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1
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Yang J, Li C, Wang Z, Jiang K. Multi-omics analysis of the biological function of the VEGF family in colon adenocarcinoma. Funct Integr Genomics 2024; 24:210. [PMID: 39527375 PMCID: PMC11554882 DOI: 10.1007/s10142-024-01493-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/10/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024]
Abstract
The vascular endothelial growth factor (VEGF) family plays a crucial role in cancer progression, but the prognostic significance and biological functions of VEGF family members in colon adenocarcinoma (COAD) remain unclear. Using data from The Cancer Genome Atlas, Gene Expression Omnibus, Gene Set Cancer Analysis, cBioPortal, GeneMANIA, String, MethSurv and starBase database, we identified vascular endothelial growth factor B (VEGFB) as a key gene associated with COAD prognosis, with its abnormal expression linked to methylation dysregulation. In vitro experiments confirmed VEGFB expression was significantly higher in colon cancer tissues compared to normal tissues, as shown by Real-time quantitative PCR and immunohistochemistry. Cell Counting Kit-8 and colony formation assay showed that decreased VEGFB expression in SW480 cells resulted in decreased cell viability and proliferation ability. Scratch assay showed that VEGFB downregulation impaired SW480 cell migration. In addition, our research suggests that VEGFB not only promotes angiogenesis but is also involved in the tumor microenvironment and immune regulation. The SHNG17-miR-375-VEGFB regulatory axis provides a potential therapeutic target for COAD, highlighting VEGFB's role in immune activation during anti-angiogenic therapy and potential reversal of drug resistance.
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Affiliation(s)
- Jianqiao Yang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Chen Li
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Zhu Wang
- Department of Gastroenterological Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Kewei Jiang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China.
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2
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He W, Zhu H, Zhang S, Shu G, Lei H, Yin G, Ni X, Wang M, Wu Q. Promoter Methylation Changes in DNA Damage-Response Genes in Ovarian Cancer and Their Correlation with Prognosis. CLIN EXP OBSTET GYN 2024; 51. [DOI: 10.31083/j.ceog5105109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2024]
Abstract
Background: Ovarian cancer has a poor prognosis, and DNA damage-response (DDR) genes are associated with both its occurrence and prognosis. However, previous studies have mostly focused on genetic mutations, with no clear conclusions on epigenetic factors such as DNA methylation. Methods: In this study, we comprehensively investigated the relationship between promoter methylation of DDR genes and ovarian cancer prognosis. We performed combined multidata analysis of the promoter methylation, expression, homologous recombination defieiency (HRD) score, and drug sensitivity of 377 DDR genes in ovarian cancer by utilizing The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. We then validated abnormal promoter methylation and its relationship with overall survival in clinical samples. Results: Our analysis identified 52 methylation-driven DDR genes that exhibited abnormal expression due to abnormal promoter methylation. These genes are mostly related to BRCA1-related DNA damage repair and cell cycle regulatory pathways. Further studies revealed six of these genes, BRCA1, PTTG1, TTK, AURKA, CDC6, and E2F1, to be significantly associated with HRD scores. Among them, E2F1, PTTG1, and CDC6 are associated with drug sensitivity. Finally, we verified in 81 ovarian cancer samples that methylation of the promoter of these three genes was significantly associated with patient survival. Conclusions: Our study identified a large number of methylation-driven aberrantly expressed DDR genes in ovarian cancer, some of which affect disease prognosis. Levels of methylation of these gene promoters may serve as potential prognostic markers.
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Affiliation(s)
- Wanhong He
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, 200237 Shanghai, China
| | - Haijun Zhu
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, 200237 Shanghai, China
| | - Sufen Zhang
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, 200237 Shanghai, China
| | - Guang Shu
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, 410013 Changsha, Hunan, China
| | - Han Lei
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, 410013 Changsha, Hunan, China
| | - Gang Yin
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, 410013 Changsha, Hunan, China
| | - Xiaohua Ni
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, 200237 Shanghai, China
| | - Maonan Wang
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, 410013 Changsha, Hunan, China
| | - Qihan Wu
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, 200237 Shanghai, China
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3
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Namikawa T, Tanaka T, Utsunomiya M, Yokota K, Munekage M, Maeda H, Kitagawa H, Kurioka Y, Satake H, Kobayashi M, Hanazaki K, Seo S. Gastric cancer with Fanconi anemia in adolescent and young adult patient diagnosed by comprehensive genome profiling using next-generation sequencing. Clin J Gastroenterol 2024; 17:12-17. [PMID: 37934348 DOI: 10.1007/s12328-023-01886-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 10/18/2023] [Indexed: 11/08/2023]
Abstract
Recently, the results of gastric cancer treatment have improved; however, its characteristics in adolescents and young adults are not well known. We report the case of a patient with advanced gastric cancer, Fanconi anemia (FA), and primary biliary cholangitis. A 26-year-old woman visited a local physician complaining of epigastralgia. Esophagogastroduodenoscopy revealed edematous changes with poor distension and circumferential thickened folds with erosions in the gastric body. Biopsy results of the lesion specimens revealed poorly differentiated adenocarcinoma. Abdominal contrast-enhanced computed tomography revealed gastric wall with irregular thickness, several nodules in the peritoneal cavity, and a mass lesion in the right ovary. We diagnosed the patient with T4N2M1 stage IV gastric cancer accompanied by peritoneal and ovarian metastases and initiated nivolumab with S-1 plus oxaliplatin as the first-line treatment regimen. Because of immune-related adverse events after one course of systemic treatment, the regimen was changed to ramucirumab combined with nab-paclitaxel chemotherapy as the second-line treatment. After three cycles of weekly nab-paclitaxel with ramucirumab, the decreased platelet count did not recover, and her general condition gradually deteriorated. Comprehensive genome profiling using next-generation sequencing was performed to determine the feasibility of genotype-matched therapies. Alterations in FA complementation group A (FANCA) F1263del (49.1%) and E484Q (12.3%), which encode a key component of the multiprotein FA complex, were identified. The patient died 10 months after treatment initiation. In conclusion, when treating malignancies in adolescent and young adult patients, the genomic background should be considered.
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Affiliation(s)
- Tsutomu Namikawa
- Department of Surgery, Kochi Medical School, Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan.
| | - Tomoki Tanaka
- Department of Surgery, Kochi Medical School, Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan
| | - Masato Utsunomiya
- Department of Surgery, Kochi Medical School, Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan
| | - Keiichiro Yokota
- Department of Surgery, Kochi Medical School, Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan
| | - Masaya Munekage
- Department of Surgery, Kochi Medical School, Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan
| | - Hiromichi Maeda
- Department of Surgery, Kochi Medical School, Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan
| | - Hiroyuki Kitagawa
- Department of Operating Room Management, Kochi Medical School Hospital, Nankoku, Japan
| | - Yusuke Kurioka
- Department of Medical Oncology, Kochi Medical School, Nankoku, Japan
| | - Hironaga Satake
- Department of Medical Oncology, Kochi Medical School, Nankoku, Japan
| | - Michiya Kobayashi
- Department of Human Health and Medical Sciences, Kochi Medical School, Nankoku, Japan
| | - Kazuhiro Hanazaki
- Integrated Center for Advanced Medical Technologies, Kochi Medical School Hospital, Nankoku, Japan
| | - Satoru Seo
- Department of Surgery, Kochi Medical School, Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan
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4
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Liu Y, Tong X, Hu W, Chen D. HDAC11: A novel target for improved cancer therapy. Biomed Pharmacother 2023; 166:115418. [PMID: 37659201 DOI: 10.1016/j.biopha.2023.115418] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 08/30/2023] [Indexed: 09/04/2023] Open
Abstract
Histone deacetylase 11 (HDAC11) is a unique member of the histone deacetylase family that plays an important role in the regulation of gene expression and protein function. In recent years, research on the role of HDAC11 in tumors has attracted increasing attention. This review summarizes the current knowledge on the subcellular localization, structure, expression, and functions of HDAC11 in tumors, as well as the regulatory mechanisms involved in its network, including ncRNA and substrates. Moreover, we focus on the progress made in targeting HDAC11 to overcome tumor therapy resistance, and the development of HDAC11 inhibitors for cancer treatment. Collectively, this review provides comprehensive insights into the potential clinical implications of HDAC11 for cancer therapy.
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Affiliation(s)
- Yan Liu
- First Department of Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning, China
| | - Xuechao Tong
- Department of Emergency, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning, China
| | - Weina Hu
- Department of General Practice, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning, China.
| | - Da Chen
- Department of Emergency, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning, China.
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5
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Li YQ, Xin L, Zhao YC, Li SQ, Li YN. Role of vascular endothelial growth factor B in nonalcoholic fatty liver disease and its potential value. World J Hepatol 2023; 15:786-796. [PMID: 37397934 PMCID: PMC10308292 DOI: 10.4254/wjh.v15.i6.786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/27/2023] [Accepted: 05/09/2023] [Indexed: 06/25/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) refers to fatty liver disease caused by liver injury factors other than alcohol. The disease is characterized by diffuse fat infiltration, including simple steatosis (no inflammatory fat deposition), nonalcoholic fatty hepatitis, liver fibrosis, and so on, which may cause liver cirrhosis, liver failure, and even liver cancer in the later stage of disease progression. At present, the pathogenesis of NAFLD is still being studied. The "two-hit" theory, represented by lipid metabolism disorder and inflammatory reactions, is gradually enriched by the "multiple-hit" theory, which includes multiple factors, such as insulin resistance and adipocyte dysfunction. In recent years, vascular endothelial growth factor B (VEGFB) has been reported to have the potential to regulate lipid metabolism and is expected to become a novel target for ameliorating metabolic diseases, such as obesity and type 2 diabetes. This review summarizes the regulatory role of VEGFB in the onset and development of NAFLD and illustrates its underlying molecular mechanism. In conclusion, the signaling pathway mediated by VEGFB in the liver may provide an innovative approach to the diagnosis and treatment of NAFLD.
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Affiliation(s)
- Yu-Qi Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Lei Xin
- Department of Gastrointestinal Surgery, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Yu-Chi Zhao
- Department of Surgery, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Shang-Qi Li
- The First School of Clinical Medicine, Binzhou Medical University, Yantai 264000, Shandong, China, Yantai 264000, Shandong Province, China
| | - Ya-Nuo Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
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6
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Lin C, Liu P, Shi C, Qiu L, Shang D, Lu Z, Tu Z, Liu H. Therapeutic targeting of DNA damage repair pathways guided by homologous recombination deficiency scoring in ovarian cancers. Fundam Clin Pharmacol 2023; 37:194-214. [PMID: 36130021 DOI: 10.1111/fcp.12834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 07/23/2022] [Accepted: 09/20/2022] [Indexed: 12/01/2022]
Abstract
The susceptibility of cells to DNA damage and their DNA repair ability are crucial for cancer therapy. Homologous recombination is one of the major repairing mechanisms for DNA double-strand breaks. Approximately half of ovarian cancer (OvCa) cells harbor homologous recombination deficiency (HRD). Considering that HRD is a major hallmark of OvCas, scholars proposed HRD scoring to evaluate the HRD degree and guide the choice of therapeutic strategies for OvCas. In the last decade, synthetic lethal strategy by targeting poly (ADP-ribose) polymerase (PARP) in HR-deficient OvCas has attracted considerable attention in view of its favorable clinical effort. We therefore suggested that the uses of other DNA damage/repair-targeted drugs in HR-deficient OvCas might also offer better clinical outcome. Here, we reviewed the current small molecule compounds that targeted DNA damage/repair pathways and discussed the HRD scoring system to guide their clinical uses.
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Affiliation(s)
- Chunxiu Lin
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Peng Liu
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Chaowen Shi
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Lipeng Qiu
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Dongsheng Shang
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Ziwen Lu
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Zhigang Tu
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Hanqing Liu
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China
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7
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Clinical Significance of NKD Inhibitor of WNT Signaling Pathway 1 (NKD1) in Glioblastoma. Genet Res (Camb) 2023; 2023:1184101. [PMID: 36969985 PMCID: PMC10038739 DOI: 10.1155/2023/1184101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/23/2023] [Accepted: 01/30/2023] [Indexed: 03/19/2023] Open
Abstract
Introduction. As the most malignant type of gliomas, glioblastoma is characterized with disappointing prognosis. Here, we aimed to investigate expression and function of NKD inhibitor of Wnt signaling pathway 1 (NKD1), an antagonist of Wnt-beta-catenin signaling pathways, in glioblastoma. Methods. The mRNA level of NKD1 was firstly retrieved from TCGA glioma dataset to evaluate its correlation with clinical characteristics and its value in prognosis prediction. Then, its protein expression level in glioblastoma was tested by immunohistochemistry staining in a retrospectively cohort collected from our medical center (n = 66). Univariate and multivariate survival analyses were conducted to assess its effect on glioma prognosis. Two glioblastoma cell lines, U87 and U251, were used to further investigate the tumor-related role of NKD1 through overexpression strategy in combination with cell proliferation assays. Immune cell enrichment in glioblastoma and its correlation with NKD1 level was finally assessed using bioinformatics analyses. Results. NKD1 shows a lower expression level in glioblastoma compared to that in the normal brain or other glioma subtypes, which is independently correlated to a worse prognosis in both the TCGA cohort and our retrospective cohort. Overexpressing NKD1 in glioblastoma cell lines can significantly attenuate cell proliferation. In addition, expression of NKD1 in glioblastoma is negatively correlated to the T cell infiltration, indicating it may have crosstalk with the tumor immune microenvironment. Conclusions. NKD1 inhibits glioblastoma progression and its downregulated expression indicates a poor prognosis.
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8
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Lu D, Ma Z, Huang D, Zhang J, Li J, Zhi P, Zhang L, Feng Y, Ge X, Zhai J, Jiang M, Zhou X, Simone CB, Neal JW, Patel SR, Yan X, Hu Y, Wang J. Clinicopathological characteristics and prognostic significance of HDAC11 protein expression in non-small cell lung cancer: a retrospective study. Transl Lung Cancer Res 2022; 11:1119-1131. [PMID: 35832445 PMCID: PMC9271448 DOI: 10.21037/tlcr-22-403] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/20/2022] [Indexed: 12/09/2022]
Abstract
Background Although the prognosis of non-small cell lung cancer (NSCLC) can be assessed based on pathological type, disease stage and inflammatory indicators, the prognostic scoring model of NSCLC still needs to improve. HDAC11 is associated with poor prognosis of partial tumors, but its prognostic relationship with NSCLC is poorly understood. In this study, the role of HDAC11 in NSCLC was studied to evaluate relationship with disease prognosis and potential therapeutic target. Methods The clinicopathological and paracancerous tissues of patients with NSCLC primarily diagnosed in Tangdu Hospital from 2009 to 2013 were collected. Follow-up of patients were made every three months and the last follow-up period was December 2018. The expression of HDAC11 was assessed by immunohistochemistry (IHC). Then, weighted gene co-expression network analysis (WGCNA) was used to analyze the relationship between HDAC11 expression and the prognosis of lung adenocarcinoma (LUAD) patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Kaplan-Meier plotter database was used to verify the connection between hub genes and tumor stage and prognosis. We accessed the relationship between HDAC11 expression and clinicopathological features, and impact on the prognosis. Results The study assessed 326 patients with NSCLC. Compared with adjacent tissues, HDAC11 expression was upregulated (HR =1.503, 95% CI: 1.172 to 1.927, P=0.001). Kaplan-Meier survival analyses showed that HDAC11 expression was closely related to OS of NSCLC patients (P=0.0011). Univariate and multivariate analyses showed that the independent risk factors of OS were clinical stage, HDAC11 expression, and HDAC11 differentiation (all P≤0.001). HDAC11 was significantly associated with prognosis in LUAD. A total of 1,174 differential genes and WGCNA were obtained to construct a co-expression network in LUAD. The GO and KEGG pathway enrichment analyses showed the relevance with staphylococcus aureus infection, NOD-like receptor signaling pathway, and others. The results of LUAD survival analysis showed that HDAC11-related genes NKX2-5 and FABP7 were significantly associated with LUAD prognosis. Conclusions The high expression of HDAC11 is related to the poor prognosis of LUAD, and it is expected to become a therapeutic target and prognostic evaluation therapy for LUAD in the future. However, the relevant results need to be further studied and verified.
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Affiliation(s)
- Di Lu
- Medical School of Chinese PLA, Beijing, China.,Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Zhiqiang Ma
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Di Huang
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jundong Zhang
- Medical School of Chinese PLA, Beijing, China.,Department of Hematology, The Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jinfeng Li
- Institute of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Peng Zhi
- Department of Hematology, The Second Medical Center of Chinese PLA General Hospital, Beijing, China.,Shanxi Medical University, Taiyuan, China
| | - Lizhong Zhang
- Department of Hematology, The Second Medical Center of Chinese PLA General Hospital, Beijing, China.,Shanxi Medical University, Taiyuan, China
| | - Yingtong Feng
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Xiangwei Ge
- Medical School of Chinese PLA, Beijing, China.,Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jinzhao Zhai
- Medical School of Chinese PLA, Beijing, China.,Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Menglong Jiang
- Department of Thoracic Surgery, 1st Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xin Zhou
- Medical School of Chinese PLA, Beijing, China.,Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Charles B Simone
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Department of Radiation Oncology, New York Proton Center, New York, NY, USA
| | - Joel W Neal
- Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Shruti Rajesh Patel
- Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Xiaolong Yan
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Yi Hu
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jinliang Wang
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
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Maity J, Horibata S, Zurcher G, Lee JM. Targeting of RecQ Helicases as a Novel Therapeutic Strategy for Ovarian Cancer. Cancers (Basel) 2022; 14:cancers14051219. [PMID: 35267530 PMCID: PMC8909030 DOI: 10.3390/cancers14051219] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/21/2022] [Accepted: 02/23/2022] [Indexed: 11/16/2022] Open
Abstract
RecQ helicases are essential for DNA replication, recombination, DNA damage repair, and other nucleic acid metabolic pathways required for normal cell growth, survival, and genome stability. More recently, RecQ helicases have been shown to be important for replication fork stabilization, one of the major mechanisms of PARP inhibitor resistance. Cancer cells often have upregulated helicases and depend on these enzymes to repair rapid growth-promoted DNA lesions. Several studies are now evaluating the use of RecQ helicases as potential biomarkers of breast and gynecologic cancers. Furthermore, RecQ helicases have attracted interest as possible targets for cancer treatment. In this review, we discuss the characteristics of RecQ helicases and their interacting partners that may be utilized for effective treatment strategies (as cancers depend on helicases for survival). We also discuss how targeting helicase in combination with DNA repair inhibitors (i.e., PARP and ATR inhibitors) can be used as novel approaches for cancer treatment to increase sensitivity to current treatment to prevent rise of treatment resistance.
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Affiliation(s)
- Jyotirindra Maity
- Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (J.M.); (G.Z.)
| | - Sachi Horibata
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Precision Health Program, Michigan State University, East Lansing, MI 48824, USA
- Department of Pharmacology and Toxicology, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
- Correspondence: (S.H.); (J.M.L.)
| | - Grant Zurcher
- Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (J.M.); (G.Z.)
| | - Jung-Min Lee
- Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (J.M.); (G.Z.)
- Correspondence: (S.H.); (J.M.L.)
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10
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Huang PY, Shih IA, Liao YC, You HL, Lee MJ. A novel HDAC11 inhibitor potentiates the tumoricidal effects of cordycepin against malignant peripheral nerve sheath tumor through the Hippo signaling pathway. Am J Cancer Res 2022; 12:873-892. [PMID: 35261809 PMCID: PMC8899988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/11/2022] [Indexed: 06/14/2023] Open
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder. Clinically, the hallmarks of NF1 include skin pigmentation and cutaneous neurofibroma. Some NF1 patients develop plexiform neurofibroma (PN) since early childhood. Pathologically, PN contains abundant Schwann cells, blood vessels and connective tissues, which may transform into a malignant peripheral nerve sheath tumor (MPNST). MPNST is a highly invasive sarcoma without any effective therapy. Recently, both in vitro and in vivo studies showed that cordycepin can inhibit the growth of MPNST cells. Cordycepin causes cell cycle arrest at G2/M phase and downregulates the protein levels of α-tubulin, p53 and Sp1. Herein, the present study revealed that the HDAC11 inhibitor, FT895, can synergistically enhance the tumoricidal effect of cordycepin against MPNST cells in vitro. Treatment with the combination of cordycepin and FT895 reduced the size of MPNST in the xenograft mouse model. The combined treatment decreased the protein levels of α-tubulin and KIF18A, which may disrupt the microtubule organization leading to the mis-segregation of chromosomes and aneuploidy. Moreover, the expression levels of TEAD1 and its co-activator TAZ, the candidate proteins in hippo signaling pathway, were suppressed after combined treatment. Sequence analysis found a few binding sites for the transcription factor, TEAD1 in the promoter regions of TUBA1B, KIF18A, TEAD1, TAZ, YAP, TP53 and SP1 genes. ChIP-qPCR assay showed that the combined treatment decreases the binding of TEAD1 to the promoters of TUBA1B, KIF18A, TEAD1, TAZ and YAP genes in STS26T cells. The reduced binding to TP53 and SP1 promoters was also found in S462TY cells, which was further confirmed by immunoblotting. The down-regulation of these important transcriptional factors may contribute to the vulnerability of MPNST. In summary, HDAC11 inhibitor, FT895 can potentiate the tumoricidal effect of cordycepin to suppress the MPNST cell growth, which was probably mediated by the dysfunction of hippo-signaling pathway.
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Affiliation(s)
- Po-Yuan Huang
- Department of Neurology, National Taiwan University Hospital, National Taiwan University College of Medicine Taipei, Taiwan
| | - I-An Shih
- Department of Neurology, National Taiwan University Hospital, National Taiwan University College of Medicine Taipei, Taiwan
| | - Ying-Chih Liao
- Department of Neurology, National Taiwan University Hospital, National Taiwan University College of Medicine Taipei, Taiwan
| | - Huey-Ling You
- Department of Neurology, National Taiwan University Hospital, National Taiwan University College of Medicine Taipei, Taiwan
| | - Ming-Jen Lee
- Department of Neurology, National Taiwan University Hospital, National Taiwan University College of Medicine Taipei, Taiwan
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11
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Wang J, Li J, Chen R, Yue H, Li W, Wu B, Bai Y, Zhu G, Lu X. DNA methylation-based profiling reveals distinct clusters with survival heterogeneity in high-grade serous ovarian cancer. Clin Epigenetics 2021; 13:190. [PMID: 34645493 PMCID: PMC8515755 DOI: 10.1186/s13148-021-01178-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 09/29/2021] [Indexed: 12/27/2022] Open
Abstract
High-grade serous ovarian cancer (HGSOC) is the most common type of epigenetically heterogeneous ovarian cancer. Methylation typing has previously been used in many tumour types but not in HGSOC. Methylation typing in HGSOC may promote the development of personalized care. The present study used DNA methylation data from The Cancer Genome Atlas database and identified four unique methylation subtypes of HGSOC. With the poorest prognosis and high frequency of residual tumours, cluster 4 featured hypermethylation of a panel of genes, which indicates that demethylation agents may be tested in this group and that neoadjuvant chemotherapy may be used to reduce the possibility of residual lesions. Cluster 1 and cluster 2 were significantly associated with metastasis genes and metabolic disorders, respectively. Two feature CpG sites, cg24673765 and cg25574024, were obtained through Cox proportional hazards model analysis of the CpG sites. Based on the methylation level of the two CpG sites, the samples were classified into high- and low-risk groups to identify the prognostic information. Similar results were obtained in the validation set. Taken together, these results explain the epigenetic heterogeneity of HGSOC and provide guidance to clinicians for the prognosis of HGSOC based on DNA methylation sites.
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Affiliation(s)
- Jieyu Wang
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No. 128, Shenyang Road, Yangpu District, Shanghai, 200090, China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Disease, Fudan University, Shanghai, China
| | - Jun Li
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No. 128, Shenyang Road, Yangpu District, Shanghai, 200090, China
| | - Ruifang Chen
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No. 128, Shenyang Road, Yangpu District, Shanghai, 200090, China
| | - Huiran Yue
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No. 128, Shenyang Road, Yangpu District, Shanghai, 200090, China
| | - Wenzhi Li
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No. 128, Shenyang Road, Yangpu District, Shanghai, 200090, China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Disease, Fudan University, Shanghai, China
| | - Beibei Wu
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No. 128, Shenyang Road, Yangpu District, Shanghai, 200090, China
| | - Yang Bai
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No. 128, Shenyang Road, Yangpu District, Shanghai, 200090, China
| | - Guohua Zhu
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No. 128, Shenyang Road, Yangpu District, Shanghai, 200090, China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Disease, Fudan University, Shanghai, China
| | - Xin Lu
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No. 128, Shenyang Road, Yangpu District, Shanghai, 200090, China. .,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Disease, Fudan University, Shanghai, China.
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12
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The critical role of peroxiredoxin-2 in colon cancer stem cells. Aging (Albany NY) 2021; 13:11170-11187. [PMID: 33819194 PMCID: PMC8109100 DOI: 10.18632/aging.202784] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 01/04/2021] [Indexed: 12/19/2022]
Abstract
Colon cancer stem cells (CCSCs) play an important role in facilitating colon cancer occurrence, metastasis and drug resistance. The results of our previous studies confirmed that the well-studied antioxidant gene peroxiredoxin-2 (PRDX2) promotes colon cancer progression. However, the underlying function and mechanisms associated with PRDX2 remodeling in the context of CCSCs have remained poorly studied. In our present study, we demonstrated that PRDX2 is highly expressed in CD133/CD44-positive colon cancer tissues and spheroid CD133+CD44+ CCSCs. PRDX2 overexpression was shown to be closely correlated with CD133+CD44+ CCSCs in colon cancer. Furthermore, PRDX2 depletion markedly suppressed CD133+CD44+ CCSC stemness maintenance, tumor initiation, migration and invasion and liver metastasis. Furthermore, the expression of various EMT markers and Wnt/β-catenin signaling proteins was altered after PRDX2 inhibition. In addition, PRDX2 knockdown led to increased ROS production in CD133+CD44+ CCSCs, sensitizing CCSCs to oxidative stress and chemotherapy. These results suggest that PRDX2 could be a possible therapeutic target in CCSCs.
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13
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Luo D, Yang Q, Wang H, Tan M, Zou Y, Liu J. A predictive model for assessing prognostic risks in gastric cancer patients using gene expression and methylation data. BMC Med Genomics 2021; 14:14. [PMID: 33407483 PMCID: PMC7789242 DOI: 10.1186/s12920-020-00856-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 12/10/2020] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND The role(s) of epigenetic reprogramming in gastric cancer (GC) remain obscure. This study was designed to identify methylated gene markers with prognostic potential for GC. METHODS Five datasets containing gene expression and methylation profiles from GC samples were collected from the GEO database, and subjected to meta-analysis. All five datasets were subjected to quality control and then differentially expressed genes (DEGs) and differentially expressed methylation genes (DEMGs) were selected using MetaDE. Correlations between gene expression and methylation status were analysed using Pearson coefficient correlation. Then, enrichment analyses were conducted to identify signature genes that were significantly different at both the gene expression and methylation levels. Cox regression analyses were performed to identify clinical factors and these were combined with the signature genes to create a prognosis-related predictive model. This model was then evaluated for predictive accuracy and then validated using a validation dataset. RESULTS This study identified 1565 DEGs and 3754 DEMGs in total. Of these, 369 were differentially expressed at both the gene and methylation levels. We identified 12 signature genes including VEGFC, FBP1, NR3C1, NFE2L2, and DFNA5 which were combined with the clinical data to produce a novel prognostic model for GC. This model could effectively split GC patients into two groups, high- and low-risk with these observations being confirmed in the validation dataset. CONCLUSION The differential methylation of the 12 signature genes, including VEGFC, FBP1, NR3C1, NFE2L2, and DFNA5, identified in this study may help to produce a functional predictive model for evaluating GC prognosis in clinical samples.
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Affiliation(s)
- Dan Luo
- Department of General Surgery, Chengdu Fifth People’s Hospital, 33 Mashi St, Chengdu, 610000 Sichuan China
| | - QingLing Yang
- Department of Pulmonary and Critical Care Medicine, Chengdu Fifth People’s Hospital, 33 Mashi St, Chengdu, 610000 Sichuan China
| | - HaiBo Wang
- Department of General Surgery, Chengdu Fifth People’s Hospital, 33 Mashi St, Chengdu, 610000 Sichuan China
| | - Mao Tan
- Department of General Surgery, Chengdu Fifth People’s Hospital, 33 Mashi St, Chengdu, 610000 Sichuan China
| | - YanLei Zou
- Department of General Surgery, Chengdu Fifth People’s Hospital, 33 Mashi St, Chengdu, 610000 Sichuan China
| | - Jian Liu
- Department of General Surgery, Chengdu Fifth People’s Hospital, 33 Mashi St, Chengdu, 610000 Sichuan China
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14
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Li S, Wang L, Zhao Q, Wang Z, Lu S, Kang Y, Jin G, Tian J. Genome-Wide Analysis of Cell-Free DNA Methylation Profiling for the Early Diagnosis of Pancreatic Cancer. Front Genet 2020; 11:596078. [PMID: 33424927 PMCID: PMC7794002 DOI: 10.3389/fgene.2020.596078] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 11/05/2020] [Indexed: 02/06/2023] Open
Abstract
As one of the most malicious cancers, pancreatic cancer is difficult to treat due to the lack of effective early diagnosis. Therefore, it is urgent to find reliable diagnostic and predictive markers for the early detection of pancreatic cancer. In recent years, the detection of circulating cell-free DNA (cfDNA) methylation in plasma has attracted global attention for non-invasive and early cancer diagnosis. Here, we carried out a genome-wide cfDNA methylation profiling study of pancreatic ductal adenocarcinoma (PDAC) patients by methylated DNA immunoprecipitation coupled with high-throughput sequencing (MeDIP-seq). Compared with healthy individuals, 775 differentially methylated regions (DMRs) located in promoter regions were identified in PDAC patients with 761 hypermethylated and 14 hypomethylated regions; meanwhile, 761 DMRs in CpG islands (CGIs) were identified in PDAC patients with 734 hypermethylated and 27 hypomethylated regions (p-value < 0.0001). Then, 143 hypermethylated DMRs were further selected which were located in promoter regions and completely overlapped with CGIs. After performing the least absolute shrinkage and selection operator (LASSO) method, a total of eight markers were found to fairly distinguish PDAC patients from healthy individuals, including TRIM73, FAM150A, EPB41L3, SIX3, MIR663, MAPT, LOC100128977, and LOC100130148. In conclusion, this work identified a set of eight differentially methylated markers that may be potentially applied in non-invasive diagnosis of pancreatic cancer.
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Affiliation(s)
- Shengyue Li
- Key laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, China
| | - Lei Wang
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Qiang Zhao
- School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, China
| | - Zhihao Wang
- Key laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, China
| | - Shuxian Lu
- Key laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, China
| | - Yani Kang
- School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, China
| | - Gang Jin
- Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Jing Tian
- Key laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, China
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15
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Liu SS, Wu F, Jin YM, Chang WQ, Xu TM. HDAC11: a rising star in epigenetics. Biomed Pharmacother 2020; 131:110607. [PMID: 32841898 DOI: 10.1016/j.biopha.2020.110607] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/31/2020] [Accepted: 08/02/2020] [Indexed: 02/08/2023] Open
Abstract
Epigenetic mechanisms, such as acetylation, methylation, and succinylation, play pivotal roles in the regulation of multiple normal biological processes, including neuron regulation, hematopoiesis, bone cell maturation, and metabolism. In addition, epigenetic mechanisms are closely associated with the pathological processes of various diseases, such as metabolic diseases, autoimmune diseases and cancers. Epigenetic changes may precede genetic mutation, so research on epigenetic changes and regulation may be important for the early detection and diagnosis of disease. Histone deacetylase11 (HDAC11) is the newest member of the histone deacetylase (HDAC) family and the only class IV histone deacetylase. HDAC11 has different expression levels and biological functions in different systems of the human body and is among the top 1 to 4% of genes overexpressed in cancers, such as breast cancer, hepatocellular carcinoma and renal pelvis urothelial carcinoma. This article analyzes the role and mechanism of HDAC11 in disease, especially in tumorigenesis, in an attempt to provide new ideas for clinical and basic research.
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Affiliation(s)
- Shan-Shan Liu
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, 130041, Jilin Province, China.
| | - Fei Wu
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, 130041, Jilin Province, China.
| | - Yue-Mei Jin
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, 130041, Jilin Province, China.
| | - Wei-Qin Chang
- Department of Surgery, The Second Hospital of Jilin University, 218 Ziqiang Road, Changchun, 130041, Jilin Province, China.
| | - Tian-Min Xu
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, 130041, Jilin Province, China.
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16
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İNANDIKLIOGLU N, DEMİRHAN O, BAYRAM İ, TANYELİ A. Çukurova Bölgesinde akut lenfoblastik lösemili çocuklarda vasküler endotelyal büyüme faktörü (VEGF-C) ve temel fibroblast büyüme faktörü (bFGF) plazma ekspresyonu ve metilasyon seviyeleri. CUKUROVA MEDICAL JOURNAL 2020. [DOI: 10.17826/cumj.676515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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17
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Singh A, Gupta S, Sachan M. Epigenetic Biomarkers in the Management of Ovarian Cancer: Current Prospectives. Front Cell Dev Biol 2019; 7:182. [PMID: 31608277 PMCID: PMC6761254 DOI: 10.3389/fcell.2019.00182] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 08/19/2019] [Indexed: 12/15/2022] Open
Abstract
Ovarian cancer (OC) causes significant morbidity and mortality as neither detection nor screening of OC is currently feasible at an early stage. Difficulty to promptly diagnose OC in its early stage remains challenging due to non-specific symptoms in the early-stage of the disease, their presentation at an advanced stage and poor survival. Therefore, improved detection methods are urgently needed. In this article, we summarize the potential clinical utility of epigenetic signatures like DNA methylation, histone modifications, and microRNA dysregulation, which play important role in ovarian carcinogenesis and discuss its application in development of diagnostic, prognostic, and predictive biomarkers. Molecular characterization of epigenetic modification (methylation) in circulating cell free tumor DNA in body fluids offers novel, non-invasive approach for identification of potential promising cancer biomarkers, which can be performed at multiple time points and probably better reflects the prevailing molecular profile of cancer. Current status of epigenetic research in diagnosis of early OC and its management are discussed here with main focus on potential diagnostic biomarkers in tissue and body fluids. Rapid and point of care diagnostic applications of DNA methylation in liquid biopsy has been precluded as a result of cumbersome sample preparation with complicated conventional methods of isolation. New technologies which allow rapid identification of methylation signatures directly from blood will facilitate sample-to answer solutions thereby enabling next-generation point of care molecular diagnostics. To date, not a single epigenetic biomarker which could accurately detect ovarian cancer at an early stage in either tissue or body fluid has been reported. Taken together, the methodological drawbacks, heterogeneity associated with ovarian cancer and non-validation of the clinical utility of reported potential biomarkers in larger ovarian cancer populations has impeded the transition of epigenetic biomarkers from lab to clinical settings. Until addressed, clinical implementation as a diagnostic measure is a far way to go.
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Affiliation(s)
- Alka Singh
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India
| | - Sameer Gupta
- Department of Surgical Oncology, King George Medical University, Lucknow, India
| | - Manisha Sachan
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India
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18
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Yi Z, Wenwen L, Kun W, Jian S. [Overexpression of histone deacetylase 11 suppresses basal-like breast cancer cell invasion and metastasis]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2019; 39:751-759. [PMID: 31340905 DOI: 10.12122/j.issn.1673-4254.2019.07.01] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
OBJECTIVE Histone deacetylase 11 (HDAC11) is a class Ⅳ member of histone deacetylase family, and its role in regulating cancer cell invasion and metastasis remains unclear. We aimed to investigate the role of HDAC11 in regulating the biological behaviors of basal-like breast cancer (BLBC) cells. METHODS We analyzed the expression of HDAC11 based on Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA). The effects of HDAC11 on the cell invasion and metastasis were examined using Transwell assay and in a mouse model. The interaction between HDAC11 and Twist was detected with immunoprecipitation. We identified HAS2 as a target gene of Twist using promoter luciferase assay and chromatin immunoprecipitation assay. RESULTS HDAC11 was lowly expressed in BLBC cells. HDAC11 overexpression suppressed BLBC cell invasion in vitro and their metastasis in nude mice. Mechanistically, HDAC11 directly interacted with Twist protein, antagonized its pro-invasive function and repressed Twist-induced HAS2 gene transcription. CONCLUSIONS Our data suggest that HDAC11 acts as a negative modulator of invasion and metastasis of BLBC cells.
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Affiliation(s)
- Zhang Yi
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.,Second Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital/Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Luo Wenwen
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Wang Kun
- Second Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital/Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Shi Jian
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
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19
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Monteiro AC, Muenzner JK, Andrade F, Rius FE, Ostalecki C, Geppert CI, Agaimy A, Hartmann A, Fujita A, Schneider-Stock R, Jasiulionis MG. Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma. Mol Oncol 2019; 13:1433-1449. [PMID: 31069961 PMCID: PMC6547615 DOI: 10.1002/1878-0261.12501] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 04/18/2019] [Accepted: 05/08/2019] [Indexed: 01/06/2023] Open
Abstract
The high mortality rate of melanoma is broadly associated with its metastatic potential. Tumor cell dissemination is strictly dependent on vascularization; therefore, angiogenesis and lymphangiogenesis play an essential role in metastasis. Hence, a better understanding of the players of tumor vascularization and establishing them as new molecular biomarkers might help to overcome the poor prognosis of melanoma patients. Here, we further characterized a linear murine model of melanoma progression and showed that the aggressiveness of melanoma cells is closely associated with high expression of angiogenic factors, such as Vegfc, Angpt2, and Six1, and that blockade of the vascular endothelial growth factor pathway by the inhibitor axitinib abrogates their tumorigenic potential in vitro and in the in vivo chicken chorioallantoic membrane assay. Furthermore, analysis of The Cancer Genome Atlas data revealed that the expression of the angiogenic factor ANGPT2 (P‐value = 0.044) and the lymphangiogenic receptor VEGFR‐3 (P‐value = 0.002) were independent prognostic factors of overall survival in melanoma patients. Enhanced reduced representation bisulfite sequencing‐based methylome profiling revealed for the first time a link between abnormal VEGFC, ANGPT2, and SIX1 gene expression and promoter hypomethylation in melanoma cells. In patients, VEGFC (P‐value = 0.031), ANGPT2 (P‐value < 0.001), and SIX1 (P‐value = 0.009) promoter hypomethylation were independent prognostic factors of shorter overall survival. Hence, our data suggest that these angio‐ and lymphangiogenesis factors are potential biomarkers of melanoma prognosis. Moreover, these findings strongly support the applicability of our melanoma progression model to unravel new biomarkers for this aggressive human disease.
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Affiliation(s)
- Ana Carolina Monteiro
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil.,Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Julienne K Muenzner
- Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Fernando Andrade
- Department of Computer Science, Institute of Mathematics and Statistics, Universidade de São Paulo, Brazil
| | - Flávia Eichemberger Rius
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil
| | - Christian Ostalecki
- Department of Dermatology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Germany
| | - Carol I Geppert
- Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Abbas Agaimy
- Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Arndt Hartmann
- Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - André Fujita
- Department of Computer Science, Institute of Mathematics and Statistics, Universidade de São Paulo, Brazil
| | - Regine Schneider-Stock
- Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
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20
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Mase S, Shinjo K, Totani H, Katsushima K, Arakawa A, Takahashi S, Lai HC, Lin RI, Chan MWY, Sugiura-Ogasawara M, Kondo Y. ZNF671 DNA methylation as a molecular predictor for the early recurrence of serous ovarian cancer. Cancer Sci 2019; 110:1105-1116. [PMID: 30633424 PMCID: PMC6398878 DOI: 10.1111/cas.13936] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 01/07/2019] [Accepted: 01/08/2019] [Indexed: 01/01/2023] Open
Abstract
Serous ovarian cancer is the most frequent type of epithelial ovarian cancer. Despite the use of surgery and platinum‐based chemotherapy, many patients suffer from recurrence within 6 months, termed platinum resistance. Currently, the lack of relevant molecular biomarkers for the prediction of the early recurrence of serous ovarian cancers is linked to the poor prognosis. To identify an effective biomarker for early recurrence, we analyzed the genome‐wide DNA methylation status characteristic of early recurrence after treatment. The patients in The Cancer Genome Atlas (TCGA) dataset who showed a complete response after the first therapy were categorized into 2 groups: early recurrence serous ovarian cancer (ERS, recurrence ≤12 months, n = 51) and late recurrence serous ovarian cancer (LRS, recurrence >12 months, n = 158). Among the 12 differently methylated probes identified between the 2 groups, we found that ZNF671 was the most significantly methylated gene in the early recurrence group. A validation cohort of 78 serous ovarian cancers showed that patients with ZNF671 DNA methylation had a worse prognosis (P < .05). The multivariate analysis revealed that the methylation status of ZNF671 was an independent factor for predicting the recurrence of serous ovarian cancer patients both in the TCGA dataset and our cohort (P = .049 and P = .021, respectively). Functional analysis revealed that the depletion of ZNF671 expression conferred a more migratory and invasive phenotype to the ovarian cancer cells. Our data indicate that ZNF671 functions as a tumor suppressor in ovarian cancer and that the DNA methylation status of ZNF671 might be an effective biomarker for the recurrence of serous ovarian cancer after platinum‐based adjuvant chemotherapy.
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Affiliation(s)
- Shoko Mase
- Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of Obstetrics and Gynecology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
| | - Keiko Shinjo
- Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Haruhito Totani
- Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keisuke Katsushima
- Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Atsushi Arakawa
- Department of Obstetrics and Gynecology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
| | - Hung-Cheng Lai
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine and Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
| | - Ru-Inn Lin
- Department of Radiation Oncology, Buddhist Dalin Tzu Chi Hospital, Chia Yi, Taiwan
| | - Michael W Y Chan
- Department of Biomedical Sciences, National Chung Cheng University, Chia-Yi, Taiwan
| | - Mayumi Sugiura-Ogasawara
- Department of Obstetrics and Gynecology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
| | - Yutaka Kondo
- Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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21
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Huang RL, Chen HJ, Chen LY, Chao TK, Lin WY, Liew PL, Su PH, Weng YC, Wang YC, Liao CC, Hsu YW, Wang HC, Lai HC. Epigenetic loss of heparan sulfate 3-O-sulfation sensitizes ovarian carcinoma to oncogenic signals and predicts prognosis. Int J Cancer 2018; 143:1943-1953. [PMID: 29732534 DOI: 10.1002/ijc.31580] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 04/02/2018] [Accepted: 04/23/2018] [Indexed: 11/05/2022]
Abstract
Precision medicine requires markers for therapeutic guidance. The purpose of this study was to determine whether epithelial ovarian cancer (EOC) epigenetics can lead to the identification of biomarkers for precision medicine. Through integrative methylomics, we discovered and validated the epigenetic signature of NEFH and HS3ST2 as an independent prognostic factor for type II EOC in our dataset (n = 84), and two independent methylomics datasets (total n = 467). Integrated transcriptomics dataset (n = 1147) and tissue microarrays (n = 54) of HS3ST2 also related to high-methylation statuses and the EOC prognosis. Mechanistic explorations of HS3ST2 have assessed responses to oncogenic stimulations such as IL-6, EGF, and FGF2 in cancer cells. The combination of HS3ST2 and various oncogenic ligands also confers the worse outcome. 3-O-sulfation of heparan sulfate by HS3ST2 makes ovarian cancer cells intrinsically sensitive to oncogenic signals, which sheds new light on the application of HS3ST2 as a companion diagnostic for targeted therapy using kinase inhibitors or therapeutic antibodies.
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Affiliation(s)
- Rui-Lan Huang
- Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.,Translational epigenetic center, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Hsiang-Ju Chen
- Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and National Defense Medical Center, Taipei, Taiwan.,Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Lin-Yu Chen
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Tai-Kuang Chao
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.,Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Wei-Yu Lin
- Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK
| | - Phui-Ly Liew
- Department of Pathology, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.,Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Po-Hsuan Su
- Translational epigenetic center, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.,Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Yu-Chun Weng
- Translational epigenetic center, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Yu-Chi Wang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.,Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan
| | - Chi-Chun Liao
- Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Yaw-Wen Hsu
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Hui-Chen Wang
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hung-Cheng Lai
- Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.,Translational epigenetic center, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.,Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, People's Republic of China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410078, People's Republic of China
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22
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Zhou N, Gu Q. Prognostic and clinicopathological value of p16 protein aberrant expression in colorectal cancer: A PRISMA-compliant Meta-analysis. Medicine (Baltimore) 2018; 97:e0195. [PMID: 29561443 PMCID: PMC5895319 DOI: 10.1097/md.0000000000010195] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
PURPOSE Several studies have examined the potential role of p16 protein expression as a diagnostic and prognostic biomarker in various cancers. However, it remains unclear whether p16 protein expression is a prognostic and diagnostic factor for colorectal cancer. Therefore, this meta-analysis is conducted to evaluate the associations of p16 protein expression with overall survival (OS) and clinicopathological characteristics of colorectal cancer. METHODS According to PRISMA guideline, relevant literatures were identified by searching Medicine, Web of Science, WanFang, and CNKI databases. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted from included studies to assess the association between p16 protein expression and OS of patients with colorectal cancer. Other relevant data were extracted to evaluate the correlations of p16 protein expression with risk and clinicopathological characteristics of colorectal cancer. Stata 12.0 software was applied to calculate the strength of association between p16 protein expression and colorectal cancer. RESULTS Forty-one studies were included to evaluate the association between p16 protein expression and colorectal cancer. Nine studies involving 1731 patients with colorectal cancer found that there was no association between p16 protein expression and OS of colorectal cancer in the overall analysis (HR = 0.78, 95% CI: 0.55-1.10). However, p16 protein overexpression was significantly associated with a better prognosis in patients with colorectal cancer when cut-off value of p16 protein expression was <10% (HR = 0.23, 95% CI: 0.08-0.66). The results of subgroup analysis based on ethnicity indicated that p16 protein overexpression was a risk factor for the occurrence of colorectal cancer in Caucasians (odds ratio = 28.95, 95% CI: 6.08-137.89), but not in Asians. Furthermore, p16 protein overexpression was significantly associated with the Dukes stage, lymph node metastasis, tumor location, and Tumor Lymph Node Metastasis-stage of colorectal cancer. CONCLUSIONS p16 protein overexpression might be a useful biomarker to predict the clinicopathological progress and prognosis of colorectal cancer.
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23
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Zhao H, Xu H, Xue L. Regulatory network involving miRNAs and genes in serous ovarian carcinoma. Oncol Lett 2017; 14:6259-6268. [PMID: 29113276 DOI: 10.3892/ol.2017.6927] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Accepted: 05/23/2017] [Indexed: 12/19/2022] Open
Abstract
Serous ovarian carcinoma (SOC) is one of the most life-threatening types of gynecological malignancy, but the pathogenesis of SOC remains unknown. Previous studies have indicated that differentially expressed genes and microRNAs (miRNAs) serve important functions in SOC. However, genes and miRNAs are identified in a disperse form, and limited information is known about the regulatory association between miRNAs and genes in SOC. In the present study, three regulatory networks were hierarchically constructed, including a differentially-expressed network, a related network and a global network to reveal associations between each factor. In each network, there were three types of factors, which were genes, miRNAs and transcription factors that interact with each other. Focus was placed on the differentially-expressed network, in which all genes and miRNAs were differentially expressed and therefore may have affected the development of SOC. Following the comparison and analysis between the three networks, a number of signaling pathways which demonstrated differentially expressed elements were highlighted. Subsequently, the upstream and downstream elements of differentially expressed miRNAs and genes were listed, and a number of key elements (differentially expressed miRNAs, genes and TFs predicted using the P-match method) were analyzed. The differentially expressed network partially illuminated the pathogenesis of SOC. It was hypothesized that if there was no differential expression of miRNAs and genes, SOC may be prevented and treatment may be identified. The present study provided a theoretical foundation for gene therapy for SOC.
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Affiliation(s)
- Haiyan Zhao
- College of Computer Science and Technology, Jilin University, Changchun, Jilin 130012, P.R. China
| | - Hao Xu
- College of Computer Science and Technology, Jilin University, Changchun, Jilin 130012, P.R. China.,Zhuhai Laboratory of Key Laboratory of Symbol Computation and Knowledge Engineering of Ministry of Education, Department of Computer Science and Technology, Zhuhai College of Jilin University, Zhuhai, Guangdong 519041, P.R. China
| | - Luchen Xue
- College of Software, Jilin University, Changchun, Jilin 130012, P.R. China
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24
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Peng L, Wang R, Shang J, Xiong Y, Fu Z. Peroxiredoxin 2 is associated with colorectal cancer progression and poor survival of patients. Oncotarget 2017; 8:15057-15070. [PMID: 28125800 PMCID: PMC5362467 DOI: 10.18632/oncotarget.14801] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 01/10/2017] [Indexed: 12/21/2022] Open
Abstract
The present study was to investigate the clinical significance of peroxiredoxin 2 (PRDX2), an oncoenzyme, in the development and progression of colorectal cancer(CRC).We found levels of PRDX2 mRNA and protein were higher in CRC cell lines than in normal human colonic epithelial cells. PRDX2 expression was significantly up-regulated in CRC lesions compared with that in the adjacent noncancerous tissues. CRC tissues from 148 of 226 (65.5%) patients revealed high level of PRDX2 protein expression in contrast to only 13 of 226 (5.8%) PRDX2 strong staining cases in the adjacent noncancerous tissues. Increased expression of PRDX2 protein was significantly associated with poor tumor differentiation (p = 0.001), advanced local invasion (p = 0.046), increased lymph node metastasis (p = 0.008), and advanced TNM stage (p = 0.020). Patients with higher PRDX2 expression had a significantly shorter disease-free survival and worse disease-specific survival than those with low expression. Importantly, PRDX2 up-regulation was an independent prognostic indicator for stage I–III, early stage (stage I-II) and advanced stage (stage III) patients. In conclusion, our findings suggest PRDX2 up-regulation correlates with tumor progression and could serve as a useful marker for the prognosis of CRC.
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Affiliation(s)
- LingLong Peng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Rong Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - JingKun Shang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - YongFu Xiong
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - ZhongXue Fu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400014, China
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25
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Bryant DT, Landles C, Papadopoulou AS, Benjamin AC, Duckworth JK, Rosahl T, Benn CL, Bates GP. Disruption to schizophrenia-associated gene Fez1 in the hippocampus of HDAC11 knockout mice. Sci Rep 2017; 7:11900. [PMID: 28928414 PMCID: PMC5605701 DOI: 10.1038/s41598-017-11630-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 08/25/2017] [Indexed: 12/18/2022] Open
Abstract
Histone Deacetylase 11 (HDAC11) is highly expressed in the central nervous system where it has been reported to have roles in neural differentiation. In contrast with previous studies showing nuclear and cytoplasmic localisation, we observed synaptic enrichment of HDAC11. Knockout mouse models for HDACs 1-9 have been important for guiding the development of isoform specific HDAC inhibitors as effective therapeutics. Given the close relationship between HDAC11 and neural cells in vitro, we examined neural tissue in a previously uncharacterised Hdac11 knockout mouse (Hdac11 KO/KO). Loss of HDAC11 had no obvious impact on brain morphology and neural stem/precursor cells isolated from Hdac11 KO/KO mice had comparable proliferation and differentiation characteristics. However, in differentiating neural cells we observed decreased expression of schizophrenia-associated gene Fez1 (fasciculation and elongation protein zeta 1), a gene previously reported to be regulated by HDAC11 activity. FEZ1 has been associated with the dendritic growth of neurons and risk of schizophrenia via its interaction with DISC1 (disrupted in schizophrenia 1). Examination of cortical, cerebellar and hippocampal tissue reveal decreased Fez1 expression specifically in the hippocampus of adult mice. The results of this study demonstrate that loss of HDAC11 has age dependent and brain-region specific consequences.
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Affiliation(s)
- Dale T Bryant
- UCL Huntington's Disease Centre, Sobell Department of Motor Neuroscience, UCL Institute of Neurology, University College London, London, United Kingdom.,Neusentis, Pfizer Ltd, The Portway, Granta Park, Abington, Cambridge, United Kingdom
| | - Christian Landles
- UCL Huntington's Disease Centre, Sobell Department of Motor Neuroscience, UCL Institute of Neurology, University College London, London, United Kingdom
| | - Aikaterini S Papadopoulou
- UCL Huntington's Disease Centre, Sobell Department of Motor Neuroscience, UCL Institute of Neurology, University College London, London, United Kingdom
| | - Agnesska C Benjamin
- UCL Huntington's Disease Centre, Sobell Department of Motor Neuroscience, UCL Institute of Neurology, University College London, London, United Kingdom
| | - Joshua K Duckworth
- Neusentis, Pfizer Ltd, The Portway, Granta Park, Abington, Cambridge, United Kingdom
| | | | - Caroline L Benn
- Neusentis, Pfizer Ltd, The Portway, Granta Park, Abington, Cambridge, United Kingdom
| | - Gillian P Bates
- UCL Huntington's Disease Centre, Sobell Department of Motor Neuroscience, UCL Institute of Neurology, University College London, London, United Kingdom.
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26
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Fan X, Wen L, Li Y, Lou L, Liu W, Zhang J. The expression profile and prognostic value of APE/Ref-1 and NPM1 in high-grade serous ovarian adenocarcinoma. APMIS 2017; 125:857-862. [PMID: 28766835 DOI: 10.1111/apm.12733] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Accepted: 05/18/2017] [Indexed: 02/01/2023]
Affiliation(s)
- Xiaomei Fan
- Department of Gynecologic Oncology; The Fourth Hospital of Hebei Medical University; Shijiazhuang China
| | - Lixuan Wen
- Department of Obstetrics and Gynecology; The Fourth Hospital of Hebei Medical University; Shijiazhuang China
| | - Yuehong Li
- Department of Pathology; The Second Hospital of Hebei Medical University; Shijiazhuang China
| | - Lei Lou
- Department of Pathology; The Second Hospital of Hebei Medical University; Shijiazhuang China
| | - Weina Liu
- Department of Pathology; The Second Hospital of Hebei Medical University; Shijiazhuang China
| | - Jun Zhang
- Department of Obstetrics and Gynecology; The Fourth Hospital of Hebei Medical University; Shijiazhuang China
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27
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E2F1-regulated long non-coding RNA RAD51-AS1 promotes cell cycle progression, inhibits apoptosis and predicts poor prognosis in epithelial ovarian cancer. Sci Rep 2017; 7:4469. [PMID: 28667302 PMCID: PMC5493660 DOI: 10.1038/s41598-017-04736-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 05/19/2017] [Indexed: 01/13/2023] Open
Abstract
Long non-coding RNA RAD51 antisense RNA 1 (RAD51-AS1, also known as TODRA) has been shown to be down-regulated by E2F1, a key cell cycle and apoptosis regulator, in breast cancer. Little is known regarding the role of RAD51-AS1 in disease. Here, we investigate the role of RAD51-AS1 in epithelial ovarian cancer (EOC). Using luciferase reporter and chromatin immunoprecipitation experiments, we verified RAD51-AS1 as a target of E2F1 under negative regulation in EOC. We then examined RAD51-AS1 expression in EOC samples using in situ hybridization (ISH). RAD51-AS1 was localized to the nucleus and found to be a critical marker for clinical features that significantly correlated with poor survival in EOC patients. RAD51-AS1 was also an independent prognostic factor for EOC. Overexpression of RAD51-AS1 promoted EOC cell proliferation, while silencing of RAD51-AS1 inhibited EOC cell proliferation, delayed cell cycle progression and promoted apoptosis in vitro and in vivo. RAD51-AS1 may participate in carcinogenesis via regulation of p53 and p53-related genes. Our study highlights the role of RAD51-AS1 as a prognostic marker of EOC. Based on its regulation of the tumor suppressor p53, RAD51-AS1-based therapy may represent a viable therapeutic option for EOC in the near future.
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28
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Tomar T, Alkema NG, Schreuder L, Meersma GJ, de Meyer T, van Criekinge W, Klip HG, Fiegl H, van Nieuwenhuysen E, Vergote I, Widschwendter M, Schuuring E, van der Zee AGJ, de Jong S, Wisman GBA. Methylome analysis of extreme chemoresponsive patients identifies novel markers of platinum sensitivity in high-grade serous ovarian cancer. BMC Med 2017; 15:116. [PMID: 28641578 PMCID: PMC5481993 DOI: 10.1186/s12916-017-0870-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 05/06/2017] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Despite an early response to platinum-based chemotherapy in advanced stage high-grade serous ovarian cancer (HGSOC), the majority of patients will relapse with drug-resistant disease. Aberrant epigenetic alterations like DNA methylation are common in HGSOC. Differences in DNA methylation are associated with chemoresponse in these patients. The objective of this study was to identify and validate novel epigenetic markers of chemoresponse using genome-wide analysis of DNA methylation in extreme chemoresponsive HGSOC patients. METHODS Genome-wide next-generation sequencing was performed on methylation-enriched tumor DNA of two HGSOC patient groups with residual disease, extreme responders (≥18 months progression-free survival (PFS), n = 8) and non-responders (≤6 months PFS, n = 10) to platinum-based chemotherapy. DNA methylation and expression data of the same patients were integrated to create a gene list. Genes were validated on an independent cohort of extreme responders (n = 21) and non-responders (n = 31) using pyrosequencing and qRT-PCR. In silico validation was performed using publicly available DNA methylation (n = 91) and expression (n = 208) datasets of unselected advanced stage HGSOC patients. Functional validation of FZD10 on chemosensitivity was carried out in ovarian cancer cell lines using siRNA-mediated silencing. RESULTS Integrated genome-wide methylome and expression analysis identified 45 significantly differentially methylated and expressed genes between two chemoresponse groups. Four genes FZD10, FAM83A, MYO18B, and MKX were successfully validated in an external set of extreme chemoresponsive HGSOC patients. High FZD10 and MKX methylation were related with extreme responders and high FAM83A and MYO18B methylation with non-responders. In publicly available advanced stage HGSOC datasets, FZD10 and MKX methylation levels were associated with PFS. High FZD10 methylation was strongly associated with improved PFS in univariate analysis (hazard ratio (HR) = 0.43; 95% CI, 0.27-0.71; P = 0.001) and multivariate analysis (HR = 0.39; 95% CI, 0.23-0.65; P = 0.003). Consistently, low FZD10 expression was associated with improved PFS (HR = 1.36; 95% CI, 0.99-1.88; P = 0.058). FZD10 silencing caused significant sensitization towards cisplatin treatment in survival assays and apoptosis assays. CONCLUSIONS By applying genome-wide integrated methylome analysis on extreme chemoresponsive HGSOC patients, we identified novel clinically relevant, epigenetically-regulated markers of platinum-sensitivity in HGSOC patients. The clinical potential of these markers in predictive and therapeutic approaches has to be further validated in prospective studies.
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Affiliation(s)
- Tushar Tomar
- Department of Gynecologic Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands
| | - Nicolette G Alkema
- Department of Gynecologic Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands
| | - Leroy Schreuder
- Department of Gynecologic Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands
| | - Gert Jan Meersma
- Department of Gynecologic Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands
| | - Tim de Meyer
- Department of Mathematical Modelling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium
| | - Wim van Criekinge
- Department of Mathematical Modelling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium
| | - Harry G Klip
- Department of Gynecologic Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands
| | - Heidi Fiegl
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Els van Nieuwenhuysen
- Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
| | - Ignace Vergote
- Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
| | - Martin Widschwendter
- Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK
| | - Ed Schuuring
- Department of Medical Biology and Pathology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ate G J van der Zee
- Department of Gynecologic Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands
| | - Steven de Jong
- Department of Medical Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands.
| | - G Bea A Wisman
- Department of Gynecologic Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands.
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29
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Phelps DL, Borley JV, Flower KJ, Dina R, Darb-Esfahani S, Braicu I, Sehouli J, Fotopoulou C, Wilhelm-Benartzi CS, Gabra H, Yazbek J, Chatterjee J, Ip J, Khan H, Likos-Corbett MT, Brown R, Ghaem-Maghami S. Methylation of MYLK3 gene promoter region: a biomarker to stratify surgical care in ovarian cancer in a multicentre study. Br J Cancer 2017; 116:1287-1293. [PMID: 28350786 PMCID: PMC5482730 DOI: 10.1038/bjc.2017.83] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 02/22/2017] [Accepted: 03/03/2017] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Survival benefit from surgical debulking of ovarian cancer (OC) is well established, but some women, despite total macroscopic clearance of disease, still have poor prognosis. We aimed to identify biomarkers to predict benefit from conventional surgery. METHODS Clinical data from women debulked for high-stage OC were analysed (Hammersmith Hospital, London, UK; 2001-2014). Infinium's HumanMethylation27 array interrogated tumour DNA for differentially methylated CpG sites, correlated to survival, in patients with the least residual disease (RD; Hammersmith Array). Validation was performed using bisulphite pyrosequencing (Charité Hospital, Berlin, Germany cohort) and The Cancer Genome Atlas' (TCGA) methylation data set. Kaplan-Meier curves and Cox models tested survival. RESULTS Altogether 803 women with serous OC were studied. No RD was associated with significantly improved overall survival (OS; hazard ratio (HR) 1.25, 95% CI 1.06-1.47; P=0.0076) and progression-free survival (PFS; HR 1.23, 95% CI 1.05-1.43; P=0.012; Hammersmith database n=430). Differentially methylated loci within FGF4, FGF21, MYLK2, MYLK3, MYL7, and ITGAE associated with survival. Patients with the least RD had significantly better OS with higher methylation of MYLK3 (Hammersmith (HR 0.51, 95% CI 0.31-0.84; P=0.01), Charité (HR 0.46, 95% CI 0.21-1.01; P=0.05), and TCGA (HR 0.64, 95% CI 0.44-0.93; P=0.02)). CONCLUSIONS MYLK3 methylation is associated with improved OS in patients with the least RD, which could potentially be used to determine response to surgery.
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Affiliation(s)
- David L Phelps
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
| | - Jane V Borley
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
| | - Kirsty J Flower
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
| | - Roberto Dina
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
| | | | - Ioana Braicu
- Department of Gynaecology, Virchow Campus, Universitätsmedizin, Berlin, Germany
| | - Jalid Sehouli
- Department of Gynaecology, Virchow Campus, Universitätsmedizin, Berlin, Germany
| | - Christina Fotopoulou
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
- Department of Gynaecology, Virchow Campus, Universitätsmedizin, Berlin, Germany
| | | | - Hani Gabra
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
| | - Joseph Yazbek
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
| | - Jayanta Chatterjee
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
| | - Jacey Ip
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
| | - Harun Khan
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
| | | | - Robert Brown
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
| | - Sadaf Ghaem-Maghami
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
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30
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Bhat AA, Wani HA, Ishaq S, Waza AA, Malik RA, Shabir I, Jeelani S, Kadla S, Qureshie W, Masood A, Majid S. Promoter Hypermethylation and Its Impact on Expression of MGMT Gene in the GIT Malignant Patients of Kashmiri Origin. Cancer Invest 2017; 35:116-121. [DOI: 10.1080/07357907.2016.1271887] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Arif Akbar Bhat
- Department of Biochemistry, Government Medical College Srinagar, Srinagar, India
| | - Hilal Ahmad Wani
- Multidisciplinary Research Unit, Government Medical College Srinagar, Srinagar, India
| | - Shiekh Ishaq
- Department of Biochemistry, Government Medical College Srinagar, Srinagar, India
| | - Ajaz Ahmad Waza
- Department of Biotechnology, University of Kashmir, Hazratbal Srinagar, India
| | | | - Iram Shabir
- Department of Biochemistry, Government Medical College Srinagar, Srinagar, India
| | - Showkat Jeelani
- Department of Surgery, Government Medical College Srinagar, Srinagar, India
| | - Showkat Kadla
- Department of Medicine, Government Medical College Srinagar, Srinagar, India
| | - Waseem Qureshie
- Registrar, Government Medical College Srinagar, Srinagar, India
| | - Akbar Masood
- Department of Biochemistry, University of Kashmir, Srinagar, India
| | - Sabhiya Majid
- Department of Biochemistry, Government Medical College Srinagar, Srinagar, India
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31
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Dong A, Lu Y, Lu B. Genomic/Epigenomic Alterations in Ovarian Carcinoma: Translational Insight into Clinical Practice. J Cancer 2016; 7:1441-51. [PMID: 27471560 PMCID: PMC4964128 DOI: 10.7150/jca.15556] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 05/24/2016] [Indexed: 12/22/2022] Open
Abstract
Ovarian carcinoma is the most lethal gynecological malignancy worldwide. Recent advance in genomic/epigenomic researches will impact on our prevention, detection and intervention on ovarian carcinoma. Detection of germline mutations in BRCA1/BRCA2, mismatch repair genes, and other genes in the homologous recombination/DNA repair pathway propelled the genetic surveillance of most hereditary ovarian carcinomas. Germline or somatic mutations in SMARCA4 in familial and sporadic small cell carcinoma of the ovary, hypercalcemia type, lead to our recognition on this rare aggressive tumor as a new entity of the atypical teratoma/rhaboid tumor family. Genome-wide association studies have identified many genetic variants that will contribute to the evaluation of ovarian carcinoma risk and prognostic prediction. Whole exome sequencing and whole genome sequencing discovered rare mutations in other drive mutations except p53, but demonstrated the presence of high genomic heterogeneity and adaptability in the genetic evolution of high grade ovarian serous carcinomas that occurs in cancer progression and chemotherapy. Gene mutations, copy number aberrations and DNA methylations provided promising biomarkers for the detection, diagnosis, prognosis, therapy response and targets of ovarian cancer. These findings underscore the necessity to translate these potential biomarkers into clinical practice.
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Affiliation(s)
- Anliang Dong
- 1. Women's Hospital & Institute of Translational Medicine, School of Medicine, Zhejiang University, China
| | - Yan Lu
- 1. Women's Hospital & Institute of Translational Medicine, School of Medicine, Zhejiang University, China
| | - Bingjian Lu
- 2. Department of Surgical Pathology, Women's Hospital, School of Medicine, Zhejiang University, China
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32
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The NKD1/Rac1 feedback loop regulates the invasion and migration ability of hepatocarcinoma cells. Sci Rep 2016; 6:26971. [PMID: 27231134 PMCID: PMC4882592 DOI: 10.1038/srep26971] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 05/10/2016] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is complicated by aggressive migration and invasion, which contribute to the increased mortality of HCC patients. The NKD1 protein is abnormally expressed in many neoplasms and plays an important role in tumor progression. However, the regulation and underlying molecular mechanisms of NKD1 in HCC cell invasion and migration remain poorly understood. In the present study, ectopic expression of NKD1 in HCC cells attenuated migration and invasion in vitro and in vivo by down-regulating Rac1 expression level and activity, which affected the HCC cell cytoskeleton and E-cadherin expression. Mechanistic studies showed that NKD1 interacted with Rac1 in the cytoplasm and promoted its degradation by the ubiquitin-proteasome pathway. Over-expression of Rac1 enhanced the transcription of the NKD1 gene and protein expression conversely owing to its negative regulation of EZH2. Analysis of clinical samples showed that abnormal expression of NKD1 and Rac1 was associated with the poor prognosis of HCC patients. In summary, our data indicate a new role for NKD1 as a regulator of HCC cell invasion and migration via a feedback loop involving Rac1.
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Ho CM, Shih DTB, Hsiao CC, Huang SH, Chang SF, Cheng WF. Gene methylation of human ovarian carcinoma stromal progenitor cells promotes tumorigenesis. J Transl Med 2015; 13:367. [PMID: 26597084 PMCID: PMC4655458 DOI: 10.1186/s12967-015-0722-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 11/02/2015] [Indexed: 01/26/2023] Open
Abstract
Background This study aimed to investigate whether the DNA methylation of human
ovarian carcinoma stromal progenitor cells (OCSPCs) could promote the tumorigenesis of ovarian carcinoma. Methods OCSPCs were first isolated from fresh tumor tissues and ascites of ovarian cancer patients. In vivo and in vitro experiments on the effect of the OCSPCs on tumorigenesis and the effects of DNA demethylation on the OCSPCs were then performed. Results The OCSPCs possessed self-renewal and multipotent differentiation capacity with elevated expressions of OCT4, NANOG, BMP2, BMP4, Rex-1, AC133 and TGF-β. The OCSPCs, when combined with tumor cells in vivo could promote tumor growth. The methylation profiles of tumor suppressor genes (TSGs) were significantly higher in the OCSPCs than in ovarian cancer cells (p < 0.001). 5-aza-2-dC could alter the methylation levels of TSGs in OCSPCs and also inhibit the tumor promoting capabilities of the OCSPCs by decreasing the proliferation of tumors cells. The expression levels of TSGs were re-expressed by 5-aza-2-dC to inhibit the self-renewal and growth of OCSPCs. Conclusions OCSPCs with decreased TSG expressions in the ovarian tumor microenvironment were able to promote tumorigenesis which could be reversed by DNA demethylation. DNA demethylation reversing the expression of TSGs in OCSPCs may represent a potential therapeutic target for ovarian cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0722-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Chih-Ming Ho
- Department of Obstetrics and Gynecology, Gynecologic Cancer Center, Cathay General Hospital, Taipei, Taiwan. .,School of Medicine, Fu Jen Catholic University, Hsinchuang, New Taipei City, Taiwan. .,School of Medicine, Taipei Medical University, Taipei, Taiwan.
| | - Daniel Tzu-Bi Shih
- Graduate Institute of Medical Sciences, School of Medicine, Taipei Medical University, #250 Wu-Hsing Street, Taipei, 110, Taiwan. .,Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan.
| | - Chih-Chiang Hsiao
- Graduate Institute of Medical Sciences, School of Medicine, Taipei Medical University, #250 Wu-Hsing Street, Taipei, 110, Taiwan.
| | - Shih-Hung Huang
- Department of Pathology, Cathay General Hospital, Taipei, Taiwan.
| | - Shwu-Fen Chang
- Graduate Institute of Medical Sciences, School of Medicine, Taipei Medical University, #250 Wu-Hsing Street, Taipei, 110, Taiwan.
| | - Wen-Fang Cheng
- Department of Obstetrics and Gynecology, National Taiwan University, #7 Chung-Shan South Road, Taipei, 100, Taiwan. .,Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan. .,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
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Cooley M, Fang P, Fang F, Nephew KP, P Nephew K, Chien J. Molecular determinants of chemotherapy resistance in ovarian cancer. Pharmacogenomics 2015; 16:1763-7. [PMID: 26554863 DOI: 10.2217/pgs.15.130] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Affiliation(s)
- Megan Cooley
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Pingping Fang
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Fang Fang
- Department of Cellular & Integrative Physiology, Medical Sciences Program, Indiana University, Bloomington, IN 47405, USA
| | | | - Kenneth P Nephew
- Department of Cellular & Integrative Physiology, Medical Sciences Program, Indiana University, Bloomington, IN 47405, USA
| | - Jeremy Chien
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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35
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Woolf EC, Curley KL, Liu Q, Turner GH, Charlton JA, Preul MC, Scheck AC. The Ketogenic Diet Alters the Hypoxic Response and Affects Expression of Proteins Associated with Angiogenesis, Invasive Potential and Vascular Permeability in a Mouse Glioma Model. PLoS One 2015; 10:e0130357. [PMID: 26083629 PMCID: PMC4470583 DOI: 10.1371/journal.pone.0130357] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 05/18/2015] [Indexed: 01/09/2023] Open
Abstract
Background The successful treatment of malignant gliomas remains a challenge despite the current standard of care, which consists of surgery, radiation and temozolomide. Advances in the survival of brain cancer patients require the design of new therapeutic approaches that take advantage of common phenotypes such as the altered metabolism found in cancer cells. It has therefore been postulated that the high-fat, low-carbohydrate, adequate protein ketogenic diet (KD) may be useful in the treatment of brain tumors. We have demonstrated that the KD enhances survival and potentiates standard therapy in a mouse model of malignant glioma, yet the mechanisms are not fully understood. Methods To explore the effects of the KD on various aspects of tumor growth and progression, we used the immunocompetent, syngeneic GL261-Luc2 mouse model of malignant glioma. Results Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B. Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin. Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4. Conclusions The KD directly or indirectly alters the expression of several proteins involved in malignant progression and may be a useful tool for the treatment of gliomas.
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MESH Headings
- Animals
- Aquaporin 4/genetics
- Aquaporin 4/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Brain Neoplasms/blood supply
- Brain Neoplasms/diet therapy
- Brain Neoplasms/metabolism
- Brain Neoplasms/pathology
- Carbonic Anhydrase IX
- Carbonic Anhydrases/genetics
- Carbonic Anhydrases/metabolism
- Cell Membrane Permeability
- Diet, Ketogenic
- Disease Models, Animal
- Female
- Glioma/blood supply
- Glioma/diet therapy
- Glioma/metabolism
- Glioma/pathology
- Hypoxia/diet therapy
- Hypoxia/metabolism
- Hypoxia/pathology
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Immunoenzyme Techniques
- Matrix Metalloproteinase 2/genetics
- Matrix Metalloproteinase 2/metabolism
- Mice
- Mice, Inbred C57BL
- NF-kappa B/genetics
- NF-kappa B/metabolism
- Neoplasm Invasiveness
- Neovascularization, Pathologic/diet therapy
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- RNA, Messenger/genetics
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Zonula Occludens-1 Protein/genetics
- Zonula Occludens-1 Protein/metabolism
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Affiliation(s)
- Eric C. Woolf
- Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute dba St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
- School of Life Sciences, Arizona State University, Tempe, Arizona, 85281, United States of America
| | - Kara L. Curley
- Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute dba St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
| | - Qingwei Liu
- BNI-ASU Center for Preclinical Imaging, Barrow Neurological Institute dba St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
| | - Gregory H. Turner
- BNI-ASU Center for Preclinical Imaging, Barrow Neurological Institute dba St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
| | - Julie A. Charlton
- Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute dba St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
| | - Mark C. Preul
- Neurosurgery Research, Barrow Neurological Institute dba St. Joseph's Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
| | - Adrienne C. Scheck
- Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute dba St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
- School of Life Sciences, Arizona State University, Tempe, Arizona, 85281, United States of America
- Neurosurgery Research, Barrow Neurological Institute dba St. Joseph's Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
- * E-mail:
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36
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Lv ZD, Zhang L, Liu XP, Jin LY, Dong Q, Li FN, Wang HB, Kong B. NKD1 down-regulation is associated with poor prognosis in breast invasive ductal carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:4015-4021. [PMID: 26097589 PMCID: PMC4466976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 03/23/2015] [Indexed: 06/04/2023]
Abstract
As a negative modulator of the canonical Wnt signaling pathway, Naked1 (NKD1) is widely expressed in many normal tissues. However, the expression and clinicopathological significance of NKD1 in patients with breast cancer is still unclear. The aim of this study was to evaluate NKD1 expression in breast cancer and to investigate the question of whether reduced expression of NKD1 may have any pathological significance in breast cancer development or progression. In this study, we performed western blotting and immunohistochemistry to evaluate the expression of NKD1 and relevance with clinicopathological factors in the breast invasive ductal carcinoma. Reduction of NKD1 was significantly correlated with lymph node metastasis, histological grade and ER expression in breast cancer. Patients with negative NKD1 expression had significantly lower cumulative postoperative 5 year survival rate than those with positive NKD1 expression. This interpretation is in keeping with the results obtained from our in vitro experiments on MDA-MB-231 cells, we demonstrated that upregulation of NKD1 expression by infect with an adenovirus containing a NKD1 vector significantly reduced the migration of breast cancer cells. These data suggest that NKD1 plays an important role in invasion in human breast cancer and it appears to be a potential prognostic marker for patients with breast cancer.
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MESH Headings
- Adaptor Proteins, Signal Transducing
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Breast Neoplasms/therapy
- Calcium-Binding Proteins
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Ductal, Breast/therapy
- Carrier Proteins/genetics
- Carrier Proteins/metabolism
- Cell Line, Tumor
- Cell Movement
- Down-Regulation
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Kaplan-Meier Estimate
- Lymphatic Metastasis
- Middle Aged
- Neoplasm Grading
- Neoplasm Invasiveness
- Receptors, Estrogen/metabolism
- Risk Factors
- Time Factors
- Transfection
- Treatment Outcome
- Young Adult
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Affiliation(s)
- Zhi-Dong Lv
- Department of Breast Surgery, The Affiliated Hospital of Qingdao UniversityQingdao 266003, P. R. China
| | - Lin Zhang
- Department of Breast Surgery, The Affiliated Hospital of Qingdao UniversityQingdao 266003, P. R. China
| | - Xiang-Ping Liu
- Department of Central Laboratory of Molecular Biology, The Affiliated Hospital of Qingdao UniversityQingdao 266003, P. R. China
| | - Li-Ying Jin
- Department of Cerebrovascular Disease Research Institute, The Affiliated Hospital of Qingdao UniversityQingdao 266003, P. R. China
| | - Qian Dong
- Department of Pediatric Surgery, The Affiliated Hospital of Qingdao UniversityQingdao 266003, P. R. China
| | - Fu-Nian Li
- Department of Breast Surgery, The Affiliated Hospital of Qingdao UniversityQingdao 266003, P. R. China
| | - Hai-Bo Wang
- Department of Breast Surgery, The Affiliated Hospital of Qingdao UniversityQingdao 266003, P. R. China
| | - Bin Kong
- Department of Breast Surgery, The Affiliated Hospital of Qingdao UniversityQingdao 266003, P. R. China
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37
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Frameshift mutation of an angiogenesis factor VEGFB and its mutational heterogeneity in colorectal cancers. Pathol Oncol Res 2015; 21:853-5. [PMID: 25633991 DOI: 10.1007/s12253-015-9900-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 01/07/2015] [Indexed: 01/19/2023]
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Abstract
Cancer is a genetic and epigenetic disease. Multiple genetic and epigenetic changes have been studied in cervical cancer; however, such changes are selected for during tumorigenesis and tumor aggression is not yet clear. Cervical cancer is a multistep process with accumulation of genetic and epigenetic alterations in regulatory genes, leading to activation of oncogenes and inactivation or loss of tumor suppressor genes. In cervical cancer, epigenetic alterations can affect the expression of papillomaviral as well as host genes in relation to stages representing the multistep process of carcinogenesis.
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39
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Wang Q, Jia P, Cheng F, Zhao Z. Heterogeneous DNA methylation contributes to tumorigenesis through inducing the loss of coexpression connectivity in colorectal cancer. Genes Chromosomes Cancer 2014; 54:110-21. [PMID: 25407423 DOI: 10.1002/gcc.22224] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Accepted: 10/16/2014] [Indexed: 12/11/2022] Open
Abstract
Increasing evidence indicates the high heterogeneity of cancer cells. Recent studies have revealed distinct subtypes of DNA methylation in colorectal cancer (CRC); however, the mechanism of heterogeneous methylation remains poorly understood. Gene expression is a natural, intermediate quantitative trait that bridges genotypic and phenotypic features. In this work, we studied the role of heterogeneous DNA methylation in tumorigenesis via gene expression analyses. Specifically, we integrated methylation and expression data in normal and tumor tissues, and examined the perturbations in coexpression patterns. We found that the heterogeneity of methylation leads to significant loss of coexpression connectivity in CRC; this finding was validated in an independent cohort. Functional analyses showed that the lost coexpression partners participate in important cancer-related pathways/networks, such as ErbB and mitogen-activated protein kinase (MAPK) signaling pathways. Our analyses suggest that the loss of coexpression connectivity induced by methylation heterogeneity might play an important role in CRC. To our knowledge, this is the first study to interpret methylation heterogeneity in cancer from the perspective of coexpression perturbation. Our results provide new perspectives in tumor biology and may facilitate the identification of potential biomedical therapies for cancer treatment.
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Affiliation(s)
- Quan Wang
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN
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40
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Somatic mutations favorable to patient survival are predominant in ovarian carcinomas. PLoS One 2014; 9:e112561. [PMID: 25390899 PMCID: PMC4229214 DOI: 10.1371/journal.pone.0112561] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Accepted: 10/09/2014] [Indexed: 11/19/2022] Open
Abstract
Somatic mutation accumulation is a major cause of abnormal cell growth. However, some mutations in cancer cells may be deleterious to the survival and proliferation of the cancer cells, thus offering a protective effect to the patients. We investigated this hypothesis via a unique analysis of the clinical and somatic mutation datasets of ovarian carcinomas published by the Cancer Genome Atlas. We defined and screened 562 macro mutation signatures (MMSs) for their associations with the overall survival of 320 ovarian cancer patients. Each MMS measures the number of mutations present on the member genes (except for TP53) covered by a specific Gene Ontology (GO) term in each tumor. We found that somatic mutations favorable to the patient survival are predominant in ovarian carcinomas compared to those indicating poor clinical outcomes. Specially, we identified 19 (3) predictive MMSs that are, usually by a nonlinear dose-dependent effect, associated with good (poor) patient survival. The false discovery rate for the 19 "positive" predictors is at the level of 0.15. The GO terms corresponding to these MMSs include "lysosomal membrane" and "response to hypoxia", each of which is relevant to the progression and therapy of cancer. Using these MMSs as features, we established a classification tree model which can effectively partition the training samples into three prognosis groups regarding the survival time. We validated this model on an independent dataset of the same disease (Log-rank p-value < 2.3 × 10(-4)) and a dataset of breast cancer (Log-rank p-value < 9.3 × 10(-3)). We compared the GO terms corresponding to these MMSs and those enriched with expression-based predictive genes. The analysis showed that the GO term pairs with large similarity are mainly pertinent to the proteins located on the cell organelles responsible for material transport and waste disposal, suggesting the crucial role of these proteins in cancer mortality.
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41
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Chen YZ, Liu D, Zhao YX, Wang HT, Gao Y, Chen Y. Relationships between p16 gene promoter methylation and clinicopathologic features of colorectal cancer: a meta-analysis of 27 cohort studies. DNA Cell Biol 2014; 33:729-38. [PMID: 24979649 DOI: 10.1089/dna.2013.2253] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Many existing studies have demonstrated that p16 promoter methylation might be correlated with the clinicopathologic features of colorectal cancer (CRC), but individually published results are inconclusive. This meta-analysis aimed to derive a more precise estimation of the relationships between p16 promoter methylation and the clinicopathologic features of CRC. We searched the CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through August 1, 2013. Meta-analysis was performed using the STATA 12.0 software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under fixed- or random-effects models. Twenty-seven clinical cohort studies were included with a total of 3311 CRC patients. Our meta-analysis results revealed that p16 promoter methylation was associated with pathological characteristics of CRC (tumor, nodes, metastasis stage: OR=1.55, 95% CI: 1.14-2.13, p=0.006; lymph node metastasis: OR=2.40, 95% CI: 1.37-4.19, p=0.002; histologic grade: OR=2.72, 95% CI: 1.63-4.54, p<0.001; Dukes stage: OR=2.06, 95% CI: 1.57-2.71, p=0.002; tumor size: OR=1.99, 95% CI: 1.03-3.85, p=0.041; location: OR=2.49, 95% CI: 1.95-3.18, p<0.001, respectively). Subgroup analysis by ethnicity suggested that there were also significant correlations between p16 gene promoter methylation and pathological characteristics of CRC among both Caucasian and Asian populations (all p<0.05). Our meta-analysis suggests that promoter methylation of the p16 gene may be strongly correlated with the clinicopathologic features of CRC. Thus, p16 gene promoter methylation may be a potential biomarker for CRC.
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Affiliation(s)
- Yan-Zhi Chen
- Department of Radiotherapy, The Fourth Affiliated Hospital of China Medical University , Shenyang, People's Republic of China
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Li Y, Li S, Chen J, Shao T, Jiang C, Wang Y, Chen H, Xu J, Li X. Comparative epigenetic analyses reveal distinct patterns of oncogenic pathways activation in breast cancer subtypes. Hum Mol Genet 2014; 23:5378-93. [DOI: 10.1093/hmg/ddu256] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
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Role of p16 gene promoter methylation in gastric carcinogenesis: a meta-analysis. Mol Biol Rep 2014; 41:4481-92. [PMID: 24610350 DOI: 10.1007/s11033-014-3319-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 02/24/2014] [Indexed: 01/30/2023]
Abstract
This meta-analysis was performed to evaluate the relationships between promoter DNA methylation in tumor suppressor gene p16 and gastric carcinogenesis. The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library and CBM databases were searched for relevant articles published before November 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated. Forty-seven clinical cohort studies that met all inclusion criteria were included in this meta-analysis. A total of 2,813 gastric cancer (GC) patients were assessed. Our meta-analysis results revealed that the frequencies of p16 promoter methylation in the GC tissues were higher than those of normal and adjacent tissues (Normal: OR = 23.04, 95% CI = 13.55-39.15, P < 0.001; Adjacent: OR = 4.42, 95% CI = 1.66-11.76, P = 0.003; respectively). Furthermore, we observed significant associations of p16 promoter methylation with TNM stage, histologic grade, invasive grade, lymph node metastasis of GC (TNM stage: OR = 3.60, 95% CI: 2.17-5.98, P < 0.001; Histologic grade: OR = 2.63, 95% CI: 1.55-4.45, P < 0.001; Invasive grade: OR = 3.44, 95% CI: 1.68-7.06, P = 0.001; Lymph node metastasis: OR = 2.68, 95% CI: 1.66-4.32, P < 0.001; respectively). However, there were no correlations of p16 promoter methylation with the TNM stage and Helicobacter pylori (HP) infection of GC (Tumor size: OR = 0.76, 95% CI: 0.14-4.07, P = 0.746; HP infection: OR = 1.31, 95% CI: 0.75-2.27, P = 0.342; respectively). Our findings provide empirical evidence that p16 promoter methylation may play an important role in gastric carcinogenesis. Thus, p16 promoter methylation may be a promising potential biomarker for the early diagnosis of GC.
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