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Ren S, Liu S, Zhang J, Liu H, Zhang D, Zheng Y, Xu X, Chen X. Identifying Hepsin as a novel biomarker for human esophageal squamous cell carcinoma (ESCC) and its application in fluorescence imaging. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 334:125707. [PMID: 40024087 DOI: 10.1016/j.saa.2025.125707] [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: 06/02/2024] [Revised: 12/25/2024] [Accepted: 01/04/2025] [Indexed: 03/04/2025]
Abstract
Human Esophageal squamous cell carcinoma (ESCC) represents a type of malignant tumor characterized by a high mortality rate and a generally poor surgical prognosis. The accurate labeling and high-specificity visualization of ESCC cells is extremely importance for its precise diagnosis and effective treatment. Fluorescence molecular imaging has emerged as one of the most critical modalities for cancer detection and therapeutic guidance, owing to its superior sensitivity, cost-effectiveness, portability, real-time imaging, and no damage. In this study, we initially verified that Hepsin, a protease, is highly expressed in ESCC through high-throughput immunocapture (HIC) and Western blot (WB) assays. Subsequently, we designed and synthesized an innovative activatable fluorescent probe, Ac-KQLR Rhodamine 110. It is specifically identified and cleaved by Hepsin, which is over-expressed in ESCC cells. Consequently, the Ac-KQLR Rhodamine 110 could be utilized for the activation fluorescence imaging of ESCC cells, providing a method for their precise visualization. In conclusion, this research highlights that the overexpression of Hepsin serves as a novel biomarker for ESCC. Based on Hepsin's high expression in ESCC, our team has developed a distinctive activation fluorescence imaging strategy that can be employed for the tracking and identification of ESCC. The implementation of this strategy could potentially revolutionize the current methodologies used for monitoring and treating cancer, thereby offering new hope and improved outcomes for patients diagnosed with ESCC.
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Affiliation(s)
- Shenghan Ren
- Center for Biomedical-photonics and Molecular Imaging, Xi'an Key Laboratory of Intelligent Sensing and Regulation of trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710126, China; Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, Xi'an, Shaanxi 710126, China
| | - Siting Liu
- Center for Biomedical-photonics and Molecular Imaging, Xi'an Key Laboratory of Intelligent Sensing and Regulation of trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710126, China; Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, Xi'an, Shaanxi 710126, China
| | - Jian Zhang
- Center for Biomedical-photonics and Molecular Imaging, Xi'an Key Laboratory of Intelligent Sensing and Regulation of trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710126, China; Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, Xi'an, Shaanxi 710126, China
| | - Huifang Liu
- Center for Biomedical-photonics and Molecular Imaging, Xi'an Key Laboratory of Intelligent Sensing and Regulation of trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710126, China; Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, Xi'an, Shaanxi 710126, China
| | - Dongjie Zhang
- Center for Biomedical-photonics and Molecular Imaging, Xi'an Key Laboratory of Intelligent Sensing and Regulation of trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710126, China; Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, Xi'an, Shaanxi 710126, China
| | - Yueting Zheng
- Key Laboratory of Animal Biochemistry and Nutrition, Key Laboratory of Veterinary Biotechnology of Henan Province, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, China.
| | - Xinyi Xu
- Center for Biomedical-photonics and Molecular Imaging, Xi'an Key Laboratory of Intelligent Sensing and Regulation of trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710126, China; Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, Xi'an, Shaanxi 710126, China.
| | - Xueli Chen
- Center for Biomedical-photonics and Molecular Imaging, Xi'an Key Laboratory of Intelligent Sensing and Regulation of trans-Scale Life Information, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710126, China; Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, Xi'an, Shaanxi 710126, China
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Wang N, Pan D, Zhu X, Ren X, Jin X, Chen X, Wang Y, Su M, Sun G, Wang S. Selenium May Be Involved in Esophageal Squamous Cancer Prevention by Affecting GPx3 and FABP1 Expression: A Case-Control Study Based on Bioinformatic Analysis. Nutrients 2024; 16:1322. [PMID: 38732573 PMCID: PMC11085500 DOI: 10.3390/nu16091322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 04/17/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
The role of selenium in the developmental process of esophageal cancer (EC) requires further investigation. To explore the relationship between selenium-related factors and EC through bioinformatic analysis, a case-control study was conducted to verify the results. Utilizing the GEPIA and TCGA databases, we delineated the differential expression of glutathione peroxidase 3 (GPx3) in EC and normal tissues, identified differentially expressed genes (DEGs), and a performed visualization analysis. Additionally, 100 pairs of dietary and plasma samples from esophageal precancerous lesions (EPLs) of esophageal squamous cancer (ESCC) cases and healthy controls from Huai'an district, Jiangsu, were screened. The levels of dietary selenium, plasma selenium, and related enzymes were analyzed using inductively coupled plasma mass spectrometry (ICP-MS) or ELISA kits. The results showed lower GPx3 expression in tumor tissues compared to normal tissues. Further analysis revealed that DEGs were mainly involved in the fat digestion and absorption pathway, and the core protein fatty acid binding protein 1 (FABP1) was significantly upregulated and negatively correlated with GPx3 expression. Our case-control study found that selenium itself was not associated with EPLs risk. However, both the decreased concentration of GPx3 and the increase in FABP1 were positively correlated with the EPLs risk (p for trend = 0.035 and 0.046, respectively). The different expressions of GPx3 and FABP1 reflect the potential of selenium for preventing ESCC at the EPLs stage. GPx3 may affect EC through FABP1, which remains to be further studied.
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Affiliation(s)
- Niannian Wang
- Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China; (N.W.); (D.P.); (X.Z.); (X.R.); (X.J.); (X.C.); (Y.W.); (G.S.)
| | - Da Pan
- Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China; (N.W.); (D.P.); (X.Z.); (X.R.); (X.J.); (X.C.); (Y.W.); (G.S.)
| | - Xiaopan Zhu
- Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China; (N.W.); (D.P.); (X.Z.); (X.R.); (X.J.); (X.C.); (Y.W.); (G.S.)
| | - Xingyuan Ren
- Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China; (N.W.); (D.P.); (X.Z.); (X.R.); (X.J.); (X.C.); (Y.W.); (G.S.)
| | - Xingyi Jin
- Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China; (N.W.); (D.P.); (X.Z.); (X.R.); (X.J.); (X.C.); (Y.W.); (G.S.)
| | - Xiangjun Chen
- Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China; (N.W.); (D.P.); (X.Z.); (X.R.); (X.J.); (X.C.); (Y.W.); (G.S.)
- Department of Public Health, School of Medicine, Xizang Minzu University, Xianyang 712000, China
| | - Yuanyuan Wang
- Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China; (N.W.); (D.P.); (X.Z.); (X.R.); (X.J.); (X.C.); (Y.W.); (G.S.)
| | - Ming Su
- Huai’an District Center for Disease Control and Prevention, Huai’an 223001, China;
| | - Guiju Sun
- Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China; (N.W.); (D.P.); (X.Z.); (X.R.); (X.J.); (X.C.); (Y.W.); (G.S.)
| | - Shaokang Wang
- Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China; (N.W.); (D.P.); (X.Z.); (X.R.); (X.J.); (X.C.); (Y.W.); (G.S.)
- Department of Public Health, School of Medicine, Xizang Minzu University, Xianyang 712000, China
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Xu YF, Dang Y, Kong WB, Wang HL, Chen X, Yao L, Zhao Y, Zhang RQ. Regulation of TMEM100 expression by epigenetic modification, effects on proliferation and invasion of esophageal squamous carcinoma. World J Clin Oncol 2024; 15:554-565. [PMID: 38689624 PMCID: PMC11056859 DOI: 10.5306/wjco.v15.i4.554] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/01/2024] [Accepted: 03/20/2024] [Indexed: 04/22/2024] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy with a high morbidity and mortality rate. TMEM100 has been shown to be suppressor gene in a variety of tumors, but there are no reports on the role of TMEM100 in esophageal cancer (EC). AIM To investigate epigenetic regulation of TMEM100 expression in ESCC and the effect of TMEM100 on ESCC proliferation and invasion. METHODS Firstly, we found the expression of TMEM100 in EC through The Cancer Genome Atlas database. The correlation between TMEM100 gene expression and the survival of patients with EC was further confirmed through Kaplan-Meier analysis. We then added the demethylating agent 5-AZA to ESCC cell lines to explore the regulation of TMEM100 expression by epigenetic modification. To observe the effect of TMEM100 expression on tumor proliferation and invasion by overexpressing TMEM100. Finally, we performed gene set enrichment analysis using the Kyoto Encyclopaedia of Genes and Genomes Orthology-Based Annotation System database to look for pathways that might be affected by TMEM100 and verified the effect of TMEM100 expression on the mitogen-activated protein kinases (MAPK) pathway. RESULTS In the present study, by bioinformatic analysis we found that TMEM100 was lowly expressed in EC patients compared to normal subjects. Kaplan-meier survival analysis showed that low expression of TMEM100 was associated with poor prognosis in patients with EC. Then, we found that the demethylating agent 5-AZA resulted in increased expression of TMEM100 in ESCC cells [quantitative real-time PCR (qRT-PCR) and western blotting]. Subsequently, we confirmed that overexpression of TMEM100 leads to its increased expression in ESCC cells (qRT-PCR and western blotting). Overexpression of TMEM100 also inhibited proliferation, invasion and migration of ESCC cells (cell counting kit-8 and clone formation assays). Next, by enrichment analysis, we found that the gene set was significantly enriched in the MAPK signaling pathway. The involvement of TMEM100 in the regulation of MAPK signaling pathway in ESCC cell was subsequently verified by western blotting. CONCLUSION TMEM100 is a suppressor gene in ESCC, and its low expression may lead to aberrant activation of the MAPK pathway. Promoter methylation may play a key role in regulating TMEM100 expression.
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Affiliation(s)
- Yue-Feng Xu
- Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230000, Anhui Province, China
| | - Yan Dang
- Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230000, Anhui Province, China
| | - Wei-Bo Kong
- Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230000, Anhui Province, China
| | - Han-Lin Wang
- Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230000, Anhui Province, China
| | - Xiu Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230000, Anhui Province, China
| | - Long Yao
- Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230000, Anhui Province, China
| | - Yuan Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230000, Anhui Province, China
| | - Ren-Quan Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230000, Anhui Province, China
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Ahuja P, Yadav R, Goyal S, Yadav C, Ranga S, Kadian L. Targeting epigenetic deregulations for the management of esophageal carcinoma: recent advances and emerging approaches. Cell Biol Toxicol 2023; 39:2437-2465. [PMID: 37338772 DOI: 10.1007/s10565-023-09818-5] [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: 03/16/2023] [Accepted: 06/08/2023] [Indexed: 06/21/2023]
Abstract
Ranking from seventh in incidence to sixth in mortality, esophageal carcinoma is considered a severe malignancy of food pipe. Later-stage diagnosis, drug resistance, and a high mortality rate contribute to its lethality. Esophageal squamous cell carcinoma and esophageal adenocarcinoma are the two main histological subtypes of esophageal carcinoma, with squamous cell carcinoma alone accounting for more than eighty percent of its cases. While genetic anomalies are well known in esophageal cancer, accountability of epigenetic deregulations is also being explored for the recent two decades. DNA methylation, histone modifications, and functional non-coding RNAs are the crucial epigenetic players involved in the modulation of different malignancies, including esophageal carcinoma. Targeting these epigenetic aberrations will provide new insights into the development of biomarker tools for risk stratification, early diagnosis, and effective therapeutic intervention. This review discusses different epigenetic alterations, emphasizing the most significant developments in esophageal cancer epigenetics and their potential implication for the detection, prognosis, and treatment of esophageal carcinoma. Further, the preclinical and clinical status of various epigenetic drugs has also been reviewed.
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Affiliation(s)
- Parul Ahuja
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India
| | - Ritu Yadav
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India.
| | - Sandeep Goyal
- Department of Internal Medicine, Pt. B.D, Sharma University of Health Sciences, (Haryana), Rohtak, 124001, India
| | - Chetna Yadav
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India
| | - Shalu Ranga
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India
| | - Lokesh Kadian
- Department of Dermatology, School of Medicine, Indiana University, Indianapolis, Indiana, 46202, USA
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Guo D, Zhang S, Gao Y, Shi J, Wang X, Zhang Z, Zhang Y, Wang Y, Zhao K, Li M, Wang A, Wang P, Gou Y, Zhang M, Liu M, Zhang Y, Chen R, Sun J, Wang S, Wu X, Liang Z, Chen J, Lang J. Exploring the cellular and molecular differences between ovarian clear cell carcinoma and high-grade serous carcinoma using single-cell RNA sequencing and GEO gene expression signatures. Cell Biosci 2023; 13:139. [PMID: 37525249 PMCID: PMC10391916 DOI: 10.1186/s13578-023-01087-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 07/13/2023] [Indexed: 08/02/2023] Open
Abstract
The two most prevalent subtypes of epithelial ovarian carcinoma (EOC) are ovarian clear cell carcinoma (OCCC) and high-grade serous ovarian carcinoma (HGSC). Patients with OCCC have a poor prognosis than those with HGSC due to chemoresistance, implying the need for novel treatment target. In this study, we applied single-cell RNA sequencing (scRNA-seq) together with bulk RNA-seq data from the GEO (Gene Expression Omnibus) database (the GSE189553 dataset) to characterize and compare tumor heterogeneity and cell-level evolution between OCCC and HGSC samples. To begin, we found that the smaller proportion of an epithelial OCCC cell subset in the G2/M phase might explain OCCC chemoresistance. Second, we identified a possible pathogenic OCCC epithelial cell subcluster that overexpresses LEFTY1. Third, novel biomarkers separating OCCC from HGSC were discovered and subsequently validated on a wide scale using immunohistochemistry. Amine oxidase copper containing 1 (AOC1) was preferentially expressed in OCCC over HGSC, while S100 calcium-binding protein A2 (S100A2) was detected less frequently in OCCC than in HGSC. In addition, we discovered that metabolic pathways were enriched in the epithelial compartment of the OCCC samples. In vitro experiments verified that inhibition of oxidative phosphorylation or glycolysis pathways exerted direct antitumor effects on both OCCC and HGSC cells, while targeting glutamine metabolism or ferroptosis greatly attenuated chemosensitivity only in OCCC cells. Finally, to determine whether there were any variations in immune cell subsets between OCCC and HGSC, data from scRNA-seq and mass cytometry were pooled for analysis. In summary, our work provides the first holistic insights into the cellular and molecular distinctions between OCCC and HGSC and is a valuable source for discovering new targets to leverage in clinical treatments to improve the poor prognosis of patients with OCCC.
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Affiliation(s)
- Dan Guo
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Sumei Zhang
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yike Gao
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Jinghua Shi
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Beijing, China
| | - Xiaoxi Wang
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zixin Zhang
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yaran Zhang
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yuming Wang
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Kun Zhao
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Mei Li
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Anqi Wang
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Pan Wang
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
- Department of Pathology, Affiliated Hospital of Hebei University, Baoding, China
| | - Yanqin Gou
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
- Department of Pathology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China
| | - Miao Zhang
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Meiyu Liu
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yuhan Zhang
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Rui Chen
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Jian Sun
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.
| | - Shu Wang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Beijing, China.
| | - Xunyao Wu
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
| | - Zhiyong Liang
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Jie Chen
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Jinghe Lang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Beijing, China
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Liu WJ, Zhao Y, Chen X, Miao ML, Zhang RQ. Epigenetic modifications in esophageal cancer: An evolving biomarker. Front Genet 2023; 13:1087479. [PMID: 36704345 PMCID: PMC9871503 DOI: 10.3389/fgene.2022.1087479] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 12/19/2022] [Indexed: 01/12/2023] Open
Abstract
Esophageal cancer is a widespread cancer of the digestive system that has two main subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EA). In the diverse range of cancer therapy schemes, the side effects of conventional treatments remain an urgent challenge to be addressed. Therefore, the pursuit of novel drugs with multiple targets, good efficacy, low side effects, and low cost has become a hot research topic in anticancer therapy. Based on this, epigenetics offers an attractive target for the treatment of esophageal cancer, where major mechanisms such as DNA methylation, histone modifications, non-coding RNA regulation, chromatin remodelling and nucleosome localization offer new opportunities for the prevention and treatment of esophageal cancer. Recently, research on epigenetics has remained at a high level of enthusiasm, focusing mainly on translating the basic research into the clinical setting and transforming epigenetic alterations into targets for cancer screening and detection in the clinic. With the increasing emergence of tumour epigenetic markers and antitumor epigenetic drugs, there are also more possibilities for anti-esophageal cancer treatment. This paper focuses on esophageal cancer and epigenetic modifications, with the aim of unravelling the close link between them to facilitate precise and personalized treatment of esophageal cancer.
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Affiliation(s)
- Wen-Jian Liu
- Department of Thoracic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yuan Zhao
- Department of Thoracic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xu Chen
- School of Basic Medicine, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Man-Li Miao
- School of Basic Medicine, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Ren-Quan Zhang
- Department of Thoracic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Zhang X, Xu H, Zhang Y, Sun C, Li Z, Hu C, Zhao D, Guo C. Immunohistochemistry and Bioinformatics Identify GPX8 as a Potential Prognostic Biomarker and Target in Human Gastric Cancer. Front Oncol 2022; 12:878546. [PMID: 35712475 PMCID: PMC9195577 DOI: 10.3389/fonc.2022.878546] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/13/2022] [Indexed: 11/13/2022] Open
Abstract
Background Glutathione peroxidase 8 (GPX8) is a type II transmembrane protein with rare structural features belonging to the glutathione peroxidase family. The function of GPX8 in stomach adenocarcinoma has not been discovered clearly. Methods In this study, we comprehensively analyzed the expression of GPX8 in stomach adenocarcinoma and discovered that it is a potential target in the treatment of stomach adenocarcinoma. The immunohistochemical staining of GPX8 and survival analysis were performed in carcinoma tissue and adjacent tissues of 83 gastric cancer patients. The Gene Expression Profiling Interactive Analysis (GEPIA) database and Kaplan–Meier plotter database were used to evaluate the prognostic survival of GPX8 in stomach adenocarcinoma. The Cancer Genome Atlas (TCGA) database was used to download the microarray mRNA data of GPX8 and clinical information for cancer patients. The TIMER database and GSEA database were used to systematically evaluate the association of GPX8 and tumor-infiltrating lymphocytes in adenocarcinoma carcinoma. The STRING database was used to analyze protein-to-protein interactions of GPX8. The ROC curve was used to analyze the diagnostic effect of GPX8 in distinguishing outcomes between different subgroups, and a nomogram was constructed based on GPX8. Top transcription factor binding sites were analyzed using the QIAGEN database in the GPX8 gene promoter, and the functional enrichment analysis of GPX8 was done by GO and KEGG pathway enrichment analyses. Result Based on the GEPIA and TCGA databases, the mRNA expression of GPX8 was significantly higher in stomach adenocarcinoma compared with the adjacent normal tissues. The GEPIA and Kaplan–Meier plotter databases showed that a higher GPX8 expression level was correlated with poor prognosis of stomach adenocarcinoma, suggesting that GPX8 was a risk factor of poor prognosis in stomach adenocarcinoma. The TIMER database showed that the GPX8 expression level was positively correlated with infiltrating levels of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells in stomach adenocarcinoma. The GSEA database indicated that GPX8 was positively correlated with B cells, dendritic cells, CD4+ T cells, CD8+ T cells, macrophages, mast cells, monocytes, and natural killer cells. At last, GO analysis indicated that the biological processes were enriched in collagen fibril organization, endodermal cell differentiation, collagen metabolic process, extracellular matrix organization, etc. KEGG signaling pathway analysis showed that GPX8 was correlated with protein digestion and absorption, extracellular matrix receptor interaction, AGE/RAGE signaling pathway, etc. The GSEA database showed that GPX8 was positively associated with angiogenesis, epithelial mesenchymal transition, hedgehog signaling, etc. The immunohistochemical staining of GPX8 and survival analysis in 83 gastric cancer patients showed that the OS rate of patients with a high GPX8 expression was significantly lower than that of the low GPX8 expression group. Conclusion GPX8 is an important factor which might be a potential target in the treatment of stomach adenocarcinoma.
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Affiliation(s)
- Xiaojie Zhang
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Heng Xu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yunan Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Chongyuan Sun
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zefeng Li
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chunfang Hu
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dongbing Zhao
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chunguang Guo
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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8
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Analysis of Influencing Factors on the Occurrence and Development of Gastric Cancer in High-Incidence Areas of Digestive Tract Tumors Based on High Methylation of GPX3 Gene. JOURNAL OF ONCOLOGY 2022; 2022:3094881. [PMID: 35069731 PMCID: PMC8769839 DOI: 10.1155/2022/3094881] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 10/29/2021] [Accepted: 11/30/2021] [Indexed: 12/26/2022]
Abstract
Stomach cancer is the second largest cause of cancer-related mortality globally, and it continues to be a reason for worry today. Inhalation of the stomach cancer risk factor H. pylori produces large levels of reactive oxygen species (ROS). When combined with glutathione reductase, glutathione peroxidase 3 (GPX3) catalyzes the reduction of hydrogen peroxide and lipid peroxides. To get a better understanding of the GPX3 gene's role in the illness, the researchers used quantitative real-time RT-PCR to examine the gene's expression and regulation in gastric cancer cell lines, original gastric cancer samples, and 45 normal stomach mucosa adjacent to malignancies. According to the research, GPX3 expression was decreased or silenced in eight of nine cancer cell lines and 83 percent of gastric cancer samples (90/108) as compared to normal gastric tissues in the vicinity of the tumor (P < 0.0001). It was found that 60 percent of stomach cancer samples exhibited DNA hypermethylation after analyzing the GPX3 promoter (P=0.007) (a methylation level of more than 10 percent, as measured by bisulfite pyrosequencing). In stomach tumors, we found a statistically significant reduction in the amount of GPX3 DNA copies (P < 0.001). The gene expression of SNU1 and MKN28 cells was restored after treatment with 5-Aza-2′ Deoxycytidine to reduce GPX3 promoter methylation. Genetic and epigenetic alterations lead GPX3 to be dysfunctional in gastric cancer. This indicates that the systems that regulate ROS have been disrupted, and GPX3 may be implicated in the development of gastric cancer, as shown by our results when evaluated alone and in combination.
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9
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Hu J, Yang Y, Ma Y, Ning Y, Chen G, Liu Y. Proliferation Cycle Transcriptomic Signatures are Strongly associated With Gastric Cancer Patient Survival. Front Cell Dev Biol 2021; 9:770994. [PMID: 34926458 PMCID: PMC8672820 DOI: 10.3389/fcell.2021.770994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 11/08/2021] [Indexed: 01/17/2023] Open
Abstract
Gastric cancer is one of the most heterogeneous tumors with multi-level molecular disturbances. Sustaining proliferative signaling and evading growth suppressors are two important hallmarks that enable the cancer cells to become tumorigenic and ultimately malignant, which enable tumor growth. Discovering and understanding the difference in tumor proliferation cycle phenotypes can be used to better classify tumors, and provide classification schemes for disease diagnosis and treatment options, which are more in line with the requirements of today's precision medicine. We collected 691 eligible samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, combined with transcriptome data, to explore different heterogeneous proliferation cycle phenotypes, and further study the potential genomic changes that may lead to these different phenotypes in this study. Interestingly, two subtypes with different clinical and biological characteristics were identified through cluster analysis of gastric cancer transcriptome data. The repeatability of the classification was confirmed in an independent Gene Expression Omnibus validation cohort, and consistent phenotypes were observed. These two phenotypes showed different clinical outcomes, and tumor mutation burden. This classification helped us to better classify gastric cancer patients and provide targeted treatment based on specific transcriptome data.
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Affiliation(s)
- Jianwen Hu
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yanpeng Yang
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yongchen Ma
- Department of Endoscopy Center, Peking University First Hospital, Beijing, China
| | - Yingze Ning
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Guowei Chen
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yucun Liu
- Department of General Surgery, Peking University First Hospital, Beijing, China
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10
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Salta S, Macedo-Silva C, Miranda-Gonçalves V, Lopes N, Gigliano D, Guimarães R, Farinha M, Sousa O, Henrique R, Jerónimo C. A DNA methylation-based test for esophageal cancer detection. Biomark Res 2020; 8:68. [PMID: 33292587 PMCID: PMC7691099 DOI: 10.1186/s40364-020-00248-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 11/16/2020] [Indexed: 12/14/2022] Open
Abstract
Background Esophageal cancer (ECa) is the 7th most incident cancer and the 6th leading cause of cancer-related death. Most patients are diagnosed with locally advanced or metastatic disease, enduring poor survival. Biomarkers enabling early cancer detection may improve patient management, treatment effectiveness, and survival, are urgently needed. In this context, epigenetic-based biomarkers such as DNA methylation are potential candidates. Methods Herein, we sought to identify and validate DNA methylation-based biomarkers for early detection and prediction of response to therapy in ECa patients. Promoter methylation levels were assessed in a series of treatment-naïve ECa, post-neoadjuvant treatment ECa, and normal esophagus tissues, using quantitative methylation-specific PCR for COL14A1, GPX3, and ZNF569. Results ZNF569 methylation (ZNF569me) levels significantly differed between ECa and normal samples (p < 0.001). Moreover, COL14A1 methylation (COL14A1me) and GPX3 methylation (GPX3me) levels discriminated adenocarcinomas and squamous cell carcinomas, respectively, from normal samples (p = 0.002 and p = 0.009, respectively). COL14A1me & ZNF569me accurately identified adenocarcinomas (82.29%) whereas GPX3me & ZNF569me identified squamous cell carcinomas with 81.73% accuracy. Furthermore, ZNF569me and GPX3me levels significantly differed between normal and pre-treated ECa. Conclusion The biomarker potential of a specific panel of methylated genes for ECa was confirmed. These might prove useful for early detection and might allow for the identification of minimal residual disease after adjuvant therapy.
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Affiliation(s)
- Sofia Salta
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Catarina Macedo-Silva
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Vera Miranda-Gonçalves
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Nair Lopes
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Davide Gigliano
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, Porto, 4200-072, Portugal
| | - Rita Guimarães
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, Porto, 4200-072, Portugal
| | - Mónica Farinha
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, Porto, 4200-072, Portugal
| | - Olga Sousa
- Department of Radiation Oncology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, Porto, 4200-072, Portugal
| | - Rui Henrique
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, Porto, 4200-072, Portugal.,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar- University of Porto , Rua de Jorge Viterbo Ferreira, 228, Porto, 4050-313, Portugal
| | - Carmen Jerónimo
- Cancer Biology & Epigenetics Group - Research Center, Portuguese Oncology Institute of Porto, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal. .,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar- University of Porto , Rua de Jorge Viterbo Ferreira, 228, Porto, 4050-313, Portugal.
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11
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Buday K, Conrad M. Emerging roles for non-selenium containing ER-resident glutathione peroxidases in cell signaling and disease. Biol Chem 2020; 402:271-287. [PMID: 33055310 DOI: 10.1515/hsz-2020-0286] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/08/2020] [Indexed: 12/16/2022]
Abstract
Maintenance of cellular redox control is pivotal for normal cellular functions and cell fate decisions including cell death. Among the key cellular redox systems in mammals, the glutathione peroxidase (GPX) family of proteins is the largest conferring multifaceted functions and affecting virtually all cellular processes. The endoplasmic reticulum (ER)-resident GPXs, designated as GPX7 and GPX8, are the most recently added members of this family of enzymes. Recent studies have provided exciting insights how both enzymes support critical processes of the ER including oxidative protein folding, maintenance of ER redox control by eliminating H2O2, and preventing palmitic acid-induced lipotoxicity. Consequently, numerous pathological conditions, such as neurodegeneration, cancer and metabolic diseases have been linked with altered GPX7 and GPX8 expression. Studies in mice have demonstrated that loss of GPX7 leads to increased differentiation of preadipocytes, increased tumorigenesis and shortened lifespan. By contrast, GPX8 deficiency in mice results in enhanced caspase-4/11 activation and increased endotoxic shock in colitis model. With the increasing recognition that both types of enzymes are dysregulated in various tumor entities in man, we deem a review of the emerging roles played by GPX7 and GPX8 in health and disease development timely and appropriate.
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Affiliation(s)
- Katalin Buday
- Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Ingolstädter Landstr. 1, D-85764Neuherberg, Germany
| | - Marcus Conrad
- Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Ingolstädter Landstr. 1, D-85764Neuherberg, Germany.,National Research Medical University, Laboratory of Experimental Oncology, Ostrovityanova 1, 117997Moscow, Russia
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12
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Yang S, Gao T, Zheng Z, Lai B, Sheng L, Xu Z, Yan X, Wang J, Duan S, Ouyang G. GPX3 methylation is associated with hematologic improvement in low-risk myelodysplastic syndrome patients treated with Pai-Neng-Da. J Int Med Res 2020; 48:300060520956894. [PMID: 32967500 PMCID: PMC7520939 DOI: 10.1177/0300060520956894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Objective The aim of this prospective randomized controlled clinical trial was to explore the relationship between GPX3 methylation and Pai-Neng-Da (PND) in the treatment of patients with low-risk myelodysplastic syndrome (MDS). Methods There were 82 low-risk MDS patients who were randomly divided into the following two groups: androl, thalidomide, and PND capsule (ATP group, n = 41); or androl and thalidomide (AT group, n = 41). Hemoglobin and neutrophil and platelet counts and changes in GPX3 methylation level were assessed. Results The plasma hemoglobin level increased in both groups after treatment. However, the platelet count increased only in the ATP group. Patients in the ATP group had a better platelet response than the AT group, and GPX3 methylation markedly decreased after treatment with ATP but not after treatment with AT. Moreover, male patients had a significantly lower GPX3 methylation level than female patients, while platelet counts from male patients increased dramatically after the ATP regimens compared with female patients. GPX3 methylation changes were negatively correlated with platelet changes in ATP group. Conclusion PND can improve hematological parameters and decrease the GPX3 methylation level. Decreasing GPX3 methylation is associated with the hematologic response that includes platelet in GPX3 methylation. China Clinical Trial Bureau (ChiCTR;http://www.chictr.org.cn/) registration number: ChiCTR-IOR-15006635.
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Affiliation(s)
- Shujun Yang
- Department of Hematology, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Tong Gao
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Zhonghua Zheng
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Binbin Lai
- Department of Hematology, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Lixia Sheng
- Department of Hematology, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Zhijuan Xu
- Department of Hematology, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Xiao Yan
- Department of Hematology, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Jiaping Wang
- Department of Hematology, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Shiwei Duan
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Guifang Ouyang
- Department of Hematology, Ningbo First Hospital, Ningbo, Zhejiang, China
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13
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Abstract
Significance: The selenium-containing Glutathione peroxidases (GPxs)1-4 protect against oxidative challenge, inhibit inflammation and oxidant-induced regulated cell death. Recent Advances: GPx1 and GPx4 dampen phosphorylation cascades predominantly via prevention of inactivation of phosphatases by H2O2 or lipid hydroperoxides. GPx2 regulates the balance between regeneration and apoptotic cell shedding in the intestine. It inhibits inflammation-induced carcinogenesis in the gut but promotes growth of established cancers. GPx3 deficiency facilitates platelet aggregation likely via disinhibition of thromboxane biosynthesis. It is also considered a tumor suppressor. GPx4 is expressed in three different forms. The cytosolic form proved to inhibit interleukin-1-driven nuclear factor κB activation and leukotriene biosynthesis. Moreover, it is a key regulator of ferroptosis, because it reduces hydroperoxy groups of complex lipids and silences lipoxygenases. By alternate substrate use, the nuclear form contributes to chromatin compaction. Mitochondrial GPx4 forms the mitochondrial sheath of spermatozoa and, thus, guarantees male fertility. Out of the less characterized GPxs, the cysteine-containing GPx7 and GPx8 are unique in contributing to oxidative protein folding in the endoplasmic reticulum by reacting with protein isomerase as an alternate substrate. A yeast 2-Cysteine glutathione peroxidase equipped with CP and CR was reported to sense H2O2 for inducing an adaptive response. Critical Issues: Most of the findings compiled are derived from tissue culture and/or animal studies only. Their impact on human physiology is sometimes questionable. Future Directions: The expression of individual GPxs and GPx-dependent regulatory phenomena are to be further investigated, in particular in respect to human health.
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Affiliation(s)
- Regina Brigelius-Flohé
- Department of Biochemistry of Micronutrients, German Institute of Human Nutrition-Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
| | - Leopold Flohé
- Depatamento de Biochímica, Universidad de la República, Montevideo, Uruguay.,Dipartimento di Medicina Moleculare, Università degli Studi di Padova, Padova, Italy
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14
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Picou F, Vignon C, Debeissat C, Lachot S, Kosmider O, Gallay N, Foucault A, Estienne MH, Ravalet N, Bene MC, Domenech J, Gyan E, Fontenay M, Herault O. Bone marrow oxidative stress and specific antioxidant signatures in myelodysplastic syndromes. Blood Adv 2019; 3:4271-4279. [PMID: 31869414 PMCID: PMC6929385 DOI: 10.1182/bloodadvances.2019000677] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 11/11/2019] [Indexed: 02/07/2023] Open
Abstract
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for transformation in secondary acute myeloid leukemia. This study focused on the redox metabolism of bone marrow (BM) cells from 97 patients compared with 25 healthy controls. The level of reactive oxygen species (ROS) was quantified by flow cytometry in BM cell subsets as well as the expression level of 28 transcripts encoding for major enzymes involved in the antioxidant cellular response. Our results highlight increased ROS levels in BM nonlymphoid cells and especially in primitive CD34posCD38low progenitor cells. Moreover, we identified a specific antioxidant signature, dubbed "antioxidogram," for the different MDS subgroups or secondary acute myeloblastic leukemia (sAML). Our results suggest that progression from MDS toward sAML could be characterized by 3 successive molecular steps: (1) overexpression of enzymes reducing proteic disulfide bonds (MDS with <5% BM blasts [GLRX family]); (2) increased expression of enzymes detoxifying H2O2 (MDS with 5% to 19% BM blasts [PRDX and GPX families]); and finally (3) decreased expression of these enzymes in sAML. The antioxidant score (AO-Score) defined by logistic regression from the expression levels of transcripts made it possible to stage disease progression and, interestingly, this AO-Score was independent of the revised International Scoring System. Altogether, this study demonstrates that MDS and sAML present an important disturbance of redox metabolism, especially in BM stem and progenitor cells and that the specific molecular antioxidant response parameters (antioxidogram, AO-Score) could be considered as useful biomarkers for disease diagnosis and follow-up.
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Affiliation(s)
- Frederic Picou
- Centre National de la Recherche Scientifique (CNRS) Equipe de Recherche Labellisée 7001, LNOX "Leukemic Niche and Redox Metabolism," Tours, France
- Equipe d'Accueil 7501, Université de Tours, Tours, France
- Service d'Hématologie Biologique, Centre Hospitalier Régional Universitaire (CHRU) de Tours, Tours, France
| | - Christine Vignon
- Centre National de la Recherche Scientifique (CNRS) Equipe de Recherche Labellisée 7001, LNOX "Leukemic Niche and Redox Metabolism," Tours, France
- Equipe d'Accueil 7501, Université de Tours, Tours, France
- Service d'Hématologie Biologique, Centre Hospitalier Régional Universitaire (CHRU) de Tours, Tours, France
| | - Christelle Debeissat
- Centre National de la Recherche Scientifique (CNRS) Equipe de Recherche Labellisée 7001, LNOX "Leukemic Niche and Redox Metabolism," Tours, France
- Equipe d'Accueil 7501, Université de Tours, Tours, France
- Service d'Hématologie Biologique, Centre Hospitalier Régional Universitaire (CHRU) de Tours, Tours, France
| | - Sébastien Lachot
- Service d'Hématologie Biologique, Centre Hospitalier Régional Universitaire (CHRU) de Tours, Tours, France
| | - Olivier Kosmider
- Service d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris, Institut Cochin, Paris, France
| | - Nathalie Gallay
- Centre National de la Recherche Scientifique (CNRS) Equipe de Recherche Labellisée 7001, LNOX "Leukemic Niche and Redox Metabolism," Tours, France
- Equipe d'Accueil 7501, Université de Tours, Tours, France
- Service d'Hématologie Biologique, Centre Hospitalier Régional Universitaire (CHRU) de Tours, Tours, France
| | - Amelie Foucault
- Centre National de la Recherche Scientifique (CNRS) Equipe de Recherche Labellisée 7001, LNOX "Leukemic Niche and Redox Metabolism," Tours, France
- Equipe d'Accueil 7501, Université de Tours, Tours, France
- Service d'Hématologie Biologique, Centre Hospitalier Régional Universitaire (CHRU) de Tours, Tours, France
| | - Marie-Hélène Estienne
- Service d'Hématologie Biologique, Centre Hospitalier Régional Universitaire (CHRU) de Tours, Tours, France
| | - Noémie Ravalet
- Centre National de la Recherche Scientifique (CNRS) Equipe de Recherche Labellisée 7001, LNOX "Leukemic Niche and Redox Metabolism," Tours, France
- Equipe d'Accueil 7501, Université de Tours, Tours, France
- Service d'Hématologie Biologique, Centre Hospitalier Régional Universitaire (CHRU) de Tours, Tours, France
| | - Marie C Bene
- Service d'Hématologie Biologique, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Jorge Domenech
- Centre National de la Recherche Scientifique (CNRS) Equipe de Recherche Labellisée 7001, LNOX "Leukemic Niche and Redox Metabolism," Tours, France
- Equipe d'Accueil 7501, Université de Tours, Tours, France
- Service d'Hématologie Biologique, Centre Hospitalier Régional Universitaire (CHRU) de Tours, Tours, France
| | - Emmanuel Gyan
- Centre National de la Recherche Scientifique (CNRS) Equipe de Recherche Labellisée 7001, LNOX "Leukemic Niche and Redox Metabolism," Tours, France
- Equipe d'Accueil 7501, Université de Tours, Tours, France
- Service d'Hématologie et Thérapie Cellulaire, CHRU de Tours, Tours, France; and
| | - Michaela Fontenay
- Service d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris, Institut Cochin, Paris, France
| | - Olivier Herault
- Centre National de la Recherche Scientifique (CNRS) Equipe de Recherche Labellisée 7001, LNOX "Leukemic Niche and Redox Metabolism," Tours, France
- Equipe d'Accueil 7501, Université de Tours, Tours, France
- Service d'Hématologie Biologique, Centre Hospitalier Régional Universitaire (CHRU) de Tours, Tours, France
- CNRS Groupement de Recherche 3697, "Microenvironment of Tumor Niches," Tours, France
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15
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Zhou C, Pan R, Li B, Huang T, Zhao J, Ying J, Duan S. GPX3 hypermethylation in gastric cancer and its prognostic value in patients aged over 60. Future Oncol 2019; 15:1279-1289. [PMID: 30924352 DOI: 10.2217/fon-2018-0674] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
AIM This study investigated the association between GPX3 methylation and gastric cancer (GC), and explored its prognostic value in patients undergoing radical gastrectomy. MATERIALS & METHODS The methylation levels of tumor and paracancerous tissues were detected by quantitative methylation-specific PCR method. RESULTS GPX3 was hypermethylated in GC (p = 4E-4), and was specific for patients with lymphatic metastasis (+), tumor invasion depth >3 cm and patients with poor differentiation. Additionally, GPX3 hypermethylation predicts a tumor recurrence in patients aged >60 (p = 0.019). Data from The Cancer Genome Atlas (TCGA) further confirmed GPX3 hypermethylation (cg21504918: -0.08 vs -0.25, p = 0.001). Additionally, TCGA showed an inverse correlation between GPX3 methylation and expression (p = 7E-18, r = -0.427). Data analysis of Gene Expression Omnibus (GEO) database showed that 5-aza-2'-deoxycytidine demethylating agent increased GPX3 expression (fold-change >2.19, p = 0.001). CONCLUSION Our results indicated GPX3 hypermethylation in GC, and predicted a shorter tumor recurrence time in patients aged >60.
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Affiliation(s)
- Cong Zhou
- Medical Genetics Center, Department of Genetics, School of Medicine, Ningbo University, Ningbo, Zhejiang, PR China
| | - Ranran Pan
- Medical Genetics Center, Department of Genetics, School of Medicine, Ningbo University, Ningbo, Zhejiang, PR China
| | - Bin Li
- Medical Genetics Center, Department of Genetics, School of Medicine, Ningbo University, Ningbo, Zhejiang, PR China
| | - Tianyi Huang
- Medical Genetics Center, Department of Genetics, School of Medicine, Ningbo University, Ningbo, Zhejiang, PR China
| | - Jun Zhao
- Medical Genetics Center, Department of Genetics, School of Medicine, Ningbo University, Ningbo, Zhejiang, PR China
| | - Jieer Ying
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, PR China
| | - Shiwei Duan
- Medical Genetics Center, Department of Genetics, School of Medicine, Ningbo University, Ningbo, Zhejiang, PR China
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16
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Zhao L, Zong W, Zhang H, Liu R. Kidney Toxicity and Response of Selenium Containing Protein-glutathione Peroxidase (Gpx3) to CdTe QDs on Different Levels. Toxicol Sci 2018; 168:201-208. [DOI: 10.1093/toxsci/kfy297] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Lining Zhao
- *School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment & Health, Shandong Province, Qingdao, Shandong 266237, P. R. China
| | - Wansong Zong
- College of Population, Resources and Environment, Shandong Normal University, Jinan 250014, P. R. China
| | - Hao Zhang
- Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, China
- Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic Diseases, Affiliated Hospital of Hubei University for Nationalities, Enshi 445000, China
| | - Rutao Liu
- *School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment & Health, Shandong Province, Qingdao, Shandong 266237, P. R. China
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17
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Han L, Yang X, Sun W, Li Z, Ren H, Li B, Zhang R, Zhang D, Shi Z, Liu J, Cao J, Zhang J, Xiong Y. The study of GPX3 methylation in patients with Kashin-Beck Disease and its mechanism in chondrocyte apoptosis. Bone 2018; 117:15-22. [PMID: 30153510 DOI: 10.1016/j.bone.2018.08.017] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 08/06/2018] [Accepted: 08/23/2018] [Indexed: 10/28/2022]
Abstract
OBJECTIVE Selenium deficiency is a risk factor for Kashin-Beck Disease (KBD), an endemic osteoarthropathy. Although promoter hypermethylation of glutathione peroxidase 3 (GPX3) (a selenoprotein) has been identified in several cancers, little is known about promoter methylation and expression of GPX3 and their relation to selenium in KBD. The present study was thus conducted to investigate this research question. METHODS Methylation and expressions of GPX3 in whole blood drawn from 288 KBD patients and 362 healthy controls and in chondrocyte cell line were evaluated using methylation-specific PCR and qRT-PCR, respectively. The protein levels of PI3K/Akt/c-fos signaling in the whole blood and chondrocyte cell line were determined with Western blotting. Chondrocytes apoptosis were detected by Hoechst 33342 and Annexin V-FITC/PI staining. RESULTS GPX3 methylation was increased, GPX3 mRNA was decreased, and protein levels in the PI3K/Akt/c-fos signaling pathway were up-regulated in the whole blood collected from KBD patients as compared with healthy controls. Similar results were obtained for chondrocytes injured by oxidative stress. There was a significant, decreasing trend in GPX3 expression across groups of unmethylation, partial methylation, and complete methylation for GPX3, in sequence. Compared with unmethylation group, protein levels in PI3K/Akt/c-fos pathway were enhanced in partial and complete methylation groups. Treatment of chondrocytes with sodium selenite resulted in reduced methylation and increased expression of GPX3 as well as down-regulated level of PI3K/Akt/c-fos proteins. CONCLUSIONS The methylation and expression of GPX3 and expression of PI3K/Akt/c-fos pathway are altered in KBD and these changes are reversible by selenium supplementation.
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Affiliation(s)
- LiXin Han
- Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China
| | - XiaoLi Yang
- Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China
| | - WenYan Sun
- Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China
| | - ZhaoFang Li
- Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China
| | - Hao Ren
- Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China
| | - BaoRong Li
- Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China
| | - RongQiang Zhang
- Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China
| | - DanDan Zhang
- Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China
| | - ZiYun Shi
- Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China
| | - JiFeng Liu
- Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China
| | - JunLing Cao
- Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China
| | - JianJun Zhang
- Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, 1050 Wishard Boulevard, IN 46202, USA
| | - YongMin Xiong
- Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China.
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18
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An BC, Choi YD, Oh IJ, Kim JH, Park JI, Lee SW. GPx3-mediated redox signaling arrests the cell cycle and acts as a tumor suppressor in lung cancer cell lines. PLoS One 2018; 13:e0204170. [PMID: 30260967 PMCID: PMC6160013 DOI: 10.1371/journal.pone.0204170] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 09/03/2018] [Indexed: 12/15/2022] Open
Abstract
Glutathione peroxidase 3 (GPx3), a major scavenger of reactive oxygen species (ROS) in plasma, acts as a redox signal modulator. However, the mechanism underlying GPx3-mediated suppression of cancer cell growth is unclear. The aim of this study was to identify these mechanisms with respect to lung cancer. To enhance the redox modulating properties of GPx3, lung cancer cells were subjected to serum starvation for 12 h, resulting in ROS generation in the absence of oxidant treatment. We then investigated whether suppression of tumorigenesis under conditions of oxidative stress was dependent on GPx3. The results showed that GPx3 effectively suppressed proliferation, migration, and invasion of lung cancer cells under oxidative stress. In addition, GPx3 expression led to a significant reduction in ROS production by cancer cells and induced G2/M phase arrest. We also found that inactivation of cyclin B1 significantly suppressed by nuclear factor-κB(NF-κB) inactivation in lung cancer cells was dependent on GPx3 expression. To further elucidate the mechanism(s) underlying GPx3-medited suppression of tumor proliferation, we next examined the effect of GPx3-mediated redox signaling on the ROS-MKP3-extracellular signal-regulated kinase (Erk)-NF-κB-cyclin B1 pathway and found that GPx3 strongly suppressed activation of the Erk-NF-κB-cyclin B1 signaling cascade by protecting MKP3 (an Erk-specific phosphatase) from the effects of ROS. Thus, this study demonstrates for the first time that the GPx3 suppresses proliferation of lung cancer cells by modulating redox-mediated signals.
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Affiliation(s)
- Byung Chull An
- Department of Anatomy, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea
| | - Yoo-Duk Choi
- Department of Pathology, Chonnam National University Hospital, Dong-gu, Gwangju, Korea
| | - In-Jae Oh
- Department of Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea
| | - Ju Han Kim
- Department of Internal Medicine, Chonnam National University Hospital, Dong-gu, Gwangju, Korea
| | - Jae-Il Park
- Animal Facility of Aging Science, Korea Basic Science Institute, Buk-gu, Gwangju, Korea
| | - Seung-won Lee
- Department of Anatomy, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea
- * E-mail:
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19
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Liu K, Jin M, Xiao L, Liu H, Wei S. Distinct prognostic values of mRNA expression of glutathione peroxidases in non-small cell lung cancer. Cancer Manag Res 2018; 10:2997-3005. [PMID: 30214294 PMCID: PMC6118261 DOI: 10.2147/cmar.s163432] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Introduction Glutathione peroxidases (GPxs) constitutes an enzyme family which has the ability to reduce free hydrogen peroxide to water and lipid hydroperoxides to their corresponding alcohols, and its main biological roles are to protect organisms from oxidative stress-induced damage. GPxs include eight members in different tissues of the body, and they play essential roles in carcinogenesis. However, the prognostic value of individual GPx in non-small cell lung cancer (NSCLC) remains elusive. Materials and methods In the current study, we investigated the prognostic value of GPxs in NSCLC patients through the “Kaplan–Meier plotter” database, wherein updated gene expression data and survival information from a total of 1,926 NSCLC patients are included. Results High expression of GPx1 mRNA was correlated with worse overall survival (OS) in adenocarcinoma patients. High expression of GPx2 mRNA was correlated with worse OS for all NSCLC patients. In contrast, high expression of GPx3 mRNA was associated with better OS for all NSCLC patients. High expression of GPx4 mRNA was significantly correlated with worsening adenocarcinoma in these patients. GPx5 mRNA high expression correlated with worsening OS for all NSCLC patients. Discussion The current findings of prognostic values of individual mRNA expression of GPxs in NSCLC patients indicate some GPxs may have prognostic value in NSCLC patients, and this needs further study.
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Affiliation(s)
- Kui Liu
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China, ;
| | - Meng Jin
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China, ;
| | - Li Xiao
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China, ;
| | - Huiguo Liu
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China, ;
| | - Shuang Wei
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China, ;
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20
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Tungekar A, Mandarthi S, Mandaviya PR, Gadekar VP, Tantry A, Kotian S, Reddy J, Prabha D, Bhat S, Sahay S, Mascarenhas R, Badkillaya RR, Nagasampige MK, Yelnadu M, Pawar H, Hebbar P, Kashyap MK. ESCC ATLAS: A population wide compendium of biomarkers for Esophageal Squamous Cell Carcinoma. Sci Rep 2018. [PMID: 30143675 DOI: 10.1038/s41598-018-30579-3,] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Esophageal cancer (EC) is the eighth most aggressive malignancy and its treatment remains a challenge due to the lack of biomarkers that can facilitate early detection. EC is identified in two major histological forms namely - Adenocarcinoma (EAC) and Squamous cell carcinoma (ESCC), each showing differences in the incidence among populations that are geographically separated. Hence the detection of potential drug target and biomarkers demands a population-centric understanding of the molecular and cellular mechanisms of EC. To provide an adequate impetus to the biomarker discovery for ESCC, which is the most prevalent esophageal cancer worldwide, here we have developed ESCC ATLAS, a manually curated database that integrates genetic, epigenetic, transcriptomic, and proteomic ESCC-related genes from the published literature. It consists of 3475 genes associated to molecular signatures such as, altered transcription (2600), altered translation (560), contain copy number variation/structural variations (233), SNPs (102), altered DNA methylation (82), Histone modifications (16) and miRNA based regulation (261). We provide a user-friendly web interface ( http://www.esccatlas.org , freely accessible for academic, non-profit users) that facilitates the exploration and the analysis of genes among different populations. We anticipate it to be a valuable resource for the population specific investigation and biomarker discovery for ESCC.
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Affiliation(s)
- Asna Tungekar
- Mbiomics, Manipal, Karnataka, India.,Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India
| | - Sumana Mandarthi
- Mbiomics, Manipal, Karnataka, India.,Department of Biochemistry, Kasturba Medical College, Manipal University, Manipal, Karnataka, India
| | - Pooja Rajendra Mandaviya
- Mbiomics, Manipal, Karnataka, India.,Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India
| | - Veerendra P Gadekar
- Mbiomics, Manipal, Karnataka, India.,Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India.,Institute for Theoretical Chemistry, University of Vienna, Währingerstrasse 17, 1090, Vienna, Austria
| | - Ananthajith Tantry
- Mbiomics, Manipal, Karnataka, India.,Manipal Center for Information Sciences, Manipal University, Manipal, Karnataka, India
| | - Sowmya Kotian
- Mbiomics, Manipal, Karnataka, India.,Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India
| | - Jyotshna Reddy
- Mbiomics, Manipal, Karnataka, India.,Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India
| | | | - Sushma Bhat
- Mbiomics, Manipal, Karnataka, India.,Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India
| | | | - Roshan Mascarenhas
- Mbiomics, Manipal, Karnataka, India.,Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India.,Newcastle University Medicine Malaysia, Johor Bahru, 79200, Malaysia
| | - Raghavendra Rao Badkillaya
- Mbiomics, Manipal, Karnataka, India.,Department of Biotechnology, Alva's college, Moodubidre, Karnataka, India
| | - Manoj Kumar Nagasampige
- Mbiomics, Manipal, Karnataka, India.,Department of Biotechnology, Sikkim Manipal University, Gangtok, Sikkim, 737102, India
| | - Mohan Yelnadu
- Mbiomics, Manipal, Karnataka, India.,Manipal Center for Information Sciences, Manipal University, Manipal, Karnataka, India.,Infosys Technologies Ltd, Bangalore, Karnataka, India.,Faculty of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel
| | - Harsh Pawar
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel
| | - Prashantha Hebbar
- Mbiomics, Manipal, Karnataka, India. .,Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India.
| | - Manoj Kumar Kashyap
- Mbiomics, Manipal, Karnataka, India. .,Faculty of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Bajhol, Solan, Himachal Pradesh 173229, India. .,School of Life and Allied Health Sciences, Glocal University, Saharanpur, Uttar Pradesh, 247001, India. .,Institute for Theoretical Chemistry, University of Vienna, Währingerstrasse 17, 1090, Vienna, Austria.
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21
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Tungekar A, Mandarthi S, Mandaviya PR, Gadekar VP, Tantry A, Kotian S, Reddy J, Prabha D, Bhat S, Sahay S, Mascarenhas R, Badkillaya RR, Nagasampige MK, Yelnadu M, Pawar H, Hebbar P, Kashyap MK. ESCC ATLAS: A population wide compendium of biomarkers for Esophageal Squamous Cell Carcinoma. Sci Rep 2018; 8:12715. [PMID: 30143675 PMCID: PMC6109081 DOI: 10.1038/s41598-018-30579-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 08/01/2018] [Indexed: 02/07/2023] Open
Abstract
Esophageal cancer (EC) is the eighth most aggressive malignancy and its treatment remains a challenge due to the lack of biomarkers that can facilitate early detection. EC is identified in two major histological forms namely - Adenocarcinoma (EAC) and Squamous cell carcinoma (ESCC), each showing differences in the incidence among populations that are geographically separated. Hence the detection of potential drug target and biomarkers demands a population-centric understanding of the molecular and cellular mechanisms of EC. To provide an adequate impetus to the biomarker discovery for ESCC, which is the most prevalent esophageal cancer worldwide, here we have developed ESCC ATLAS, a manually curated database that integrates genetic, epigenetic, transcriptomic, and proteomic ESCC-related genes from the published literature. It consists of 3475 genes associated to molecular signatures such as, altered transcription (2600), altered translation (560), contain copy number variation/structural variations (233), SNPs (102), altered DNA methylation (82), Histone modifications (16) and miRNA based regulation (261). We provide a user-friendly web interface ( http://www.esccatlas.org , freely accessible for academic, non-profit users) that facilitates the exploration and the analysis of genes among different populations. We anticipate it to be a valuable resource for the population specific investigation and biomarker discovery for ESCC.
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Affiliation(s)
- Asna Tungekar
- Mbiomics, Manipal, Karnataka, India
- Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India
| | - Sumana Mandarthi
- Mbiomics, Manipal, Karnataka, India
- Department of Biochemistry, Kasturba Medical College, Manipal University, Manipal, Karnataka, India
| | - Pooja Rajendra Mandaviya
- Mbiomics, Manipal, Karnataka, India
- Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India
| | - Veerendra P Gadekar
- Mbiomics, Manipal, Karnataka, India
- Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India
- Institute for Theoretical Chemistry, University of Vienna, Währingerstrasse 17, 1090, Vienna, Austria
| | - Ananthajith Tantry
- Mbiomics, Manipal, Karnataka, India
- Manipal Center for Information Sciences, Manipal University, Manipal, Karnataka, India
| | - Sowmya Kotian
- Mbiomics, Manipal, Karnataka, India
- Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India
| | - Jyotshna Reddy
- Mbiomics, Manipal, Karnataka, India
- Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India
| | | | - Sushma Bhat
- Mbiomics, Manipal, Karnataka, India
- Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India
| | | | - Roshan Mascarenhas
- Mbiomics, Manipal, Karnataka, India
- Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India
- Newcastle University Medicine Malaysia, Johor Bahru, 79200, Malaysia
| | - Raghavendra Rao Badkillaya
- Mbiomics, Manipal, Karnataka, India
- Department of Biotechnology, Alva's college, Moodubidre, Karnataka, India
| | - Manoj Kumar Nagasampige
- Mbiomics, Manipal, Karnataka, India
- Department of Biotechnology, Sikkim Manipal University, Gangtok, Sikkim, 737102, India
| | - Mohan Yelnadu
- Mbiomics, Manipal, Karnataka, India
- Manipal Center for Information Sciences, Manipal University, Manipal, Karnataka, India
- Infosys Technologies Ltd, Bangalore, Karnataka, India
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel
| | - Harsh Pawar
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel
| | - Prashantha Hebbar
- Mbiomics, Manipal, Karnataka, India.
- Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India.
| | - Manoj Kumar Kashyap
- Mbiomics, Manipal, Karnataka, India.
- Faculty of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Bajhol, Solan, Himachal Pradesh 173229, India.
- School of Life and Allied Health Sciences, Glocal University, Saharanpur, Uttar Pradesh, 247001, India.
- Institute for Theoretical Chemistry, University of Vienna, Währingerstrasse 17, 1090, Vienna, Austria.
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22
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Chang SN, Lee JM, Oh H, Kim U, Ryu B, Park JH. Troglitazone inhibits the migration and invasion of PC-3 human prostate cancer cells by upregulating E-cadherin and glutathione peroxidase 3. Oncol Lett 2018; 16:5482-5488. [PMID: 30250621 DOI: 10.3892/ol.2018.9278] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 04/28/2017] [Indexed: 11/06/2022] Open
Abstract
Troglitazone (TGZ) is a synthetic peroxisome proliferator-activated receptor γ (PPARγ) ligand that exhibits potential antitumor effects on a number of cancer subtypes, including prostate cancer. However, little is known about the effect of TGZ on metastasis in prostate cancer. The aim of the present study was to determine the inhibitory effect and mechanism underlying TGZ on cell growth, migration and invasion using the prostate cancer PC-3 cell line. Cellular migration and invasion were evaluated by performing a wound healing assay and Matrigel assay, respectively. The expression levels of mRNA and protein were determined by reverse transcription-quantitative polymerase chain reaction and western blotting. The results demonstrated that TGZ dose-dependently inhibited cell migration and invasion of PC-3 cells. The present study also revealed that TGZ increased the mRNA and protein levels of E-cadherin and glutathione peroxidase 3 (GPx3) in human prostate cancer PC-3 cells. In addition, GW9662, a PPARγ antagonist, attenuated the increased mRNA and protein levels of E-cadherin and GPx3, suggesting that the PPARγ-dependent signaling pathway was involved. Taken together, these results suggested that the anti-migration and anti-invasion effect of TGZ on PC-3 prostate cancer cells is, at least in part, mediated via upregulation of E-cadherin and GPx3. The present study also concluded that PPARγ may be used as a potential remedial target for the prevention and treatment of prostate cancer cell invasion and metastasis.
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Affiliation(s)
- Seo-Na Chang
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
| | - Ji Min Lee
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
| | - Hanseul Oh
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
| | - Ukjin Kim
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
| | - Bokyeong Ryu
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
| | - Jae-Hak Park
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
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23
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Hui L, Zhang J, Ding X, Guo X, Jang X. Identification of potentially critical differentially methylated genes in nasopharyngeal carcinoma: A comprehensive analysis of methylation profiling and gene expression profiling. Oncol Lett 2017; 14:7171-7178. [PMID: 29344148 PMCID: PMC5754830 DOI: 10.3892/ol.2017.7083] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 08/17/2017] [Indexed: 12/21/2022] Open
Abstract
The present study aimed to identify potentially critical differentially methylated genes associated with the progression of nasopharyngeal carcinoma (NPC). Methylation profiling data of GSE62336 deposited in the Gene Expression Omnibus database were used to identify differentially methylated regions (DMRs) and differentially methylated CpG islands (DMIs). Concurrently, differentially expressed genes (DEGs) were identified using a meta-analysis of three gene expression datasets (GSE53819, GSE13597 and GSE12452). Subsequently, methylated DEGs were identified by comparing DMRs and DEGs. Furthermore, functional associations of these methylated DEGs were analyzed via constructing a functional network using GeneMANIA prediction server. In total, 1,676 hypermethylated genes, 28 hypomethylated genes, 17 DMIs and 2,983 DEGs (1,655 upregulated and 1,328 downregulated) were identified. Among these DEGs, 135 downregulated genes were hypermethylated; of these, dual specificity phosphatase 6 (DUSP6) and tenascin XB (TNXB) contained DMIs. In the functional network, 154 genes and 1,651 association pairs were included. DUSP6 was predicted to exhibit genetic interactions with other hypermethylated DEGs such as malic enzyme 3 and ST3 β-galactoside α-2,3-sialyltransferase 5; TNXB was predicted to be co-expressed with a set of hypermethylated DEGs, including EPH receptor B6, aldehyde dehydrogenase 1 family, member L1 and glutathione peroxidase 3. The hypermethylated DEGs may be involved in the progression of NPC, and they may become novel therapeutic targets for NPC.
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Affiliation(s)
- Lian Hui
- Department of Otolaryngology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Jingru Zhang
- Department of Otolaryngology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xiaoxu Ding
- Department of Otolaryngology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xing Guo
- Department of Otolaryngology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xuejun Jang
- Department of Otolaryngology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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24
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Abstract
Chemopreventive activity of selenium (Se) may influence epigenome. In this review, we have discussed two aspects of Se and epigenetics in cancer, related to (1) the association between Se and epigenetic regulation in cancer development and prevention; (2) epigenetic modification of selenoprotein-encoding genes in different cancers. In both issues, we focused on DNA methylation as the most investigated epigenetic mechanism. The existing evidence from experimental data in human cancer cell lines, rodents, and human studies in cancer-free subjects indicates that: high Se exposure leads to the inhibition of DNA methyltransferase expression/activity; the association between Se and global methylation remains unclear and requires further investigation with respect to the underlying mechanisms and possible nonlinear character of this relationship; Se affects methylation of specific tumor suppressor genes, possibly in a sex-dependent manner; and cancer phenotype is often characterized by altered methylation of selenoprotein-encoding genes, mainly glutathione peroxidase 3.
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Affiliation(s)
- Ewa Jabłońska
- Nofer Institute of Occupational Medicine, Lodz, Poland.
| | - Edyta Reszka
- Nofer Institute of Occupational Medicine, Lodz, Poland
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25
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Jiao Y, Wang Y, Guo S, Wang G. Glutathione peroxidases as oncotargets. Oncotarget 2017; 8:80093-80102. [PMID: 29108391 PMCID: PMC5668124 DOI: 10.18632/oncotarget.20278] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 06/20/2017] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress is a disturbance in the equilibrium among free radicals, reactive oxygen species, and endogenous antioxidant defense mechanisms. Oxidative stress is a result of imbalance between the production of reactive oxygen and the biological system's ability to detoxify the reactive intermediates or to repair the resulting damage. Mounting evidence has implicated oxidative stress in various physiological and pathological processes, including DNA damage, proliferation, cell adhesion, and survival of cancer cells. Glutathione peroxidases (GPxs) (EC 1.11.1.9) are an enzyme family with peroxidase activity whose main biological roles are to protect organisms from oxidative damage by reducing lipid hydroperoxides as well as free hydrogen peroxide. Currently, 8 sub-members of GPxs have been identified in humans, all capable of reducing H2O2 and soluble fatty acid hydroperoxides. A large number of publications has demonstrated that GPxs have significant roles in different stages of carcinogenesis. In this review, we will update recent progress in the study of the roles of GPxs in cancer. Better mechanistic understanding of GPxs will potentially contribute to the development and advancement of improved cancer treatment models.
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Affiliation(s)
- Yang Jiao
- Department of Stomatology, PLA Army General Hospital, Beijing, P.R. China
| | - Yirong Wang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Department of Operative Dentistry and Endodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, P.R. China
| | - Shanchun Guo
- RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, New Orleans, LA, USA
| | - Guangdi Wang
- RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, New Orleans, LA, USA
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26
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Kanno SI, Tomizawa A, Yomogida S, Hara A. Glutathione peroxidase 3 is a protective factor against acetaminophen‑induced hepatotoxicity in vivo and in vitro. Int J Mol Med 2017; 40:748-754. [PMID: 28677736 PMCID: PMC5547967 DOI: 10.3892/ijmm.2017.3049] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 06/06/2017] [Indexed: 11/10/2022] Open
Abstract
Acetaminophen (APAP) is a widely available antipyretic and analgesic; however, overdose of the drug inflicts severe damage to the liver. It is well established that the hepatotoxicity of APAP is initiated by formation of a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which can be detoxified by conjugation with reduced glutathione (GSH), a typical antioxidant. We recently found that the blood mRNA expression level of glutathione peroxidase 3 (Gpx3), which catalyzes the oxidation of GSH, is associated with the extent of APAP-induced hepatotoxicity in mice. The present study was carried out to determine the in vivo and in vitro role of GPx3 in APAP-induced hepatotoxicity. In in vivo experiments, oral administration of APAP to mice induced liver injury. Such liver injury was greater in males than in females, although no gender difference in the plasma concentration of APAP was found. Female mice had a 2-fold higher expression of Gpx3 mRNA and higher plasma GPx activity than male mice. 17β-estradiol, a major female hormone, decreased APAP-induced hepatotoxicity and increased both the expression of blood Gpx3 mRNA and plasma GPx activity, suggesting that the cytoprotective action of this hormone is mediated by the increase in GPx3. To further clarify the role of GPx3 in APAP-induced hepatotoxicity, we evaluated the effect of a change in cellular GPx3 expression resulting from transfection of either siRNA-GPx3 or a GPx3 expression vector on NAPQI-induced cellular injury (as assessed by a tetrazolium assay) in in vitro experiments using heterogeneous cultured human cell lines (Huh-7 or K562). NAPQI-induced cell death was reduced by increased GPx3 and was enhanced by decreased GPx3. These results suggest that GPx3 is an important factor for inhibition of APAP-induced hepatotoxicity both in vivo and in vitro. To our knowledge, this is the first report to show a hepatoprotective role of cellular GPx3 against APAP-induced liver damage.
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Affiliation(s)
- Syu-Ichi Kanno
- Department of Clinical Pharmacotherapeutics, Tohoku Medical and Pharmaceutical University, Aoba‑ku, Sendai 981‑8558, Japan
| | - Ayako Tomizawa
- Department of Clinical Pharmacotherapeutics, Tohoku Medical and Pharmaceutical University, Aoba‑ku, Sendai 981‑8558, Japan
| | - Shin Yomogida
- Department of Clinical Pharmacotherapeutics, Tohoku Medical and Pharmaceutical University, Aoba‑ku, Sendai 981‑8558, Japan
| | - Akiyoshi Hara
- Department of Clinical Pharmacotherapeutics, Tohoku Medical and Pharmaceutical University, Aoba‑ku, Sendai 981‑8558, Japan
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Zhou JD, Lin J, Zhang TJ, Ma JC, Yang L, Wen XM, Guo H, Yang J, Deng ZQ, Qian J. GPX3 methylation in bone marrow predicts adverse prognosis and leukemia transformation in myelodysplastic syndrome. Cancer Med 2016; 6:267-274. [PMID: 27891827 PMCID: PMC5269561 DOI: 10.1002/cam4.984] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 10/11/2016] [Accepted: 11/07/2016] [Indexed: 02/06/2023] Open
Abstract
Epigenetic inactivation of GPX3 has been identified in various cancers including leukemia. Moreover, aberrant DNA methylation was also found as a dominant mechanism of disease progression in myelodysplastic syndrome (MDS). This study intended to explore GPX3 promoter methylation and its clinical relevance in 110 patients with MDS. GPX3 methylation was examined by real-time quantitative methylation-specific PCR (RQ-MSP) and bisulfite sequencing PCR (BSP). GPX3 methylation was identified in 15% (17/110) MDS patients, and significantly higher than controls, and lower than acute myeloid leukemia (AML) patients (P = 0.024 and 0.041). GPX3 methylated patients had older age and higher frequency of DNMT3A mutation (P = 0.015 and 0.066). Cases with GPX3 methylation showed significantly shorter overall survival (OS) time than those with GPX3 unmethylation analyzed with Kaplan-Meier analysis (P = 0.012). Moreover, Cox regression analysis revealed that GPX3 methylation might act as an independent prognostic indicator in MDS (HR = 1.847, P = 0.072). GPX3 methylation density was significantly increased during the progression from MDS to secondary acute myeloid leukemia (sAML) in three follow-up paired patients. Our study concludes that GPX3 methylation in bone marrow is associated with adverse prognosis and leukemia transformation in MDS.
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Affiliation(s)
- Jing-Dong Zhou
- Department of Hematology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jiang Lin
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Ting-Juan Zhang
- Department of Hematology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Ji-Chun Ma
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Lei Yang
- Department of Hematology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xiang-Mei Wen
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Hong Guo
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jing Yang
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Zhao-Qun Deng
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jun Qian
- Department of Hematology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
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Chang SN, Lee JM, Oh H, Park JH. Glutathione Peroxidase 3 Inhibits Prostate Tumorigenesis in TRAMP Mice. Prostate 2016; 76:1387-98. [PMID: 27325372 DOI: 10.1002/pros.23223] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 06/07/2016] [Indexed: 01/06/2023]
Abstract
BACKGROUND Glutathione peroxidase 3 (GPx3) is involved in protecting cells from oxidative damage, and down-regulated levels of expression have been found in prostate cancer samples. We hypothesize that loss of the GPx3 increases the rate of prostate carcinogenesis and generated GPx3-deficient transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. METHODS Prostate cancer incidence and progression were determined in TRAMP, TRAMP/GPx3 (+/-) HET, and TRAMP/GPx3 (-/-) KO mice at 8, 16, and 20 weeks of age. RESULTS We found that GPx3 expression was decreased in TRAMP mice and not detected in GPx3 KO mice both in mRNA and protein levels. Disruption of GPx3 expression in TRAMP mice increased the GU tract weights and the histopathological scores in each lobes with increased proliferation rates. Moreover, inactivation of one (+/-) or both (-/-) alleles of GPx3 resulted in increase in prostate cancer incidence with activated Wnt/β-catenin pathway. CONCLUSIONS Our results provide the first in vivo molecular genetic evidence that GPx3 does indeed function as a tumor suppressor during prostate carcinogenesis. Prostate 76:1387-1398, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Seo-Na Chang
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Ji Min Lee
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Hanseul Oh
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Jae-Hak Park
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
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An BC, Jung NK, Park CY, Oh IJ, Choi YD, Park JI, Lee SW. Epigenetic and Glucocorticoid Receptor-Mediated Regulation of Glutathione Peroxidase 3 in Lung Cancer Cells. Mol Cells 2016; 39:631-8. [PMID: 27484907 PMCID: PMC4990756 DOI: 10.14348/molcells.2016.0164] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 07/20/2016] [Accepted: 07/22/2016] [Indexed: 11/27/2022] Open
Abstract
Glutathione peroxidase 3 (GPx3), an antioxidant enzyme, acts as a modulator of redox signaling, has immunomodulatory function, and catalyzes the detoxification of reactive oxygen species (ROS). GPx3 has been identified as a tumor suppressor in many cancers. Although hyper-methylation of the GPx3 promoter has been shown to down-regulate its expression, other mechanisms by which GPx3 expression is regulated have not been reported. The aim of this study was to further elucidate the mechanisms of GPx3 regulation. GPx3 gene analysis predicted the presence of ten glucocorticoid response elements (GREs) on the GPx3 gene. This result prompted us to investigate whether GPx3 expression is regulated by the glucocorticoid receptor (GR), which is implicated in tumor response to chemotherapy. The corticosteroid dexamethasone (Dex) was used to examine the possible relationship between GR and GPx3 expression. Dex significantly induced GPx3 expression in H1299, H1650, and H1975 cell lines, which exhibit low levels of GPx3 expression under normal conditions. The results of EMSA and ChIP-PCR suggest that GR binds directly to GRE 6 and 7, both of which are located near the GPx3 promoter. Assessment of GPx3 transcription efficiency using a luciferase reporter system showed that blocking formation of the GR-GRE complexes reduced luciferase activity by 7-8-fold. Suppression of GR expression by siRNA transfection also induced down-regulation of GPx3. These data indicate that GPx3 expression can be regulated independently via epigenetic or GR-mediated mechanisms in lung cancer cells, and suggest that GPx3 could potentiate glucocorticoid (GC)-mediated anti-inflammatory signaling in lung cancer cells.
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Affiliation(s)
- Byung Chull An
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128,
Korea
| | - Nak-Kyun Jung
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128,
Korea
- Research Institute of Medical Sciences, Chonnam National University, Hwasun 58128,
Korea
| | - Chun Young Park
- Department of Pathology, Chonnam National University Medical School, Hwasun 58128,
Korea
| | - In-Jae Oh
- Department of Internal Medicine, Chonnam National University Medical School, Hwasun 58128,
Korea
| | - Yoo-Duk Choi
- Department of Pathology, Chonnam National University Medical School, Hwasun 58128,
Korea
| | - Jae-Il Park
- Animal Facility of Aging Science, Korea Basic Science Institute, Gwangju 61186,
Korea
| | - Seung-won Lee
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128,
Korea
- Research Institute of Medical Sciences, Chonnam National University, Hwasun 58128,
Korea
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Qi X, Ng KTP, Lian QZ, Liu XB, Li CX, Geng W, Ling CC, Ma YY, Yeung WH, Tu WW, Fan ST, Lo CM, Man K. Clinical significance and therapeutic value of glutathione peroxidase 3 (GPx3) in hepatocellular carcinoma. Oncotarget 2015; 5:11103-20. [PMID: 25333265 PMCID: PMC4294380 DOI: 10.18632/oncotarget.2549] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 09/30/2014] [Indexed: 12/22/2022] Open
Abstract
AIMS We aimed to investigate the clinical significance of GPx3 in hepatocellular carcinoma (HCC) and to characterize its tumor suppressive role. METHODS HCC patients (113) who underwent hepatectomy were recruited to examine the clinical relevance of GPx3. The tumor suppressive role of GPx3 was studied by administration of recombinant GPx3 (rGPx3) or over-expression of GPx3 in HCC cells in vitro and in vivo. The therapeutic value of GPx3 for HCC was further investigated using human induced pluripotent stem cell derived mesenchymal stem cells (hiPSC-MSCs) as its delivery vehicle. RESULTS Down-regulation of GPx3 significantly correlated with advanced tumor stage (P = 0.024), venous infiltration (P = 0.043) and poor overall survival (P = 0.007) after hepatectomy. Lower plasma GPx3 in HCC patients was significantly associated with larger tumor size (P = 0.011), more tumor nodules (P = 0.032) and higher recurrence (P = 0.016). Over-expression of GPx3 or administration of rGPx3 significantly inhibited proliferation and invasiveness of HCC cells in vitro and in vivo. Tumor suppressive activity of GPx3 was mediated through Erk-NFκB-SIP1 pathway. GPx3 could be delivered by hiPSC-MSCs into the tumor and exhibited tumor suppressive activity in vivo. CONCLUSIONS GPx3 is a tumor suppressor gene in HCC and may possess prognostic and therapeutic value for HCC patients.
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Affiliation(s)
- Xiang Qi
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Kevin Tak Pan Ng
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Qi Zhou Lian
- Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Xiao Bing Liu
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Chang Xian Li
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Wei Geng
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Chang Chun Ling
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Yuen Yuen Ma
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Wai Ho Yeung
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Wen Wei Tu
- Department of Paediatrics & Adolescent Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Sheung Tat Fan
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Chung Mau Lo
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Kwan Man
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
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Liu Q, Jin J, Ying J, Sun M, Cui Y, Zhang L, Xu B, Fan Y, Zhang Q. Frequent epigenetic suppression of tumor suppressor gene glutathione peroxidase 3 by promoter hypermethylation and its clinical implication in clear cell renal cell carcinoma. Int J Mol Sci 2015; 16:10636-49. [PMID: 25970749 PMCID: PMC4463666 DOI: 10.3390/ijms160510636] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2015] [Revised: 04/30/2015] [Accepted: 05/05/2015] [Indexed: 02/07/2023] Open
Abstract
The goal of this study is to identify novel tumor suppressor genes silenced by promoter methylation in clear cell renal cell carcinoma (ccRCC) and discover new epigenetic biomarkers for early cancer detection. Reactive oxygen species (ROS) is a major cause of DNA damage that correlates with cancer initiation and progression. Glutathione peroxidase 3 (GPX3), the only known extracellular glycosylated enzyme of GPXs, is a major scavenger of ROS. GPX3 has been identified as a tumor suppressor in many cancers. However, the role of GPX3 in ccRCC remains unclear. This study aimed to investigate its epigenetic alteration in ccRCC and possible clinicopathological association. In our study, GPX3 methylation and down-regulation were detected in 5 out of 6 ccRCC cell lines and the GPX3 mRNA and protein expression level in ccRCC tumors was significantly lower than in adjacent non-malignant renal tissues (p < 0.0001). Treatment with 5-Aza-2'-deoxycytidine restored GPX3 expression in ccRCC cells. Aberrant methylation was further detected in 77.1% (162/210) of RCC primary tumors, but only 14.6% (7/48) in adjacent non-malignant renal tissues. GPX3 methylation status was significantly associated with higher tumor nuclear grade (p = 0.014). Thus, our results showing frequent GPX3 inactivation by promoter hypermethylation in ccRCC may reveal the failure in the cellular antioxidant system in ccRCC and may be associated with renal tumorigenesis. GPX3 tumor specific methylation may serve as a biomarker for early detection and prognosis prediction of ccRCC.
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Affiliation(s)
- Qianling Liu
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
| | - Jie Jin
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
| | - Jianming Ying
- Department of Pathology, Cancer Institute and Cancer Hospital, Peking Union Medical College (PUMC), Chinese Academy of Medical Sciences, Beijing 100021, China.
| | - Mengkui Sun
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
| | - Yun Cui
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
| | - Lian Zhang
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
| | - Ben Xu
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
| | - Yu Fan
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
| | - Qian Zhang
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
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Li X, Zhou F, Jiang C, Wang Y, Lu Y, Yang F, Wang N, Yang H, Zheng Y, Zhang J. Identification of a DNA methylome profile of esophageal squamous cell carcinoma and potential plasma epigenetic biomarkers for early diagnosis. PLoS One 2014; 9:e103162. [PMID: 25050929 PMCID: PMC4106874 DOI: 10.1371/journal.pone.0103162] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 06/26/2014] [Indexed: 01/05/2023] Open
Abstract
DNA methylation is a critical epigenetic mechanism involved in key cellular processes. Its deregulation has been linked to many human cancers including esophageal squamous cell carcinoma (ESCC). This study was designed to explore the whole methylation status of ESCC and to identify potential plasma biomarkers for early diagnosis. We used Infinium Methylation 450k array to analyze ESCC tissues (n = 4), paired normal surrounding tissues (n = 4) and normal mucosa from healthy individuals (n = 4), and combined these with gene expression data from the GEO database. One hundred and sixty eight genes had differentially methylated CpG sites in their promoter region and a gene expression pattern inverse to the direction of change in DNA methylation. These genes were involved in several cancer-related pathways. Three genes were validated in additional 42 ESCC tissues and paired normal surrounding tissues. The methylation frequency of EPB41L3, GPX3, and COL14A1 were higher in tumor tissues than in normal surrounding tissues (P<0.017). The higher methylation frequency of EPB41l3 was correlated with large tumor size (P = 0.044) and advanced pT tumor stage (P = 0.001). The higher methylation frequency of GPX3 and COL14A1 were correlated with advanced pN tumor stage (P = 0.001 and P<0.001). The methylation of EPB41L3, GPX3, and COL14A1 genes were only found in ESCC patients' plasma, but not in normal individuals upon testing 42 ESCC patients and 50 healthy individuals. Diagnostic sensitivity was increased when methylation of any of the 3 genes were counted (64.3% sensitivity and 100% specificity). These differentially methylated genes in plasma may be used as biomarkers for early diagnosis of ESCC.
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Affiliation(s)
- Xufeng Li
- Oncology Center, ZhuJiang Hospital of Southern Medical University, Guangzhou, China
| | | | - Chunyu Jiang
- Oncology Center, ZhuJiang Hospital of Southern Medical University, Guangzhou, China
| | - Yinuo Wang
- Institute of Targeted Molecular Medicine, Shanghai, China
| | - Yanqiang Lu
- Institute of Targeted Molecular Medicine, Shanghai, China
| | - Fei Yang
- Institute of Targeted Molecular Medicine, Shanghai, China
| | | | | | - Yanfang Zheng
- Oncology Center, ZhuJiang Hospital of Southern Medical University, Guangzhou, China
- * E-mail: (YZ); (JZ)
| | - Jiren Zhang
- Oncology Center, ZhuJiang Hospital of Southern Medical University, Guangzhou, China
- Institute of Targeted Molecular Medicine, Shanghai, China
- * E-mail: (YZ); (JZ)
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Zhang X, Zheng Z, Yingji S, Kim H, Jin R, Renshu L, Lee DY, Roh MR, Yang S. Downregulation of glutathione peroxidase 3 is associated with lymph node metastasis and prognosis in cervical cancer. Oncol Rep 2014; 31:2587-92. [PMID: 24788695 DOI: 10.3892/or.2014.3152] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Accepted: 03/21/2014] [Indexed: 11/06/2022] Open
Abstract
Glutathione peroxidase 3 (GPX3) is a member of the glutathione peroxidase family of selenoproteins and is one of the key defensive enzymes against oxidative damages to host cells. Downregulation of GPX3 due to its promoter hypermethylation has been documented in several different types of cancer, indicating that GPX3 functions as a possible tumor suppressor. In the present study, we showed that GPX3 is also significantly downregulated in cervical cancer tissues compared to normal cervical tissues by qRT-PCR analyses and immunohistostainings. GPX3 expression was significantly related to lymph node metastasis and prognosis in cervical cancer patients. Treatment of cervical cancer cells with 5-aza-2'-deoxycytidine restored the expression of GPX3 and methylation-specific PCR (MSP) confirmed the CpG methylation of the GPX3 gene. Our results indicate that promoter methylation is one of the major causes of GPX3 downregulation in cervical cancer and GPX3 could serve as a predictive biomarker for lymph node metastasis and prognosis of cervical cancer.
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Affiliation(s)
- Xianglan Zhang
- Department of Pathology, Yanbian University Hospital, Yanji, Jilin, P.R. China
| | - Zhenlong Zheng
- Department of Dermatology, Yanbian University Hospital, Yanji, Jilin, P.R. China
| | - Shen Yingji
- Department of Gynecology, Maternal and Child Health Hospital, Dalian, Liaoning, P.R. China
| | - Hyeyeon Kim
- Department of Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Renshun Jin
- Department of Pathology, Yanbian University Hospital, Yanji, Jilin, P.R. China
| | - Li Renshu
- Department of Anesthesia and Pain, Yanbian University Hospital, Yanji, Jilin, P.R. China
| | - Doo Young Lee
- Oral Cancer Research Institute, College of Dentistry, Yonsei University, Seoul, Republic of Korea
| | - Mi Ryung Roh
- Department of Dermatology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sanghwa Yang
- National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea
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Mohamed MM, Sabet S, Peng DF, Nouh MA, El-Shinawi M, El-Rifai W. Promoter hypermethylation and suppression of glutathione peroxidase 3 are associated with inflammatory breast carcinogenesis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:787195. [PMID: 24790704 PMCID: PMC3980917 DOI: 10.1155/2014/787195] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 01/22/2014] [Accepted: 01/30/2014] [Indexed: 11/17/2022]
Abstract
Reactive oxygen species (ROS) play a crucial role in breast cancer initiation, promotion, and progression. Inhibition of antioxidant enzymes that remove ROS was found to accelerate cancer growth. Studies showed that inhibition of glutathione peroxidase-3 (GPX3) was associated with cancer progression. Although the role of GPX3 has been studied in different cancer types, its role in breast cancer and its epigenetic regulation have not yet been investigated. The aim of the present study was to investigate GPX3 expression and epigenetic regulation in carcinoma tissues of breast cancer patients' in comparison to normal breast tissues. Furthermore, we compared GPX3 level of expression and methylation status in aggressive phenotype inflammatory breast cancer (IBC) versus non-IBC invasive ductal carcinoma (IDC). We found that GPX3 mRNA and protein expression levels were downregulated in the carcinoma tissues of IBC compared to non-IBC. However, we did not detect significant correlation between GPX3 and patients' clinical-pathological prosperities. Promoter hypermethylation of GPX3 gene was detected in carcinoma tissues not normal breast tissues. In addition, IBC carcinoma tissues showed a significant increase in the promoter hypermethylation of GPX3 gene compared to non-IBC. Our results propose that downregulation of GPX3 in IBC may play a role in the disease progression.
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Affiliation(s)
- Mona M. Mohamed
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Salwa Sabet
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Dun-Fa Peng
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - M. Akram Nouh
- Department of Pathology, National Cancer Institute, Cairo University, Giza 12613, Egypt
| | - Mohamed El-Shinawi
- Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Wael El-Rifai
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Abelson S, Shamai Y, Berger L, Skorecki K, Tzukerman M. Niche-dependent gene expression profile of intratumoral heterogeneous ovarian cancer stem cell populations. PLoS One 2013; 8:e83651. [PMID: 24358304 PMCID: PMC3866276 DOI: 10.1371/journal.pone.0083651] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Accepted: 11/06/2013] [Indexed: 12/24/2022] Open
Abstract
Intratumoral heterogeneity challenges existing paradigms for anti-cancer therapy. We have previously demonstrated that the human embryonic stem cells (hESC)-derived cellular microenvironment in immunocompromised mice, enables functional distinction of heterogeneous tumor cells, including cells which do not grow into a tumor in a conventional direct tumor xenograft platform. We have identified and characterized six cancer cell subpopulations each clonally expanded from a single cell, derived from human ovarian clear cell carcinoma of a single tumor, to demonstrate striking intratumoral phenotypic heterogeneity that is dynamically dependent on the tumor growth microenvironment. These cancer cell subpopulations, characterized as cancer stem cell subpopulations, faithfully recapitulate the full spectrum of histological phenotypic heterogeneity known for human ovarian clear cell carcinoma. Each of the six subpopulations displays a different level of morphologic and tumorigenic differentiation wherein growth in the hESC-derived microenvironment favors growth of CD44+/aldehyde dehydrogenase positive pockets of self-renewing cells that sustain tumor growth through a process of tumorigenic differentiation into CD44-/aldehyde dehydrogenase negative derivatives. Strikingly, these derivative cells display microenvironment-dependent plasticity with the capacity to restore self-renewal markers and CD44 expression. In the current study, we delineate the distinct gene expression and epigenetic profiles of two such subpopulations, representing extremes of phenotypic heterogeneity in terms of niche-dependent self-renewal and tumorigenic differentiation. By combining Gene Set Enrichment, Gene Ontology and Pathway-focused array analyses with methylation status, we propose a suite of robust differences in tumor self-renewal and differentiation pathways that underlie the striking intratumoral phenotypic heterogeneity which characterize this and other solid tumor malignancies.
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Affiliation(s)
- Sagi Abelson
- Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Rambam Medical Center, Haifa, Israel
| | - Yeela Shamai
- Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Rambam Medical Center, Haifa, Israel
| | - Liron Berger
- Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Rambam Medical Center, Haifa, Israel
| | - Karl Skorecki
- Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Rambam Medical Center, Haifa, Israel
- Rambam Medical Center, Haifa, Israel
- * E-mail: (MT); (KS)
| | - Maty Tzukerman
- Rambam Medical Center, Haifa, Israel
- * E-mail: (MT); (KS)
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Shen L, He YL, Zhang WW, Geng CX. Clinical significance of expression of glutathione peroxidase 3 in esophageal squamous cell carcinoma. Shijie Huaren Xiaohua Zazhi 2013; 21:3252-3256. [DOI: 10.11569/wcjd.v21.i30.3252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of glutathione peroxidase 3 (GPX3) in esophageal squamous cell carcinoma and to analyze its clinical significance.
METHODS: GPX3 protein expression was detected by immunohistochemistry in 42 cases of esophageal intraepithelial neoplasia, 86 cases of esophageal squamous cell carcinoma and 37 cases of normal esophageal mucosa tissue.
RESULTS: The expression of GPX3 in normal esophageal mucosa was significantly higher than that in esophageal intraepithelial neoplasia and esophageal squamous cell carcinoma (75.7% vs 38.1%, 18.6%, both P < 0.01). Moreover, the expression of GPX3 in esophageal intraepithelial neoplasia was significantly higher than that in esophageal squamous cell carcinoma (P < 0.05). The expression of GPX3 was significantly higher in esophageal squamous cell carcinoma without lymph node metastasis than in that with lymph node metastasis (30.8% vs 8.5%, P < 0.01).
CONCLUSION: The expression of GPX3 in esophageal intraepithelial neoplasia and esophageal squamous cell carcinomas is significantly lower than that in normal esophageal mucosa, and the expression of GPX3 is associated with lymph node metastasis. GPX3 may be used as a candidate marker for esophageal squamous cell carcinoma.
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Abstract
BACKGROUND With increasing evidence that hydroperoxides are not only toxic but rather exert essential physiological functions, also hydroperoxide removing enzymes have to be re-viewed. In mammals, the peroxidases inter alia comprise the 8 glutathione peroxidases (GPx1-GPx8) so far identified. SCOPE OF THE REVIEW Since GPxs have recently been reviewed under various aspects, we here focus on novel findings considering their diverse physiological roles exceeding an antioxidant activity. MAJOR CONCLUSIONS GPxs are involved in balancing the H2O2 homeostasis in signalling cascades, e.g. in the insulin signalling pathway by GPx1; GPx2 plays a dual role in carcinogenesis depending on the mode of initiation and cancer stage; GPx3 is membrane associated possibly explaining a peroxidatic function despite low plasma concentrations of GSH; GPx4 has novel roles in the regulation of apoptosis and, together with GPx5, in male fertility. Functions of GPx6 are still unknown, and the proposed involvement of GPx7 and GPx8 in protein folding awaits elucidation. GENERAL SIGNIFICANCE Collectively, selenium-containing GPxs (GPx1-4 and 6) as well as their non-selenium congeners (GPx5, 7 and 8) became key players in important biological contexts far beyond the detoxification of hydroperoxides. This article is part of a Special Issue entitled Cellular functions of glutathione.
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Affiliation(s)
- Regina Brigelius-Flohé
- Department of Biochemistry of Micronutrients, German Institute of Human Nutrition, Nuthetal, Germany.
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Silencing of glutathione peroxidase 3 through DNA hypermethylation is associated with lymph node metastasis in gastric carcinomas. PLoS One 2012; 7:e46214. [PMID: 23071548 PMCID: PMC3468580 DOI: 10.1371/journal.pone.0046214] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Accepted: 08/29/2012] [Indexed: 01/06/2023] Open
Abstract
Gastric cancer remains the second leading cause of cancer-related death in the world. H. pylori infection, a major risk factor for gastric cancer, generates high levels of reactive oxygen species (ROS). Glutathione peroxidase 3 (GPX3), a plasma GPX member and a major scavenger of ROS, catalyzes the reduction of hydrogen peroxide and lipid peroxides by reduced glutathione. To study the expression and gene regulation of GPX3, we examined GPX3 gene expression in 9 gastric cancer cell lines, 108 primary gastric cancer samples and 45 normal gastric mucosa adjacent to cancers using quantitative real-time RT-PCR. Downregulation or silencing of GPX3 was detected in 8 of 9 cancer cell lines, 83% (90/108) gastric cancers samples, as compared to non-tumor adjacent normal gastric samples (P<0.0001). Examination of GPX3 promoter demonstrated DNA hypermethylation (≥10% methylation level determined by Bisulfite Pyrosequencing) in 6 of 9 cancer cell lines and 60% of gastric cancer samples (P = 0.007). We also detected a significant loss of DNA copy number of GPX3 in gastric cancers (P<0.001). Treatment of SNU1 and MKN28 cells with 5-Aza-2′ Deoxycytidine restored the GPX3 gene expression with a significant demethylation of GPX3 promoter. The downregulation of GPX3 expression and GPX3 promoter hypermethylation were significantly associated with gastric cancer lymph node metastasis (P = 0.018 and P = 0.029, respectively). We also observed downregulation, DNA copy number losses, and promoter hypermethylation of GPX3 in approximately one-third of tumor-adjacent normal gastric tissue samples, suggesting the presence of a field defect in areas near tumor samples. Reconstitution of GPX3 in AGS cells reduced the capacity of cell migration, as measured by scratch wound healing assay. Taken together, the dysfunction of GPX3 in gastric cancer is mediated by genetic and epigenetic alterations, suggesting impairment of mechanisms that regulate ROS and its possible involvement in gastric tumorigenesis and metastasis.
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Wang H, Luo K, Tan LZ, Ren BG, Gu LQ, Michalopoulos G, Luo JH, Yu YP. p53-induced gene 3 mediates cell death induced by glutathione peroxidase 3. J Biol Chem 2012; 287:16890-16902. [PMID: 22461624 PMCID: PMC3351337 DOI: 10.1074/jbc.m111.322636] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2011] [Revised: 03/28/2012] [Indexed: 11/06/2022] Open
Abstract
Expression of glutathione peroxidase 3 (GPx3) is down-regulated in a variety of human malignancies. Both methylation and deletion of GPx3 gene underlie the alterations of GPx3 expression in prostate cancer. A strong correlation between the down-regulation of GPx3 expression and progression of prostate cancer and the suppression of prostate cancer xenografts in SCID mice by forced expression of GPx3 suggests a tumor suppression role of GPx3 in prostate cancer. However, the mechanism of GPx3-mediated tumor suppression remains unclear. In this report, GPx3 was found to interact directly with p53-induced gene 3 (PIG3). Forced overexpression of GPx3 in prostate cancer cell lines DU145 and PC3 as well as immortalized prostate epithelial cells RWPE-1 increased apoptotic cell death. Expression of GPx3(x73c), a peroxidase-negative OPAL codon mutant, in DU145 and PC3 cells also increased cell death. The induced expression of GPx3 in DU145 and PC3 cells resulted in an increase in reactive oxygen species and caspase-3 activity. These activities were abrogated by either knocking down PIG3 or mutating the PIG3 binding motif in GPx3 or binding interference from a peptide corresponding to PIG3 binding motif in GPx3. In addition, UV-treated RWPE-1 cells underwent apoptotic death, which was partially prevented by knocking down GPx3 or PIG3, suggesting that GPx3-PIG3 signaling is critical for UV-induced apoptosis. Taken together, these results reveal a novel signaling pathway of GPx3-PIG3 in the regulation of cell death in prostate cancer.
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Affiliation(s)
- Hui Wang
- From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
| | - Katherine Luo
- From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
| | - Lang-Zhu Tan
- From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
| | - Bao-Guo Ren
- From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
| | - Li-Qun Gu
- From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
| | - George Michalopoulos
- From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
| | - Jian-Hua Luo
- From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
| | - Yan P. Yu
- From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
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Li JS, Ying JM, Wang XW, Wang ZH, Tao Q, Li LL. Promoter methylation of tumor suppressor genes in esophageal squamous cell carcinoma. CHINESE JOURNAL OF CANCER 2012; 32:3-11. [PMID: 22572016 PMCID: PMC3845589 DOI: 10.5732/cjc.011.10381] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a prevalent and fatal cancer in China and other Asian countries. Epigenetic silencing of key tumor suppressor genes (TSGs) is critical to ESCC initiation and progression. Recently, many novel TSGs silenced by promoter methylation have been identified in ESCC, and these genes further serve as potential tumor markers for high-risk group stratification, early detection, and prognosis prediction. This review summarizes recent discoveries on aberrant promoter methylation of TSGs in ESCC, providing better understanding of the role of disrupted epigenetic regulation in tumorigenesis and insight into diagnostic and prognostic biomarkers for this malignancy.
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Affiliation(s)
- Ji-Sheng Li
- Department of Chemotherapy, Shandong University, Jinan, Shandong, People's Republic of China
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Meng Y, Wang QG, Wang JX, Zhu ST, Jiao Y, Li P, Zhang ST. Epigenetic inactivation of the SFRP1 gene in esophageal squamous cell carcinoma. Dig Dis Sci 2011; 56:3195-203. [PMID: 21567192 DOI: 10.1007/s10620-011-1734-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2011] [Accepted: 04/18/2011] [Indexed: 01/21/2023]
Abstract
INTRODUCTION The secreted frizzled-related protein 1 (SFRP1) gene, as a Wnt signaling modulator, is frequently inactivated by promoter methylation in many tumors including gastric cancer, breast cancer, oral squamous cell carcinoma, and esophageal adenocarcinoma. However, the role of SFRP1 in esophageal squamous cell carcinoma (ESCC) is not clear. In this study, we investigated the epigenetic inactivation of the SFRP1 gene in ESCC. METHODS Nine ESCC cell lines, two immortalized human esophageal epithelial cell lines, twenty ESCC tissues, and paired adjacent nontumor tissues were analyzed in the study. Methylation-specific polymerase chain reaction (PCR), bisulfite sequencing, reverse-transcription PCR, immunohistochemistry, and chromatin immunoprecipitation assay were used to detect SFRP1 promoter methylation, expression of the SFRP1 gene, and histone modification in the SFRP1 promoter region. RESULTS The SFRP1 promoter was found to be highly methylated in 95% (19/20) of the ESCC tissues and in nine ESCC cell lines, compared with 65% (13/20) of the paired nontumor tissues. Moreover, we confirmed that complete methylation of the SFRP1 gene promoter was correlated with its greatly reduced expression level. After individual treatment with 5-aza-2'-deoxycytidine (DAC) and trichostatin A (TSA), the messenger RNA (mRNA) level of the SFRP1 gene was not obviously rescued in the EC9706 cell line. Combined incubation with DAC and TSA can, however, substantially increase the SFRP1 mRNA expression level in the EC9706 cell line. Chromatin immunoprecipitation assay showed that acetylated histone H3 and H4 were found in the SFRP1 promoter region. CONCLUSION Promoter hypermethylation of SFRP1 is a frequent event in ESCC. Promoter methylation and histone acetylation may cooperatively regulate expression of the SFRP1 gene.
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Affiliation(s)
- Ying Meng
- Department of Gastroenterology, Beijing Friendship Hospital Affiliated to the Capital Medical University, 95 Yong'an Road, 100050 Beijing, China
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Agnani D, Camacho-Vanegas O, Camacho C, Lele S, Odunsi K, Cohen S, Dottino P, Martignetti JA. Decreased levels of serum glutathione peroxidase 3 are associated with papillary serous ovarian cancer and disease progression. J Ovarian Res 2011; 4:18. [PMID: 22017790 PMCID: PMC3213073 DOI: 10.1186/1757-2215-4-18] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Accepted: 10/22/2011] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Glutathione peroxidase 3 (GPX3) is a selenocysteine-containing antioxidant enzyme that reacts with hydrogen peroxide and soluble fatty acid hydroperoxides, thereby helping to maintain redox balance within cells. Serum levels of GPX3 have been found to be reduced in various cancers including prostrate, thyroid, colorectal, breast and gastric cancers. Intriguingly, GPX3 has been reported to be upregulated in clear cell ovarian cancer tissues and thus may have implications in chemotherapeutic resistance. Since clear cell and serous subtypes of ovarian cancer represent two distinct disease entities, the aim of this study was to determine GPX3 levels in serous ovarian cancer patients and establish its potential as a biomarker for detection and/or surveillance of papillary serous ovarian cancer, the most frequent form of ovarian tumors in women. PATIENTS AND METHODS Serum was obtained from 66 patients (median age: 62 years, range: 22-89) prior to surgery and 65 controls with a comparable age-range (median age: 53 years, range: 25-83). ELISA was used to determine the levels of serum GPX3. The Mann Whitney U test was performed to determine statistical significance between the levels of serum GPX3 in patients and controls. RESULTS Serum levels of GPX3 were found to be significantly lower in patients than controls (p = 1 × 10-2). Furthermore, this was found to be dependent on the stage of disease. While levels in early stage (I/II) patients showed no significant difference when compared to controls, there was a significant reduction in late stage (III/IV, p = 9 × 10-4) and recurrent (p = 1 × 10-2) patients. There was a statistically significant reduction in levels of GPX3 between early and late stage (p = 5 × 10-4) as well as early and recurrent (p = 1 × 10-2) patients. Comparison of women and controls stratified to include only women at or above 50 years of age shows that the same trends were maintained and the differences became more statistically significant. CONCLUSIONS Serum GPX3 levels are decreased in women with papillary serous ovarian cancer in a stage-dependent manner and also decreased in women with disease recurrence. Whether this decrease represents a general feature in response to the disease or a link to the progression of the cancer is unknown. Understanding this relationship may have clinical and therapeutic consequences for women with papillary serous adenocarcinoma.
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Affiliation(s)
- Deep Agnani
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
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