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Parisi GF, Papale M, Pecora G, Rotolo N, Manti S, Russo G, Leonardi S. Cystic Fibrosis and Cancer: Unraveling the Complex Role of CFTR Gene in Cancer Susceptibility. Cancers (Basel) 2023; 15:4244. [PMID: 37686519 PMCID: PMC10486401 DOI: 10.3390/cancers15174244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/06/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
Cystic fibrosis (CF) is a genetic disorder affecting multiple organs, primarily the lungs and digestive system. Over the years, advancements in medical care and treatments have significantly increased the life expectancy of individuals with CF. However, with this improved longevity, concerns about the potential risk of developing certain types of cancers have arisen. This narrative review aims to explore the relationship between CF, increased life expectancy, and the associated risk for cancers. We discuss the potential mechanisms underlying this risk, including chronic inflammation, immune system dysregulation, and genetic factors. Additionally, we review studies that have examined the incidence and types of cancers seen in CF patients, with a focus on gastrointestinal, breast, and respiratory malignancies. We also explore the impact of CFTR modulator therapies on cancer risk. In the gastrointestinal tract, CF patients have an elevated risk of developing colorectal cancer, pancreatic cancer, and possibly esophageal cancer. The underlying mechanisms contributing to these increased risks are not fully understood, but chronic inflammation, altered gut microbiota, and genetic factors are believed to play a role. Regular surveillance and colonoscopies are recommended for early detection and management of colorectal cancer in CF patients. Understanding the factors contributing to cancer development in CF patients is crucial for implementing appropriate surveillance strategies and improving long-term outcomes. Further research is needed to elucidate the molecular mechanisms involved and develop targeted interventions to mitigate cancer risk in individuals with CF.
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Affiliation(s)
- Giuseppe Fabio Parisi
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
| | - Maria Papale
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
| | - Giulia Pecora
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
| | - Novella Rotolo
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
| | - Sara Manti
- Pediatric Unit, Department of Human and Pediatric Pathology “Gaetano Barresi”, AOUP G. Martino, University of Messina, Via Consolare Valeria, 1, 98124 Messina, Italy;
| | - Giovanna Russo
- Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy;
| | - Salvatore Leonardi
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
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Yi TT, Yu JM, Liang YY, Wang SQ, Lin GC, Wu XD. Identification of cystic fibrosis transmembrane conductance regulator as a prognostic marker for juvenile myelomonocytic leukemia via the whole-genome bisulfite sequencing of monozygotic twins and data mining. Transl Pediatr 2022; 11:1521-1533. [PMID: 36247890 PMCID: PMC9561505 DOI: 10.21037/tp-22-381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 09/08/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Linked deoxyribonucleic acid (DNA) hypermethylation investigations of promoter methylation levels of candidate genes may help to increase the progressiveness and mortality rates of juvenile myelomonocytic leukemia (JMML), which is a unique myelodysplastic/myeloproliferative neoplasm caused by excessive monocyte and granulocyte proliferation in infancy/early childhood. However, the roles of hypermethylation in this malignant disease are uncertain. METHODS Bone marrow samples from a JMML patient and peripheral blood samples from a healthy monozygotic twin and an unrelated healthy donor were collected with the informed consent of the participant's parents. Whole-genome bisulfite sequencing (WGBS) was then performed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to analyze specific differentially methylated region (DMG) related genes. The target genes were screened with Cytoscape and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), which are gene/protein interaction databases. A data mining platform was used to examine the expression level data of the healthy control and JMML patient tissues in Gene Expression Omnibus data sets, and a survival analysis was performed for all the JMML patients. RESULTS The STRING analysis revealed that the red node [i.e., the cystic fibrosis transmembrane conductance regulator (CFTR)] was the gene of interest. The gene-expression microarray data set analysis suggested that the CFTR expression levels did not differ significantly between the JMML patients and healthy controls (P=0.81). A statistically significant difference was observed in the CFTR promoter methylation level but not in the CFTR gene body methylation level. The overall survival analysis demonstrated that a high level of CFTR expression was associated with a worse survival rate in patients with JMML (P=0.039). CONCLUSIONS CFTR promoter hypermethylation may be a novel biomarker for the diagnosis, monitoring of disease progression, and prognosis of JMML.
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Affiliation(s)
- Tian-Tian Yi
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jie-Ming Yu
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yi-Yang Liang
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Si-Qi Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Guan-Chuan Lin
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xue-Dong Wu
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Koudonas A, Papaioannou M, Kampantais S, Anastasiadis A, Hatzimouratidis K, Dimitriadis G. Methylation of PCDH17 and NEFH as prognostic biomarker for nonmetastatic RCC: A cohort study. Medicine (Baltimore) 2022; 101:e29599. [PMID: 35838992 PMCID: PMC11132415 DOI: 10.1097/md.0000000000029599] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 05/01/2022] [Indexed: 11/27/2022] Open
Abstract
DNA methylation makes up a main part of the molecular mechanism of cancer evolution and has shown promising results in the prognosis of renal cell cancer (RCC). In this study, we investigated the possible association of promoter methylation of PCDH17, NEFH, RASSF1A, and FHIT, genes with the prognosis of nonmetastatic RCC patients. Cancerous and normal adjacent tissues from surgical specimens of 41 patients with long follow-up were treated for DNA isolation and bisulfite conversion. The gene promoter methylation was determined with quantitative methylation-specific PCR (qMSP). Wilcoxon signed-rank test was used for paired methylation comparisons, while univariate linear regression and Mann-Whitney test were applied for associating methylation status with clinical and disease characteristics. Cox regression proportional hazards models and Kaplan-Meier plots were used for survival analyses in reference to methylation status. Paired comparisons showed tissue-specific hypermethylation for PCDH17 (P < .001), NEFH (P < .001), RASSF1A (P = .032), while a positive association of methylation in normal tissues with age was demonstrated for PCDH17 (P < .001), RASSF1A (P < .001), FHIT (P < .001). PCDH17 was more methylated in cases with clear cell RCC (P = .015) and high-grade tumor (P = .013), while NEFH methylation was higher in locally advanced cases (P = .032). PCDH17 hypermethylation in cancerous and normal tissues was linked to shorter disease-specific survival (DSS, P = .026, P = .004), disease-free survival (DFS, P = .004, P = .019) while NEFH hypermethylation in cancerous tissues was related to shorter DSS (P = .032). Increased methylation difference of NEFH was also associated with shorter DSS (P = .041) and DFS (P = .020), while the corresponding parameter for PCDH17 was associated with poor DFS (P = .014). Kaplan-Meier curves for hypermethylation in cancer tissues demonstrated different clinical courses for PCDH17 (P = .017), NEFH (P = .023) regarding DSS, and PCDH17 (P = .001) regarding DFS. Our study not only highlights the prognostic value of promoter methylation of PCDH17 and NEFH in cancer tissues but also is the first report of the prognostic value of methylation alterations in normal tissues. Our findings are the first report of the prognostic value of methylation alterations in normal tissues, which can contribute to improved assessment of recurrence risk.
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Affiliation(s)
- Antonios Koudonas
- First Department of Urology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Maria Papaioannou
- Laboratory of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Spyridon Kampantais
- First Department of Urology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Anastasios Anastasiadis
- First Department of Urology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Georgios Dimitriadis
- First Department of Urology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Analysis of CFTR gene expression as an immunological and prognostic biomarker in pan-cancers. Comput Biol Med 2022; 146:105614. [DOI: 10.1016/j.compbiomed.2022.105614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 05/09/2022] [Accepted: 05/10/2022] [Indexed: 11/23/2022]
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Bhattacharya R, Blankenheim Z, Scott PM, Cormier RT. CFTR and Gastrointestinal Cancers: An Update. J Pers Med 2022; 12:868. [PMID: 35743652 PMCID: PMC9224611 DOI: 10.3390/jpm12060868] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/21/2022] [Accepted: 05/23/2022] [Indexed: 11/17/2022] Open
Abstract
Cystic Fibrosis (CF) is a disease caused by mutations in the CFTR gene that severely affects the lungs as well as extra-pulmonary tissues, including the gastrointestinal (GI) tract. CFTR dysfunction resulting from either mutations or the downregulation of its expression has been shown to promote carcinogenesis. An example is the enhanced risk for several types of cancer in patients with CF, especially cancers of the GI tract. CFTR also acts as a tumor suppressor in diverse sporadic epithelial cancers in many tissues, primarily due to the silencing of CFTR expression via multiple mechanisms, but especially due to epigenetic regulation. This review provides an update on the latest research linking CFTR-deficiency to GI cancers, in both CF patients and in sporadic GI cancers, with a particular focus on cancer of the intestinal tract. It will discuss changes in the tissue landscape linked to CFTR-deficiency that may promote cancer development such as breakdowns in physical barriers, microbial dysbiosis and inflammation. It will also discuss molecular pathways and mechanisms that act upstream to modulate CFTR expression, such as by epigenetic silencing, as well as molecular pathways that act downstream of CFTR-deficiency, such as the dysregulation of the Wnt/β-catenin and NF-κB signaling pathways. Finally, it will discuss the emerging CFTR modulator drugs that have shown promising results in improving CFTR function in CF patients. The potential impact of these modulator drugs on the treatment and prevention of GI cancers can provide a new example of personalized cancer medicine.
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Affiliation(s)
| | | | - Patricia M. Scott
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA or (R.B.); (Z.B.)
| | - Robert T. Cormier
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA or (R.B.); (Z.B.)
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6
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Parisi GF, Mòllica F, Giallongo A, Papale M, Manti S, Leonardi S. Cystic fibrosis transmembrane conductance regulator (CFTR): beyond cystic fibrosis. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022. [DOI: 10.1186/s43042-022-00308-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The cystic fibrosis transmembrane conductance regulator (CFTR) gene has been traditionally linked to cystic fibrosis (CF) inheritance in an autosomal recessive manner. Advances in molecular biology and genetics have expanded our understanding of the CFTR gene and its encoding products expressed in different tissues.
Aim
The study’s aim consists of reviewing the different pathological CF phenotypes using the existing literature. We know that alterations of the CFTR protein’s structure may result in different pathological phenotypes.
Methods
Open sources such as PubMed and Science Direct databases have been used for this review. We focused our selection on articles published within the last 15 years. Critical terms related to the CFTR protein have been used: “CFTR AND cancer,” “CFTR AND celiac disease,” “CFTR AND pancreatitis,” “children,” “adults,” “genotype,” “phenotype,” “correlation,” “mutation,” “CFTR,” “diseases,” “disorders,” and “no cystic fibrosis.”
Results
We analyzed 1,115 abstracts in total. Moreover, only 189 were suitable for the topic. We focused on the role of CFTR in cancer, gastrointestinal disorders, respiratory diseases, reproductive system, and systemic hypertension.
Conclusions
Mutations in CFTR gene are often associated with CF. In this review, we highlighted the broad spectrum of alterations reported for this gene, which may be involved in the pathogenesis of other diseases. The importance of these new insights in the role of CFTR relies on the possibility of considering this protein/gene as a novel therapeutic target for CF- and CFTR-related diseases.
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Karaglani M, Panagopoulou M, Baltsavia I, Apalaki P, Theodosiou T, Iliopoulos I, Tsamardinos I, Chatzaki E. Tissue-Specific Methylation Biosignatures for Monitoring Diseases: An In Silico Approach. Int J Mol Sci 2022; 23:2959. [PMID: 35328380 PMCID: PMC8952417 DOI: 10.3390/ijms23062959] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/01/2022] [Accepted: 03/03/2022] [Indexed: 02/06/2023] Open
Abstract
Tissue-specific gene methylation events are key to the pathogenesis of several diseases and can be utilized for diagnosis and monitoring. Here, we established an in silico pipeline to analyze high-throughput methylome datasets to identify specific methylation fingerprints in three pathological entities of major burden, i.e., breast cancer (BrCa), osteoarthritis (OA) and diabetes mellitus (DM). Differential methylation analysis was conducted to compare tissues/cells related to the pathology and different types of healthy tissues, revealing Differentially Methylated Genes (DMGs). Highly performing and low feature number biosignatures were built with automated machine learning, including: (1) a five-gene biosignature discriminating BrCa tissue from healthy tissues (AUC 0.987 and precision 0.987), (2) three equivalent OA cartilage-specific biosignatures containing four genes each (AUC 0.978 and precision 0.986) and (3) a four-gene pancreatic β-cell-specific biosignature (AUC 0.984 and precision 0.995). Next, the BrCa biosignature was validated using an independent ccfDNA dataset showing an AUC and precision of 1.000, verifying the biosignature's applicability in liquid biopsy. Functional and protein interaction prediction analysis revealed that most DMGs identified are involved in pathways known to be related to the studied diseases or pointed to new ones. Overall, our data-driven approach contributes to the maximum exploitation of high-throughput methylome readings, helping to establish specific disease profiles to be applied in clinical practice and to understand human pathology.
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Affiliation(s)
- Makrina Karaglani
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, GR-68100 Alexandroupolis, Greece; (M.K.); (M.P.); (P.A.); (T.T.)
| | - Maria Panagopoulou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, GR-68100 Alexandroupolis, Greece; (M.K.); (M.P.); (P.A.); (T.T.)
| | - Ismini Baltsavia
- Department of Basic Sciences, School of Medicine, University of Crete, GR-71003 Heraklion, Greece; (I.B.); (I.I.)
| | - Paraskevi Apalaki
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, GR-68100 Alexandroupolis, Greece; (M.K.); (M.P.); (P.A.); (T.T.)
| | - Theodosis Theodosiou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, GR-68100 Alexandroupolis, Greece; (M.K.); (M.P.); (P.A.); (T.T.)
| | - Ioannis Iliopoulos
- Department of Basic Sciences, School of Medicine, University of Crete, GR-71003 Heraklion, Greece; (I.B.); (I.I.)
| | - Ioannis Tsamardinos
- JADBio Gnosis DA S.A., Science and Technology Park of Crete, GR-70013 Heraklion, Greece;
- Department of Computer Science, University of Crete, GR-70013 Heraklion, Greece
- Institute of Applied and Computational Mathematics, Foundation for Research and Technology—Hellas, GR-70013 Heraklion, Greece
| | - Ekaterini Chatzaki
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, GR-68100 Alexandroupolis, Greece; (M.K.); (M.P.); (P.A.); (T.T.)
- Institute of Agri-Food and Life Sciences, Hellenic Mediterranean University Research Centre, GR-71410 Heraklion, Greece
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Cui D, Li W, Jiang D, Wu J, Xie J, Wu Y. Advances in Multi-Omics Applications in HBV-Associated Hepatocellular Carcinoma. Front Med (Lausanne) 2021; 8:754709. [PMID: 34660653 PMCID: PMC8514776 DOI: 10.3389/fmed.2021.754709] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 08/31/2021] [Indexed: 12/15/2022] Open
Abstract
Hepatitis B virus (HBV) specifically infects liver cells, leading to progressive liver cirrhosis and significantly increasing the risk of hepatocellular carcinoma (HCC). The maturity of sequencing technology, improvement in bioinformatics data analysis and progress of omics technologies had improved research efficiency. The occurrence and progression of HCC are affected by multisystem and multilevel pathological changes. With the application of single-omics technologies, including genomics, transcriptomics, metabolomics and proteomics in tissue and body fluid samples, and even the novel development of multi-omics analysis on a single-cell platform, HBV-associated HCC changes can be better analyzed. The review summarizes the application of single omics and combined analysis of multi-omics data in HBV-associated HCC and proposes the importance of multi-omics analysis in the type of HCC, which provide the possibility for the precise diagnosis and therapy of HBV-associated HCC.
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Affiliation(s)
- Dawei Cui
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Li
- Center of Research Laboratory, The First People's Hospital of Lianyungang, Lianyungang, China
| | - Daixi Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianguo Wu
- Department of Laboratory Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
| | - Jue Xie
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yingping Wu
- Department of Laboratory Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
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9
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Zhu L, Guo W. Combined DNA Methylation and Transcriptomic Assessments to Determine a Prognostic Model for PD-1-Negative Hepatocellular Carcinoma. Front Cell Dev Biol 2021; 9:708819. [PMID: 34458266 PMCID: PMC8385720 DOI: 10.3389/fcell.2021.708819] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 07/23/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has the highest incidence and mortality of any malignancy in the world. Immunotherapy has been a major breakthrough for HCC treatment, but immune checkpoint inhibitors (ICIs) are effective in only a small percentage of HCC patients. In the present study, we screened programmed cell death protein 1 (PD-1) -negative HCC samples, which are frequently resistant to ICIs, and identified their methylation and transcription characteristics through the assessment of differential gene methylation and gene expression. We also screened for potential targeted therapeutic drugs using the DrugBank database. Finally, we used a LASSO (least absolute shrinkage and selection operator) regression analysis to construct a prognostic model based on three differentially methylated and expressed genes (DMEGs). The results showed that ESTIMATE (Estimation of Stromal and Immune Cells in Malignant Tumors using Expression Data) scores for the tumor samples were significantly lower compared to normal sample ESTIMATE scores. In addition, we identified 31 DMEGs that were able to distinguish PD-1-negative samples from normal samples. A functional enrichment analysis showed that these genes were involved in a variety of tumor-related pathways and immune-related pathways, and the DrugBank screening identified potential therapeutic drugs. Finally, the prognostic model based on three DMEGs (UBD, CD5L, and CD213A2) demonstrated good predictive power for HCC prognosis and was verified using an independent cohort. The present study demonstrated the methylation characteristics of PD-1-negative HCC samples, identified several potential therapeutic drugs, and proposed a prognostic model based on UBD, CD5L, and CD213A2 methylation expression. In conclusion, this work provides an in-depth understanding of methylation in HCC samples that are not sensitive to ICIs.
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Affiliation(s)
- Lixu Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
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10
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Chong H, Zhou P, Yang C, Zeng M. An excellent nomogram predicts microvascular invasion that cannot independently stratify outcomes of small hepatocellular carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:757. [PMID: 34268370 PMCID: PMC8246205 DOI: 10.21037/atm-20-7952] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 03/05/2021] [Indexed: 01/27/2023]
Abstract
Background Whether microvascular invasion is a prognosis factor for small hepatocellular carcinoma (sHCC) is controversial, and a preoperatively predictive model based on gadoxetate disodium (Gd-EOB-DTPA) MRI is clinically needed for MVI in sHCC. Methods Between March 2012 and September 2020, 455 consecutive patients with pathologically confirmed HCC ≤3 cm who underwent hepatectomy and preoperative Gd-EOB-DTPA MRI were retrospectively enrolled. Univariate and multivariate logistic regression combined with cox regression were conducted to find the confounding factors in the cohorts. Propensity score matching (PSM) was employed to balance the biases between MVI and non-MVI groups. Nomogram with C-index visualized the predictive model of MVI. Results Multivariate logistic regression identified that 5 characteristics (AFP, tumor size, tumor margin, peritumoral enhancement, radiologic capsule) were markedly associated with MVI of sHCC and incorporated into the nomogram with excellent predictive performance in the training (AUC/C-index: 0.884/0.874, n=288), validation (AUC/C-index: 0.845/0.828, n=123) and test cohorts (AUC/C-index: 0.903/0.954, n=44). Before PSM, histologic MVI independently affected tumor recurrence (hazard ratio: 1.555, 95% CI: 1.055–2.293, P=0.026). However, due to the confounder of tumor size, there was a significant bias between MVI-positive and MVI-negative groups (propensity score: 0.249±0.105 vs. 0.179±0.106, P<0.001). Meanwhile, the frequency of MVI significantly increased as tumor size growing (P<0.001). After PSM, 70 of 79 MVI cases matched with 171 non-MVI (total 332), and no biases were observed between the two groups (propensity score: 0.238±0.104 vs. 0.217±0.109, P=0.186). Although the median recurrence time in non-MVI sHCC was still longer than that in MVI group (74.3 vs. 43.0 months, P=0.063), MVI was not an independent risk factor for RFS in sHCC. Additionally, MVI was not independently vulnerable to mortality in our population. Conclusions A preoperative model, mainly based on the peritumoral hallmarks of Gd-EOB-DTPA MRI, showed an excellent performance to predict the occurrence of MVI. Nevertheless, MVI was a potential but not an independent risk factor for recurrence and mortality in sHCC ≤3 cm.
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Affiliation(s)
- Huanhuan Chong
- Shanghai Institute of Medical Imaging, Shanghai, China.,Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Peiyun Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.,Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Chun Yang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mengsu Zeng
- Shanghai Institute of Medical Imaging, Shanghai, China.,Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Medical Imaging, Shanghai Medical College, Fudan University, Shanghai, China
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11
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Qian Y, Wang H, Zhang Y, Wang JW, Fan YC, Gao S, Wang K. Hypermethylation of Cyclin D2 Predicts Poor Prognosis of Hepatitis B Virus-Associated Hepatocellular Carcinoma after Hepatectomy. TOHOKU J EXP MED 2021; 254:233-243. [PMID: 34334537 DOI: 10.1620/tjem.254.233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Prognosis of patients with hepatocellular carcinoma remains poor because of progression of hepatocellular carcinoma and high recurrence rates. Cyclin D2 (CCND2) plays a vital role in regulating the cell cycle; indeed, aberrant methylation of CCND2 is involved in the development of hepatocellular carcinoma. Therefore, we aimed to investigate levels of CCND2 methylation in patients with hepatitis B virus (HBV)-associated hepatocellular carcinoma and to evaluate its prognostic significance after hepatectomy. In total, 257 subjects were enrolled (166 hepatocellular carcinoma patients undergoing surgical resection, 61 chronic hepatitis B (CHB) patients, and 30 healthy controls). CCND2 methylation in peripheral blood mononuclear cells was measured quantitatively using MethyLight. We found that CCND2 methylation levels in patients with HBV-associated hepatocellular carcinoma were significantly higher than in CHB patients (P < 0.001) or healthy controls (P < 0.001). Within the hepatocellular carcinoma group, CCND2 methylation levels were higher in patients with portal vein invasion, early tumor recurrence, TNM III/IV stage, and tumor size ≥ 5 cm (P < 0.05). Furthermore, higher levels of CCND2 methylation were associated with worse overall survival and disease-free survival (P = 0.005 and P < 0.001, respectively). Multivariate analysis identified CCND2 methylation as an independent prognostic factor for early tumor recurrence (P = 0.021), overall survival (P = 0.022), and disease-free survival (P < 0.001) in hepatocellular carcinoma patients after resection. In conclusion, hypermethylation of CCND2 may have clinical utility for predicting a high risk of poor prognosis and early tumor recurrence in patients with HBV-associated hepatocellular carcinoma after hepatectomy.
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Affiliation(s)
- Yu Qian
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University
| | - He Wang
- Department of Hepatopathy, Qingdao Sixth People's Hospital
| | - Ying Zhang
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University
| | - Jing-Wen Wang
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University.,Institute of Hepatology, Shandong University
| | - Shuai Gao
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University.,Institute of Hepatology, Shandong University
| | - Kai Wang
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University.,Institute of Hepatology, Shandong University
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12
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Liu C, Song C, Li J, Sun Q. CFTR Functions as a Tumor Suppressor and Is Regulated by DNA Methylation in Colorectal Cancer. Cancer Manag Res 2020; 12:4261-4270. [PMID: 32606923 PMCID: PMC7292251 DOI: 10.2147/cmar.s248539] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 05/13/2020] [Indexed: 12/12/2022] Open
Abstract
Purpose Cystic fibrosis transmembrane conductance regulator (CFTR) was shown to be downregulated or silenced in carcinomas and acts as a candidate tumor suppressor gene. However, the function of CFTR gene in colorectal cancer (CRC) is still unclear. This aim of this study was to investigate the CFTR promoter methylation status and its impact on the expression and functional role of CFTR in CRC development. Patients and Methods CFTR expression in CRC tissues and CRC cell lines was detected via quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The promoter methylation status of CFTR was measured using methylation-specific PCR (MSP). colony formation, transwell, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were used to evaluate the effect of CFTR overexpression in CRC cell lines. Results qRT-PCR and IHC results indicated that CFTR expression was downregulated in the CRC tissues compared to the adjacent normal tissues. The promoter methylation status of CFTR was further analyzed in 70 CRC specimens. MSP validation showed methylation of CFTR promoter in 62.2% (45/70) of CRC tissues. The methylation of CFTR promoter was significantly associated with age (P=0.013) and lymph node metastasis (P=0.026) in CRC tissues. Results of transwell, MTT, and colony formation assays showed that CFTR overexpression inhibited the migration, invasion, and proliferation of CRC cells. Conclusion CFTR expression was downregulated in CRC and promoter methylation may be responsible for this downregulation. Overexpression of CFTR may suppress CRC tumor growth by inhibiting the proliferation, migration, and invasion of CRC cells. CFTR promoter methylation was significantly correlated with lymph node metastasis; thus, CFTR may be a potential marker for lymph node metastasis of CRC.
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Affiliation(s)
- Can Liu
- Department of Pathology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, People's Republic of China
| | - Chao Song
- Department of Pathology, Zibo Central Hospital, Zibo, Shandong Province, People's Republic of China
| | - Jiaxi Li
- Department of Pathology, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong Province, People's Republic of China
| | - Qing Sun
- Department of Pathology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, People's Republic of China.,Department of Pathology, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong Province, People's Republic of China
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13
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What Role Does CFTR Play in Development, Differentiation, Regeneration and Cancer? Int J Mol Sci 2020; 21:ijms21093133. [PMID: 32365523 PMCID: PMC7246864 DOI: 10.3390/ijms21093133] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 04/21/2020] [Accepted: 04/27/2020] [Indexed: 02/08/2023] Open
Abstract
One of the key features associated with the substantial increase in life expectancy for individuals with CF is an elevated predisposition to cancer, firmly established by recent studies involving large cohorts. With the recent advances in cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and the increased long-term survival rate of individuals with cystic fibrosis (CF), this is a novel challenge emerging at the forefront of this disease. However, the mechanisms linking dysfunctional CFTR to carcinogenesis have yet to be unravelled. Clues to this challenging open question emerge from key findings in an increasing number of studies showing that CFTR plays a role in fundamental cellular processes such as foetal development, epithelial differentiation/polarization, and regeneration, as well as in epithelial–mesenchymal transition (EMT). Here, we provide state-of-the-art descriptions on the moonlight roles of CFTR in these processes, highlighting how they can contribute to novel therapeutic strategies. However, such roles are still largely unknown, so we need rapid progress in the elucidation of the underlying mechanisms to find the answers and thus tailor the most appropriate therapeutic approaches.
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14
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Anderson KJ, Cormier RT, Scott PM. Role of ion channels in gastrointestinal cancer. World J Gastroenterol 2019; 25:5732-5772. [PMID: 31636470 PMCID: PMC6801186 DOI: 10.3748/wjg.v25.i38.5732] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 07/26/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023] Open
Abstract
In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell. The functions of ion channels in the gastrointestinal (GI) tract influence a variety of cellular processes, many of which overlap with these hallmarks of cancer. In this review we focus on the roles of the calcium (Ca2+), sodium (Na+), potassium (K+), chloride (Cl-) and zinc (Zn2+) transporters in GI cancer, with a special emphasis on the roles of the KCNQ1 K+ channel and CFTR Cl- channel in colorectal cancer (CRC). Ca2+ is a ubiquitous second messenger, serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle, apoptosis, and migration. Various members of the TRP superfamily, including TRPM8, TRPM7, TRPM6 and TRPM2, have been implicated in GI cancers, especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer. Voltage-gated sodium channels (VGSCs) are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells. The VGSC NaV1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples. Studies have demonstrated that conductance through NaV1.5 contributes significantly to CRC cell invasiveness and cancer progression. Zn2+ transporters of the ZIP/SLC39A and ZnT/SLC30A families are dysregulated in all major GI organ cancers, in particular, ZIP4 up-regulation in pancreatic cancer (PC). More than 70 K+ channel genes, clustered in four families, are found expressed in the GI tract, where they regulate a range of cellular processes, including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract. Several distinct types of K+ channels are found dysregulated in the GI tract. Notable are hERG1 upregulation in PC, gastric cancer (GC) and CRC, leading to enhanced cancer angiogenesis and invasion, and KCNQ1 down-regulation in CRC, where KCNQ1 expression is associated with enhanced disease-free survival in stage II, III, and IV disease. Cl- channels are critical for a range of cellular and tissue processes in the GI tract, especially fluid balance in the colon. Most notable is CFTR, whose deficiency leads to mucus blockage, microbial dysbiosis and inflammation in the intestinal tract. CFTR is a tumor suppressor in several GI cancers. Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC. Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels (CLIC1, 3 & 4) and the chloride channel accessory proteins (CLCA1,2,4). CLIC1 & 4 are upregulated in PC, GC, gallbladder cancer, and CRC, while the CLCA proteins have been reported to be down-regulated in CRC. In summary, it is clear, from the diverse influences of ion channels, that their aberrant expression and/or activity can contribute to malignant transformation and tumor progression. Further, because ion channels are often localized to the plasma membrane and subject to multiple layers of regulation, they represent promising clinical targets for therapeutic intervention including the repurposing of current drugs.
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Affiliation(s)
- Kyle J Anderson
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
| | - Robert T Cormier
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
| | - Patricia M Scott
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
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Chen M, Du D, Zheng W, Liao M, Zhang L, Liang G, Gong M. Small hepatitis delta antigen selectively binds to target mRNA in hepatic cells: a potential mechanism by which hepatitis D virus downregulates glutathione S-transferase P1 and induces liver injury and hepatocarcinogenesis. Biochem Cell Biol 2018; 97:130-139. [PMID: 30153423 DOI: 10.1139/bcb-2017-0321] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Liver coinfection by hepatitis B virus (HBV) and hepatitis D virus (HDV) can result in a severe form of hepatocellular carcinoma with poor prognosis. Coinfection with HDV and HBV causes more deleterious effects than infection with HBV alone. Clinical research has shown that glutathione S-transferase P1 (GSTP1), a tumor suppressor gene, is typically downregulated in liver samples from hepatitis-infected patients. In the present study, our data indicated that small HDV antigen (s-HDAg) could specifically bind to GSTP1 mRNA and significantly downregulate GSTP1 protein expression. For the human fetal hepatocyte cell line L-02, cells transfected with s-HDAg, along with decreased GSTP1 expression, there was a significant accumulation of reactive oxygen species (ROS) and increased apoptotic ratios. Restoring GSTP1 expression through silencing s-HDAg via RNAi or overexpressing exogenous GSTP1 could largely recover the abnormal cell status. Our results revealed a novel potential mechanism of HDV-induced liver injury and hepatocarcinogenesis: s-HDAg can inhibit GSTP1 expression by directly binding to GSTP1 mRNA, which leads to accumulation of cellular ROS, resulting in high cellular apoptotic ratios and increased selective pressure for malignant transformation. To our knowledge, this is the first study to examine s-HDAg-specific pathogenic mechanisms through potential protein-RNA interactions.
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Affiliation(s)
- Mianzhi Chen
- a Huaxi-Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Dan Du
- a Huaxi-Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wen Zheng
- a Huaxi-Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Mingheng Liao
- b Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lu Zhang
- a Huaxi-Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ge Liang
- a Huaxi-Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Meng Gong
- a Huaxi-Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
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16
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Zhang J, Wang Y, Jiang X, Chan HC. Cystic fibrosis transmembrane conductance regulator-emerging regulator of cancer. Cell Mol Life Sci 2018; 75:1737-1756. [PMID: 29411041 PMCID: PMC11105598 DOI: 10.1007/s00018-018-2755-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 12/27/2017] [Accepted: 01/17/2018] [Indexed: 12/11/2022]
Abstract
Mutations of cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis, the most common life-limiting recessive genetic disease among Caucasians. CFTR mutations have also been linked to increased risk of various cancers but remained controversial for a long time. Recent studies have begun to reveal that CFTR is not merely an ion channel but also an important regulator of cancer development and progression with multiple signaling pathways identified. In this review, we will first present clinical findings showing the correlation of genetic mutations or aberrant expression of CFTR with cancer incidence in multiple cancers. We will then focus on the roles of CFTR in fundamental cellular processes including transformation, survival, proliferation, migration, invasion and epithelial-mesenchymal transition in cancer cells, highlighting the signaling pathways involved. Finally, the association of CFTR expression levels with patient prognosis, and the potential of CFTR as a cancer prognosis indicator in human malignancies will be discussed.
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Affiliation(s)
- Jieting Zhang
- Faculty of Medicine, Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China
- Key Laboratory for Regenerative Medicine of the Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China
- School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China
| | - Yan Wang
- Faculty of Medicine, Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China
- Key Laboratory for Regenerative Medicine of the Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China
- School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China
| | - Xiaohua Jiang
- Faculty of Medicine, Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China.
- Key Laboratory for Regenerative Medicine of the Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China.
- School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China.
| | - Hsiao Chang Chan
- Faculty of Medicine, Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China.
- Key Laboratory for Regenerative Medicine of the Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, People's Republic of China.
- School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China.
- Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Chengdu, People's Republic of China.
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Serine peptidase inhibitor Kunitz type 2 (SPINT2) in cancer development and progression. Biomed Pharmacother 2018; 101:278-286. [PMID: 29499401 DOI: 10.1016/j.biopha.2018.02.100] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 02/19/2018] [Accepted: 02/21/2018] [Indexed: 02/07/2023] Open
Abstract
Understanding the molecular basis and mechanisms involved in neoplastic transformation and progression is important for the development of novel selective target therapeutic strategies. Hepatocyte growth factor (HGF)/c-MET signaling plays an important role in cell proliferation, survival, migration and motility of cancer cells. Serine peptidase inhibitor Kunitz type 2 (SPINT2) binds to and inactivates the HGF activator (HGFA), behaving as an HGFA inhibitor (HAI) and impairing the conversion of pro-HGF into bioactive HGF. The scope of the present review is to recapitulate and review the evidence of SPINT2 participation in cancer development and progression, exploring the clinical, biological and functional descriptions of the involvement of this protein in diverse neoplasias. Most studies are in agreement as to the belief that, in a large range of human cancers, the SPINT2 gene promoter is frequently methylated, resulting in the epigenetic silence of this gene. Functional assays indicate that SPINT2 reactivation ameliorates the malignant phenotype, specifically reducing cell viability, migration and invasion in diverse cancer cell lines. In sum, the SPINT2 gene is epigenetically silenced or downregulated in human cancers, altering the balance of HGF activation/inhibition ratio, which contributes to cancer development and progression.
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18
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Zhang W, Lai SL, Chen J, Xie D, Wu FX, Jin GQ, Su DK. Validated preoperative computed tomography risk estimation for postoperative hepatocellular carcinoma recurrence. World J Gastroenterol 2017; 23:6467-6473. [PMID: 29085196 PMCID: PMC5643272 DOI: 10.3748/wjg.v23.i35.6467] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 07/26/2017] [Accepted: 08/15/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To develop and validate a risk estimation of tumor recurrence following curative resection of operable hepatocellular carcinoma (HCC).
METHODS Data for 128 patients with operable HCC (according to Barcelona Clinic Liver Cancer imaging criteria) who underwent preoperative computed tomography (CT) evaluation at our hospital from May 1, 2013 through May 30, 2014 were included in this study. Follow-up data were obtained from hospital medical records. Follow-up data through May 30, 2016 were used to retrospectively analyze preoperative multiphasic CT findings, surgical histopathology results, and serum α-fetoprotein and thymidine kinase-1 levels. The χ2 test, independent t-test, and Mann-Whitney U test were used to analyze data. A P-value of < 0.05 was considered statistically significant.
RESULTS During the follow-up period, 38 of 128 patients (29.7%) had a postoperative HCC recurrence. Microvascular invasion (MVI) was associated with HCC recurrence (χ2 = 13.253, P < 0.001). Despite postoperative antiviral therapy and chemotherapy, 22 of 44 patients with MVI experienced recurrence after surgical resection. The presence of MVI was 57.9% sensitive, 75.6% specific and 70.3% accurate in predicting postoperative recurrence. Of 84 tumors without MVI, univariate analysis confirmed that tumor margins, tumor margin grade, and tumor capsule detection on multiphasic CT were associated with HCC recurrence (P < 0.05). Univariate analyses showed no difference between groups with respect to hepatic capsular invasion, Ki-67 proliferation marker value, Edmondson-Steiner grade, largest tumor diameter, necrosis, arterial phase enhanced ratio, portovenous phase enhanced ratio, peritumoral enhancement, or serum α-fetoprotein level.
CONCLUSION Non-smooth tumor margins, incomplete tumor capsules and missing tumor capsules correlated with postoperative HCC recurrence. HCC recurrence following curative resection may be predicted using CT.
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Affiliation(s)
- Wei Zhang
- Departments of Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shao-Lv Lai
- Departments of Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jie Chen
- Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Dong Xie
- Departments of Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Fei-Xiang Wu
- Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guan-Qiao Jin
- Departments of Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Dan-Ke Su
- Departments of Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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19
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Li L, Lei QS, Kong LN, Zhang SJ, Qin B. Gene expression profile after knockdown of USP18 in Hepg2.2.15 cells. J Med Virol 2017; 89:1920-1930. [PMID: 28369997 DOI: 10.1002/jmv.24819] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 03/13/2017] [Indexed: 01/18/2023]
Abstract
In our previous work, we found that the expression of ubiquitin-specific protease 18 (USP18), also known as UBP43, is associated with the efficiency of interferon alpha (IFN-α) treatment in patients with chronic hepatitis B (CHB). To elucidate the influence of USP18 on hepatitis B virus (HBV) replication and the mechanism of this activity, we silenced USP18 by introducing short hairpin RNA (shRNA) into Hepg2.2.15 cells. To identify the changed genes and pathways in Hepg2.2.15-shRNA-USP18 cells, we performed a microarray gene expression analysis to compare the Hepg2.2.15 stably expressing USP18-shRNA cells versus control cells using the Affymetrix Human Transcriptome Array (HTA) 2.0 microarrays. Microarray analysis indicated that genes involved in regulation of thyroid hormone signaling pathway, complement, and coagulation cascades, PERK-mediated unfolded protein response, and insulin-like growth factor-activated receptor activity were significantly altered after USP18 knockdown for 72 h. Furthermore, genes involved in hepatocyte proliferation, liver fibrosis, such as cell cycle regulatory gene CCND1, were also altered after USP18 knockdown in Hepg2.2.15 cells. In conclusion, USP18 is critical for regulating the replication of HBV in Hepg2.2.15 cells, which suggest that USP18 may be a candidate target for HBV treatment.
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Affiliation(s)
- Lin Li
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qing-Song Lei
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ling-Na Kong
- School of Nursing, Chongqing Medical University, Chongqing, China
| | - Shu-Jun Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bo Qin
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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20
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Chen D, Jain S, Su YH, Song W. Building Classification Models with Combined Biomarker Tests: Application to Early Detection of Liver Cancer. ACTA ACUST UNITED AC 2017; 5:91-103. [PMID: 29152526 DOI: 10.17265/2328-224x/2017.0506.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Early detection of hepatocellular carcinoma (HCC) is critical for the effective treatment. Alpha fetoprotein (AFP) serum level is currently used for HCC screening, but the cutoff of the AFP test has limited sensitivity (~50%), indicating a high false negative rate. We have successfully demonstrated that cancer derived DNA biomarkers can be detected in urine of patients with cancer and can be used for the early detection of cancer (Jain et al., 2015; Lin et al., 2011; Song et al., 2012; Su, Lin, Song, & Jain, 2014; Su, Wang, Norton, Brenner, & Block, 2008). By combining urine biomarkers (uBMK) values and serum AFP (sAFP) level, a new classification model has been proposed for more efficient HCC screening. Several criterions have been discussed to optimal the cutoff for uBMK score and sAFP score. A joint distribution of sAFP and uBMK with point mass has been fitted using maximum likelihood method. Numerical results show that the sAFP data and uBMK data are very well described by proposed model. A tree-structured sequential test can be optimized by selecting the cutoffs. Bootstrap simulations also show the robust classification results with the optimal cutoff.
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Affiliation(s)
- Dion Chen
- Biostatistics, Janssen R&D, LLC, Spring House, PA 19477, USA
| | - Surbhi Jain
- Biomarkers, JBS Science, Inc., Doylestown, PA 18902, USA
| | - Ying-Hsu Su
- Biomarkers, The Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - Wei Song
- Biomarkers, JBS Science, Inc., Doylestown, PA 18902, USA
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21
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Wang F, Wang R, Li Q, Qu X, Hao Y, Yang J, Zhao H, Wang Q, Li G, Zhang F, Zhang H, Zhou X, Peng X, Bian Y, Xiao W. A transcriptome profile in hepatocellular carcinomas based on integrated analysis of microarray studies. Diagn Pathol 2017; 12:4. [PMID: 28086821 PMCID: PMC5237304 DOI: 10.1186/s13000-016-0596-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 12/30/2016] [Indexed: 02/06/2023] Open
Abstract
Background Despite new treatment options for hepatocellular carcinomas (HCC) recently, 5-year survival remains poor, ranging from 50 to 70%, which may attribute to the lack of early diagnostic biomarkers. Thus, developing new biomarkers for early diagnosis of HCC, is extremely urgent, aiming to decrease HCC-related deaths. Methods In the study, we conducted a comprehensive characterization of gene expression data of HCC based on a bioinformatics method. The results were confirmed by real time polymerase chain reaction (RT-PCR) and TCGA database to prove the credibility of this integrated analysis. Results After integrating analysis of seven HCC gene expression datasets, 1167 differential expressed genes (DEGs) were identified. These genes mainly participated in the process of cell cycle, oocyte meiosis, and oocyte maturation mediated by progesterone. The results of experiments and TCGA database validation in 10 genes was in full accordance with findings in integrated analysis, indicating the high credibility of our integrated analysis of different gene expression datasets. ASPM, CCT3, and NEK2 was showed to be significantly associated with overall survival of HCC patients in TCGA database. Conclusion This method of integrated analysis may be a useful tool to minish the heterogeneity of individual microarray, hopefully outputs more accurate HCC transcriptome profiles based on large sample size, and explores some potential biomarkers and therapy targets for HCC. Electronic supplementary material The online version of this article (doi:10.1186/s13000-016-0596-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Feifei Wang
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Fucheng Road 51, Beijing, 100048, China
| | - Ruliang Wang
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Fucheng Road 51, Beijing, 100048, China
| | - Qiuwen Li
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Fucheng Road 51, Beijing, 100048, China
| | - Xueling Qu
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Fucheng Road 51, Beijing, 100048, China
| | - Yixin Hao
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Fucheng Road 51, Beijing, 100048, China
| | - Jingwen Yang
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Fucheng Road 51, Beijing, 100048, China
| | - Huixia Zhao
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Fucheng Road 51, Beijing, 100048, China
| | - Qian Wang
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Fucheng Road 51, Beijing, 100048, China
| | - Guanghui Li
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Fucheng Road 51, Beijing, 100048, China
| | - Fengyun Zhang
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Fucheng Road 51, Beijing, 100048, China
| | - He Zhang
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Fucheng Road 51, Beijing, 100048, China
| | - Xuan Zhou
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Fucheng Road 51, Beijing, 100048, China
| | - Xioumei Peng
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Fucheng Road 51, Beijing, 100048, China
| | - Yang Bian
- Department of Bioinformatics, Beijing Medintell Biomed Co., Ltd, Beijing, China
| | - Wenhua Xiao
- Department of Oncology, The First Affiliated Hospital of PLA General Hospital, Fucheng Road 51, Beijing, 100048, China.
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Cong WM, Bu H, Chen J, Dong H, Zhu YY, Feng LH, Chen J, Committee G. Practice guidelines for the pathological diagnosis of primary liver cancer: 2015 update. World J Gastroenterol 2016; 22:9279-9287. [PMID: 27895416 PMCID: PMC5107692 DOI: 10.3748/wjg.v22.i42.9279] [Citation(s) in RCA: 272] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 06/15/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
In 2010, a panel of Chinese pathologists reported the first expert consensus for the pathological diagnosis of primary liver cancers to address the many contradictions and inconsistencies in the pathological characteristics and diagnostic criteria for PLC. Since then considerable clinicopathological studies have been conducted globally, prompting us to update the practice guidelines for the pathological diagnosis of PLC. In April 18, 2014, a Guideline Committee consisting of 40 specialists from seven Chinese Societies (including Chinese Society of Liver Cancer, Chinese Anti-Cancer Association; Liver Cancer Study Group, Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Pathology, Chinese Anti-Cancer Association; Digestive Disease Group, Chinese Society of Pathology, Chinese Medical Association; Chinese Society of Surgery, Chinese Medical Association; Chinese Society of Clinical Oncology, Chinese Anti-Cancer Association; Pathological Group of Hepatobiliary Tumor and Liver Transplantation, Chinese Society of Pathology, Chinese Medical Association) was created for the formulation of the first guidelines for the standardization of the pathological diagnosis of PLC, mainly focusing on the following topics: gross specimen sampling, concepts and diagnostic criteria of small hepatocellular carcinoma (SHCC), microvascular invasion (MVI), satellite nodules, and immunohistochemical and molecular diagnosis. The present updated guidelines are reflective of current clinicopathological studies, and include a novel 7-point baseline sampling protocol, which stipulate that at least four tissue specimens should be sampled at the junction of the tumor and adjacent liver tissues in a 1:1 ratio at the 12, 3, 6 and 9 o’clock reference positions. For the purposes of molecular pathological examination, at least one specimen should be sampled at the intratumoral zone, but more specimens should be sampled for tumors harboring different textures or colors. Specimens should be sampled at both adjacent and distant peritumoral liver tissues or the tumor margin in order to observe MVI, satellite nodules and dysplastic foci/nodules distributed throughout the background liver tissues. Complete sampling of whole SHCC ≤ 3 cm should be performed to assess its biological behavior, and in clinical practice, therapeutic borders should be also preserved, even in SHCC. The diagnostic criteria of MVI and satellite nodules, immunohistochemical panels, as well as molecular diagnostic principles, such as clonal typing, for recurrent HCC and multinodule HCC were also proposed and recommended. The standardized process of pathological examination is aimed at ensuring the accuracy of pathological PLC diagnoses as well as providing a valuable frame of reference for the clinical assessment of tumor invasive potential, the risk of postoperative recurrence, long-term survival, and the development of individualized treatment regimens. The updated guidelines could ensure the accuracy of pathological diagnoses of PLC, and provide a valuable frame of reference for its clinical assessment.
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Epigenetic mechanisms regulating the development of hepatocellular carcinoma and their promise for therapeutics. Hepatol Int 2016; 11:45-53. [PMID: 27271356 DOI: 10.1007/s12072-016-9743-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 05/17/2016] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers around the globe and third most fatal malignancy. Chronic liver disorders such as chronic hepatitis and liver cirrhosis often lead to the development of HCC. Accumulation of genetic and epigenetic alterations are involved in the development of HCC. Genetic research sparked by recent developments in next generation sequencing has identified the frequency of genetic alterations that occur in HCC and has led to the identification of genetic hotspots. Emerging evidence suggests that epigenetic aberrations are strongly associated with the initiation and development of HCC. Various important genes encoding tumor suppressors including P16, RASSF1A, DLC-1, RUNX3 and SOCS-1 are targets of epigenetic dysregulation during the development of HCC. The present review discusses the importance of epigenetic regulations including DNA methylation, histone modification and microRNA mediated regulation of gene expression during tumorigenesis and their use as disease biomarkers. Furthermore, these epigenetic alterations have been discussed in relationship with promising therapeutic perspectives for HCC and related cancers.
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Song MA, Kwee SA, Tiirikainen M, Hernandez BY, Okimoto G, Tsai NC, Wong LL, Yu H. Comparison of genome-scale DNA methylation profiles in hepatocellular carcinoma by viral status. Epigenetics 2016; 11:464-74. [PMID: 27248055 DOI: 10.1080/15592294.2016.1151586] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Hepatocellular carcinoma (HCC) incidence has steadily increased in the US over the past 30 years. Our understanding of epigenetic regulation in HCC is still limited, especially the impact of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection on aberrant DNA methylation. We performed genome-wide DNA methylation profiling in 33 fresh frozen tumor samples, including 10 HBV-HCC, 13 HCV-HCC, and 10 non-infected (NIV-HCC) using the Illumina HumanMethylation450 BeadChip. Gene expression profiling was also performed using the Illumina whole-genome DASL HT Assay. Biological influences and gene networks of the differentially-methylated (DM) CpG loci were predicted using the Ingenuity Pathway Analysis. Genome-wide methylation analysis identified 7, 26, and 98 DM loci between HBV-HCC vs. HCV-HCC, HBV-HCC vs. NIV-HCC, and HCV-HCC vs. NIV-HCC, respectively, at P < 5 × 10(-5) for each. Overall, the DM loci were highly enriched for enhancers (48%), promoters (37%), or CpG islands and surrounding regions (37%). Most DM loci were hypermethylated in HCV-HCC compared to HBV-HCC or NIV-HCC. The DM loci were associated with a variety of biological functions including Cell Morphology (HBV-HCC vs. NIV-HCC), Cell Death/ Survival (HBV-HCC vs. NIV-HCC), or Cellular Growth and Proliferation (HCV-HCC vs. NIV-HCC). A subset of the DM loci were correlated (either positively or negatively) with their gene expression or associated with alcohol consumption, BMI, cirrhosis, diabetes, and cigarette smoking. Our findings of differential methylation by viral infection lend insights into the potential effects of viral infection on the epigenetic regulation and further the development and progression of HCC.
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Affiliation(s)
- Min-Ae Song
- a Genomics Shared Resource , University of Hawaii Cancer Center , Honolulu , Hawaii , USA.,b Comprehensive Cancer Center, Ohio State University and James Cancer Hospital , Columbus , Ohio
| | - Sandi A Kwee
- c John A. Burns School of Medicine, University of Hawaii , Honolulu , Hawaii , USA.,d Hamamatsu/Queen's PET Imaging Center, Queen's Medical Center , Honolulu , Hawaii , USA
| | - Maarit Tiirikainen
- a Genomics Shared Resource , University of Hawaii Cancer Center , Honolulu , Hawaii , USA
| | - Brenda Y Hernandez
- e Cancer Epidemiology Program, University of Hawaii Cancer Center , Honolulu , Hawaii , USA
| | - Gordon Okimoto
- e Cancer Epidemiology Program, University of Hawaii Cancer Center , Honolulu , Hawaii , USA
| | - Naoky C Tsai
- f Cancer Biology Program, University of Hawaii Cancer Center , Honolulu , Hawaii , USA
| | - Linda L Wong
- c John A. Burns School of Medicine, University of Hawaii , Honolulu , Hawaii , USA.,f Cancer Biology Program, University of Hawaii Cancer Center , Honolulu , Hawaii , USA
| | - Herbert Yu
- e Cancer Epidemiology Program, University of Hawaii Cancer Center , Honolulu , Hawaii , USA
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Ye C, Tao R, Cao Q, Zhu D, Wang Y, Wang J, Lu J, Chen E, Li L. Whole-genome DNA methylation and hydroxymethylation profiling for HBV-related hepatocellular carcinoma. Int J Oncol 2016; 49:589-602. [PMID: 27221337 DOI: 10.3892/ijo.2016.3535] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 05/13/2016] [Indexed: 11/06/2022] Open
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Hou Y, Guan X, Yang Z, Li C. Emerging role of cystic fibrosis transmembrane conductance regulator - an epithelial chloride channel in gastrointestinal cancers. World J Gastrointest Oncol 2016; 8:282-288. [PMID: 26989463 PMCID: PMC4789613 DOI: 10.4251/wjgo.v8.i3.282] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Revised: 10/21/2015] [Accepted: 12/21/2015] [Indexed: 02/05/2023] Open
Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR), a glycoprotein with 1480 amino acids, has been well established as a chloride channel mainly expressed in the epithelial cells of various tissues and organs such as lungs, sweat glands, gastrointestinal system, and reproductive organs. Although defective CFTR leads to cystic fibrosis, a common genetic disorder in the Caucasian population, there is accumulating evidence that suggests a novel role of CFTR in various cancers, especially in gastroenterological cancers, such as pancreatic cancer and colon cancer. In this review, we summarize the emerging findings that link CFTR with various cancers, with focus on the association between CFTR defects and gastrointestinal cancers as well as the underlying mechanisms. Further study of CFTR in cancer biology may help pave a new way for the diagnosis and treatment of gastrointestinal cancers.
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Niccum DE, Billings JL, Dunitz JM, Khoruts A. Colonoscopic screening shows increased early incidence and progression of adenomas in cystic fibrosis. J Cyst Fibros 2016; 15:548-53. [PMID: 26851188 DOI: 10.1016/j.jcf.2016.01.002] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 12/08/2015] [Accepted: 01/11/2016] [Indexed: 12/24/2022]
Abstract
BACKGROUND Colorectal cancer is an emerging problem in cystic fibrosis (CF). The goal of this study was to evaluate adenoma detection by systematic colonoscopic screening and surveillance. METHODS We analyzed prospectively collected results of colonoscopies initiated at age 40years from 88 CF patients at a single Cystic Fibrosis Center. We also reviewed results of diagnostic colonoscopies from 27 patients aged 30-39years performed during the same time period at the Center. RESULTS The incidence of polyp detection increased markedly after age 40 in CF patients. Greater than 50% were found to have adenomatous polyps; approximately 25% had advanced adenomas as defined by size and/or histopathology; 3% were found to have colon cancer. Multivariate analysis demonstrated specific risk factors for adenoma formation and progression. CONCLUSIONS Early screening and more frequent surveillance should be considered in patients with CF due to early incidence and progression of adenomas in this patient population.
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Affiliation(s)
- David E Niccum
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, United States
| | - Joanne L Billings
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, United States
| | - Jordan M Dunitz
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, United States
| | - Alexander Khoruts
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, United States.
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Jain S, Xie L, Boldbaatar B, Lin SY, Hamilton JP, Meltzer SJ, Chen SH, Hu CT, Block TM, Song W, Su YH. Differential methylation of the promoter and first exon of the RASSF1A gene in hepatocarcinogenesis. Hepatol Res 2015; 45:1110-23. [PMID: 25382672 PMCID: PMC4426255 DOI: 10.1111/hepr.12449] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 10/29/2014] [Accepted: 11/04/2014] [Indexed: 12/19/2022]
Abstract
AIM Aberrant methylation of the promoter, P2, and the first exon, E1, regions of the tumor suppressor gene RASSF1A, have been associated with hepatocellular carcinoma (HCC), albeit with poor specificity. This study analyzed the methylation profiles of P1, P2 and E1 regions of the gene to identify the region of which methylation most specifically corresponds to HCC and to evaluate the potential of this methylated region as a biomarker in urine for HCC screening. METHODS Bisulfite DNA sequencing and quantitative methylation-specific polymerase chain reaction assays were performed to compare methylation of the 56 CpG sites in regions P1, P2 and E1 in DNA isolated from normal, hepatitic, cirrhotic, adjacent non-HCC, and HCC liver tissue and urine samples for the characterization of hypermethylation of the RASSF1A gene as a biomarker for HCC screening. RESULTS In tissue, comparing HCC (n = 120) with cirrhosis and hepatitis together (n = 70), methylation of P1 had an area under the receiver operating characteristics curve (AUROC) of 0.90, whereas methylation of E1 and P2 had AUROC of 0.84 and 0.72, respectively. At 90% sensitivity, specificity for P1 methylation was 72.9% versus 38.6% for E1 and 27.1% for P2. Methylated P1 DNA was detected in urine in association with cirrhosis and HCC. It had a sensitivity of 81.8% for α-fetoprotein negative HCC. CONCLUSION Among the three regions analyzed, methylation of P1 is the most specific for HCC and holds great promise as a DNA marker in urine for screening of cirrhosis and HCC.
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Affiliation(s)
- Surbhi Jain
- JBS Science Inc., Doylestown, University College of Medicine, Philadelphia, Pennsylvania
| | - Lijia Xie
- JBS Science Inc., Doylestown, University College of Medicine, Philadelphia, Pennsylvania
| | - Batbold Boldbaatar
- JBS Science Inc., Doylestown, University College of Medicine, Philadelphia, Pennsylvania
| | - Selena Y. Lin
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - James P. Hamilton
- Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine
| | - Stephen J. Meltzer
- Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine,Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland; USA
| | - Shun-Hua Chen
- Department of Microbiology, Medical College, National Cheng Kung University, Tainan
| | - Chi-Tan Hu
- Department of Medicine, Buddhist Tzu Chi General Hospital, Hualien, Taiwan, China,Tzu Chi University, Hualien, Taiwan, China
| | - Timothy M. Block
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Wei Song
- JBS Science Inc., Doylestown, University College of Medicine, Philadelphia, Pennsylvania
| | - Ying-Hsiu Su
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania
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Misiewicz-Krzeminska I, Sarasquete ME, Vicente-Dueñas C, Krzeminski P, Wiktorska K, Corchete LA, Quwaider D, Rojas EA, Corral R, Martín AA, Escalante F, Bárez A, García JL, Sánchez-García I, García-Sanz R, San Miguel JF, Gutiérrez NC. Post-transcriptional Modifications Contribute to the Upregulation of Cyclin D2 in Multiple Myeloma. Clin Cancer Res 2015; 22:207-17. [PMID: 26341922 DOI: 10.1158/1078-0432.ccr-14-2796] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 08/14/2015] [Indexed: 11/16/2022]
Abstract
PURPOSE Dysregulation of one of the three D-cyclin genes has been observed in virtually all multiple myeloma tumors. The mechanisms by which CCND2 is upregulated in a set of multiple myeloma are not completely deciphered. We investigated the role of post-transcriptional regulation through the interaction between miRNAs and their binding sites at 3'UTR in CCND2 overexpression in multiple myeloma. EXPERIMENTAL DESIGN Eleven myeloma cell lines and 45 primary myeloma samples were included in the study. Interactions between miRNAs deregulated in multiple myeloma and mRNA targets were analyzed by 3'UTR-luciferase plasmid assay. The presence of CCND2 mRNA isoforms different in length was explored using qRT-PCR, Northern blot, mRNA FISH, and 3' rapid amplification of cDNA ends (RACE)-PCR. RESULTS We detected the presence of short CCND2 mRNA, both in the multiple myeloma cell lines and primary cells. The results obtained by 3'RACE experiments revealed that changes in CCND2 3'UTR length are explained by alternative polyadenylation. The luciferase assays using plasmids harboring the truncated CCND2 mRNA strongly confirmed the loss of miRNA sites in the shorter CCND2 mRNA isoform. Those multiple myelomas with greater abundance of the shorter 3'UTR isoform were associated with significant higher level of total CCND2 mRNA expression. Furthermore, functional analysis showed significant CCND2 mRNA shortening after CCND1 silencing and an increased relative expression of longer isoform after CCND1 and CCND3 overexpression, suggesting that cyclin D1 and D3 could regulate CCND2 levels through modifications in polyadenylation-cleavage reaction. CONCLUSIONS Overall, these results highlight the impact of CCND2 3'UTR shortening on miRNA-dependent regulation of CCND2 in multiple myeloma.
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Affiliation(s)
- Irena Misiewicz-Krzeminska
- Centro de Investigacion del Cancer-IBMCC (USAL-CSIC), Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. National Medicines Institute, Warsaw, Poland
| | - María E Sarasquete
- Centro de Investigacion del Cancer-IBMCC (USAL-CSIC), Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Carolina Vicente-Dueñas
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. Experimental Therapeutics and Translational Oncology Program, Instituto de Biologia Molecular y Celular del Cancer, CSIC/Universidad de Salamanca, Salamanca, Spain
| | - Patryk Krzeminski
- Centro de Investigacion del Cancer-IBMCC (USAL-CSIC), Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | | | - Luis Antonio Corchete
- Centro de Investigacion del Cancer-IBMCC (USAL-CSIC), Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Dalia Quwaider
- Centro de Investigacion del Cancer-IBMCC (USAL-CSIC), Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Elizabeta A Rojas
- Centro de Investigacion del Cancer-IBMCC (USAL-CSIC), Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Rocío Corral
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. Servicio de Hematología, Hospital Universitario, Salamanca, Spain
| | - Ana A Martín
- Servicio de Hematología, Hospital Universitario, Salamanca, Spain
| | | | | | - Juan Luis García
- Centro de Investigacion del Cancer-IBMCC (USAL-CSIC), Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Isidro Sánchez-García
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. Experimental Therapeutics and Translational Oncology Program, Instituto de Biologia Molecular y Celular del Cancer, CSIC/Universidad de Salamanca, Salamanca, Spain
| | - Ramón García-Sanz
- Centro de Investigacion del Cancer-IBMCC (USAL-CSIC), Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. Servicio de Hematología, Hospital Universitario, Salamanca, Spain
| | - Jesús F San Miguel
- Clinica Universidad de Navarra, Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain
| | - Norma C Gutiérrez
- Centro de Investigacion del Cancer-IBMCC (USAL-CSIC), Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. Servicio de Hematología, Hospital Universitario, Salamanca, Spain.
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Ramadan RA, Zaki MA, Awad AM, El-Ghalid LA. Aberrant methylation of promoter region of SPINT2/HAI-2 gene: an epigenetic mechanism in hepatitis C virus-induced hepatocarcinogenesis. Genet Test Mol Biomarkers 2015; 19:399-404. [PMID: 26030814 DOI: 10.1089/gtmb.2015.0025] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Epigenetic changes, including DNA methylation, are recognized as one of the potential mechanisms involved in the pathogenesis of hepatocellular carcinoma (HCC). AIMS We aimed to study the methylation status of the promoter region of Serine peptidase inhibitor/hepatocyte growth factor activator inhibitor type 2 (SPINT2/HAI-2) tumor suppressor gene in hepatitis C virus (HCV)-infected cirrhotic patients with and without HCC. METHODS Methyl-specific polymerase (MSP) chain reaction was used to detect CpG methylation of the SPINT2/HAI-2 gene promoter in peripheral blood samples of 30 HCC and 50 HCV cirrhotic cases, along with 50 normal individuals. RESULTS Aberrant methylation showed a stepwise increase in frequency from 40% in controls to 64% in HCV cirrhotics, and 66.7% in HCC cases with a significant difference among the studied groups (p=0.021). The combined patient groups had an increased risk of aberrant methylation with an odds ratio (OR) of 2.52, a 95% confidence interval (CI) of 1.23-5.14, and a p-value of 0.05 that became more statistically significant after adjusting for age (OR=2.4, 95% CI=1.13-5.26, p-value=0.012), thereby confirming the association between HCV infection and aberrant methylation. CONCLUSIONS Our study highlights the role of promoter hypermethylation in the multistep process of hepatocarcinogenesis, providing potential clinical applications in diagnosis and prognosis.
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Affiliation(s)
- Ragaa A Ramadan
- 1 Department of Chemical Pathology, Alexandria University , Alexandria, Egypt
| | - Moyassar A Zaki
- 1 Department of Chemical Pathology, Alexandria University , Alexandria, Egypt
| | - Ahmed M Awad
- 1 Department of Chemical Pathology, Alexandria University , Alexandria, Egypt
| | - Lamiaa A El-Ghalid
- 2 Department of Internal Medicine, Medical Research Institute, Alexandria University , Alexandria, Egypt
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Jain S, Chang TT, Chen S, Boldbaatar B, Clemens A, Lin SY, Yan R, Hu CT, Guo H, Block TM, Song W, Su YH. Comprehensive DNA methylation analysis of hepatitis B virus genome in infected liver tissues. Sci Rep 2015; 5:10478. [PMID: 26000761 PMCID: PMC4650678 DOI: 10.1038/srep10478] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 04/15/2015] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus (HBV) is a hepatotropic virus causing hepatitis, cirrhosis and hepatocellular carcinoma (HCC). The methylation status of the HBV DNA in its different forms can potentially provide insight into the pathogenesis of HBV-related liver diseases, including HCC, however this is unclear. The goal of this study is to obtain comprehensive DNA methylation profiles of the three putative CpG islands in the HBV DNA in infected livers, with respect to liver disease progression. The extent of methylation in these CpG islands was first assessed using bisulfite PCR sequencing with a small set of tissue samples, followed by analysis using both quantitative bisulfite-specific PCR and quantitative methylation-specific PCR assays in a larger sample size (n = 116). The level of HBV CpG island 3 methylation significantly correlated with hepatocarcinogenesis. We also obtained, for the first time, evidence of rare, non-CpG methylation in CpG island 2 of the HBV genome in infected liver. Comparing methylation of the HBV genome to three known HCC-associated host genes, APC, GSTP1, and RASSF1A, we did not identify a significant correlation between these two groups.
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Affiliation(s)
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan, Republic of China
| | | | | | | | - Selena Y Lin
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Ran Yan
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Chi-Tan Hu
- Department of Medicine, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan, Republic of China
| | - Haitao Guo
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Timothy M Block
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Wei Song
- JBS Science, Inc., Doylestown, Pennsylvania
| | - Ying-Hsiu Su
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania
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Huang W, Li T, Yang W, Chai X, Chen K, Wei L, Duan S, Li B, Qin Y. Analysis of DNA methylation in plasma for monitoring hepatocarcinogenesis. Genet Test Mol Biomarkers 2015; 19:295-302. [PMID: 25923138 DOI: 10.1089/gtmb.2014.0292] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
AIM To explore whether the aberrant DNA methylation status in plasma could be used as a biomarker for hepatocellular carcinoma (HCC) screening among high-risk individuals. METHODS The promoter methylation status of ELF, RASSF1A, p16, and GSTP1 was investigated by methylation-specific polymerase chain reaction (PCR) in 34 paired HCC and nontumor liver tissue from HCC patients and 10 tissues from patients with liver cirrhosis (LC). Plasma samples from 31 HCC patients, 10 LC patients as well as 7 patients with benign hepatic conditions were also collected and characterized using the same method. RESULTS Among liver specimens, HCC tissues displayed a significantly higher methylation frequency of each gene compared with nontumor tissue (p<0.05). Moreover, the frequency was much higher in tumor tissues than in nontumor tissue, when the data from two or three genes were combined (p=0.001 and p<0.001, respectively). Among plasma samples, either the frequency of at least one methylated gene (p<0.001) or the average number of methylated genes (p<0.05) demonstrated a stepwise increase in patients with benign lesions, LC, and HCC. Furthermore, when positive results, that is, plasma methylation status of at least one gene were combined with the elevated AFP400 level (serum alpha-fetoprotein [AFP] level at a cutoff of 400 ng/mL), the diagnostic sensitivity of HCC could increase to 93.55%. CONCLUSIONS These results suggested that the methylation of tumor suppressor genes may participate in the development and progression of HCC. Additionally, it may be useful to combine the plasma DNA methylation status of a panel of gene markers and the serum AFP for HCC screening.
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Affiliation(s)
- Wenqing Huang
- 1 Department of Biochemistry and Molecular Biology, School of Preclinical and Forensic Medicine, West China Medical Center , Sichuan University, Chengdu, China
| | - Tong Li
- 2 Department of Dermatology, West China Hospital, Sichuan University , Chengdu, China
| | - Wenli Yang
- 1 Department of Biochemistry and Molecular Biology, School of Preclinical and Forensic Medicine, West China Medical Center , Sichuan University, Chengdu, China
| | - Xinjuan Chai
- 1 Department of Biochemistry and Molecular Biology, School of Preclinical and Forensic Medicine, West China Medical Center , Sichuan University, Chengdu, China
| | - Kefei Chen
- 3 Division of Liver Transplantation, Department of Surgery, West China Hospital , Chengdu, China
| | - Ling Wei
- 1 Department of Biochemistry and Molecular Biology, School of Preclinical and Forensic Medicine, West China Medical Center , Sichuan University, Chengdu, China
| | - Shuwang Duan
- 1 Department of Biochemistry and Molecular Biology, School of Preclinical and Forensic Medicine, West China Medical Center , Sichuan University, Chengdu, China
| | - Bo Li
- 3 Division of Liver Transplantation, Department of Surgery, West China Hospital , Chengdu, China
| | - Yang Qin
- 1 Department of Biochemistry and Molecular Biology, School of Preclinical and Forensic Medicine, West China Medical Center , Sichuan University, Chengdu, China
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Rebbani K, Marchio A, Ezzikouri S, Afifi R, Kandil M, Bahri O, Triki H, El Feydi AE, Dejean A, Benjelloun S, Pineau P. TP53 R72P polymorphism modulates DNA methylation in hepatocellular carcinoma. Mol Cancer 2015; 14:74. [PMID: 25889455 PMCID: PMC4393630 DOI: 10.1186/s12943-015-0340-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 03/11/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is characterized by widespread epidemiological and molecular heterogeneity. Previous work showed that in the western part of North Africa, a region of low incidence of HCC, mutations are scarce for this tumor type. As epigenetic changes are considered possible surrogates to mutations in human cancers, we decided, thus, to characterize DNA methylation in HCC from North-African patients. METHODS A set of 11 loci was investigated in a series of 45 tumor specimens using methylation-specific and combined-bisulfite restriction assay PCR. Results obtained on clinical samples were subsequently validated in liver cancer cell lines. RESULTS DNA methylation at tumor suppressor loci is significantly higher in samples displaying chromosome instability. More importantly, DNA methylation was significantly higher in Arg/Arg when compared to Pro/Pro genotype carriers at codon 72 rs1042522 of TP53 (65% vs 20% methylated loci, p = 0.0006), a polymorphism already known to affect somatic mutation rate in human carcinomas. In vitro experiments in cell lines indicated that enzymes controlling DNA methylation were differentially regulated by codon 72 Arg or Pro isoforms of p53. Furthermore, the Arg72-carrying version of p53 was shown to re-methylate DNA more rapidly than the pro-harboring isoform. Finally, Pro-carrying cell lines were shown to be significantly more resistant to decitabine treatment (two-fold, p = 0.005). CONCLUSIONS Our data suggest that Arg72Pro polymorphism in a WT p53 context may act as a primary driver of epigenetic changes in HCC. It suggests, in addition, that rs1042522 genotype may predict sensitivity to epigenetic-targeted therapy. This model of liver tumorigenesis that associates low penetrance genetic predisposition to epigenetic changes emerges from a region of low HCC incidence and it may, therefore, apply essentially to population living in similar areas. Surveys on populations submitted to highly mutagenic conditions as perinatally-acquired chronic hepatitis B or aflatoxin B1 exposure remained to be conducted to validate our observations as a general model.
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Affiliation(s)
- Khadija Rebbani
- Unité d'Organisation Nucléaire et Oncogenèse, INSERM U993, Institut Pasteur, 28 rue du Docteur Roux, F-75724, Paris, Cedex 15, France. .,Laboratoire des Hépatites Virales, Institut Pasteur du Maroc, 1 Place Louis Pasteur, 20360, Casablanca, Morocco.
| | - Agnès Marchio
- Unité d'Organisation Nucléaire et Oncogenèse, INSERM U993, Institut Pasteur, 28 rue du Docteur Roux, F-75724, Paris, Cedex 15, France.
| | - Sayeh Ezzikouri
- Laboratoire des Hépatites Virales, Institut Pasteur du Maroc, 1 Place Louis Pasteur, 20360, Casablanca, Morocco.
| | - Rajaa Afifi
- Service de Médecine C-Gastroentérologie, CHU Ibn-Sina, Rabat, Morocco.
| | - Mostafa Kandil
- Equipe d'Anthropogénétique et de Biotechnologies, Faculté des Sciences Chouaib Doukkali, El Jadida, Morocco.
| | - Olfa Bahri
- Laboratoire de Virologie Clinique, Institut Pasteur de Tunis, Tunis, Tunisie.
| | - Henda Triki
- Laboratoire de Virologie Clinique, Institut Pasteur de Tunis, Tunis, Tunisie.
| | | | - Anne Dejean
- Unité d'Organisation Nucléaire et Oncogenèse, INSERM U993, Institut Pasteur, 28 rue du Docteur Roux, F-75724, Paris, Cedex 15, France.
| | - Soumaya Benjelloun
- Laboratoire des Hépatites Virales, Institut Pasteur du Maroc, 1 Place Louis Pasteur, 20360, Casablanca, Morocco.
| | - Pascal Pineau
- Unité d'Organisation Nucléaire et Oncogenèse, INSERM U993, Institut Pasteur, 28 rue du Docteur Roux, F-75724, Paris, Cedex 15, France.
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Zhang X, Liu S, Shen C, Wu Y, Zhang L, Chen X, Lu F. DNA methylation consistency implicates the primary tumor cell origin of recurrent hepatocellular carcinoma. Epigenomics 2015; 7:581-92. [PMID: 25815780 DOI: 10.2217/epi.15.23] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
AIMS To investigate if DNA methylation pattern assay could be a new approach to identifying the primary tumor cell origin of the recurrent hepatocellular carcinoma (HCC). MATERIALS & METHODS Methylation of 24 genes and expression of 22 cancer stem cell (CSC) biomarkers were quantitatively measured in 10 paired primary and recurrent HCC specimens. The HBV viral-host junctions were determined in six pairs of them with HBV infection. RESULTS Similar DNA methylation patterns were observed among nine of ten pairs of primary and recurrent tumors. In five of six paired specimens with HBV infection, exactly same HBV DNA integrations were identified in each paired tumors. The expression of seven CSC biomarkers increased significantly in either primary or recurrent tumor tissues. CONCLUSION Recurrent HCCs mostly originate from their primary tumors. Assay of DNA methylation patterns could provide a new approach to determining the origin of recurrent HCC.
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Affiliation(s)
- Xiaolei Zhang
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China
| | - Shuang Liu
- Beijing Artificial Liver Treatment & Training Center, Beijing Youan Hospital, Capital Medical University, 8 Xi Tou Tiao, Beijing 100069, China
| | - Congle Shen
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China
| | - Yali Wu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China
| | - Ling Zhang
- Department of Hepatobiliary Surgery, Henan Cancer Hospital, 127 Dongming Road, Jinshui District, Zhengzhou 450008, Henan, China
| | - Xiangmei Chen
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China
| | - Fengmin Lu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China
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Lambert MP, Ancey PB, Esposti DD, Cros MP, Sklias A, Scoazec JY, Durantel D, Hernandez-Vargas H, Herceg Z. Aberrant DNA methylation of imprinted loci in hepatocellular carcinoma and after in vitro exposure to common risk factors. Clin Epigenetics 2015; 7:15. [PMID: 25755686 PMCID: PMC4353474 DOI: 10.1186/s13148-015-0053-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 02/06/2015] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is among the most frequent human malignancies and a major cause of cancer-related death worldwide. It is characterized by late detection and fast progression, and it is believed that epigenetic disruption may be one of the molecular mechanisms leading to hepatocarcinogenesis. Previous studies from our group revealed that HCC tumors exhibit specific DNA methylation signatures associated with major risk factors and tumor progression. Imprinted genes are mono-allelically expressed in a parent-of-origin-dependent manner and have been suggested to be more susceptible to deregulation in cancer. To test this notion, we performed a targeted analysis of DNA methylation in known imprinted genes, using HCC samples and in vitro models of carcinogenic exposure. RESULTS Analysis of HCC DNA methylation in two independent datasets showed that differentially methylated loci are significantly enriched in imprinted genes. Most of the promoters of imprinted genes were found hypomethylated in HCC tumors compared to surrounding tissues, contrasting with the frequent promoter hypermethylation observed in tumors. We next investigated the status of methylation of the imprinting control region (ICR) of different imprinted clusters and found that the 15q11-13 ICR was significantly hypomethylated in tumors relative to their surrounding tissues. In addition, expression of imprinted genes within this cluster was frequently deregulated in a gene-specific manner, suggesting distinct mechanisms of regulation in this region. Finally, primary human hepatocytes and hepatocyte-like HepaRG cells displayed higher methylation variability in certain imprinted loci after natural hepatitis B virus (HBV) infection and after lipid accumulation, respectively. CONCLUSION The methylation status of a large panel of imprinted genes was found deregulated in HCC, suggesting a major role of this mechanism during hepatocarcinogenesis. In vitro models support the hypothesis of imprinted gene methylation as a potential marker of environmental exposures.
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Affiliation(s)
- Marie-Pierre Lambert
- />Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, 69008 Lyon, France
- />Current address: Epissage alternatif et progression tumorale, Centre de Recherche en Cancérologie de Lyon (CRCL), 28 rue Laennec, 69008 Lyon, France
| | - Pierre-Benoit Ancey
- />Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, 69008 Lyon, France
| | - Davide Degli Esposti
- />Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, 69008 Lyon, France
| | - Marie-Pierre Cros
- />Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, 69008 Lyon, France
| | - Athena Sklias
- />Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, 69008 Lyon, France
| | - Jean-Yves Scoazec
- />Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France
| | - David Durantel
- />INSERM U871, Molecular physiopathology and new treatments of viral hepatitis, Centre de recherche en cancérologie (CRCL), 151 Cours Albert-Thomas, 69008 Lyon, France
| | - Hector Hernandez-Vargas
- />Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, 69008 Lyon, France
| | - Zdenko Herceg
- />Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, 69008 Lyon, France
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Ouadid-Ahidouch H, Rodat-Despoix L, Matifat F, Morin G, Ahidouch A. DNA methylation of channel-related genes in cancers. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2015; 1848:2621-8. [PMID: 25703813 DOI: 10.1016/j.bbamem.2015.02.015] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 02/04/2015] [Accepted: 02/12/2015] [Indexed: 12/31/2022]
Abstract
DNA methylation at CpG sites is an epigenetic mechanism that regulates cellular gene expression. In cancer cells, aberrant methylation is correlated with the abnormalities in expression of genes that are known to be involved in the particular characteristics of cancer cells such as proliferation, apoptosis, migration or invasion. During the past 30 years, accumulating data have definitely convinced the scientific community that ion channels are involved in cancerogenesis and cancer properties. As they are situated at the cell surface, they might be prime targets in the development of new therapeutic strategies besides their potential use as prognostic factors. Despite the progress in our understanding of the remodeling of ion channels in cancer cells, the molecular mechanisms underlying their over- or down-expression remained enigmatic. In this review, we aimed to summarize the available data on gene promoter methylation of ion channels and to investigate their clinical significance as novel biomarkers in cancer. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
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Affiliation(s)
- Halima Ouadid-Ahidouch
- UFR Sciences, EA 4667, Laboratory of Cell and Molecular Physiology, University of Picardie Jules Verne, SFR CAP-SANTE (FED 4231), Amiens, France.
| | - Lise Rodat-Despoix
- UFR Sciences, EA 4667, Laboratory of Cell and Molecular Physiology, University of Picardie Jules Verne, SFR CAP-SANTE (FED 4231), Amiens, France
| | - Fabrice Matifat
- UFR Sciences, EA 4667, Laboratory of Cell and Molecular Physiology, University of Picardie Jules Verne, SFR CAP-SANTE (FED 4231), Amiens, France
| | - Gilles Morin
- EA 4666 and Department of Molecular and Clinical Genetics, Amiens University Hospital, University of Picardie Jules Verne, Amiens, France
| | - Ahmed Ahidouch
- UFR Sciences, EA 4667, Laboratory of Cell and Molecular Physiology, University of Picardie Jules Verne, SFR CAP-SANTE (FED 4231), Amiens, France; Department of Biology, Faculty of Sciences, Ibn Zohr University, Agadir Morocco
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Zhang X, He H, Zhang X, Guo W, Wang Y. RUNX3 Promoter Methylation Is Associated with Hepatocellular Carcinoma Risk: A Meta-Analysis. Cancer Invest 2015; 33:121-5. [DOI: 10.3109/07357907.2014.1003934] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Leung TW, Liu SS, Leung RCY, Chu MMY, Cheung ANY, Ngan HYS. HPV 16 E2 binding sites 1 and 2 become more methylated than E2 binding site 4 during cervical carcinogenesis. J Med Virol 2015; 87:1022-33. [PMID: 25648229 DOI: 10.1002/jmv.24129] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/28/2014] [Indexed: 02/01/2023]
Abstract
E2 protein binding to the four E2 binding sites (E2BSs) at the long control region of Human Papillomavirus (HPV) 16/18 genome may exert either transcriptional activation/repression on E6 and E7 oncoproteins. Methylation status at the E2BSs may affect the relative binding of E2 protein to them. In this study, methylation percentage at E2BS 1, 2 (promoter-proximal), and 4 (promoter-distal) were assessed by pyrosequencing and compared among HPV 16/18-positive cervical cancer, high-grade, and low-grade Cervical Intraepithelial Neoplasia, Atypical Squamous Cells of Undetermined Significance, and normal cervical epithelium. HPV 16 E2BS1&2 were more methylated than HPV 16 E2BS4 in cervical cancer whereas in cervical premalignant lesions and normal epithelium, HPV 16 E2BS1&2 were less methylated than HPV 16 E2BS4. HPV 18 E2BS1&2 remained more methylated than E2BS4 in all histological groups. HPV 16 E2BS1&2 methylation increased from high-grade lesions to cervical cancer (P < 0.001). HPV 16 E2BS4 methylation increased from low-grade to high-grade premalignant lesions (P = 0.041). Both HPV 18 E2BS1&2 and E2BS4 methylation increased from low-grade to high-grade Cervical Intraepithelial Neoplasia (P = 0.019 and 0.001 respectively) and further increased form high-grade lesions to cervical cancer (P < 0.001 and 0.005 respectively). Conclusively, HPV 16 E2BS1&2 (for transcriptional repression of E6/E7 oncoproteins) became more heavily methylated than E2BS4 (for transcriptional activation of E6/E7) in cervical cancer, favouring the differential binding of E2 protein to E2BS4. Increasing methylation at HPV 16/18 E2BSs are potentially useful adjunctive molecular markers for predicting progression from low-grade to high-grade cervical premalignant lesions and from high-grade lesions to cervical cancer.
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Affiliation(s)
- Tsin-Wah Leung
- Department of Obstetrics & Gynaecology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
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Wu J, Salva KA, Stutz N, Longley BJ, Spiegelman VS, Wood GS. Quantitative gene analysis of methylation and expression (Q-GAME) in fresh or fixed cells and tissues. Exp Dermatol 2014; 23:304-9. [PMID: 24646432 DOI: 10.1111/exd.12374] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/15/2014] [Indexed: 12/27/2022]
Abstract
Epigenetic regulation of gene expression by DNA methylation is a central mechanism governing the silencing of tumor suppressor genes in many forms of cancer. Current methods have not proven optimal for the quantitative analysis of DNA methylation and corresponding in situ protein expression within cells in small specimens like skin biopsies. We have overcome this limitation by combining and modifying several techniques: target cell enrichment, DNA micro-isolation, one-step denaturation/bisulphite conversion/in-column desulphonation, specially designed PCR amplification, pyrosequencing and multispectral image analysis. Using this approach optimized for small samples, we can quantify minor alterations in gene methylation and protein expression using minimal amounts of tissue. Comparative studies of fresh and processed cells showed that our method is valid for DNA in both fresh and formalin-fixed, paraffin-embedded specimens. We can measure the effects of DNA methylation inhibitors, administered in vitro or in vivo, on the promoter methylation and protein expression of selected genes in specific cells. This novel approach should prove useful for a wide variety of investigative and clinical applications in dermatology and other specialties where the collection of small, routinely processed biopsy specimens is common. We refer to this method as Q-GAME (quantitative gene analysis of methylation and expression).
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Affiliation(s)
- Jianqiang Wu
- Department of Dermatology, University of Wisconsin, Madison, WI, USA; The Middleton VA Medical Center, Madison, WI, USA
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40
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Ashour N, Angulo JC, Andrés G, Alelú R, González-Corpas A, Toledo MV, Rodríguez-Barbero JM, López JI, Sánchez-Chapado M, Ropero S. A DNA hypermethylation profile reveals new potential biomarkers for prostate cancer diagnosis and prognosis. Prostate 2014; 74:1171-82. [PMID: 24961912 DOI: 10.1002/pros.22833] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Accepted: 05/12/2014] [Indexed: 01/05/2023]
Abstract
BACKGROUND DNA hypermethylation has emerged as a novel molecular biomarker for the evaluation of prostate cancer diagnosis and prognosis. Defining the specific gene hypermethylation profile for prostate cancer could involve groups of genes that specifically discriminate patients with indolent and aggressive tumors. METHODS Genome-wide methylation analysis was performed on 83 tumor and 10 normal prostate samples using the GoldenGate Methylation Cancer Panel I (Illumina, Inc.). All clinical stages of disease were considered. RESULTS We found 41 genes hypermethylated in more than 20% of the tumors analyzed (P < 0.01). Of these, we newly identified GSTM2 and PENK as being genes that are hypermethylated in prostate cancer and that were simultaneously methylated in 40.9% of the tumors analyzed. We also identified panels of genes that are more frequently methylated in tumor samples with clinico-pathological indicators of poor prognosis: a high Gleason score, elevated Ki-67, and advanced disease. Of these, we found simultaneous hypermethylation of CFTR and HTR1B to be common in patients with a high Gleason score and high Ki-67 levels; this might indicate the population at higher risk of therapeutic failure. The DNA hypermethylation profile was associated with cancer-specific mortality (log-rank test, P = 0.007) and biochemical recurrence-free survival (log-rank test, P = 0.0008). CONCLUSIONS Our findings strongly indicate that epigenetic silencing of GSTM2 and PENK is a common event in prostate cancer that could be used as a molecular marker for prostate cancer diagnosis. In addition, simultaneous HTR1B and CFTR hypermethylation could help discriminate aggressive from indolent prostate tumors.
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Affiliation(s)
- Nadia Ashour
- Departamento de Biología de Sistemas, Unidad Docente de Bioquímica y Biología Molecular, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
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41
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Li CC, Yu Z, Cui LH, Piao JM, Liu M. Role of P14 and MGMT Gene Methylation in Hepatocellular Carcinomas: a Meta-analysis. Asian Pac J Cancer Prev 2014; 15:6591-6. [DOI: 10.7314/apjcp.2014.15.16.6591] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Duan CL, Hou GH, Liu YP, Liang T, Song J, Han JK, Zhang C. Tumor vascular homing endgolin-targeted radioimmunotherapy in hepatocellular carcinoma. Tumour Biol 2014; 35:12205-15. [PMID: 25164610 DOI: 10.1007/s13277-014-2529-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2014] [Accepted: 08/20/2014] [Indexed: 12/29/2022] Open
Abstract
Endoglin is a proliferation-associated cell membrane antigen and overexpressed in the angiogenic vasculature of solid tumors. However, the applications of endoglin (ENG)-targeted radioimmunotheray in hepatocellular carcinoma have not been reported yet. Therefore, the aim of this study was the visualization of both the development of hepatocellular carcinoma (HCC) tumor burden and therapeutic effect with ENG-targeted (131)I-anti-ENG mAb (A8), via in vivo noninvasive fluorescence imaging (NIFLI) of SMMC7721-green fluorescent protein (GFP) cells. A8 showed a dose-dependent, time-dependent suppression on the proliferation of SMMC7721-GFP cells and human umbilical vein endothelial cells (HUVECs) in vitro. Tube formation assay showed that (131)I-A8 markedly inhibits HUVECs to form extensive and enclosed tube networks. The results showed that the radiochemical purity of (131)I-A8 was 92.8 % and (131)I-A8 maintained more stable in serum than in saline and had high affinity against SMMC7721-GFP cells. The pharmacokinetics of (131)I-A8 was in accordance with the two-compartment model, with a rapid distribution phase and a slow decline phase. NIFLI exhibited a good relation between the fluorescent signal and tumor volume in vivo. Furthermore, treatment with (131)I-A8 resulted in significant tumor-growth suppression on the basis of the reducing fluorescent signal and a remarkably decreased tumor weight in treated animals. These results were further verified by RT-PCR and immunohistochemistry staining. Our findings indicate that (131)I-A8 can be used as ENG-targeted therapy for hepatocellular carcinoma, and noninvasive fluorescence imaging provides valuable information on tumor burden and effectiveness of therapy.
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Affiliation(s)
- Chong-Ling Duan
- Key Laboratory for Experimental Teratology of the Ministry of Education and Institute of Experimental Nuclear Medicine, School of Medicine, Shandong University, Jinan, China
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43
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Ma HL, Yu C, Liu Y, Tan YR, Qiao JK, Yang X, Wang LZ, Li J, Chen Q, Chen FX, Zhang ZY, Zhong LP. Decreased expression of glutathione S-transferase pi correlates with poorly differentiated grade in patients with oral squamous cell carcinoma. J Oral Pathol Med 2014; 44:193-200. [PMID: 25047743 DOI: 10.1111/jop.12229] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2014] [Indexed: 12/20/2022]
Affiliation(s)
- Hai-long Ma
- Department of Oral & Maxillofacial-Head & Neck Oncology; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Cong Yu
- Department of Oral & Maxillofacial-Head & Neck Oncology; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Ying Liu
- Department of Oral & Maxillofacial-Head & Neck Oncology; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Yi-ran Tan
- Department of Oral & Maxillofacial-Head & Neck Oncology; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Jin-ke Qiao
- Department of Oral & Maxillofacial-Head & Neck Oncology; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Xi Yang
- Department of Oral & Maxillofacial-Head & Neck Oncology; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Li-zhen Wang
- Department of Oral Pathology; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Jiang Li
- Department of Oral Pathology; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Qiong Chen
- Department of Clinical Laboratories; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Fu-xiang Chen
- Department of Clinical Laboratories; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Zhi-yuan Zhang
- Department of Oral & Maxillofacial-Head & Neck Oncology; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Lai-ping Zhong
- Department of Oral & Maxillofacial-Head & Neck Oncology; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai China
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Yang Y, Ye Z, Zou Z, Xiao G, Luo G, Yang H. Clinicopathological significance of RUNX3 gene hypermethylation in hepatocellular carcinoma. Tumour Biol 2014; 35:10333-40. [DOI: 10.1007/s13277-014-2329-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2014] [Accepted: 07/07/2014] [Indexed: 12/16/2022] Open
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Anwar SL, Lehmann U. DNA methylation, microRNAs, and their crosstalk as potential biomarkers in hepatocellular carcinoma. World J Gastroenterol 2014; 20:7894-7913. [PMID: 24976726 PMCID: PMC4069317 DOI: 10.3748/wjg.v20.i24.7894] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 01/24/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
Epigenetic alterations have been identified as a major characteristic in human cancers. Advances in the field of epigenetics have contributed significantly in refining our knowledge of molecular mechanisms underlying malignant transformation. DNA methylation and microRNA expression are epigenetic mechanisms that are widely altered in human cancers including hepatocellular carcinoma (HCC), the third leading cause of cancer related mortality worldwide. Both DNA methylation and microRNA expression patterns are regulated in developmental stage specific-, cell type specific- and tissue-specific manner. The aberrations are inferred in the maintenance of cancer stem cells and in clonal cell evolution during carcinogenesis. The availability of genome-wide technologies for DNA methylation and microRNA profiling has revolutionized the field of epigenetics and led to the discovery of a number of epigenetically silenced microRNAs in cancerous cells and primary tissues. Dysregulation of these microRNAs affects several key signalling pathways in hepatocarcinogenesis suggesting that modulation of DNA methylation and/or microRNA expression can serve as new therapeutic targets for HCC. Accumulative evidence shows that aberrant DNA methylation of certain microRNA genes is an event specifically found in HCC which correlates with unfavorable outcomes. Therefore, it can potentially serve as a biomarker for detection as well as for prognosis, monitoring and predicting therapeutic responses in HCC.
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Sun TT, Wang Y, Cheng H, Xiao HZ, Xiang JJ, Zhang JT, Yu SBS, Martin TA, Ye L, Tsang LL, Jiang WG, Xiaohua J, Chan HC. Disrupted interaction between CFTR and AF-6/afadin aggravates malignant phenotypes of colon cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1843:618-28. [PMID: 24373847 DOI: 10.1016/j.bbamcr.2013.12.013] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 11/26/2013] [Accepted: 12/16/2013] [Indexed: 12/16/2022]
Abstract
How mutations or dysfunction of CFTR may increase the risk of malignancies in various tissues remains an open question. Here we report the interaction between CFTR and an adherens junction molecule, AF-6/afadin, and its involvement in the development of colon cancer. We have found that CFTR and AF-6/afadin are co-localized at the cell-cell contacts and physically interact with each other in colon cancer cell lines. Knockdown of CFTR results in reduced epithelial tightness and enhanced malignancies, with increased degradation and reduced stability of AF-6/afadin protein. The enhanced invasive phenotype of CFTR-knockdown cells can be completely reversed by either AF-6/afadin over-expression or ERK inhibitor, indicating the involvement of AF-6/MAPK pathway. More interestingly, the expression levels of CFTR and AF-6/afadin are significantly downregulated in human colon cancer tissues and lower expression of CFTR and/or AF-6/afadin is correlated with poor prognosis of colon cancer patients. The present study has revealed a previously unrecognized interaction between CFTR and AF-6/afadin that is involved in the pathogenesis of colon cancer and indicated the potential of the two as novel markers of metastasis and prognostic predictors for human colon cancer.
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Genome-wide and gene-specific epigenomic platforms for hepatocellular carcinoma biomarker development trials. Gastroenterol Res Pract 2014; 2014:597164. [PMID: 24829571 PMCID: PMC4009191 DOI: 10.1155/2014/597164] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 02/04/2014] [Accepted: 02/07/2014] [Indexed: 12/31/2022] Open
Abstract
The majority of the epigenomic reports in hepatocellular carcinoma have focused on identifying novel differentially methylated drivers or passengers of the oncogenic process. Few reports have considered the technologies in place for clinical translation of newly identified biomarkers. The aim of this study was to identify epigenomic technologies that need only a small number of samples to discriminate HCC from non-HCC tissue, a basic requirement for biomarker development trials. To assess that potential, we used quantitative Methylation Specific PCR, oligonucleotide tiling arrays, and Methylation BeadChip assays. Concurrent global DNA hypomethylation, gene-specific hypermethylation, and chromatin alterations were observed as a hallmark of HCC. A global loss of promoter methylation was observed in HCC with the Illumina BeadChip assays and the Nimblegen oligonucleotide arrays. HCC samples had lower median methylation peak scores and a reduced number of significant promoter-wide methylated probes. Promoter hypermethylation of RASSF1A, SSBP2, and B4GALT1 quantified by qMSP had a sensitivity ranging from 38% to 52%, a specificity of 100%, and an AUC from 0.58 to 0.75. A panel combining these genes with HCC risk factors had a sensitivity of 87%, a specificity of 100%, and an AUC of 0.91.
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Xu B, Nie Y, Liu X, Feng S, Yang Z, Wang Z, Zheng Q, Luo X. Quantitative analysis of APC promoter methylation in hepatocellular carcinoma and its prognostic implications. Oncol Lett 2014; 7:1683-1688. [PMID: 24765201 PMCID: PMC3997703 DOI: 10.3892/ol.2014.1951] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Accepted: 02/11/2014] [Indexed: 12/14/2022] Open
Abstract
The present study aimed to quantitatively determine the aberrant methylation signal of the adenomatous polyposis coli (APC) gene in hepatocellular carcinoma (HCC), and to evaluate whether hypermethylation of the APC promoter could be a prognostic biomarker for HCC. Taqman probe-based quantitative methylation-specific polymerase chain reaction was performed to identify the APC promoter methylation levels in 57 HCC and corresponding non-tumorous liver tissues. In the present study, the methylation level of the APC promoter was upregulated by 4.51-fold in the HCC tissues compared with the non-cancerous tissues (P=0.0003). With regard to the clinicopathological data, the methylation level of the APC promoter in the HCC samples was higher in the patients with larger tumors when the cut-off was set at 4 cm (P=0.0008), and in the older patients when the cut-off was set at 60 years old (P=0.0438). However, the methylation status in the HCC samples appeared not to affect the overall patient survival rate (P=0.1684). The findings of the present study showed that APC promoter hypermethylation accumulates during the development of HCC, but that it may not be a promising prognostic biomarker for HCC.
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Affiliation(s)
- Baiying Xu
- Department of General Surgery, Shanghai No. 6 People's Hospital, Medical School of Shanghai Jiaotong University, Shanghai, P.R. China
| | - Yanfang Nie
- Department of Nephrology, Taizhou Central Hospital, Taizhou, Zhejiang, P.R. China
| | - Xiaoxia Liu
- The Obstetrics and Gynecology Hospital, Fudan University, Shanghai, P.R. China
| | - Shuqin Feng
- Shanxi Province Industry and Trade College, Taiyuan, Shanxi, P.R. China
| | - Zhili Yang
- Department of General Surgery, Shanghai No. 6 People's Hospital, Medical School of Shanghai Jiaotong University, Shanghai, P.R. China
| | - Zhigang Wang
- Department of General Surgery, Shanghai No. 6 People's Hospital, Medical School of Shanghai Jiaotong University, Shanghai, P.R. China
| | - Qi Zheng
- Department of General Surgery, Shanghai No. 6 People's Hospital, Medical School of Shanghai Jiaotong University, Shanghai, P.R. China
| | - Xiaoying Luo
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Medical School of Shanghai Jiaotong University, Shanghai, P.R. China
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Zhao X, Yang F, Li S, Liu M, Ying S, Jia X, Wang X. CpG island methylator phenotype of myelodysplastic syndrome identified through genome-wide profiling of DNA methylation and gene expression. Br J Haematol 2014; 165:649-58. [PMID: 24601943 DOI: 10.1111/bjh.12811] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Accepted: 01/10/2014] [Indexed: 12/13/2022]
Abstract
The CpG island methylator phenotype (CIMP) is an epigenetic phenomenon and plays an important role in tumourigenesis in various cancers. The identification of aberrant DNA methylation can be exploited for early diagnosis and risk assessment of patients. We identified a CIMP in myelodysplastic syndrome (MDS). Genes were screened for hypermethylation and transcription downregulation through genome-wide DNA methylation profiling and gene expression microarrays. Methylation-specific, real-time, and bisulfite-sequencing polymerase chain reaction were performed to validate selected genes. The hypermethylation of genes as a diagnostic tool for the detection of MDS was evaluated. Kaplan-Meier survival analysis and Cox regression were performed. A draft of an MDS CIMP was established and revised to 6 genes after validation in 20 patients and 20 controls. Further large-scale analysis showed that the majority of 211 MDS patients were hypermethylated in 6 genes. The area under the curve of CIMP was 0·9768 (95% confidence interval 0·9609-0·9928). A combination of 5 or more of the methylated genes showed a specificity of 95% and sensitivity of 91% for the diagnosis of MDS. We found CIMP positivity to be a significantly unfavourable prognostic factor for MDS. These results indicate that the newly established CIMP may improve diagnostic accuracy and prognosis assessment in MDS.
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Affiliation(s)
- Xiaoli Zhao
- Department of Haematology, Huashan Hospital, Fudan University, Shanghai, China
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50
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Shimizu D, Kanda M, Nomoto S, Oya H, Takami H, Hibino S, Suenaga M, Inokawa Y, Hishida M, Takano N, Nishikawa Y, Yamada S, Fujii T, Nakayama G, Sugimoto H, Koike M, Fujiwara M, Kodera Y. Identification of intragenic methylation in the TUSC1 gene as a novel prognostic marker of hepatocellular carcinoma. Oncol Rep 2013; 31:1305-13. [PMID: 24366000 DOI: 10.3892/or.2013.2939] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 11/20/2013] [Indexed: 12/16/2022] Open
Abstract
Patients with hepatocellular carcinoma (HCC) have a poor prognosis, and novel molecular targets for treating recurrence and progression of the disease along with associated biomarkers are urgently required. In the present study, expression and the regulatory mechanism of TUSC1 (tumor suppressor candidate 1) were investigated to determine if it is a candidate tumor suppressor gene for HCC, which shows repressed transcription that involves aberrant DNA methylation. TUSC1 mRNA expression levels in HCC cell lines and 94 pairs of surgical specimens were determined using quantitative real-time reverse transcription polymerase chain reaction assay. Methylation status of HCC cell lines and clinical samples were analyzed to investigate the regulatory mechanism of TUSC1 transcription and the relationship between the methylation status of the TUSC1 gene and clinicopathological factors. The expression and distribution of the TUSC1 protein in liver tissues were determined using immunohistochemistry. A majority of HCC cell lines (89%) and surgical specimens (84%) demonstrated reduced expression levels of TUSC1 mRNA compared with paired non-cancerous liver tissues. The mean mRNA expression level in HCC was significantly lower than in corresponding non-cancerous liver. In contrast, no significant difference was found in TUSC1 mRNA expression level between adjacent normal and cirrhotic liver tissue from HCC patients. The TUSC1 protein expression pattern in HCC and liver tissues was consistent with TUSC1 mRNA expression. Twenty-nine (31%) of 94 patients showed intragenic hypermethylation of the TUSC1 gene in HCC, and hypermethylation was significantly associated with advanced pathological stage. Subsequently, patients with hypermethylation of the TUSC1 gene had a significantly poorer prognosis than patients without hypermethylation. Our results suggest that TUSC1 is a candidate tumor suppressor gene and intragenic hypermethylation is one of the suppressive mechanisms that regulate TUSC1 transcription in HCC. Intragenic methylation of the TUSC1 gene may serve as a novel prognostic marker of HCC.
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Affiliation(s)
- Dai Shimizu
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shuji Nomoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hisaharu Oya
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideki Takami
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Soki Hibino
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masaya Suenaga
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshikuni Inokawa
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuhiro Hishida
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Nao Takano
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoko Nishikawa
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiko Koike
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
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