [95% confidence interval (CI), 56%-89%]. As a reference, DNA methylation of VIM and SEPT9 was evaluated in a subset of stool samples yielding sensitivities of 55% and 20%, respectively. Moreover, our panel may complement histologic and endoscopic diagnosis of inflammatory bowel disease (IBD)-associated neoplasia, as it was also efficient detecting aberrant DNA methylation in non-neoplastic tissue samples from affected patients. This novel panel of specific methylation markers can be useful for early diagnosis of CRC using stool DNA and may help in the follow-up of high-risk patients with IBD.
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Affiliation(s)
- F Javier Carmona
- Cancer Epigenetics and Biology Program (PEBC), Catalan Institute of Oncology (ICO-IDIBELL), Barcelona 08908, Spain
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Sinha R, Hussain S, Mehrotra R, Kumar RS, Kumar K, Pande P, Doval DC, Basir SF, Bharadwaj M. Kras gene mutation and RASSF1A, FHIT and MGMT gene promoter hypermethylation: indicators of tumor staging and metastasis in adenocarcinomatous sporadic colorectal cancer in Indian population. PLoS One 2013; 8:e60142. [PMID: 23573237 PMCID: PMC3616004 DOI: 10.1371/journal.pone.0060142] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 02/21/2013] [Indexed: 12/24/2022] Open
Abstract
Objective Colorectal cancer (CRC) development involves underlying modifications at genetic/epigenetic level. This study evaluated the role of Kras gene mutation and RASSF1A, FHIT and MGMT gene promoter hypermethylation together/independently in sporadic CRC in Indian population and correlation with clinicopathological variables of the disease. Methods One hundred and twenty four consecutive surgically resected tissues (62 tumor and equal number of normal adjacent controls) of primary sporadic CRC were included and patient details including demographic characteristics, lifestyle/food or drinking habits, clinical and histopathological profiles were recorded. Polymerase chain reaction - Restriction fragment length polymorphism and direct sequencing for Kras gene mutation and Methylation Specific-PCR for RASSF1A, FHIT and MGMT genes was performed. Results Kras gene mutation at codon 12 & 13 and methylated RASSF1A, FHIT and MGMT gene was observed in 47%, 19%, 47%, 37% and 47% cases, respectively. Alcohol intake and smoking were significantly associated with presence of Kras mutation (codon 12) and MGMT methylation (p-value <0.049). Tumor stage and metastasis correlated with presence of mutant Kras codon 12 (p-values 0.018, 0.044) and methylated RASSF1A (p-values 0.034, 0.044), FHIT (p-values 0.001, 0.047) and MGMT (p-values 0.018, 0.044) genes. Combinatorial effect of gene mutation/methylation was also observed (p-value <0.025). Overall, tumor stage 3, moderately differentiated tumors, presence of lymphatic invasion and absence of metastasis was more frequently observed in tumors with mutated Kras and/or methylated RASSF1A, FHIT and MGMT genes. Conclusion Synergistic interrelationship between these genes in sporadic CRC may be used as diagnostic/prognostic markers in assessing the overall pathological status of CRC.
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Affiliation(s)
- Rupal Sinha
- Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
- Division of Molecular Genetics and Biochemistry, Institute of Cytology and Preventive Oncology, Noida, India
- Department of Surgical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
| | - Showket Hussain
- Division of Molecular Genetics and Biochemistry, Institute of Cytology and Preventive Oncology, Noida, India
| | - Ravi Mehrotra
- Division of Cytopathology, Institute of Cytology and Preventive Oncology, Noida, India
| | - R. Suresh Kumar
- Division of Molecular Genetics and Biochemistry, Institute of Cytology and Preventive Oncology, Noida, India
| | - Kapil Kumar
- Department of Surgical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
| | - Pankaj Pande
- Department of Surgical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
| | - Dinesh Chandra Doval
- Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
| | | | - Mausumi Bharadwaj
- Division of Molecular Genetics and Biochemistry, Institute of Cytology and Preventive Oncology, Noida, India
- * E-mail:
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Nagaraju GP, EI-Rayes BF. SPARC and DNA methylation: Possible diagnostic and therapeutic implications in gastrointestinal cancers. Cancer Lett 2013; 328:10-7. [DOI: 10.1016/j.canlet.2012.08.028] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Revised: 07/17/2012] [Accepted: 08/22/2012] [Indexed: 02/06/2023]
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Cui Z, Cao W, Li J, Song X, Mao L, Chen W. TRIM24 overexpression is common in locally advanced head and neck squamous cell carcinoma and correlates with aggressive malignant phenotypes. PLoS One 2013; 8:e63887. [PMID: 23717505 PMCID: PMC3661592 DOI: 10.1371/journal.pone.0063887] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 04/08/2013] [Indexed: 02/05/2023] Open
Abstract
Tripartite motif-containing 24 (TRIM24), a member of the transcriptional intermediary factor 1 family, functions as a co-regulator that positively or negatively modulates the transcriptional activities of several nuclear receptors. The aim of this study was to investigate TRIM24 expression and its clinical significance in head and neck squamous cell carcinoma. The expression levels of TRIM24 variants were examined in head and neck squamous cell carcinoma (HNSCC) samples and cell lines by real-time PCR and WB. The expression levels of TRIM24 measured in 91 locally advanced HNSCC tumors were measured by immunohistochemistry and correlated with clinical and pathological parameters. The functional role of TRIM24 in HNSCC was further investigated by silencing its expression in HNSCC cell lines. TRIM24 variants were up-regulated in 56 HNSCC samples (P<.001) and 9 HNSCC cell lines (P<.05). TRIM24 protein was overexpressed in 6 of 8 HNSCC cell lines and in 2 of 3 HNSCC samples. Furthermore, 54.95% (50/91) of HNSCC samples exhibited remarkably elevated expression of TRIM24 by immunohistochemistry. Univariate analysis revealed that high TRIM24 expression was associated with worse overall survival (P = .020). In multivariate analysis, TRIM24 expression was identified as an independent predictor of overall survival (P = .030), after adjusting for other clinicopathological parameters. Upon TRIM24 silencing, the proliferation of HNSCC cells was notably inhibited due to the induction of apoptosis. These results suggest that aberrant TRIM24 expression may play an important role in the development of HNSCC and is a promising prognostic indicator for patients with locally advanced HNSCC.
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Affiliation(s)
- Zhibin Cui
- Department of Oral and Maxillofacial Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Wei Cao
- Department of Oral and Maxillofacial Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Jiang Li
- Department of Oral and Maxillofacial Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Oral Pathology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaomeng Song
- Department of Oral and Maxillofacial Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Li Mao
- Department of Oral and Maxillofacial Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, Baltimore, Maryland, United States of America
- * E-mail: (LM); (WC)
| | - Wantao Chen
- Department of Oral and Maxillofacial Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- * E-mail: (LM); (WC)
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Cui W, Li SY, Du JF, Zhu ZM, An P. Silencing phospholipid scramblase 1 expression by RNA interference in colorectal cancer and metastatic liver cancer. Hepatobiliary Pancreat Dis Int 2012; 11:393-400. [PMID: 22893466 DOI: 10.1016/s1499-3872(12)60197-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Phospholipid scramblase 1 (PLSCR1) not only participates in the transbilayer movement of phospholipids, but also plays a role in the pathogenesis and progression of cancers. The present study aimed to evaluate the effect of silencing PLSCR1 expression by RNA interference in colorectal cancer (CRC) and metastatic liver cancer. METHODS The expression of PLSCR1 in CRC and metastatic liver cancer samples was assessed by immunohistochemistry. The cultured cells with the highest expression were selected for subsequent experiments. We designed three siRNA oligonucleotide segments targeted at PLSCR1. Successful transfection was confirmed. The biological behavior of the cells in proliferation, adhesion, migration and invasion was determined. RESULTS PLSCR1 protein expression increased significantly in the majority of CRC and metastatic liver cancer samples compared with normal samples. Lovo cells had the highest expression of PLSCR1. The siRNA-390 oligonucleotide segment had the best silencing effect. After transfection, Lovo cell proliferation was significantly inhibited compared with the controls in the MTT assay. Laminin and fibronectin adhesion assays showed Lovo cell adhesion was also significantly inhibited. In the migration assay, the number of migrating cells in the PLSCR1 siRNA-390 group was 50+/-12, significantly lower than the number in the siRNA-N group (115+/-28) and in the control group (118+/-31). In an invasion test, the number of invading cells in the PLSCR1 siRNA-390 group was 60+/-18, significantly lower than that in the siRNA-N group (97+/-26) and the control group (103+/-24). CONCLUSIONS PLSCR1 is overexpressed in CRC and metastatic liver cancer. Silencing of PLSCR1 by siRNA inhibits the proliferation, adhesion, migration and invasion of Lovo cells, which suggests that PLSCR1 contributes to the tumorigenesis and tumor progression of CRC. PLSCR1 may be a potential gene therapy target for CRC and associated metastatic liver cancer.
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Affiliation(s)
- Wei Cui
- Third Military Medical University, Chongqing 400038, China; [corrected] Department of General Surgery, General Surgery Center of the PLA, General Hospital of Beijing Military Command, Beijing 100700, China
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