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Abou Zeid AA, El-Sayed ET, Ahdy JK, Tawfik MR. Ras Association Domain Family 1A Gene Promoter Methylation as a Biomarker for Chronic Viral Hepatitis C-related Hepatocellular Carcinoma. Cureus 2023; 15:e45687. [PMID: 37868533 PMCID: PMC10590080 DOI: 10.7759/cureus.45687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2023] [Indexed: 10/24/2023] Open
Abstract
Background One of the most prevalent aberrant epigenetic modifications found in hepatocellular carcinoma (HCC) is abnormal DNA methylation. Our study aimed to evaluate serum Ras association domain family 1A (RASSF1A) gene promoter methylation in patients with chronic viral hepatitis C (HCV)-associated liver cirrhosis with and without HCC as a potential new marker for the early detection of HCC. Methodology The 60 participants who participated in the trial were divided into the following three groups: 20 patients with newly diagnosed primary HCC on top of HCV-related liver cirrhosis, 20 patients with HCV-related liver cirrhosis, and 20 age- and sex-matched healthy individuals as a control group. All participants underwent methylation-specific polymerase chain reaction testing to detect the blood level of the RASSF1A gene's methylated promoter. Results Methylated RASSF1A was found in 30% of patients with liver cirrhosis caused by HCV and in 65% of patients with HCC, but not in any of the controls. It was discovered that the serum methylation RASSF1A had an accuracy of 82.50% and an area under the curve (AUC) of 0.825 for separating HCC patients from healthy controls. With an AUC of 0.675 and an accuracy of 67.50%, it was able to differentiate patients with HCC from those with HCV-related liver cirrhosis. Additionally, there was no statistically significant association between RASSF1A methylation status and HCC mass size (p = 0.449). Conclusions Serum RASSF1A promoter methylation status detection could be useful for detecting HCC early, especially in high-risk individuals such as those with HCV.
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Affiliation(s)
- Abla A Abou Zeid
- Clinical and Chemical Pathology, Alexandria Faculty of Medicine, Alexandria University, Alexandria, EGY
| | - Eman T El-Sayed
- Clinical and Chemical Pathology, Alexandria Faculty of Medicine, Alexandria University, Alexandria, EGY
| | - Jylan K Ahdy
- Clinical and Chemical Pathology, Al Ramel Pediatric Hospital, Ministry of Health, Alexandria, EGY
| | - Marwa R Tawfik
- Hepatobiliary Unit, Internal Medicine Department, Alexandria Faculty of Medicine, Alexandria University, Alexandria, EGY
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Zhang C, Zhang W, Yuan Z, Yang W, Hu X, Duan S, Wei Q. Contribution of DNA methylation to the risk of hepatitis C virus-associated hepatocellular carcinoma: A meta-analysis. Pathol Res Pract 2022; 238:154136. [PMID: 36155324 DOI: 10.1016/j.prp.2022.154136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 09/07/2022] [Accepted: 09/16/2022] [Indexed: 10/14/2022]
Abstract
DNA methylation is a crucial epigenetic modification in hepatocellular carcinoma (HCC), and hepatitis C virus (HCV) can induce hepatocarcinogenesis. Nevertheless, the interaction mechanism between DNA methylation and HCV infection in HCC is still ambiguous. In this study, we performed a comprehensive meta-analysis to assess the contribution of DNA methylation in HCV-associated HCC. After four steps of literature screening, we finally obtained 33 qualified case-control studies for this meta-analysis. These studies consisted of 587 HCV-positive cancer tissues and 326 HCV-negative cancer tissues. Our results revealed that four genes (p16, GSTP1, APC, and RUNX3) were more hypermethylated in the HCV-positive liver cancer tissues than in the HCV-negative liver cancer tissues. In addition, the p16 gene was more hypermethylated in the HCV-positive paracancerous tissues than in the HCV-negative paracancerous tissues. Subgroup meta-analysis by geographical populations showed that p16 methylation was significantly higher in HCV-positive cancerous tissues from Japanese and Chinese. Besides, p16 methylation was significantly higher among patients (> 60 years) but not among the others (≤ 60 years). However, there was no obvious association between DNA methylation and other clinicopathological characteristics, including gender, tumor size, differentiation, and clinical stage. Our study suggested that DNA methylation could become potential biomarkers for HCV-associated HCC. DNA methylation contributed to the risk of HCV-associated HCC.
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Affiliation(s)
- Cheng Zhang
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Wangjian Zhang
- Department of Medical Statistics, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhijun Yuan
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Wenjun Yang
- Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Xiangrong Hu
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shiwei Duan
- School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang, China.
| | - Qichun Wei
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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Tian Z, Xu C, Yang P, Lin Z, Wu W, Zhang W, Ding J, Ding R, Zhang X, Dou K. Molecular pathogenesis: Connections between viral hepatitis-induced and non-alcoholic steatohepatitis-induced hepatocellular carcinoma. Front Immunol 2022; 13:984728. [PMID: 36189208 PMCID: PMC9520190 DOI: 10.3389/fimmu.2022.984728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/31/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatocellular carcinoma(HCC) is the sixth most common cancer in the world and is usually caused by viral hepatitis (HBV and HCV), alcoholic, and non-alcoholic fatty liver disease(NAFLD). Viral hepatitis accounts for 80% of HCC cases worldwide. In addition, With the increasing incidence of metabolic diseases, NAFLD is now the most common liver disease and a major risk factor for HCC in most developed countries. This review mainly described the specificity and similarity between the pathogenesis of viral hepatitis(HBV and HCV)-induced HCC and NAFLD-induced HCC. In general, viral hepatitis promotes HCC development mainly through specific encoded viral proteins. HBV can also exert its tumor-promoting mechanism by integrating into the host chromosome, while HCV cannot. Viral hepatitis-related HCC and NASH-related HCC differ in terms of genetic factors, and epigenetic modifications (DNA methylation, histone modifications, and microRNA effects). In addition, both of them can lead to HCC progression through abnormal lipid metabolism, persistent inflammatory response, immune and intestinal microbiome dysregulation.
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Affiliation(s)
- Zelin Tian
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Chen Xu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Peijun Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Zhibin Lin
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Wenlong Wu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Wenjie Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- Chinese Education Ministry’s Key Laboratory of Western Resources and Modern Biotechnology, Key Laboratory of Biotechnology Shaanxi Province, College of Life Sciences, Northwest University, Xi’an, China
| | - Jian Ding
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Rui Ding
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Xuan Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- *Correspondence: Xuan Zhang, ; Kefeng Dou,
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- *Correspondence: Xuan Zhang, ; Kefeng Dou,
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4
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Yang Z, Chen W, Zhu H, Zhang L, Zhou K, Tang H, Sun R, Huang Y, Xie H, Zheng S, Jia C. Methylation site APC112043544 as a potential biomarker for post-transplant hepatocellular carcinoma recurrence. Future Oncol 2022; 18:2401-2413. [PMID: 35502765 DOI: 10.2217/fon-2021-1608] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 04/13/2022] [Indexed: 11/21/2022] Open
Abstract
Objective: To investigate the prognostic value of DNA methylation of tumor suppressor genes for hepatocellular carcinoma (HCC) recurrence after liver transplantation. Methods: APC gene was selected according to The Cancer Genome Atlas dataset. Tumor tissues and clinical data of 85 HCC patients who received a liver transplantation were retrospectively enrolled and next-generation methylation sequencing was performed. Risk factors were determined using the Cox proportional-hazard-regression model. Results: The APC methylation site (chromosome 5, position 112043544) was an independent predictor of post-transplant HCC recurrence. Patients with hyper-methylated APC112043544 experienced superior recurrence-free survival (p = 0.021) and had a decreased proportion of microvascular invasion (p = 0.017). APC112043544 also predicted recurrence risk in patients beyond selection criteria. Conclusions: APC112043544 methylation may serve as a potential biomarker for post-transplant HCC recurrence.
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Affiliation(s)
- Zhentao Yang
- Department of Surgery, Division of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Wei Chen
- Department of Hepatopancreatobiliary Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Research Center of Diagnosis & Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, 310000, China
| | - Hai Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Road 6, Nanning, 530021, China
| | - Liang Zhang
- Department of Surgery, Division of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Ke Zhou
- Department of Surgery, Division of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Hong Tang
- Department of Surgery, Division of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Ruiqi Sun
- Department of Surgery, Division of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Yiqian Huang
- Department of Pharmacy, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, China
| | - Haiyang Xie
- Department of Surgery, Division of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310000, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis & Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou, 310000, China
| | - Shusen Zheng
- Department of Surgery, Division of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310000, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis & Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou, 310000, China
| | - Changku Jia
- Department of Hepatopancreatobiliary Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Research Center of Diagnosis & Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, 310000, China
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Chen Z, Qi L, Fu H, Ma L. Long non-coding RNA X-inactive specific transcript suppresses the progression of hepatocellular carcinoma through microRNA-221-3p-targeted regulation of O6-methylguanine-DNA methyltransferase. Bioengineered 2022; 13:14013-14027. [PMID: 35723009 PMCID: PMC9275909 DOI: 10.1080/21655979.2022.2086382] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
MicroRNA-221-3p (miR-221-3p) is an important regulator involved in the progression and prognosis of various cancers. In this study, we aimed to investigate the diagnostic and prognostic value of miR-221-3p expression along with long non-coding RNA X–inactive specific transcript (XIST), which was identified as its upstream regulator in hepatocellular carcinoma (HCC) by bioinformatics analysis, and further validated by RNA immunoprecipitation (RIP) and dual-luciferase reporter assays. Their expression was measured in tumor tissues and corresponding non-tumor tissues by quantitative real-time PCR (qRT-PCR), which revealed that XIST was weakly expressed in HCC cells and tumors, while miR-221-3p was overexpressed. Complete knockdown of XIST enhanced HCC cell proliferation and migration and inhibited apoptosis, as observed by MTT, transwell, and flow cytometry experiments, respectively. Animal studies validated that XIST knockdown induces tumor growth in vivo. In contrast, upregulation of XIST in HCC cells suppressed their proliferation and migration, stimulated apoptosis, and retarded the growth rate of tumors in vivo. These effects were partially reversed by upregulating miR-221-3p expression. Furthermore, we demonstrated that O6-methylguanine-DNA methyltransferase (MGMT) is a downstream target of miR-221-3p. It was weakly expressed in HCC cells and tumors and showed a negative correlation with miR-221-3p. Forced MGMT expression repressed proliferation and migration and enhanced apoptosis in HCC cells. Nevertheless, these anti-tumor effects induced by MGMT overexpression could be abolished by miR-221-3p upregulation. Collectively, our findings reveal that XIST blocks the development of HCC through miR-221-3p-targeted regulation of MGMT. This reveals a new mechanism involved in the development of HCC.
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Affiliation(s)
- Zushun Chen
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Lunan Qi
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Hongyuan Fu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Liang Ma
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
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6
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Abo El-Khair SM, Elalfy H, Diasty M, Ebrahim EE, Elsamanoudy AZ. Methylation degree of metalloproteinase inhibitor RECK gene: Links to RECK protein level and hepatocellular carcinoma in chronic HCV infection patients. J Biochem Mol Toxicol 2021; 35:e22886. [PMID: 34392581 DOI: 10.1002/jbt.22886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 07/21/2021] [Accepted: 08/06/2021] [Indexed: 11/11/2022]
Abstract
The RECK gene, a tumor suppressor gene, inhibits angiogenesis, invasion, and tumor metastasis. Epigenetic regulation of the RECK gene constitutes a potent approach to the molecular basis of liver malignancy. This study aims to evaluate the promoter methylation status of the RECK gene and its serum level in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) and the potential association of RECK gene methylation with clinical criteria of HCC. One hundred and fifty-five subjects were included (healthy control [55], chronic HCV patients [55], HCV-related HCC patients [45]). The methylation status of the RECK gene promoter and serum RECK level were investigated by methylation-specific PCR and enzyme-linked immunosorbent assay techniques, respectively. RECK gene promoter hypermethylation was recorded in 46.7% of HCC patients, and 10.9% of HCV patients, but not in control subjects (0%). It was related to RECK protein level, varices, edema, ascites, lymph node metastasis, vascular invasion, and the largest diameter of focal lesions. Meanwhile, it was not associated with focal lesion number nor distant metastasis of HCC. In conclusion, RECK gene promoter hypermethylation is linked to HCV genotype-4-related HCC. Moreover, different degrees of RECK gene promoter methylation are associated with serum RECK level, lymph node metastasis, and vascular invasion, which could prove its pathogenic role in hepatocarcinogenesis in chronic HCV-infected patients.
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MESH Headings
- Adult
- Aged
- Carcinogenesis/genetics
- Carcinogenesis/metabolism
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/complications
- Carcinoma, Hepatocellular/genetics
- Case-Control Studies
- DNA Methylation/genetics
- Epigenesis, Genetic
- Female
- GPI-Linked Proteins/blood
- GPI-Linked Proteins/genetics
- Genes, Tumor Suppressor
- Genotype
- Hepacivirus/genetics
- Hepacivirus/immunology
- Hepatitis C, Chronic/blood
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/virology
- Humans
- Liver Neoplasms/blood
- Liver Neoplasms/complications
- Liver Neoplasms/genetics
- Lymphatic Metastasis/genetics
- Male
- Metalloproteases/antagonists & inhibitors
- Middle Aged
- Promoter Regions, Genetic/genetics
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Affiliation(s)
- Salwa M Abo El-Khair
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Hatem Elalfy
- Tropical Medicine Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Muhammad Diasty
- Tropical Medicine Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Eman E Ebrahim
- Tropical Medicine Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ayman Z Elsamanoudy
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Clinical Biochemistry Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
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Tan YL, Chen H, Wu ZK, He J, Jiang JH. Digital Loop-Mediated Isothermal Amplification-Based Absolute Methylation Quantification Revealed Hypermethylated DAPK1 in Cervical Cancer Patients. Anal Chem 2021; 93:8077-8083. [PMID: 34019386 DOI: 10.1021/acs.analchem.1c01510] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The aberrant methylation of many genes has been reported to be associated with various carcinomas. Accurate detection of the methylation level could provide critical insights into the diagnostic analysis of diseases. Here, a sensitive HpaII-edited absolute droplet loop-mediated isothermal amplification (HEADLAMP) method based on methylation-sensitive restriction enzyme (MSRE) HpaII was developed for the digital quantification of DNA methylation. Methylation levels of the death-associated protein kinase 1 (DAPK1) gene that is associated with many cancers were studied using β-actin as an internal reference. DAPK1 (2.5 pM) with 0.01% methylation (250 aM) can be detected with the conventional HpaII-edited LAMP assay. Using HEADLAMP, as low as 1% methylation level can be distinguished with an estimated limit of detection of 5 aM (ca. 3 copies/μL). Moreover, HEADLAMP can detect low levels of methylated DAPK1 in normal L-02 cells, while the conventional assay cannot. Finally, HEADLAMP was applied to the detection of DAPK1 methylation in 20 clinical tissue samples, which revealed hypermethylated DAPK1 in cervical cancer patients. We envisage potential applications of this robust, specific, and sensitive HEADLAMP assay in epigenetic studies and early clinical diagnosis.
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Affiliation(s)
- Ya-Ling Tan
- State Key Laboratory of Chemo/BioSensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
| | - Hongjian Chen
- State Key Laboratory of Chemo/BioSensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
| | - Zhen-Kun Wu
- State Key Laboratory of Chemo/BioSensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
| | - Jianjun He
- State Key Laboratory of Chemo/BioSensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
| | - Jian-Hui Jiang
- State Key Laboratory of Chemo/BioSensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
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8
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Zidan AM, Saad EA, Ibrahim NE, Hashem MH, Mahmoud A, Hemeida AA. Host pharmacogenetic factors that may affect liver neoplasm incidence upon using direct-acting antivirals for treating hepatitis C infection. Heliyon 2021; 7:e06908. [PMID: 34013078 PMCID: PMC8113831 DOI: 10.1016/j.heliyon.2021.e06908] [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: 02/23/2021] [Revised: 04/07/2021] [Accepted: 04/21/2021] [Indexed: 02/07/2023] Open
Abstract
Introduction Direct-acting antivirals (DAAs) represent a breakthrough in hepatitis C virus (HCV) treatment as they directly inhibit HCV nonstructural (NS) proteins (NS3/4A, NS5A, and NS5B). However, ongoing debates exist regarding their relationship with hepatocellular carcinoma (HCC) whose incidence is widely debated among investigators. This study was conducted to identify host pharmacogenetic factors that may influence HCC incidence upon using HCV DAAs. Materials and methods Details regarding 16 HCV DAAs were collected from literature and DrugBank database. Digital structures of these drugs were fed into the pharmacogenomics/pharmacovigilance in-silico pipeline (PHARMIP) to predict the genetic factors that may underpin HCC development. Results We identified 184 unique genes and 40 unique variants that may have key answers for the DAA/HCC paradox. These findings could be used in different methods to aid in the precise application of HCV DAAs and minimize the proposed risk for HCC. All results could be accessed at: https://doi.org/10.17632/8ws8258hn3.2. Discussion All the identified factors are evidence related to HCC and significantly predicted by PHARMIP as DAA targets. We discuss some examples of the methods of using these results to address the DAA/HCC controversy based on the following three primary levels: 1 - individual DAA drug, 2 - DAA subclass, and 3 - the entire DAA class. Further wet laboratory investigation is required to evaluate these results.
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Affiliation(s)
- Ahmad M Zidan
- Department of Bioinformatics, Genetic Engineering & Biotechnology Research Institute, University of Sadat City, Egypt.,Clinical Research Department, Monof Chest Hospital, Menoufia directorate, Ministry of health & population (MOHP), Egypt
| | - Eman A Saad
- Department of Bioinformatics, Genetic Engineering & Biotechnology Research Institute, University of Sadat City, Egypt
| | - Nasser E Ibrahim
- Department of Bioinformatics, Genetic Engineering & Biotechnology Research Institute, University of Sadat City, Egypt
| | - Medhat H Hashem
- Department of Animal Biotechnology, Genetic Engineering & Biotechnology Research Institute, University of Sadat City, Egypt
| | - Amal Mahmoud
- Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, 31441, Dammam, Saudi Arabia
| | - Alaa A Hemeida
- Department of Bioinformatics, Genetic Engineering & Biotechnology Research Institute, University of Sadat City, Egypt
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9
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Teuber-Hanselmann S, Worm K, Macha N, Junker A. MGMT-Methylation in Non-Neoplastic Diseases of the Central Nervous System. Int J Mol Sci 2021; 22:ijms22083845. [PMID: 33917711 PMCID: PMC8068191 DOI: 10.3390/ijms22083845] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/05/2021] [Accepted: 04/05/2021] [Indexed: 12/11/2022] Open
Abstract
Quantifying O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation plays an essential role in assessing the potential efficacy of alkylating agents in the chemotherapy of malignant gliomas. MGMT promoter methylation is considered to be a characteristic of subgroups of certain malignancies but has also been described in various peripheral inflammatory diseases. However, MGMT promoter methylation levels have not yet been investigated in non-neoplastic brain diseases. This study demonstrates for the first time that one can indeed detect slightly enhanced MGMT promoter methylation in individual cases of inflammatory demyelinating CNS diseases such as multiple sclerosis and progressive multifocal leucencephalopathy (PML), as well as in other demyelinating diseases such as central pontine and exptrapontine myelinolysis, and diseases with myelin damage such as Wallerian degeneration. In this context, we identified a reduction in the expression of the demethylase TET1 as a possible cause for the enhanced MGMT promoter methylation. Hence, we show for the first time that MGMT hypermethylation occurs in chronic diseases that are not strictly associated to distinct pathogens, oncogenic viruses or neoplasms but that lead to damage of the myelin sheath in various ways. While this gives new insights into epigenetic and pathophysiological processes involved in de- and remyelination, which might offer new therapeutic opportunities for demyelinating diseases in the future, it also reduces the specificity of MGMT hypermethylation as a tumor biomarker.
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Affiliation(s)
- Sarah Teuber-Hanselmann
- Institute of Neuropathology, University Hospital Essen, D-45147 Essen, Germany; (S.T.-H.); (N.M.)
| | - Karl Worm
- Institute of Pathology, University Hospital Essen, D-45147 Essen, Germany;
| | - Nicole Macha
- Institute of Neuropathology, University Hospital Essen, D-45147 Essen, Germany; (S.T.-H.); (N.M.)
| | - Andreas Junker
- Institute of Neuropathology, University Hospital Essen, D-45147 Essen, Germany; (S.T.-H.); (N.M.)
- Correspondence: ; Tel.: +49-201-723-3315
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10
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Xu G, Zhou X, Xing J, Xiao Y, Jin B, Sun L, Yang H, Du S, Xu H, Mao Y. Identification of RASSF1A promoter hypermethylation as a biomarker for hepatocellular carcinoma. Cancer Cell Int 2020; 20:547. [PMID: 33292241 PMCID: PMC7653745 DOI: 10.1186/s12935-020-01638-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 11/02/2020] [Indexed: 02/07/2023] Open
Abstract
Background RAS association domain family protein 1A (RASSF1A) promoter hypermethylation is suggested to be linked to hepatocellular carcinoma (HCC), but the results remained controversial. Methods We evaluated how RASSF1A promoter hypermethylation affects HCC risk and its clinicopathological characteristics through meta-analysis. Data on DNA methylation in HCC and relevant clinical data were also collected based on The Cancer Genome Atlas (TCGA) database to investigate the prognostic role of RASSF1A promoter hypermethylation in HCC. Results Forty-four articles involving 4777 individuals were enrolled in the pooled analyses. The RASSF1A promoter methylation rate was notably higher in the HCC cases than the non-tumor cases and healthy individuals, and was significantly related to hepatitis B virus (HBV) infection-positivity and large tumor size. Kaplan–Meier survival analysis revealed that HCC cases with RASSF1A promoter hypermethylation had worse outcomes. Receiver operating characteristic curves confirmed that RASSF1A promoter methylation may be a marker of HCC-related prognoses. Conclusions RASSF1A promoter hypermethylation is a promising biomarker for the diagnosis of HCC from tissue and peripheral blood, and is an emerging therapeutic target against HCC.
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Affiliation(s)
- Gang Xu
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Xiaoxiang Zhou
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Jiali Xing
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yao Xiao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Bao Jin
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Lejia Sun
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Huayu Yang
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Haifeng Xu
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China.
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China.
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Vidal RIDO, Vidal EIDO, Pereira BDB, Assane CC, Ribeiro A, do Nascimento EM, Romeiro FG, Ribeiro Filho J. Risk Factors for Hepatocellular Carcinoma Recurrence and Survival after Liver Transplantation in Patients with HCV-Related Cirrhosis. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1487593. [PMID: 33134370 PMCID: PMC7591978 DOI: 10.1155/2020/1487593] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/05/2020] [Indexed: 12/25/2022]
Abstract
PURPOSE We aimed to identify prognostic factors for survival and recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) for patients with HCC and hepatitis C virus-related cirrhosis (HCV-cirrhosis). METHODS This retrospective cohort study followed all adult patients with HCV-cirrhosis who underwent LT because of HCC or had incidental HCC identified through pathologic examination of the explanted liver at a university hospital in Rio de Janeiro, Brazil, over 11 years (1998-2008). We used Cox regression models to assess the following risk factors regarding HCC recurrence or death after LT: age, Model for End-stage Liver Disease score, Child-Pugh classification, alpha-fetoprotein (AFP), whether patients had undergone locoregional treatment before transplantation, the number of packed red blood cell units (PRBCU) transfused during surgery, the number and size of HCC lesions in the explanted liver, and the presence of microvascular invasion and necrotic areas within HCC lesions. RESULTS Seventy-six patients were followed up for a median (interquartile range (IQR)) of 4.4 (0.7-6.6) years. Thirteen (17%) patients had HCC recurrence during the follow-up period, and 26 (34%) died. The median survival time was 6.6 years (95% CI: 2.4-12.0), and the 5-year survival was 52.5% (95% CI: 42.3-65.0%). The final regression model for overall survival included four variables: age (hazard ratio (HR): 1.02, 95% CI: 0.96-1.08, P = 0.603), transplantation waiting time (HR: 1.00, 95% CI: 1.00-1.00, P = 0.190), preoperative AFP serum levels (HR: 1.01, 95% CI: 1.00-1.02, P = 0.006), and whether >4 PRBCU were transfused during surgery (HR: 1.15, 95% CI: 1.05-1.25, P = 0.001). The final cause-specific Cox regression model for HCC recurrence included only microvascular invasion (HR: 14.86, 95% CI: 4.47-49.39, P < 0.001). CONCLUSION In this study of LT for HCV-cirrhosis, preoperative AFP levels and the number of PRBCU transfused during surgery were associated with overall survival, whereas microvascular invasion with HCC recurrence.
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Affiliation(s)
- Raphael Iglesias de Oliveira Vidal
- Department of Surgery, Faculty of Medicine, Federal University of Rio de Janeiro (UFRJ), Rua Rodolpho Paulo Rocco, 255-Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, Brazil 21941-902
| | - Edison Iglesias de Oliveira Vidal
- Internal Medicine Department, Botucatu Medical School, Sao Paulo State University (UNESP), Av. Prof. Mario Rubens Guimaraes Montenegro, S/N, Botucatu, SP, Brazil 18618-687
| | - Basilio de Bragança Pereira
- Preventive Medicine Department, Faculty of Medicine, Federal University of Rio de Janeiro (UFRJ), Cidade Universitária, Ilha do Fundão, P.O. Box: 68507, Rio de Janeiro, RJ, Brazil 21941-972
| | - Cachimo Combo Assane
- Department of Mathematics and Informatics, Faculty of Sciences, Universidade Eduardo Mondlane, Av. Julius Nyerere/Campus 3453, P.O. Box 257, Maputo, Mozambique
| | - Alexandre Ribeiro
- Department of Surgery, Faculty of Medicine, Federal University of Rio de Janeiro (UFRJ), Rua Rodolpho Paulo Rocco, 255-Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, Brazil 21941-902
| | - Emilia Matos do Nascimento
- Centro Universitário da Zona Oeste, UEZO-Unidade de Engenharia de Produção, Engenharia de Produção, Avenida Manuel Caldeira de Alvarenga, Campo Grande, Rio de Janeiro, RJ, Brazil 23070-200
| | - Fernando Gomes Romeiro
- Internal Medicine Department, Botucatu Medical School, Sao Paulo State University (UNESP), Av. Prof. Mario Rubens Guimaraes Montenegro, S/N, Botucatu, SP, Brazil 18618-687
| | - Joaquim Ribeiro Filho
- Department of Surgery, Faculty of Medicine, Federal University of Rio de Janeiro (UFRJ), Rua Rodolpho Paulo Rocco, 255-Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, Brazil 21941-902
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Chen Z, Xiang B, Qi L, Zhu S, Li L. miR-221-3p promotes hepatocellular carcinogenesis by downregulating O6-methylguanine-DNA methyltransferase. Cancer Biol Ther 2020; 21:915-926. [PMID: 33023393 DOI: 10.1080/15384047.2020.1806642] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
This study aimed to investigate the influence of miR-221-3p and O6-methylguanine-DNA methyltransferase (MGMT) interaction in human hepatocellular carcinoma (HCC), thereby revealing a novel molecular mechanism of hepatic carcinogenesis involving miR-221-3p and MGMT. Fluorescence qPCR and immunoblot assays were performed to determine the expression of RNA and protein in HCC tissues and cell lines. We also employed the firefly and Renilla luciferase assay to verify the target relationship between miR-221-3p and MGMT mRNA. Assessments including the MTT assay, wound-healing assay, transwell assay, colony foci formation experiment, and flow cytometric experiment were carried out to determine the viability, migration, invasion, proliferation, cell cycle progression, and apoptosis of SMMC-7721 and BEL-7404 cell lines with the modulated expression of miR-221-3p and MGMT. Compared to healthy tissues and cell line HL7702, miR-221-3p was significantly upregulated but MGMT was significantly downregulated in carcinomas and cancerous cell lines. Forced miR-221-3p overexpression was found to enhance the proliferation, migration, invasion, and clonogenicity of cell lines, but it suppressed cell apoptosis. Findings also revealed that forced miR-221-3p overexpression had little effect on cell cycle progression. After MGMT was confirmed to be atarget gene of miR-221-3p, it was found that the forced upregulation of miR-221-3p downregulated MGMT mRNA and protein levels significantly. MiR-221-3p was identified as an HCC promoting factor, and it specifically inhibited the expression of the MGMT. Besides, the upregulation of miR-221-3p had apositive influence on HCC pathogenesis by inhibiting MGMT expression.
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Affiliation(s)
- Zushun Chen
- Department of Hepatobiliary Surgery, Guangxi Medical University Affiliated Tumor Hospital , Nanning, Guangxi, China
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Guangxi Medical University Affiliated Tumor Hospital , Nanning, Guangxi, China
| | - Lunan Qi
- Department of Hepatobiliary Surgery, Guangxi Medical University Affiliated Tumor Hospital , Nanning, Guangxi, China
| | - Shaoliang Zhu
- Department of Hepatobiliary Surgery, Guangxi Medical University Affiliated Tumor Hospital , Nanning, Guangxi, China
| | - Lequn Li
- Department of Hepatobiliary Surgery, Guangxi Medical University Affiliated Tumor Hospital , Nanning, Guangxi, China
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Association of RASSF1A hypermethylation with risk of HBV/HCV-induced hepatocellular carcinoma: A meta-analysis. Pathol Res Pract 2020; 216:153099. [PMID: 32853942 DOI: 10.1016/j.prp.2020.153099] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/19/2020] [Accepted: 03/07/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Researchers have discovered a large number of DNA methylation patterns in human cancer. These cancer-specific methylation patterns can provide information for the diagnosis, treatment, and prognosis of cancer. Methylation studies can find new biomarkers based on epigenetic analysis and apply these biomarkers to clinical oncology. Many studies on the association between RAASF1A methylation status and susceptibility to hepatitis B virus (HBV)/hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) have reached controversial conclusions. Hence, the current review comprehensively assessed the correlation between Ras association domain family 1A (RASSF1A) methylation and the risk of the HCV/HBV-induced HCC. METHODS The appropriated publications were extracted in EMBASE, PubMed, Web of Science, Cochrane Library, and China National Knowledge Infrastructure databases using STATA 5.0 software. The odds ratios (ORs) with 95 % confidence interval (95 % CI) of RASSF1A methylation were computed. RESULTS A total of 1015 HBV/HCV-related HCC samples, 124 non-HBV/HCV-related HCC (NBNC-HCC) samples, and 1225 nontumorous controls were extracted and examined in this research. The frequency of the methylated RASSF1A in the HBV/HCV-related tumor cases displayed a significantly increased OR compared with the overall nontumor samples (OR = 19.372, 95 % CI = 11.060-33.931, P = 0.000). The frequency of the methylated RASSF1A in HBV/HCV-related neoplasm cases displayed a significantly increased OR compared with the non-HBV/HCV-related neoplasm (NBNC-neoplasm) samples (OR = 2.150, 95 % CI = 1.398-3.308, P = 0.000). Compared with normal, chronic hepatitis B or C, cirrhosis, and paracancerous samples, the pooled OR of the RASSF1A promoter methylation in the HBV/HCV-induced HCC samples was 62.785(95 % CI = 35.224-111.909), 25.07 (95 % CI = 13.85-45.36), 6.89 (95 % CI = 3.33-14.264) and 9.02 (95 % CI = 0.91-89.80), respectively. The rate of RASSF1A hypermethylation was robustly correlated with tumor size and vascular invasion, and the pooled OR was 0.346 (95 % CI = 0.210 - 0.569) and 0.081 (95 % CI = 0.022 - 0.303), respectively. CONCLUSION Results showed robust associations between RASSF1A gene methylation in promoter region and enhanced HBV/HCV-related HCC susceptibility, thereby revealing that RASSF1A methylation status may serve as an important indicator for HCC oncogenesis.
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García-Gutiérrez L, McKenna S, Kolch W, Matallanas D. RASSF1A Tumour Suppressor: Target the Network for Effective Cancer Therapy. Cancers (Basel) 2020; 12:cancers12010229. [PMID: 31963420 PMCID: PMC7017281 DOI: 10.3390/cancers12010229] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 01/12/2020] [Accepted: 01/14/2020] [Indexed: 02/06/2023] Open
Abstract
The RASSF1A tumour suppressor is a scaffold protein that is involved in cell signalling. Increasing evidence shows that this protein sits at the crossroad of a complex signalling network, which includes key regulators of cellular homeostasis, such as Ras, MST2/Hippo, p53, and death receptor pathways. The loss of expression of RASSF1A is one of the most common events in solid tumours and is usually caused by gene silencing through DNA methylation. Thus, re-expression of RASSF1A or therapeutic targeting of effector modules of its complex signalling network, is a promising avenue for treating several tumour types. Here, we review the main modules of the RASSF1A signalling network and the evidence for the effects of network deregulation in different cancer types. In particular, we summarise the epigenetic mechanism that mediates RASSF1A promoter methylation and the Hippo and RAF1 signalling modules. Finally, we discuss different strategies that are described for re-establishing RASSF1A function and how a multitargeting pathway approach selecting druggable nodes in this network could lead to new cancer treatments.
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Affiliation(s)
- Lucía García-Gutiérrez
- Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; (L.G.-G.); (S.M.); (W.K.)
| | - Stephanie McKenna
- Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; (L.G.-G.); (S.M.); (W.K.)
| | - Walter Kolch
- Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; (L.G.-G.); (S.M.); (W.K.)
- School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
- Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - David Matallanas
- Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; (L.G.-G.); (S.M.); (W.K.)
- School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
- Correspondence:
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Mostafa WSEM, Al-Dahr MHS, Omran DAH, Abdullah ZF, Elmasry SH, Ibrahim MN. Influence of some methylated hepatocarcinogenesis-related genes on the response to antiviral therapy and development of fibrosis in chronic hepatitis C patients. Clin Mol Hepatol 2019; 26:60-69. [PMID: 31630500 PMCID: PMC6940485 DOI: 10.3350/cmh.2019.0051] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 08/29/2019] [Indexed: 12/17/2022] Open
Abstract
Background and Aim Epigenetics involved in multiple normal cellular processes. Previous research have revealed the role of hepatitis C virus infection in accelerating methylation process and affecting response to treatment in chronic hepatitis patients. This work aimed to elucidate the role of promoter methylation (PM) in response to antiviral therapy, and its contribution to the development of fibrosis through hepatocarcinogenesis-related genes. Methods A total of 159 chronic hepatitis Egyptian patients versus 100 healthy control group were included. The methylation profile of a panel 9 genes (SFRP1, p14, p73, APC, DAPK, RASSF1A, LINE1, O6MGMT, and p16) was detected in patients’ plasma using methylation-specific polymerase chain reaction (MSP). Results Clinical and laboratory findings were gathered for patients with combined pegylated interferon and ribavirin antiviral therapy. Regarding the patients’ response to antiviral therapy, the percentage of non-responders for APC, O6MGMT, RASSF1A, SFRP1, and p16 methylated genes were significantly higher versus responders (P<0.05). Of the 159 included patients, the most frequent methylated genes were SFRP1 (102/159), followed by p16 (100/159), RASSF1A (98/159), then LINE1 (81/159), P73 (81/159), APC (78/159), DAPK (66/159), O6MGMT (66/159), and p14 (54/159). A total of 67/98 (68.4%) cases of RASSF1A methylated gene (P=0.0.024), and 62/100 (62%) cases of P16 methylated gene (P=0.03) were associated with mild-degree fibrosis. Conclusions To recapitulate, the PM of SFRP1, APC, RASSF1A, O6MGMT, and p16 genes increases in chronic hepatitis C patients, and can affect patients’ response to antiviral therapy. The RASSF1A and P16 genes might have a role in the distinction between mild and marked fibrosis.
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Affiliation(s)
- Waleed Seif Eldin Mohamed Mostafa
- Virology and Immunology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt.,Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyate, Kingdom of Saudi Arabia
| | - Mohammed Hassan Saiem Al-Dahr
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyate, Kingdom of Saudi Arabia
| | - Dalia Abdel Hamid Omran
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Zeinab Fathy Abdullah
- Virology and Immunology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Suzan Hamdy Elmasry
- Department of Biochemistry, Ibn Sina National College for Medical Studies, Jeddah, Kingdom of Saudi Arabia
| | - Mohamed Nabil Ibrahim
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyate, Kingdom of Saudi Arabia
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Ma Z, Liu Y, Hao Z, Hua X, Li W. DNA hypermethylation of aurora kinase A in hepatitis C virus‑positive hepatocellular carcinoma. Mol Med Rep 2019; 20:2519-2532. [PMID: 31322223 PMCID: PMC6691273 DOI: 10.3892/mmr.2019.10487] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 03/05/2019] [Indexed: 12/12/2022] Open
Abstract
Changes in the methylation levels of tumor suppressor genes or proto-oncogenes are involved in the pathogenesis of hepatitis C virus (HCV) infection-induced hepatocellular carcinoma (HCC). The aim of the present study was to identify novel aberrantly methylated differentially expressed genes by integrating mRNA expression profile (GSE19665 and GSE62232) and methylation profile (GSE60753) microarrays downloaded from the Gene Expression Omnibus database. Functional enrichment analysis of screened genes was performed using the DAVID software and BinGO database. Protein-protein interaction (PPI) networks were constructed using the STRING database, followed by module analysis with MCODE software. The transcriptional and translational expression levels of crucial genes were confirmed using The Cancer Genome Atlas (TCGA) datasets and Human Protein Atlas database (HPA). A total of 122 downregulated/hypermethylated genes and 63 upregulated/hypomethylated genes were identified. These genes were enriched in the Gene Ontology biological processes terms of ‘inflammatory response’ [Fos proto-oncogene, AP-1 transcription factor subunit (FOS)] and ‘cell cycle process’ [aurora kinase A (AURKA), cyclin dependent kinase inhibitor 3 (CDKN3) and ubiquitin conjugating enzyme E2 C (UBE2C)]. PPI network and module analysis indicated that human oncogenes FOS, AURKA, CDKN3 and UBE2C may be hub genes. mRNA, protein expression and methylation levels of AURKA and FOS were validated by TCGA and HPA data. In conclusion, aberrantly methylated AURKA and FOS may be potential therapeutic targets for HCV-positive HCC.
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Affiliation(s)
- Zuohong Ma
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Shenyang, Liaoning 110042, P.R. China
| | - Yefu Liu
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Shenyang, Liaoning 110042, P.R. China
| | - Zhiqiang Hao
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Shenyang, Liaoning 110042, P.R. China
| | - Xiangdong Hua
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Shenyang, Liaoning 110042, P.R. China
| | - Wenxin Li
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Shenyang, Liaoning 110042, P.R. China
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Malpeli G, Innamorati G, Decimo I, Bencivenga M, Nwabo Kamdje AH, Perris R, Bassi C. Methylation Dynamics of RASSF1A and Its Impact on Cancer. Cancers (Basel) 2019; 11:959. [PMID: 31323949 PMCID: PMC6678546 DOI: 10.3390/cancers11070959] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 07/03/2019] [Accepted: 07/08/2019] [Indexed: 01/15/2023] Open
Abstract
5-methyl cytosine (5mC) is a key epigenetic mark entwined with gene expression and the specification of cellular phenotypes. Its distribution around gene promoters sets a barrier for transcriptional enhancers or inhibitor proteins binding to their target sequences. As a result, an additional level of regulation is added to the signals that organize the access to the chromatin and its structural components. The tumor suppressor gene RASSF1A is a microtubule-associated and multitasking scaffold protein communicating with the RAS pathway, estrogen receptor signaling, and Hippo pathway. RASSF1A action stimulates mitotic arrest, DNA repair and apoptosis, and controls the cell cycle and cell migration. De novo methylation of the RASSF1A promoter has received much attention due to its increased frequency in most cancer types. RASSF1A methylation is preceded by histones modifications and could represent an early molecular event in cell transformation. Accordingly, RASSF1A methylation is proposed as an epigenetic candidate marker in many cancer types, even though an inverse correlation of methylation and expression remains to be fully ascertained. Some findings indicate that the epigenetic abrogation of RASSF1A can promote the alternative expression of the putative oncogenic isoform RASSF1C. Understanding the complexity and significance of RASSF1A methylation is instrumental for a more accurate determination of its biological and clinical role. The review covers the molecular events implicated in RASSF1A methylation and gene silencing and provides a deeper view into the significance of the RASSF1A methylation patterns in a number of gastrointestinal cancer types.
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Affiliation(s)
- Giorgio Malpeli
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Section of Surgery, University of Verona, 37134 Verona, Italy.
- Department of Diagnostics and Public Health, Section of Anatomic Pathology, University of Verona, 37134 Verona, Italy.
| | - Giulio Innamorati
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Section of Surgery, University of Verona, 37134 Verona, Italy
| | - Ilaria Decimo
- Department of Medicine, Section of Pharmacology, University of Verona, 37134 Verona, Italy
| | - Maria Bencivenga
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Section of Surgery, University of Verona, 37134 Verona, Italy
| | | | - Roberto Perris
- Department of Biosciences, COMT-Centre for Molecular and Translational Oncology, University of Parma, 43124 Parma, Italy
| | - Claudio Bassi
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Section of Surgery, University of Verona, 37134 Verona, Italy
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Xu W, Qi X, Wang X, Sun J. Effect of interventional embolotherapy on FHIT and p16 expression in hepatocellular carcinoma patients. Oncol Lett 2019; 17:871-876. [PMID: 30655841 PMCID: PMC6313009 DOI: 10.3892/ol.2018.9648] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 10/08/2018] [Indexed: 01/26/2023] Open
Abstract
Effects of interventional embolotherapy on the expression of fragile histidine triad (FHIT) and p16 in hepatocellular carcinoma (HCC) patients were investigated. Patients with primary HCC who were definitely diagnosed and treated in the Department of Gastroenterology in Qingdao Central Hospital from March 2014 to March 2016 were selected, and they underwent interventional embolotherapy. HCC and cancer-adjacent tissues of the patients were harvested for immunohistochemical staining. The correlation between the expression levels of FHIT and p16 was analyzed at the gene and protein level. Clinical data were collected, and whether they were correlated with the expression of FHIT and p16 was investigated. The expression levels of FHIT and p16 in primary HCC tissues were remarkably lower than that in cancer-adjacent tissues (P<0.05). In HCC tissues, FHIT expression was obviously positively correlated with p16 expression (Spearman's correlation coefficient, r=0.308; P=0.025). FHIT was related to HCC tumor-node-metastasis (TNM) staging, the differentiation degree in Edmondson-Steiner grading, lymph node metastasis and portal vein thrombosis (P<0.05 in all comparisons), whereas, p16 was associated with tumor size and the differentiation degree in Edmondson-Steiner grading (P<0.05 in all comparisons). The expression of FHIT and p16 genes and proteins in HCC tissues were obviously lower than those in cancer-adjacent tissues (P<0.05 in all comparisons). FHIT and p16 genes, as tumor suppressor genes, inhibit the proliferation of HCC, and there is a positive correlation between them. The proteins of the FHIT and p16 can be used as new indicators for clinical detection, thus providing a new method for clinical diagnosis.
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Affiliation(s)
- Wei Xu
- Department of Intervention, Qingdao Central Hospital, Qingdao Cancer Hospital, Qingdao, Shandong 266042, P.R. China
| | - Xiaogai Qi
- Department of Radiotherapy, Qingdao Cancer Hospital, Qingdao, Shandong 266042, P.R. China
| | - Xia Wang
- Department of Ultrasound, Qingdao Cancer Hospital, Qingdao, Shandong 266042, P.R. China
| | - Jize Sun
- Department of Intervention, Qingdao Central Hospital, Qingdao Cancer Hospital, Qingdao, Shandong 266042, P.R. China
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Wu X, Yao X, Cao Q, Wu Z, Wang Z, Liu F, Shen L. Clinicopathological and prognostic significance of CDH1 hypermethylation in hepatocellular carcinoma: a meta-analysis. Cancer Manag Res 2019; 11:857-864. [PMID: 30697077 PMCID: PMC6340500 DOI: 10.2147/cmar.s179710] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background The patients with hepatocellular carcinoma (HCC) have poor prognosis due to being diagnosed at late stage or recurrence following surgery. It’s critical to identify effective biomarkers that can improve overall diagnosis and treatment of HCC. Methods We performed a meta-analysis of all relative studies reporting the clinicopathological significance of CDH1 hypermethylation in HCC by using Review Manager 5.2. A comprehensive literature search was performed in EMBASE, PubMed, Web of Science and Google Scholar databases. Kaplan Meier Plotter online database was used for the determination of correlation between CDH1 mRNA expression and overall survival in patients with HCC. Odds Ratios (OR) with 95% corresponding confidence intervals (CIs) were calculated. A total of 12 relevant studies were included in the meta-analysis with 981 patients. Results The positive rate of CDH1 hypermethylation was significantly higher in HCC than in normal liver tissue; and the pooled OR was 4.34 with 95% CI 2.50–7.56, P<0.00001. CDH1 promoter in HCC was more frequently hypermethylated compared to the group of chronic liver disease (CLD); OR was 4.83 with 95% CI 2.67–8.72, P<0.00001. However, the rate of CDH1 promoter hypermethylation was not correlated with different grades as well as stages. High CDH1 mRNA expression was significantly correlated to better overall survival in all 231 HCC patients compared to 133 HCC patients with low level CDH1 mRNA expression; HR was 0.6 with 95% CI 0.42–0.85, P=0.0034. Conclusion In summary, CDH1 promoter hypermethylation is a risk factor and promising biomarker for HCC carcinogenesis and diagnosis, as well as a predictor of poor prognosis.
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Affiliation(s)
- Xiaoyu Wu
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Xuequan Yao
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Qinhong Cao
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Zhenfeng Wu
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Zhaojing Wang
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Fukun Liu
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Lizong Shen
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China,
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Zhou Y, Wang XB, Qiu XP, Shuai Zhang, Wang C, Zheng F. CDKN2A promoter methylation and hepatocellular carcinoma risk: A meta-analysis. Clin Res Hepatol Gastroenterol 2018; 42:529-541. [PMID: 30143452 DOI: 10.1016/j.clinre.2017.07.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 07/17/2017] [Accepted: 07/28/2017] [Indexed: 02/04/2023]
Abstract
AIM Lots of studies have explored cyclin-dependent kinase inhibitor 2A (CDKN2A) promoter methylation in hepatocellular carcinoma (HCC), but the established results were controversial. Hence, we conducted the meta-analysis to comprehensively investigate the association between CDKN2A promoter methylation and HCC risk. METHODS A comprehensive search was implemented through searching PubMed, Web of Science and Embase. Associations of CDKN2A promoter methylation with HCC risk, clinicopathological features, and CDKN2A expression were assessed by the pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Subgroup analyses and meta-regression were served for exploring the potential sources of heterogeneity. RESULTS A total of 59 articles including 3067 cases and 2951 controls were incorporated in this meta-analysis. Overall, we observed a high CDKN2A promoter methylation rate (58.18%) in HCC and a significant association between the methylation and HCC risk (OR, 7.07; 95% CI, 5.67-8.80). Furthermore, CDKN2A promoter methylation was robustly associated with decreased mRNA (OR, 13.89; 95% CI, 5.44-35.45) and protein (OR, 48.19; 95% CI, 5.56-417.29). In addition, we found the methylation was related with HBV infection (OR, 3.31; 95% CI, 1.47-7.47), HCV infection (OR, 2.76; 95% CI, 1.80-4.23), cirrhosis status (OR, 1.57; 95% CI, 1.01-2.44) and older age (OR, 1.83; 95% CI, 1.14-2.94). CONCLUSIONS Our results indicated that CDKN2A promoter methylation was associated with an enhancive HCC risk and played a crucial role in the process of HCC with a potential value to being a triage marker for HCC.
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Affiliation(s)
- Ye Zhou
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei, China
| | - Xue-Bin Wang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei, China
| | - Xue-Ping Qiu
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei, China
| | - Shuai Zhang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei, China
| | - Chen Wang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei, China
| | - Fang Zheng
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei, China.
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Mekky MA, Salama RH, Abdel-Aal MF, Ghaliony MA, Zaky S. Studying the frequency of aberrant DNA methylation of APC, P14, and E-cadherin genes in HCV-related hepatocarcinogenesis. Cancer Biomark 2018; 22:503-509. [PMID: 29865038 DOI: 10.3233/cbm-171156] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Data about the molecular pathogenesis of hepatitis C-related hepatocellular carcinoma (HCC) are still challenging. OBJECTIVES Therefore, we tried to investigate the epigenetic study of three nominated genes (APC, P14, and E-cadherin) in the pathogenesis of HCV-related HCC in Egyptian. METHODS Between March 2016 and March 2017, the DNA methylation, and quantification using (epigenetic ELISA kit) for E-cadherin, APC, and P14 genes were studied in three groups of patients: HCV related liver cirrhosis without HCC group (LC-group; n= 20), HCC on top of HCV-related cirrhosis (HCC-group; n= 20), and a third apparently healthy control group (control-group; n= 10). RESULTS E-cad methylation showed non-significant differences between groups. P14 methylation was occurred only in HCC-group (45%). APC methylation was the highest in HCC group (70%). Methylation level was high in HCC group in comparison to both LC and control groups (P< 0.001). DNA methylation at a cutoff point > 2.9 ng/ml predicts HCC in LC-group with 90% sensitivity and 80% specificity and at level > 2.3 ng/ml had 95% sensitivity and 90% specificity in control-group. The pooled sensitivity, specificity, positive and negative predictive values and accuracy were 90%, 60%, 69.2, 85.7 and 75% respectively. CONCLUSION Aberrant DNA methylation of multiple genes is associated with disease progression in HCV related cirrhosis. Moreover, early detection of promotor methylation of these may sever as good biomarker for early detection and therapeutic targets in high risk patients.
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Affiliation(s)
- Mohamed A Mekky
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Rgaa H Salama
- Department of Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mahmoud F Abdel-Aal
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A Ghaliony
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Saad Zaky
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
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Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection. Viruses 2018; 10:v10100531. [PMID: 30274202 PMCID: PMC6212901 DOI: 10.3390/v10100531] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 09/25/2018] [Accepted: 09/27/2018] [Indexed: 02/07/2023] Open
Abstract
Despite the success of direct-acting antiviral (DAA) agents in treating chronic hepatitis C virus (HCV) infection, the number of cases of HCV-related hepatocellular carcinoma (HCC) is expected to increase over the next five years. HCC develops over the span of decades and is closely associated with fibrosis stage. HCV both directly and indirectly establishes a pro-inflammatory environment favorable for viral replication. Repeated cycles of cell death and regeneration lead to genomic instability and loss of cell cycle control. DAA therapy offers >90% sustained virological response (SVR) rates with fewer side effects and restrictions than interferon. While elimination of HCV helps to restore liver function and reverse mild fibrosis, post-SVR patients remain at elevated risk of HCC. A series of studies reporting higher than expected rates of HCC development among DAA-treated patients ignited debate over whether use of DAAs elevates HCC risk compared to interferon. However, recent prospective and retrospective studies based on larger patient cohorts have found no significant difference in risk between DAA and interferon therapy once other factors are taken into account. Although many mechanisms and pathways involved in hepatocarcinogenesis have been elucidated, our understanding of drivers specific to post-SVR hepatocarcinogenesis is still limited, and lack of suitable in vivo and in vitro experimental systems has hampered efforts to examine etiology-specific mechanisms that might serve to answer this question more thoroughly. Further research is needed to identify risk factors and biomarkers for post-SVR HCC and to develop targeted therapies based on more complete understanding of the molecules and pathways implicated in hepatocarcinogenesis.
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Lv X, Ye G, Zhang X, Huang T. p16 Methylation was associated with the development, age, hepatic viruses infection of hepatocellular carcinoma, and p16 expression had a poor survival: A systematic meta-analysis (PRISMA). Medicine (Baltimore) 2017; 96:e8106. [PMID: 28930859 PMCID: PMC5617726 DOI: 10.1097/md.0000000000008106] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Loss of tumor suppressor gene p16 expression via promoter methylation has been reported in hepatocellular carcinoma (HCC). This meta-analysis was conducted to evaluate the correlation between p16 methylation and HCC. Additionally, we also analyzed the potential prognostic role of p16 methylation, expression or alteration-associated HCC. METHODS Online databases based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline were performed to analyze the role of p16 gene in HCC. The combined odds ratios (ORs) or hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were summarized. RESULTS Final 3105 HCCs and 808 non-tumor controls (chronic hepatitis and liver cirrhosis) were performed in this meta-analysis. p16 promoter methylation in HCC was significantly higher than in chronic hepatitis and chronic hepatitis in tissue and blood samples. In addition, p16 promoter methylation was notably higher in patients >50 years' old than in patients aged <50 years, and it was higher in hepatitis B virus (HBV) or hepatitis C virus (HCV)-positive HCC than in hepatic viruses-negative HCC. However, p16 promoter methylation was not correlated with sex, cirrhosis, tumor differentiation, clinical stage. No association was found between p16 methylation or alteration and the prognosis of patients with HCC in overall survival (OS) and disease-free survival (DFS). Although p16 expression was significantly correlated with a poor prognosis in OS and DFS (P < .05) CONCLUSIONS:: Our results indicate that p16 methylation was linked to the development, age, HBV, and HCV infection of HCC. p16 methylation or alteration was not associated with the prognosis, but p16 expression was linked to a poor survival.
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Zhang Y, Xu X, Chen Z, Zhao Z. Association of FHIT expression and FHIT gene hypermethylation with liver cancer risk: a PRISMA-compliant meta-analysis. Onco Targets Ther 2017; 10:3083-3093. [PMID: 28790842 PMCID: PMC5488786 DOI: 10.2147/ott.s138036] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background There have been suggestions that fragile histidine triad protein (FHIT) expression and FHIT gene hypermethylation were crucial to the pathogenesis of liver cancer. However, the conclusions remained unclear because of small sample size, disease subtype, and different detection techniques. Therefore, we performed a meta-analysis to estimate the associations of FHIT expression and FHIT gene hypermethylation with liver cancer pathogenesis. Methods Studies that were published in electronic databases, such as PubMed, Web of Knowledge, China National Knowledge Infrastructure (CNKI), VIP, and WanFang, were retrieved and selected for the meta-analysis. Relative risk (RR) and 95% confidence interval (CI) were calculated to determine the correlations of FHIT expression and FHIT gene hyper-methylation with liver cancer pathogenesis with Stata 12.0 software. Results A total of 17 papers that evaluated the associations of FHIT expression (14 articles) and FHIT gene methylation (3 articles) with liver cancer pathogenesis were included in this meta-analysis. In the overall analysis, the pooled relative risk was 1.93 (95% CI =1.72–2.17), which indicated a significant association between FHIT low expression and liver cancer risk. According to the results of clinical information, there were significant associations of FHIT expression with TNM-stage (RR =2.13, 95% CI =1.72–2.64), tumor size (RR =1.67, 95% CI =1.36–2.05), and merger of cirrhosis (RR =1.34, 95% CI =1.06–1.69) of liver cancer in the Chinese population. In addition, the FHIT gene hypermethylation was significantly associated with the risk of liver cancer (RR =1.45, 95% CI =1.08–1.93). Conclusion The FHIT expression and hypermethylation of FHIT gene were significantly associated with the risk of liver cancer, especially in the Chinese population. Furthermore, the results indicated significant associations between FHIT low expression and TNM-stage, tumor size, and merging of cirrhosis of liver cancer in the Chinese population.
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Affiliation(s)
| | | | - Zhiliang Chen
- Department of Hepatobiliary Surgery, Shaoxing City People's Hospital, Shaoxing, Zhejiang Province, People's Republic of China
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Zhu C, Feng X, Ye G, Huang T. Meta-analysis of possible role of cadherin gene methylation in evolution and prognosis of hepatocellular carcinoma with a PRISMA guideline. Medicine (Baltimore) 2017; 96:e6650. [PMID: 28422868 PMCID: PMC5406084 DOI: 10.1097/md.0000000000006650] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Cadherins (CDHs) have been reported to be associated with cancer. However, the clinical significance of CDH gene methylation in hepatocellular carcinoma (HCC) remains unclear. METHODS Based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement criteria, available studies were identified from online electronic database. The overall odds ratio (OR) and the corresponding 95% confidence interval (95% CI) were calculated and analyzed. RESULTS A total of 29 eligible studies with 2562 HCC samples and 1685 controls were included. E-cadherin (CDH1) hypermethylation was observed to be significantly higher in HCC than in benign, adjacent, or normal samples. Moreover, CDH1 hypermethylation was not associated with gender, tumor grade, clinical stage, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection in HCC patients. H-cadherin (CDH13), protocadherin-10 (PCDH10), P-cadherin (CDH3), and M-cadherin (CDH15) methylation may have an increased risk of HCC in fewer than 4 studies, and methylated cadherin 8, type 2 (CDH8) and OB-cadherin (CDH11) had a similar OR in HCC and adjacent samples. When HCC samples were compared with normal samples, the analysis of sample type revealed a significantly higher OR in normal blood samples than in normal tissues for hypermethylated CDH1 (50.82 vs 4.44). CONCLUSION CDH1 hypermethylation may play a key role in the carcinogenesis of HCC. However, CDH1 hypermethylation was not correlated with clinicopathological features. Methylated CDH13, PCDH10, CDH3, and CDH15, but not methylated CDH8 or CDH11, may lead to an increased risk of HCC. Hypermethylated CDH1 may become a noninvasive blood biomarker. Further studies with more data are necessary.
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Use of an anti-viral drug, Ribavirin, as an anti-glioblastoma therapeutic. Oncogene 2016; 36:3037-3047. [DOI: 10.1038/onc.2016.457] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 10/26/2016] [Accepted: 11/03/2016] [Indexed: 02/06/2023]
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Fallahi E, O'Driscoll NA, Matallanas D. The MST/Hippo Pathway and Cell Death: A Non-Canonical Affair. Genes (Basel) 2016; 7:genes7060028. [PMID: 27322327 PMCID: PMC4929427 DOI: 10.3390/genes7060028] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 06/07/2016] [Accepted: 06/09/2016] [Indexed: 01/06/2023] Open
Abstract
The MST/Hippo signalling pathway was first described over a decade ago in Drosophila melanogaster and the core of the pathway is evolutionary conserved in mammals. The mammalian MST/Hippo pathway regulates organ size, cell proliferation and cell death. In addition, it has been shown to play a central role in the regulation of cellular homeostasis and it is commonly deregulated in human tumours. The delineation of the canonical pathway resembles the behaviour of the Hippo pathway in the fly where the activation of the core kinases of the pathway prevents the proliferative signal mediated by the key effector of the pathway YAP. Nevertheless, several lines of evidence support the idea that the mammalian MST/Hippo pathway has acquired new features during evolution, including different regulators and effectors, crosstalk with other essential signalling pathways involved in cellular homeostasis and the ability to actively trigger cell death. Here we describe the current knowledge of the mechanisms that mediate MST/Hippo dependent cell death, especially apoptosis. We include evidence for the existence of complex signalling networks where the core proteins of the pathway play a central role in controlling the balance between survival and cell death. Finally, we discuss the possible involvement of these signalling networks in several human diseases such as cancer, diabetes and neurodegenerative disorders.
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Affiliation(s)
- Emma Fallahi
- Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland. emma.fallahi---
- School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland. emma.fallahi---
| | - Niamh A O'Driscoll
- Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
- School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
| | - David Matallanas
- Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
- School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
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Hu ZB, Liao XH, Xu ZY, Yang X, Dong C, Jin AM, Lu H. PLK2 phosphorylates and inhibits enriched TAp73 in human osteosarcoma cells. Cancer Med 2015; 5:74-87. [PMID: 26625870 PMCID: PMC4708894 DOI: 10.1002/cam4.558] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 09/12/2015] [Accepted: 09/14/2015] [Indexed: 01/01/2023] Open
Abstract
TAp73, a member of the p53 tumor suppressor family, can substitute for p53 function, especially in p53‐null and p53‐mutant cells. However, TAp73 enrichment and phosphorylation change its transcriptional activity. Previously, we found that the antitumor function of TAp73 was reactivated by dephosphorylation. Polo‐like kinase 2 (PLK2) plays an important role in bone development. Using a biological information database and phosphorylation prediction software, we hypothesized that PLK2 phosphorylates TAp73 and inhibits TAp73 function in osteosarcomas. Actually,we determined that PLK2 physically binds to and phosphorylates TAp73 when TAp73 protein abundance is up‐regulated by cisplatin. PLK2‐phosphorylated TAp73 at residue Ser48 within the TA domain; phosphorylation of TAp73 was abolished by mutating this residue. Moreover, PLK2 inhibition combined with cisplatin treatment in osteosarcoma Saos2 cells up‐regulated p21 and puma mRNA expression to a greater extent than cisplatin treatment alone. Inhibiting PLK2 in TAp73‐enriched Saos2 cells resulted in inhibited cell proliferation, increased apoptosis, G1 phase arrest, and decreased cell invasion. However, these changes did not occur in TAp73 knockdown Saos2 cells. In conclusion, these findings reveal a novel PLK2 function in the phosphorylation of TAp73, which prevents TAp73 activity in osteosarcoma cells. Thereby, this research provides an insight into the clinical treatment of malignant tumors overexpressing TAp73.
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Affiliation(s)
- Zheng Bo Hu
- Department of Orthopedics, Zhu Jiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510280, China
| | - Xiao Hong Liao
- The State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510280, China
| | - Zun Ying Xu
- Department of Orthopedics, Zhu Jiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510280, China
| | - Xiao Yang
- Department of Orthopedics, Zhu Jiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510280, China
| | - Chao Dong
- Department of Orthopedics, Zhu Jiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510280, China
| | - An Min Jin
- Department of Orthopedics, Zhu Jiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510280, China
| | - Hai Lu
- Department of Orthopaedics, The Third Affiliated Hospital of Southern Medical University, Academy of Orthopedics, Guangzhou, Guangdong, 510665, China
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Mileo AM, Mattarocci S, Matarrese P, Anticoli S, Abbruzzese C, Catone S, Sacco R, Paggi MG, Ruggieri A. Hepatitis C virus core protein modulates pRb2/p130 expression in human hepatocellular carcinoma cell lines through promoter methylation. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2015; 34:140. [PMID: 26576645 PMCID: PMC4650920 DOI: 10.1186/s13046-015-0255-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 11/09/2015] [Indexed: 12/14/2022]
Abstract
Background Hepatitis C Virus (HCV) infection is associated with chronically evolving disease and development of hepatocellular carcinoma (HCC), albeit the mechanism of HCC induction by HCV is still controversial. The nucleocapsid (core) protein of HCV has been shown to be directly implicated in cellular transformation and immortalization, enhancing the effect of oncogenes and decreasing the one of tumor suppressor genes, as RB1 and its protein product pRB. With the aim of identifying novel molecular mechanisms of hepatocyte transformation by HCV, we examined the effect of HCV core protein on the expression of the whole Retinoblastoma (RB) family of tumor and growth suppressor factors, i.e. pRb, p107 and pRb2/p130. Methods We used a model system consisting of the HuH-7, HCV-free, human hepatocellular carcinoma cell line and of the HuH-7-CORE cells derived from the former and constitutively expressing the HCV core protein. We determined pRb, p107 and pRb2/p130 protein and mRNA amount of the respective genes RB1, RBL1 and RBL2, RBL2 promoter activity and methylation as well as DNA methyltransferase 1 (DNMT1) and 3b (DNMT3b) expression level. The effect of pRb2/p130 over-expression on the HCV core-expressing HuH-7-CORE cells was also evaluated. Results We found that the HCV core protein expression down-regulated pRb2/p130 protein and mRNA levels in HuH-7-CORE cells by inducing promoter hyper-methylation with the concomitant up-regulation of DNMT1 and DNMT3b expression. When pRb2/p130 expression was artificially re-established in HuH-7-CORE cells, cell cycle analysis outlined an accumulation in the G0/G1 phase, as expected. Conclusions HCV core appears indeed able to significantly down-regulate the expression and the function of two out of three RB family tumor and growth suppressor factors, i.e. pRb and pRb2/p130. The functional consequences at the level of cell cycle regulation, and possibly of more complex cell homeostatic processes, may represent a plausible molecular mechanism involved in liver transformation by HCV.
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Affiliation(s)
- Anna Maria Mileo
- Experimental Oncology, "Regina Elena" National Cancer Institute, IRCCS, Via Elio Chianesi, 53, 00144, Rome, Italy
| | - Stefano Mattarocci
- Department of Molecular Biology, University of Geneva, 1211, Geneva, Switzerland
| | - Paola Matarrese
- Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, 00161, Rome, Italy
| | - Simona Anticoli
- National AIDS Center, Istituto Superiore di Sanità, 00161, Rome, Italy
| | - Claudia Abbruzzese
- Experimental Oncology, "Regina Elena" National Cancer Institute, IRCCS, Via Elio Chianesi, 53, 00144, Rome, Italy
| | - Stefania Catone
- Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, 00161, Rome, Italy
| | - Rodolfo Sacco
- Gastroenterology and Metabolic Diseases, Department of Gastroenterology, 56124 Pisa University Hospital, Pisa, Italy
| | - Marco G Paggi
- Experimental Oncology, "Regina Elena" National Cancer Institute, IRCCS, Via Elio Chianesi, 53, 00144, Rome, Italy.
| | - Anna Ruggieri
- Department of Veterinary Public Health & Food Safety, Istituto Superiore di Sanità, 00161, Rome, Italy
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Gao JJ, Shi ZY, Xia JF, Inagaki Y, Tang W. Sorafenib-based combined molecule targeting in treatment of hepatocellular carcinoma. World J Gastroenterol 2015; 21:12059-12070. [PMID: 26576091 PMCID: PMC4641124 DOI: 10.3748/wjg.v21.i42.12059] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 07/28/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase III studies, its clinical benefits remain modest and most often consist of temporary tumor stabilization, indicating that more effective first-line treatment regimens or second-line salvage therapies are required. The molecular pathogenesis of HCC is very complex, involving hyperactivated signal transduction pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/mTOR and aberrant expression of molecules such as receptor tyrosine kinases and histone deacetylases. Simultaneous or sequential abrogation of these critical pathways or the functions of these key molecules involved in angiogenesis, proliferation, and apoptosis may yield major improvements in the management of HCC. In this review, we summarize the emerging sorafenib-based combined molecule targeting for HCC treatment and analyze the rationales of these combinations.
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N Zekri AR, Raafat AM, Elmasry S, Bahnassy AA, Saad Y, Dabaon HA, El-Kassas M, Shousha HI, Nassar AA, El-Dosouky MA, Hussein N. Promotor methylation: does it affect response to therapy in chronic hepatitis C (G4) or fibrosis? Ann Hepatol 2014; 13:518-524. [PMID: 25152984 DOI: 10.1016/s1665-2681(19)31251-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/03/2023]
Abstract
BACKGROUND AND AIM DNA methylation plays a critical role in the control of important cellular processes. The present study assessed the impact of promoter methylation (PM) of some genes on the antiviral response to antiviral therapy and it's relation to the presence of fibrosis in HCV-4 infected patients from Egypt. MATERIAL AND METHODS Clinical, laboratory and histopathological data of 53 HCV-4 infected patients who were subjected to combined antiviral therapy were collected; patients were classified according to their response to treatment and the fibrosis status. The methylation profiles of the studied groups were determined using the following genes: APC, P14ARF, P73, DAPK, RASSF1A, and O6MGMT in patients' plasma. RESULTS O6MGMT and P73 showed the highest methylation frequencies (64.2 and 50.9%) while P14 showed the lowest frequency (34%). Sustained virological response (SVR) was 54.7%with no significant difference in clinico-pathological or laboratory features between the studied groups. PM of O6MGM was significantly higher in non-responders (p value 0.045) while DAPK showed high methylation levels in responders with no significance (p value: 0.09) andPM of RASSF1A was significantly related to mild fibrosis (p value: 0.019). No significant relations were reported between PM of any of the studied genes and patients' features. CONCLUSION PM of some Tumor Suppressor genes increases in chronic active HCV-4. However, only 06MGMT can be used as a predictor of antiviral response and RASSF1A as a marker of marked fibrosis in this small set of patients. An extended study, including more patients is required to validate the results of this preliminary study.
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Affiliation(s)
- Abdel-Rahman N Zekri
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Ahmed M Raafat
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Suzan Elmasry
- Biochemistry Department, Faculty of Science, Cairo University, Cairo, Egypt
| | - Abeer A Bahnassy
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Yasmin Saad
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hamed A Dabaon
- Organic Chemistry Department, Faculty of Science, Cairo University, Cairo, Egypt
| | - Mohamed El-Kassas
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hend I Shousha
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Auhood A Nassar
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | | | - Nehal Hussein
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
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