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Wan Q, Ren Q, Qiao S, Lyu A, He X, Li F. Therapeutic potential of flavonoids from traditional Chinese medicine in pancreatic cancer treatment. Front Nutr 2024; 11:1477140. [PMID: 39650709 PMCID: PMC11620852 DOI: 10.3389/fnut.2024.1477140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 11/04/2024] [Indexed: 12/11/2024] Open
Abstract
Pancreatic cancer (PC) is a highly aggressive malignancy with rising mortality rates globally. Its diagnosis is often challenging due to its asymptomatic nature in the early stages. Consequently, most patients receive a poor prognosis, with low survival rates within 5 years, as the disease is typically detected at an advanced stage, complicating effective treatment. Flavonoids, especially those derived from traditional Chinese herbal medicines, have attracted considerable attention for their potent anti-PC properties. This review highlights the therapeutic potential of these bioactive compounds, which modulate key biological pathways, making them promising candidates for PC intervention. Their mechanisms of action include the regulation of autophagy, apoptosis, cell growth, epithelial-mesenchymal transition, and oxidative stress, as well as enhancing chemotherapeutic sensitivity, exerting antiangiogenic effects, and potentially boosting immunomodulatory responses. The demonstrated benefits of these natural compounds in cancer management have spurred extensive academic interest. Beyond their role as anti-cancer agents, flavonoids may provide both preventive and therapeutic advantages for PC, resonating with the core principles of traditional Chinese medicine for disease prevention and holistic treatment.
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Affiliation(s)
- Qi Wan
- Acupuncture Department, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
- Graduate School, Jiangxi University of Chinese Medicine, Nanchang, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Qing Ren
- Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Shuangying Qiao
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Aiping Lyu
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Xingwei He
- Acupuncture Department, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Fangfei Li
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
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2
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Zhao B, Jiang W, Wang J, Sheng G, Wang Y, Meng K, Yang T. A prognostic signature of fatty acid metabolism-related genes for predicting survival of gastric cancer patients. J Biochem Mol Toxicol 2024; 38:e23687. [PMID: 38515005 DOI: 10.1002/jbt.23687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/13/2024] [Accepted: 03/07/2024] [Indexed: 03/23/2024]
Abstract
To analyze the expression profile of fatty acid metabolism (FAM)-related genes, identify a prognostic signature, and evaluate its clinical value for gastric cancer (GC) patients. The mRNA expression profiles of 493 FAM-related genes were obtained from TCGA database. Differentially expressed genes (DEGs) between cancer and non-cancer samples were identified, and their relationships with overall survival (OS) of GC patients were evaluated. A prognostic signature of FAM-related genes was identified by the LASSO regression model, and its predictive performance was tested by an independent external cohort. Ninety-three DEGs were identified, of which 44 were downregulated and 49 were upregulated. After optimizing risk characteristics, a prognostic signature of four FAM-related genes (ACBD5, AVPR1A, ELOVL4, and FAAH) were developed. All patients were divided into high-risk (>1.020) and low-risk groups (≤1.020) on the basis of the median risk score. Survival analysis indicated that high-risk patients had a shorter OS than low-risk patients (5-year OS rate, 26.3% vs. 45.0%, p < 0.001). The AUC values for the prediction of 3-year and 5-year OS were 0.664 and 0.624, respectively. In the GSE62254 data set, the 5-year OS rate of high-risk and low-risk patients were 44.7% versus 61.5%, respectively (p = 0.003). The AUC values were 0.632 and 0.627 at 3-year and 5-year prediction. The prognostic signature of FAM-related genes was an independent predictor of OS (hanzard ratio [HR] for TCGA cohort: 1.851, 95% confidence interval [CI]: 1.394-2.458, p < 0.001; HR for GSE62254: 1.549, 95% CI: 1.098-2.185, p = 0.013). The risk signature of four FAM-related genes was a valuable prognostic tool, and it might be helpful for clinical management and therapeutic decision of gastric cancer patients.
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Affiliation(s)
- Bochao Zhao
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, Nankai District, Tianjin, China
| | - Wei Jiang
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, Nankai District, Tianjin, China
| | - Jingchao Wang
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, Nankai District, Tianjin, China
| | - Guannan Sheng
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, Nankai District, Tianjin, China
| | - Yiming Wang
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, Nankai District, Tianjin, China
| | - Kewei Meng
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, Nankai District, Tianjin, China
| | - Tao Yang
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, Nankai District, Tianjin, China
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3
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Xu PF, Li C, Chen YS, Li DP, Xi SY, Chen FR, Li X, Chen ZP. Radiomics-based survival risk stratification of glioblastoma is associated with different genome alteration. Comput Biol Med 2023; 159:106878. [PMID: 37060774 DOI: 10.1016/j.compbiomed.2023.106878] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 02/04/2023] [Accepted: 03/30/2023] [Indexed: 04/17/2023]
Abstract
BACKGROUND Glioblastoma (GBM) is a remarkable heterogeneous tumor with few non-invasive, repeatable, and cost-effective prognostic biomarkers reported. In this study, we aim to explore the association between radiomic features and prognosis and genomic alterations in GBM. METHODS A total of 180 GBM patients (training cohort: n = 119; validation cohort 1: n = 37; validation cohort 2: n = 24) were enrolled and underwent preoperative MRI scans. From the multiparametric (T1, T1-Gd, T2, and T2-FLAIR) MR images, the radscore was developed to predict overall survival (OS) in a multistep postprocessing workflow and validated in two external validation cohorts. The prognostic accuracy of the radscore was assessed with concordance index (C-index) and Brier scores. Furthermore, we used hierarchical clustering and enrichment analysis to explore the association between image features and genomic alterations. RESULTS The MRI-based radscore was significantly correlated with OS in the training cohort (C-index: 0.70), validation cohort 1 (C-index: 0.66), and validation cohort 2 (C-index: 0.74). Multivariate analysis revealed that the radscore was an independent prognostic factor. Cluster analysis and enrichment analysis revealed that two distinct phenotypic clusters involved in distinct biological processes and pathways, including the VEGFA-VEGFR2 signaling pathway (q-value = 0.033), JAK-STAT signaling pathway (q-value = 0.049), and regulation of MAPK cascade (q-value = 0.0015/0.025). CONCLUSIONS Radiomic features and radiomics-derived radscores provided important phenotypic and prognostic information with great potential for risk stratification in GBM.
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Affiliation(s)
- Peng-Fei Xu
- Sun Yat-sen University Cancer Center, Guandong, 510060, PR China; Shenzhen Peking University-The Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Peking University Shenzhen Hospital, 518035, Shenzhen, PR China
| | - Cong Li
- Sun Yat-sen University Cancer Center, Guandong, 510060, PR China; The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guandong, 510120, PR China; Guangdong Province Hospital of Chinese Medical, Guangzhou, Guandong, 510120, PR China
| | - Yin-Sheng Chen
- Sun Yat-sen University Cancer Center, Guandong, 510060, PR China
| | - De-Pei Li
- Sun Yat-sen University Cancer Center, Guandong, 510060, PR China
| | - Shao-Yan Xi
- Sun Yat-sen University Cancer Center, Guandong, 510060, PR China
| | - Fu-Rong Chen
- Sun Yat-sen University Cancer Center, Guandong, 510060, PR China
| | - Xin Li
- Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, PR China.
| | - Zhong-Ping Chen
- Sun Yat-sen University Cancer Center, Guandong, 510060, PR China.
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4
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Chia L, Wang B, Kim JH, Luo LZ, Shuai S, Herrera I, Chen SY, Li L, Xian L, Huso T, Heydarian M, Reddy K, Sung WJ, Ishiyama S, Guo G, Jaffee E, Zheng L, Cope LM, Gabrielson K, Wood L, Resar L. HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation. J Clin Invest 2023; 133:151601. [PMID: 36919699 PMCID: PMC10014113 DOI: 10.1172/jci151601] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 01/25/2023] [Indexed: 03/15/2023] Open
Abstract
High mobility group A1 (HMGA1) chromatin regulators are upregulated in diverse tumors where they portend adverse outcomes, although how they function in cancer remains unclear. Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors characterized by dense desmoplastic stroma composed predominantly of cancer-associated fibroblasts and fibrotic tissue. Here, we uncover an epigenetic program whereby HMGA1 upregulates FGF19 during tumor progression and stroma formation. HMGA1 deficiency disrupts oncogenic properties in vitro while impairing tumor inception and progression in KPC mice and subcutaneous or orthotopic models of PDAC. RNA sequencing revealed HMGA1 transcriptional networks governing proliferation and tumor-stroma interactions, including the FGF19 gene. HMGA1 directly induces FGF19 expression and increases its protein secretion by recruiting active histone marks (H3K4me3, H3K27Ac). Surprisingly, disrupting FGF19 via gene silencing or the FGFR4 inhibitor BLU9931 recapitulates most phenotypes observed with HMGA1 deficiency, decreasing tumor growth and formation of a desmoplastic stroma in mouse models of PDAC. In human PDAC, overexpression of HMGA1 and FGF19 defines a subset of tumors with extremely poor outcomes. Our results reveal what we believe is a new paradigm whereby HMGA1 and FGF19 drive tumor progression and stroma formation, thus illuminating FGF19 as a rational therapeutic target for a molecularly defined PDAC subtype.
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Affiliation(s)
- Lionel Chia
- Pathobiology Graduate Program, Department of Pathology and.,Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Bowen Wang
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Jung-Hyun Kim
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Li Z Luo
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Shuai Shuai
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Iliana Herrera
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Liping Li
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Lingling Xian
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Tait Huso
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | | | - Woo Jung Sung
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Shun Ishiyama
- Department of Pathology.,Department of Molecular and Comparative Pathobiology
| | - Gongbo Guo
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | | | - Leslie M Cope
- Department of Oncology, and.,Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Laura Wood
- Pathobiology Graduate Program, Department of Pathology and.,Department of Pathology.,Department of Oncology, and
| | - Linda Resar
- Pathobiology Graduate Program, Department of Pathology and.,Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.,Department of Pathology.,Department of Oncology, and
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5
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Mazer BL, Lee JW, Roberts NJ, Chu LC, Lennon AM, Klein AP, Eshleman JR, Fishman EK, Canto MI, Goggins MG, Hruban RH. Screening for pancreatic cancer has the potential to save lives, but is it practical? Expert Rev Gastroenterol Hepatol 2023; 17:555-574. [PMID: 37212770 PMCID: PMC10424088 DOI: 10.1080/17474124.2023.2217354] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/21/2023] [Accepted: 05/19/2023] [Indexed: 05/23/2023]
Abstract
INTRODUCTION Most patients with pancreatic cancer present with advanced stage, incurable disease. However, patients with high-grade precancerous lesions and many patients with low-stage disease can be cured with surgery, suggesting that early detection has the potential to improve survival. While serum CA19.9 has been a long-standing biomarker used for pancreatic cancer disease monitoring, its low sensitivity and poor specificity have driven investigators to hunt for better diagnostic markers. AREAS COVERED This review will cover recent advances in genetics, proteomics, imaging, and artificial intelligence, which offer opportunities for the early detection of curable pancreatic neoplasms. EXPERT OPINION From exosomes, to circulating tumor DNA, to subtle changes on imaging, we know much more now about the biology and clinical manifestations of early pancreatic neoplasia than we did just five years ago. The overriding challenge, however, remains the development of a practical approach to screen for a relatively rare, but deadly, disease that is often treated with complex surgery. It is our hope that future advances will bring us closer to an effective and financially sound approach for the early detection of pancreatic cancer and its precursors.
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Affiliation(s)
- Benjamin L. Mazer
- The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jae W. Lee
- The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD
| | - Nicholas J. Roberts
- The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Linda C. Chu
- Department of Radiology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Anne Marie Lennon
- Department of Medicine, Division of Gastroenterology and Hepatology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alison P. Klein
- The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - James R. Eshleman
- The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elliot K. Fishman
- Department of Radiology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Marcia Irene Canto
- Department of Medicine, Division of Gastroenterology and Hepatology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael G. Goggins
- The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ralph H. Hruban
- The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
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6
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Sammallahti H, Sarhadi VK, Kokkola A, Ghanbari R, Rezasoltani S, Asadzadeh Aghdaei H, Puolakkainen P, Knuutila S. Oncogenomic Changes in Pancreatic Cancer and Their Detection in Stool. Biomolecules 2022; 12:652. [PMID: 35625579 PMCID: PMC9171580 DOI: 10.3390/biom12050652] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/26/2022] [Accepted: 04/27/2022] [Indexed: 02/04/2023] Open
Abstract
Pancreatic cancer (PC) is an aggressive malignancy with a dismal prognosis. To improve patient survival, the development of screening methods for early diagnosis is pivotal. Oncogenomic alterations present in tumor tissue are a suitable target for non-invasive screening efforts, as they can be detected in tumor-derived cells, cell-free nucleic acids, and extracellular vesicles, which are present in several body fluids. Since stool is an easily accessible source, which enables convenient and cost-effective sampling, it could be utilized for the screening of these traces. Herein, we explore the various oncogenomic changes that have been detected in PC tissue, such as chromosomal aberrations, mutations in driver genes, epigenetic alterations, and differentially expressed non-coding RNA. In addition, we briefly look into the role of altered gut microbiota in PC and their possible associations with oncogenomic changes. We also review the findings of genomic alterations in stool of PC patients, and the potentials and challenges of their future use for the development of stool screening tools, including the possible combination of genomic and microbiota markers.
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Affiliation(s)
- Heidelinde Sammallahti
- Department of Pathology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland;
- Department of Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland; (A.K.); (P.P.)
| | - Virinder Kaur Sarhadi
- Department of Oral and Maxillofacial Diseases, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland;
| | - Arto Kokkola
- Department of Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland; (A.K.); (P.P.)
| | - Reza Ghanbari
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran P.O. Box 1411713135, Iran;
| | - Sama Rezasoltani
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box 1985717411, Iran;
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box 1985717411, Iran;
| | - Pauli Puolakkainen
- Department of Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland; (A.K.); (P.P.)
| | - Sakari Knuutila
- Department of Pathology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland;
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7
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Song Z, Yang Y, Wu Y, Zheng M, Sun D, Li H, Chen L. Glutamic oxaloacetic transaminase 1 as a potential target in human cancer. Eur J Pharmacol 2022; 917:174754. [PMID: 35007521 DOI: 10.1016/j.ejphar.2022.174754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 12/08/2021] [Accepted: 01/06/2022] [Indexed: 12/31/2022]
Abstract
Glutamic Oxaloacetic Transaminase 1 (GOT1) is one distinct isoenzyme of glutamic oxaloacetic transaminase in eukaryotic cells, which is located in the cytoplasm. To date, several studies have shown that GOT1 plays a critical role in regulating cell proliferation by participating in amino acid metabolism, especially in glutamine metabolism. In addition, GOT1 is overexpressed in many cancer, so GOT1 has been identified as a potentially therapeutic target. Herein, this review summarizes the structure and function of GOT1 and the important roles of GOT1 in some tumor progress, as well as the characterization of GOT1 inhibitors. It may provide new insight into the discovery of small compounds as potential anti-GOT1 drugs for treatment of cancer.
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Affiliation(s)
- Zhuorui Song
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yueying Yang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yanli Wu
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mengzhu Zheng
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dejuan Sun
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Hua Li
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Lixia Chen
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
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8
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Xu F, Tang Q, Wang Y, Wang G, Qian K, Ju L, Xiao Y. Development and Validation of a Six-Gene Prognostic Signature for Bladder Cancer. Front Genet 2021; 12:758612. [PMID: 34938313 PMCID: PMC8685517 DOI: 10.3389/fgene.2021.758612] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 11/08/2021] [Indexed: 12/14/2022] Open
Abstract
Human bladder cancer (BCa) is the most common urogenital system malignancy. Patients with BCa have limited treatment efficacy in clinical practice. Novel biomarkers could provide more crucial information conferring to cancer diagnosis, treatment, and prognosis. Here, we aimed to explore and identify novel biomarkers associated with cancer-specific survival of patients with BCa to build a prognostic signature. Based on univariate Cox regression, Lasso regression, and multivariate Cox regression analysis, we conducted an integrated analysis in the training set (GSE32894) and established a six-gene signature to predict the cancer-specific survival for human BCa. The six genes were Cyclin Dependent Kinase 4 (CDK4), E2F Transcription Factor 7 (E2F7), Collagen Type XI Alpha 1 Chain (COL11A1), Bradykinin Receptor B2 (BDKRB2), Yip1 Interacting Factor Homolog B (YIF1B), and Zinc Finger Protein 415 (ZNF415). Then, we validated the prognostic value of the model by using two other datasets (GSE13507 and TCGA). Also, we conducted univariate and multivariate Cox regression analyses, and results indicated that the six-gene signature was an independent prognostic factor of cancer-specific survival of patients with BCa. Functional analysis was performed based on the differentially expressed genes of low- and high-risk patients, and we found that they were enriched in lipid metabolic and cell division-related biological processes. Meanwhile, the gene set enrichment analysis (GSEA) revealed that high-risk samples were enriched in cell cycle and cancer-related pathways [G2/M checkpoint, E2F targets, mitotic spindle, mTOR signaling, spermatogenesis, epithelial–mesenchymal transition (EMT), DNA repair, PI3K/AKT/mTOR signaling, unfolded protein response (UPR), and MYC targets V2]. Lastly, we detected the relative expression of each signature in BCa cell lines by quantitative real-time PCR (qRT-PCR). As far as we know, currently, the present study is the first research that developed and validated a cancer-specific survival prognostic index based on three independent cohorts. The results revealed that this six-gene signature has a predictive ability for cancer-specific prognosis. Moreover, we also verified the relative expression of these six signatures between the bladder cell line and four BCa cell lines by qRT-PCR. Nevertheless, experiments to further explore the function of six genes are lacking.
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Affiliation(s)
- Fei Xu
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qianqian Tang
- Department of Breast and Thyroid Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yejinpeng Wang
- Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Gang Wang
- Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.,Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.,Human Genetic Resource Preservation Center of Wuhan University, Wuhan, China
| | - Kaiyu Qian
- Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.,Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.,Human Genetic Resource Preservation Center of Wuhan University, Wuhan, China
| | - Lingao Ju
- Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.,Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.,Human Genetic Resource Preservation Center of Wuhan University, Wuhan, China
| | - Yu Xiao
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.,Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.,Human Genetic Resource Preservation Center of Wuhan University, Wuhan, China
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9
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Sankarasubramanian S, Pfohl U, Regenbrecht CRA, Reinhard C, Wedeken L. Context Matters-Why We Need to Change From a One Size Fits all Approach to Made-to-Measure Therapies for Individual Patients With Pancreatic Cancer. Front Cell Dev Biol 2021; 9:760705. [PMID: 34805167 PMCID: PMC8599957 DOI: 10.3389/fcell.2021.760705] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer is one of the deadliest cancers and remains a major unsolved health problem. While pancreatic ductal adenocarcinoma (PDAC) is associated with driver mutations in only four major genes (KRAS, TP53, SMAD4, and CDKN2A), every tumor differs in its molecular landscape, histology, and prognosis. It is crucial to understand and consider these differences to be able to tailor treatment regimens specific to the vulnerabilities of the individual tumor to enhance patient outcome. This review focuses on the heterogeneity of pancreatic tumor cells and how in addition to genetic alterations, the subsequent dysregulation of multiple signaling cascades at various levels, epigenetic and metabolic factors contribute to the oncogenesis of PDAC and compensate for each other in driving cancer progression if one is tackled by a therapeutic approach. This implicates that besides the need for new combinatorial therapies for PDAC, a personalized approach for treating this highly complex cancer is required. A strategy that combines both a target-based and phenotypic approach to identify an effective treatment, like Reverse Clinical Engineering® using patient-derived organoids, is discussed as a promising way forward in the field of personalized medicine to tackle this deadly disease.
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Affiliation(s)
| | - Ulrike Pfohl
- CELLphenomics GmbH, Berlin, Germany
- ASC Oncology GmbH, Berlin, Germany
- Institute for Molecular Bio Science, Goethe University Frankfurt Am Main, Frankfurt, Germany
| | - Christian R. A. Regenbrecht
- CELLphenomics GmbH, Berlin, Germany
- ASC Oncology GmbH, Berlin, Germany
- Institute for Pathology, Universitätsklinikum Göttingen, Göttingen, Germany
| | | | - Lena Wedeken
- CELLphenomics GmbH, Berlin, Germany
- ASC Oncology GmbH, Berlin, Germany
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10
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Thompson JK, Bednar F. Clinical Utility of Epigenetic Changes in Pancreatic Adenocarcinoma. EPIGENOMES 2021; 5:20. [PMID: 34968245 PMCID: PMC8715475 DOI: 10.3390/epigenomes5040020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 09/22/2021] [Accepted: 09/22/2021] [Indexed: 12/17/2022] Open
Abstract
Pancreatic cancer is a molecularly heterogeneous disease. Epigenetic changes and epigenetic regulatory mechanisms underlie at least some of this heterogeneity and contribute to the evolution of aggressive tumor biology in patients and the tumor's intrinsic resistance to therapy. Here we review our current understanding of epigenetic dysregulation in pancreatic cancer and how it is contributing to our efforts in early diagnosis, predictive and prognostic biomarker development and new therapeutic approaches in this deadly cancer.
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Affiliation(s)
| | - Filip Bednar
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA;
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11
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Suresh R, Diaz RJ. The remodelling of actin composition as a hallmark of cancer. Transl Oncol 2021; 14:101051. [PMID: 33761369 PMCID: PMC8008238 DOI: 10.1016/j.tranon.2021.101051] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/01/2021] [Accepted: 02/17/2021] [Indexed: 02/06/2023] Open
Abstract
Actin is a key structural protein that makes up the cytoskeleton of cells, and plays a role in functions such as division, migration, and vesicle trafficking. It comprises six different cell-type specific isoforms: ACTA1, ACTA2, ACTB, ACTC1, ACTG1, and ACTG2. Abnormal actin isoform expression has been reported in many cancers, which led us to hypothesize that it may serve as an early biomarker of cancer. We show an overview of the different actin isoforms and highlight mechanisms by which they may contribute to tumorigenicity. Furthermore, we suggest how the aberrant expression of actin subunits can confer cells with greater proliferation ability, increased migratory capability, and chemoresistance through incorporation into the normal cellular F-actin network and altered actin binding protein interaction. Studying this fundamental change that takes place within cancer cells can further our understanding of neoplastic transformation in multiple tissue types, which can ultimately aid in the early-detection, diagnosis and treatment of cancer.
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Affiliation(s)
- Rahul Suresh
- Montreal Neurological Institute, Integrated Program in Neuroscience, McGill University, Montreal, Canada
| | - Roberto J Diaz
- Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, Faculty of Medicine, McGill University, Montreal, Canada.
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12
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Abeni E, Grossi I, Marchina E, Coniglio A, Incardona P, Cavalli P, Zorzi F, Chiodera PL, Paties CT, Crosatti M, De Petro G, Salvi A. DNA methylation variations in familial female and male breast cancer. Oncol Lett 2021; 21:468. [PMID: 33907578 PMCID: PMC8063268 DOI: 10.3892/ol.2021.12729] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 02/16/2021] [Indexed: 01/21/2023] Open
Abstract
In total, ~25% of familial breast cancer (BC) is attributed to germline mutations of the BRCA1 and BRCA2 genes, while the rest of the cases are included in the BRCAX group. BC is also known to affect men, with a worldwide incidence of 1%. Epigenetic alterations, including DNA methylation, have been rarely studied in male breast cancer (MBC) on a genome-wide level. The aim of the present study was to examine the global DNA methylation profiles of patients with BC to identify differences between familial female breast cancer (FBC) and MBC, and according to BRCA1, BRCA2 or BRCAX mutation status. The genomic DNA of formalin-fixed paraffin-embedded tissues from 17 women and 7 men with BC was subjected to methylated DNA immunoprecipitation and hybridized on human promoter microarrays. The comparison between FBC and MBC revealed 2,846 significant differentially methylated regions corresponding to 2,486 annotated genes. Gene Ontology enrichment analysis revealed molecular function terms, such as the GTPase superfamily genes (particularly the GTPase Rho GAP/GEF and GTPase RAB), and cellular component terms associated with cytoskeletal architecture, such as 'cytoskeletal part', 'keratin filament' and 'intermediate filament'. When only FBC was considered, several cancer-associated pathways were among the most enriched KEGG pathways of differentially methylated genes when the BRCA2 group was compared with the BRCAX or BRCA1+BRCAX groups. The comparison between the BRCA1 and BRCA2+BRCAX groups comprised the molecular function term 'cytoskeletal protein binding'. Finally, the functional annotation of differentially methylated genes between the BRCAX and BRCA1+BRCA2 groups indicated that the most enriched molecular function terms were associated with GTPase activity. In conclusion, to the best of our knowledge, the present study was the first to compare the global DNA methylation profile of familial FBC and MBC. The results may provide useful insights into the epigenomic subtyping of BC and shed light on a possible novel molecular mechanism underlying BC carcinogenesis.
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Affiliation(s)
- Edoardo Abeni
- Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, I-25123 Brescia, Italy
| | - Ilaria Grossi
- Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, I-25123 Brescia, Italy
| | - Eleonora Marchina
- Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, I-25123 Brescia, Italy
| | - Arianna Coniglio
- Department of Clinical and Experimental Sciences, Surgical Clinic, University of Brescia, I-25123 Brescia, Italy
| | - Paolo Incardona
- Anatomic Pathology, Spedali Civili Brescia, I-25123 Brescia, Italy
| | - Pietro Cavalli
- Breast Unit, ASST-Bergamo Est, I-24068 Bergamo, Italy.,ASST of Cremona, Hospital of Cremona, I-26100 Cremona, Italy
| | - Fausto Zorzi
- Department of Pathology, Fondazione Poliambulanza, I-25124 Brescia, Italy
| | | | - Carlo Terenzio Paties
- Department of Oncology and Hematology, Pathology Unit, 'Guglielmo da Saliceto' Hospital, I-29121 Piacenza, Italy
| | - Marialuisa Crosatti
- Department of Respiratory Sciences, University of Leicester, LE1 7RH Leicester, UK
| | - Giuseppina De Petro
- Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, I-25123 Brescia, Italy
| | - Alessandro Salvi
- Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, I-25123 Brescia, Italy
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13
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Lee SY, Kwon J, Lee KA. Bcl2l10 induces metabolic alterations in ovarian cancer cells by regulating the TCA cycle enzymes SDHD and IDH1. Oncol Rep 2021; 45:47. [PMID: 33649794 PMCID: PMC7934226 DOI: 10.3892/or.2021.7998] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 02/03/2021] [Indexed: 01/07/2023] Open
Abstract
Bcl2‑like‑10 (Bcl2l10) has both oncogenic and tumor suppressor functions depending on the type of cancer. It has been previously demonstrated that the suppression of Bcl2l10 in ovarian cancer SKOV3 and A2780 cells causes cell cycle arrest and enhances cell proliferation, indicating that Bcl2l10 is a tumor suppressor gene in ovarian cancer cells. The aim of the present study was to identify possible downstream target genes and investigate the underlying mechanisms of action of Bcl2l10 in ovarian cancer cells. RNA sequencing (RNA‑Seq) was performed to obtain a list of differentially expressed genes (DEGs) in Bcl2l10‑suppressed SKOV3 and A2780 cells. The RNA‑Seq data were validated by reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis, and the levels of metabolites after Bcl2l10‑knockdown were measured using colorimetric assay kits. Pathway enrichment analysis revealed that the commonly downregulated genes in SKOV3 and A2780 cells after Bcl2l10‑knockdown were significantly enriched in metabolic pathways. The analysis of the DEGs identified from RNA‑Seq and validated by RT‑qPCR revealed that succinate dehydrogenase complex subunit D (SDHD) and isocitrate dehydrogenase 1 (IDH1), which are key enzymes of the TCA cycle that regulate oncometabolite production, may be potential downstream targets of Bcl2l10. Furthermore, Bcl2l10‑knockdown induced the accumulation of succinate and isocitrate through the downregulation of SDHD and IDH1. The present study was the first to elucidate the metabolic regulatory functions of Bcl2l10 in ovarian cancer cells, and the results indicated that Bcl2l10 may serve as a potential therapeutic target in ovarian cancer.
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Affiliation(s)
- Su-Yeon Lee
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Gyeonggi 13488, Republic of Korea
| | - Jinie Kwon
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Gyeonggi 13488, Republic of Korea
| | - Kyung-Ah Lee
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Gyeonggi 13488, Republic of Korea,Correspondence to: Professor Kyung-Ah Lee, Department of Biomedical Science, College of Life Science, CHA University, 335 Pangyo-ro, Bundang, Seongnam, Gyeonggi 13488, Republic of Korea, E-mail:
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14
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Hussen BM, Hidayat HJ, Salihi A, Sabir DK, Taheri M, Ghafouri-Fard S. MicroRNA: A signature for cancer progression. Biomed Pharmacother 2021; 138:111528. [PMID: 33770669 DOI: 10.1016/j.biopha.2021.111528] [Citation(s) in RCA: 177] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 03/05/2021] [Accepted: 03/17/2021] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are a group of small non-coding RNAs that post-transcriptionally control expression of genes by targeting mRNAs. miRNA alterations partake in the establishment and progression of different types of human cancer. Consequently, expression profiling of miRNA in human cancers has correlations with cancer detection, staging, progression, and response to therapies. Particularly, amplification, deletion, abnormal pattern of epigenetic factors and the transcriptional factors that mediate regulation of primary miRNA frequently change the landscape of miRNA expression in cancer. Indeed, changes in the quantity and quality of miRNAs are associated with the initiation of cancer, its progression and metastasis. Additionally, miRNA profiling has been used to categorize genes that can affect oncogenic pathways in cancer. Here, we discuss several circulating miRNA signatures, their expression profiles in different types of cancer and their impacts on cellular processes.
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Affiliation(s)
- Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Iraq
| | - Hazha Jamal Hidayat
- Department of Biology, College of Education, Salahaddin University-Erbil, Kurdistan Region, Iraq
| | - Abbas Salihi
- Department of Biology, College of Science, Salahaddin University-Erbil, Kurdistan Region, Iraq; Department of Medical Analysis, Faculty of Science, Tishk International University, Erbil, Iraq
| | - Dana K Sabir
- Department of Medical Laboratory Sciences, Charmo University, Kurdistan Region, Iraq
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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15
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Khan AA, Liu X, Yan X, Tahir M, Ali S, Huang H. An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression. Cancer Metastasis Rev 2021; 40:245-272. [PMID: 33423164 DOI: 10.1007/s10555-020-09952-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 12/23/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer (PC) is assumed to be an intimidating and deadly malignancy due to being the leading cause of cancer-led mortality, predominantly affecting males of older age. The overall (5 years) survival rate of PC is less than 9% and is anticipated to be aggravated in the future due to the lack of molecular acquaintance and diagnostic tools for its early detection. Multiple factors are involved in the course of PC development, including genetics, cigarette smoking, alcohol, family history, and aberrant epigenetic signatures of the epigenome. In this review, we will mainly focus on the genetic mutations and epigenetic signature of PC. Multiple tumor suppressor and oncogene mutations are involved in PC initiation, including K-RAS, p53, CDKN2A, and SMAD4. The mutational frequency of these genes ranges from 50 to 98% in PC. The nature of mutation diagnosis is mostly homozygous deletion, point mutation, and aberrant methylation. In addition to genetic modification, epigenetic alterations particularly aberrant hypermethylation and hypomethylation also predispose patients to PC. Hypermethylation is mostly involved in the downregulation of tumor suppressor genes and leads to PC, while multiple genes also represent a hypomethylation status in PC. Several renewable drugs and detection tools have been developed to cope with this aggressive malady, but all are futile, and surgical resection remains the only choice for prolonged survival if diagnosed before metastasis. However, the available therapeutic development is insufficient to cure PC. Therefore, novel approaches are a prerequisite to elucidating the genetic and epigenetic mechanisms underlying PC progression for healthier lifelong survival.
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Affiliation(s)
- Aamir Ali Khan
- College of Life Science and Bioengineering, Beijing University of Technology, 100 Ping Le Yuan, Chaoyang, Beijing, 100124, China
| | - Xinhui Liu
- College of Life Science and Bioengineering, Beijing University of Technology, 100 Ping Le Yuan, Chaoyang, Beijing, 100124, China
| | - Xinlong Yan
- College of Life Science and Bioengineering, Beijing University of Technology, 100 Ping Le Yuan, Chaoyang, Beijing, 100124, China.
| | - Muhammad Tahir
- College of Life Science and Bioengineering, Beijing University of Technology, 100 Ping Le Yuan, Chaoyang, Beijing, 100124, China
| | - Sakhawat Ali
- College of Life Science, Beijing Institute of Technology, 5 South Zhongguancun Street, Haidian District, Beijing, 100081, China
| | - Hua Huang
- College of Life Science and Bioengineering, Beijing University of Technology, 100 Ping Le Yuan, Chaoyang, Beijing, 100124, China.
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16
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Chakma K, Gu Z, Abudurexiti Y, Hata T, Motoi F, Unno M, Horii A, Fukushige S. Epigenetic inactivation of IRX4 is responsible for acceleration of cell growth in human pancreatic cancer. Cancer Sci 2020; 111:4594-4604. [PMID: 32894817 PMCID: PMC7734003 DOI: 10.1111/cas.14644] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 08/29/2020] [Accepted: 09/01/2020] [Indexed: 12/19/2022] Open
Abstract
Epigenetic gene silencing by aberrant DNA methylation is one of the important mechanisms leading to loss of key cellular pathways in tumorigenesis. Methyl-CpG-targeted transcriptional activation (MeTA) reactivates hypermethylation-mediated silenced genes in a different way from DNA-demethylating agents. Microarray coupled with MeTA (MeTA-array) identified seven commonly hypermethylation-mediated silenced genes in 12 pancreatic ductal adenocarcinoma (PDAC) cell lines. Among these, we focused on IRX4 (Iroquois homeobox 4) because IRX4 is located at chromosome 5p15.33 where PDAC susceptibility loci have been identified through genome-wide association study. IRX4 was greatly downregulated in all of the analyzed 12 PDAC cell lines by promoter hypermethylation. In addition, the IRX4 promoter region was found to be frequently and specifically hypermethylated in primary resected PDACs (18/28: 64%). Reexpression of IRX4 inhibited colony formation and proliferation in two PDAC cell lines, PK-1 and PK-9. In contrast, knockdown of IRX4 accelerated cell proliferation in an IRX4-expressing normal pancreatic ductal epithelial cell line, HPDE-1. Because IRX4 is a sequence-specific transcription factor, downstream molecules of IRX4 were pursued by microarray analyses utilizing tetracycline-mediated IRX4 inducible PK-1 and PK-9 cells; CRYAB, CD69, and IL32 were identified as IRX4 downstream candidate genes. Forced expression of these genes suppressed colony formation abilities for both PK-1 and PK-9. These results suggest that DNA methylation-mediated silencing of IRX4 contributes to pancreatic tumorigenesis through aberrant transcriptional regulation of several cancer-related genes.
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MESH Headings
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antigens, Differentiation, T-Lymphocyte/genetics
- Antigens, Differentiation, T-Lymphocyte/metabolism
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Cell Line, Tumor
- Cell Proliferation/genetics
- DNA Methylation
- Down-Regulation
- Gene Knockdown Techniques/methods
- Gene Silencing
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism
- Humans
- Interleukins/genetics
- Interleukins/metabolism
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Plasmids
- Protein Array Analysis
- Tumor Stem Cell Assay
- Up-Regulation
- alpha-Crystallin B Chain/genetics
- alpha-Crystallin B Chain/metabolism
- Pancreatic Neoplasms
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Affiliation(s)
- Kanchan Chakma
- Division of PathologyTohoku University School of MedicineSendaiJapan
- Present address:
Department of Biochemistry and Molecular BiologyUniversity of ChittagongChittagongBangladesh
| | - Zhaodi Gu
- Division of PathologyTohoku University School of MedicineSendaiJapan
| | | | - Tatsuo Hata
- Department of Gastroenterological SurgeryTohoku University School of MedicineSendaiJapan
| | - Fuyuhiko Motoi
- Department of Gastroenterological SurgeryTohoku University School of MedicineSendaiJapan
- Present address:
Department of Surgery IYamagata University Graduate School of Medical ScienceYamagataJapan
| | - Michiaki Unno
- Department of Gastroenterological SurgeryTohoku University School of MedicineSendaiJapan
| | - Akira Horii
- Division of PathologyTohoku University School of MedicineSendaiJapan
- Present address:
Saka General HospitalShiogamaJapan
| | - Shinichi Fukushige
- Division of PathologyTohoku University School of MedicineSendaiJapan
- Center for Regulatory Epigenome and DiseasesTohoku University School of MedicineSendaiJapan
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17
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Dong M, Yang Z, Li X, Zhang Z, Yin A. Screening of Methylation Gene Sites as Prognostic Signature in Lung Adenocarcinoma. Yonsei Med J 2020; 61:1013-1023. [PMID: 33251775 PMCID: PMC7700873 DOI: 10.3349/ymj.2020.61.12.1013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 09/05/2020] [Accepted: 10/18/2020] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Most lung adenocarcinoma (LUAD) patients are diagnosed at the advanced stage and have poor prognosis. DNA methylation plays an important role in the prognosis prediction of cancers. The objective of this study was to identify new DNA methylation sites as biomarkers for LUAD prognosis. MATERIALS AND METHODS We downloaded DNA methylation data from The Cancer Genome Atlas data portal. Cox proportional hazard regression model and random survival forest algorithm were applied to identify the DNA-methylation sites. Methylation of sites were validated in the Gene Expression Omnibus cohorts. Function annotation were done to explore the biological function of DNA methylated sites signature. RESULTS Six DNA methylation sites were identified as prognosis signature. The signature yielded acceptable discrimination between the high-risk group and low-risk group. The discrimination effect of this DNA methylation signature for the OS was obvious, with a median OS of 21.89 months vs. 17.74 months for high-risk vs. low-risk groups. This prognostic prediction model was validated by the test group and GEO dataset. The predictive survival value was higher for the prognostic prediction model than that for the tumor node metastasis stage. Adjuvant hemotherapy could not affect the prediction of the signature. Functional analysis indicated that these signature genes were involved in protein binding and cytoplasm. CONCLUSION We identified the prognostic signature for LUAD by combining six DNA methylation sites. This could service as potential robust and specificity signature in the prognosis prediction of LUAD.
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Affiliation(s)
- Min Dong
- Pulmonology Respiratory and Critical Care Unit, Gansu Province Hospital of Traditional Chinese Medicine, Lanzhou, China
| | - Zengli Yang
- Infectious Diseases Unit, First People's Hospital of Guannan County, Guannan, China
| | - Xingfang Li
- Pulmonology Respiratory and Critical Care Unit, Gansu Province Hospital of Traditional Chinese Medicine, Lanzhou, China
| | - Zhenxiang Zhang
- Orthopedics, Lanzhou Traditional Chinese Medicine Hospital, Lanzhou, China
| | - Ankang Yin
- Department of General Medicine, Affiliated Hospital of Yangzhou University, Yangzhou, China.
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18
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Luo H, Ma C. Identification of prognostic genes in uveal melanoma microenvironment. PLoS One 2020; 15:e0242263. [PMID: 33196683 PMCID: PMC7668584 DOI: 10.1371/journal.pone.0242263] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 10/30/2020] [Indexed: 12/22/2022] Open
Abstract
Background Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Many previous studies have demonstrated that the infiltrating of immune and stromal cells in the tumor microenvironment contributes significantly to prognosis. Methods Dataset TCGA-UVM, download from TCGA portal, was taken as the training cohort, and GSE22138, obtained from GEO database, was set as the validation cohort. ESTIMATE algorithm was applied to find intersection differentially expressed genes (DEGs) among tumor microenvironment. Kaplan-Meier analysis and univariate Cox regression model were performed on intersection DEGs to initial screen for potential prognostic genes. Then these genes entered into the validation cohort for validation using the same methods as that in the training cohort. Moreover, we conducted correlation analyses between the genes obtained in the validation cohort and the status of chromosome 3, chromosome 8q, and tumor metastasis to get prognosis genes. At last, the immune infiltration analysis was performed between the prognostic genes and 6 main kinds of tumor-infiltrating immune cells (TICs) for understanding the role of the genes in the tumor microenvironment. Results 959 intersection DEGs were found in the UM microenvironment. Kaplan-Meier and Cox analysis was then performed in the training and validation cohorts on these DEGs, and 52 genes were identified with potential prognostic value. After comparing the 52 genes to chromosome 3, chromosome 8q, and metastasis, we obtained 21 genes as the prognostic genes. The immune infiltration analysis showed that Neutrophil had the potential prognostic ability, and almost every prognostic gene we had identified was correlated with abundances of Neutrophil and CD8+ T Cell. Conclusions Identifying 21 prognosis genes (SERPINB9, EDNRB, RAPGEF3, HFE, RNF43, ZNF415, IL12RB2, MTUS1, NEDD9, ZNF667, AZGP1, WARS, GEM, RAB31, CALHM2, CA12, MYEOV, CELF2, SLCO5A1, ISM1, and PAPSS2) could accurately identify patients' prognosis and had close interactions with Neutrophil in the tumor environment, which may provide UM patients with personalized prognosis prediction and new treatment insights.
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Affiliation(s)
- Huan Luo
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Berlin, Germany
- Klinik für Augenheilkunde, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Chao Ma
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Berlin, Germany
- BCRT—Berlin Institute of Health Center for Regenerative Therapies, Charité—Universitätsmedizin Berlin, Berlin, Germany
- * E-mail:
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19
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Karimzadeh MR, Pourdavoud P, Ehtesham N, Qadbeigi M, Asl MM, Alani B, Mosallaei M, Pakzad B. Regulation of DNA methylation machinery by epi-miRNAs in human cancer: emerging new targets in cancer therapy. Cancer Gene Ther 2020; 28:157-174. [PMID: 32773776 DOI: 10.1038/s41417-020-00210-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 07/24/2020] [Accepted: 07/29/2020] [Indexed: 12/13/2022]
Abstract
Disruption in DNA methylation processes can lead to alteration in gene expression and function that would ultimately result in malignant transformation. In this way, studies have shown that, in cancers, methylation-associated silencing inactivates tumor suppressor genes, as effectively as mutations. DNA methylation machinery is composed of several genes, including those with DNA methyltransferases activity, proteins that bind to methylated cytosine in the promoter region, and enzymes with demethylase activity. Based on a prominent body of evidence, DNA methylation machinery could be regulated by microRNAs (miRNAs) called epi-miRNAs. Numerous studies demonstrated that dysregulation in DNA methylation regulators like upstream epi-miRNAs is indispensable for carcinogenesis; consequently, the malignant capacity of these cells could be reversed by restoring of this regulatory system in cancer. Conceivably, recognition of these epi-miRNAs in cancer cells could not only reveal novel molecular entities in carcinogenesis, but also render promising targets for cancer therapy. In this review, at first, we have an overview of the methylation alteration in cancers, and the effect of this phenomenon in miRNAs expression and after that, we conduct an in-depth discussion about the regulation of DNA methylation regulators by epi-miRNAs in cancer cells.
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Affiliation(s)
- Mohammad Reza Karimzadeh
- Department of medical Genetics, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | | | - Naeim Ehtesham
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Masood Movahedi Asl
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Behrang Alani
- Department of Applied Cell Sciences, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Meysam Mosallaei
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Bahram Pakzad
- Department of Internal Medicine, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran.
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20
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Bararia A, Dey S, Gulati S, Ghatak S, Ghosh S, Banerjee S, Sikdar N. Differential methylation landscape of pancreatic ductal adenocarcinoma and its precancerous lesions. Hepatobiliary Pancreat Dis Int 2020; 19:205-217. [PMID: 32312637 DOI: 10.1016/j.hbpd.2020.03.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 03/18/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Pancreatic cancer is one of the most lethal diseases with an incidence almost equal to the mortality. In addition to having genetic causes, cancer can also be considered an epigenetic disease. DNA methylation is the premier epigenetic modification and patterns of aberrant DNA methylation are recognized to be a common hallmark of human tumor. In the multistage carcinogenesis of pancreas starting from precancerous lesions to pancreatic ductal adenocarcinoma (PDAC), the epigenetic changes play a significant role. DATA SOURCES Relevant studies for this review were derived via an extensive literature search in PubMed via using various keywords such as pancreatic ductal adenocarcinoma, precancerous lesions, methylation profile, epigenetic biomarkers that are relevant directly or closely associated with the concerned area of our interest. The literature search was intensively done considering a time frame of 20 years (1998-2018). RESULT In this review we have highlighted the hypermethylation and hypomethylation of the precancerous PDAC lesions (pancreatic intra-epithelial neoplasia, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm and chronic pancreatitis) and PDAC along with the potential biomarkers. We have also achieved the early epigenetic driver that leads to progression from precancerous lesions to PDAC. A bunch of epigenetic driver genes leads to progression of precancerous lesions to PDAC (ppENK, APC, p14/5/16/17, hMLH1 and MGMT) are also documented. We summarized the importance of these observations in therapeutics and diagnosis of PDAC hence identifying the potential use of epigenetic biomarkers in epigenetic targeted therapy. Epigenetic inactivation occurs by hypermethylation of CpG islands in the promoter regions of tumor suppressor genes. We listed all hyper- and hypomethylation of CpG islands of several genes in PDAC including its precancerous lesions. CONCLUSIONS The concept of the review would help to understand their biological effects, and to determine whether they may be successfully combined with other epigenetic drugs. However, we need to continue our research to develop more specific DNA-demethylating agents, which are the targets for hypermethylated CpG methylation sites.
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Affiliation(s)
- Akash Bararia
- Human Genetics Unit, Indian Statistical Institute, Kolkata, India
| | - Subhankar Dey
- Department of Zoology, New Alipore College, University of Calcutta, Kolkata, India
| | - Sumit Gulati
- Department of Gastroenterological Surgery, Calcutta Medical Research Institute, Kolkata, India
| | - Supriyo Ghatak
- Department of Gastroenterological Surgery, Calcutta Medical Research Institute, Kolkata, India
| | - Shibajyoti Ghosh
- Department of General Surgery, Medical College and Hospital, Kolkata, India
| | - Sudeep Banerjee
- Department of Gastrointestinal Surgery, Tata Medical Center, Rajarhat, Kolkata, India
| | - Nilabja Sikdar
- Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
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21
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Dissecting miRNA facilitated physiology and function in human breast cancer for therapeutic intervention. Semin Cancer Biol 2020; 72:46-64. [PMID: 32497683 DOI: 10.1016/j.semcancer.2020.05.017] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 05/17/2020] [Accepted: 05/27/2020] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are key epigenomic regulators of biological processes in animals and plants. These small non coding RNAs form a complex networks that regulate cellular function and development. MiRNAs prevent translation by either inactivation or inducing degradation of mRNA, a major concern in post-transcriptional gene regulation. Aberrant regulation of gene expression by miRNAs is frequently observed in cancer. Overexpression of various 'oncomiRs' and silencing of tumor suppressor miRNAs are associated with various types of human cancers, although overall downregulation of miRNA expression is reported as a hallmark of cancer. Modulations of the total pool of cellular miRNA by alteration in genetic and epigenetic factors associated with the biogenesis of miRNA machinery. It also depends on the availability of cellular miRNAs from its store in the organelles which affect tumor development and cancer progression. Here, we have dissected the roles and pathways of various miRNAs during normal cellular and molecular functions as well as during breast cancer progression. Recent research works and prevailing views implicate that there are two major types of miRNAs; (i) intracellular miRNAs and (ii) extracellular miRNAs. Concept, that the functions of intracellular miRNAs are driven by cellular organelles in mammalian cells. Extracellular miRNAs function in cell-cell communication in extracellular spaces and distance cells through circulation. A detailed understanding of organelle driven miRNA function and the precise role of extracellular miRNAs, pre- and post-therapeutic implications of miRNAs in this scenario would open several avenues for further understanding of miRNA function and can be better exploited for the treatment of breast cancers.
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22
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Wu H, Li X, Zhang T, Zhang G, Chen J, Chen L, He M, Hao B, Wang C. Overexpression miR-486-3p Promoted by Allicin Enhances Temozolomide Sensitivity in Glioblastoma Via Targeting MGMT. Neuromolecular Med 2020; 22:359-369. [PMID: 32086739 PMCID: PMC7417398 DOI: 10.1007/s12017-020-08592-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 02/03/2020] [Indexed: 02/07/2023]
Abstract
Glioblastoma is the most common primary tumor of the central nervous system that develops chemotherapy resistance. Previous studies showed that Allicin could inhibit multiple cancer cells including glioblastoma, but the function of Allicin in glioblastoma is still unclear. Our work aimed to investigate the underlying molecular mechanism. The results showed that miR-486-3p levels were greatly increased in glioblastoma during Allicin treatment. Overexpression of miR-486-3p increased chemosensitivity to temozolomide (TMZ) in vitro and in vivo. O6-methylguanine-DNA methyltransferase (MGMT) was identified as a direct target of miR-486-3p, and miR-486-3p overexpression prevented the protein translation of MGMT. Moreover, overexpression of MGMT restored miR-486-3p-induced chemosensitivity to TMZ. Taken together, our studies revealed that Allicin could upregulate miR-486-3p and enhance TMZ sensitivity in glioblastoma. The results suggested that in the future, Allicin can be used as an adjuvant therapy with TMZ to improve the prognosis of patients, and miR-486-3p may be a potential target for glioblastoma treatment to improve the curative effects.
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Affiliation(s)
- Henggang Wu
- Department of Neurosurgery, Wenrong Hospital of Hengdian, Jinhua, 322118, Zhejiang, China
| | - Xu Li
- Department of Neurosurgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310002, Zhejiang, China
| | - Tiehui Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310002, Zhejiang, China
| | - Guojun Zhang
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310011, Zhejiang, China
| | - Jingnan Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310011, Zhejiang, China
| | - Li Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310011, Zhejiang, China
| | - Min He
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310011, Zhejiang, China
| | - Bilie Hao
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310011, Zhejiang, China
| | - Cheng Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310011, Zhejiang, China.
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23
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Natale F, Vivo M, Falco G, Angrisano T. Deciphering DNA methylation signatures of pancreatic cancer and pancreatitis. Clin Epigenetics 2019; 11:132. [PMID: 31492175 PMCID: PMC6729090 DOI: 10.1186/s13148-019-0728-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 08/16/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Chronic pancreatitis presents a high risk of inflammation-related progression to pancreatic cancer. Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. The high mortality rate is directly related to the difficulty in promptly diagnosing the disease, which often presents as overt and advanced. Hence, early diagnosis for pancreatic cancer becomes crucial, propelling research into the molecular and epigenetic landscape of the disease. MAIN BODY Recent studies have shown that cell-free DNA methylation profiles from inflammatory diseases or cancer can vary, thus opening a new venue for the development of biomarkers for early diagnosis. In particular, cell-free DNA methylation could be employed in the identification of pre-neoplastic signatures in individuals with suspected pancreatic conditions, representing a specific and non-invasive method of early diagnosis of pancreatic cancer. In this review, we describe the molecular determinants of pancreatic cancer and how these are related to chronic pancreatitis. We will then present an overview of differential methylated genes in the two conditions, highlighting their diagnostic or prognostic potential. CONCLUSION Exploiting the relation between abnormally methylated cell-free DNA and pre-neoplastic lesions or chronic pancreatitis may become a game-changing approach for the development of tools for the early diagnosis of pancreatic cancer.
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Affiliation(s)
- Francesco Natale
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy.
| | - Maria Vivo
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy
| | - Geppino Falco
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy.,Biogem Scarl, Istituto di Ricerche Genetiche "Gaetano Salvatore", 83031, Ariano Irpino, Italy
| | - Tiziana Angrisano
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy.
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24
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Li Q, Chang Y, Mu L, Song Y. MicroRNA-9 enhances chemotherapy sensitivity of glioma to TMZ by suppressing TOPO II via the NF-κB signaling pathway. Oncol Lett 2019; 17:4819-4826. [PMID: 31186688 PMCID: PMC6507329 DOI: 10.3892/ol.2019.10158] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 02/08/2019] [Indexed: 01/13/2023] Open
Abstract
Glioma is the most common primary tumor of the central nervous system (CNS) that develops chemotherapy resistance. The microRNA (miRNA) miR-9 is a tissue-specific miRNA of the CNS that may serve a key role in the modulation of chemotherapy sensitivity. The aim of the present study was to investigate the effect of miR-9 on glioma chemotherapy sensitivity by altering the expression of miR-9 in U251 glioma cells by viral transfection and subsequently treating with gradient concentrations of temozolomide (TMZ). Cell viability, apoptosis and the cell cycle were examined, and drug resistance genes were analyzed by western blotting. The role of nuclear factor κB (NF-κB) in this regulation was also examined. The results revealed that the susceptibility of glioma cells to TMZ was enhanced by miR-9 overexpression. When miR-9 and TMZ were applied together, the apoptotic rate and percentage of cells arrested at the G2/M stage were significantly higher compared with either treatment alone. Topoisomerase II expression was suppressed by miR-9 via the NF-κB signaling pathway, which may be responsible for the sensitization. The results of the present study suggested that miR-9 may be a potential target for glioma chemotherapy.
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Affiliation(s)
- Qingla Li
- Second Department of Minimal Invasive Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yingnan Chang
- First Department of Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Luyan Mu
- Second Department of Minimal Invasive Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yuwen Song
- Second Department of Minimal Invasive Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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25
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Zhang X, Liu Z, Liu X, Wang S, Zhang Y, He X, Sun S, Ma S, Shyh-Chang N, Liu F, Wang Q, Wang X, Liu L, Zhang W, Song M, Liu GH, Qu J. Telomere-dependent and telomere-independent roles of RAP1 in regulating human stem cell homeostasis. Protein Cell 2019; 10:649-667. [PMID: 30796637 PMCID: PMC6711945 DOI: 10.1007/s13238-019-0610-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Accepted: 01/03/2019] [Indexed: 01/19/2023] Open
Abstract
RAP1 is a well-known telomere-binding protein, but its functions in human stem cells have remained unclear. Here we generated RAP1-deficient human embryonic stem cells (hESCs) by using CRISPR/Cas9 technique and obtained RAP1-deficient human mesenchymal stem cells (hMSCs) and neural stem cells (hNSCs) via directed differentiation. In both hMSCs and hNSCs, RAP1 not only negatively regulated telomere length but also acted as a transcriptional regulator of RELN by tuning the methylation status of its gene promoter. RAP1 deficiency enhanced self-renewal and delayed senescence in hMSCs, but not in hNSCs, suggesting complicated lineage-specific effects of RAP1 in adult stem cells. Altogether, these results demonstrate for the first time that RAP1 plays both telomeric and nontelomeric roles in regulating human stem cell homeostasis.
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Affiliation(s)
- Xing Zhang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zunpeng Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaoqian Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.,National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yiyuan Zhang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaojuan He
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
| | - Shuhui Sun
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Shuai Ma
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Ng Shyh-Chang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China.,Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
| | - Feng Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China.,Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
| | - Qiang Wang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China.,Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xiaoqun Wang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China.,Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
| | - Lin Liu
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China
| | - Weiqi Zhang
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China. .,National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China. .,Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Moshi Song
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China. .,Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Guang-Hui Liu
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China. .,National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China. .,Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China. .,Beijing Institute for Brain Disorders, Capital Medical University, Beijing, 100069, China.
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China. .,Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
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Abstract
Several challenges present themselves when discussing current approaches to the prevention or treatment of pancreatic cancer. Up to 45% of the risk of pancreatic cancer is attributed to unknown causes, making effective prevention programs difficult to design. The most common type of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), is generally diagnosed at a late stage, leading to a poor prognosis and 5-year survival estimate. PDAC tumors are heterogeneous, leading to many identified cell subtypes within one patient’s primary tumor. This explains why there is a high frequency of tumors that are resistant to standard treatments, leading to high relapse rates. This review will discuss how epigenetic technologies and epigenome-wide association studies have been used to address some of these challenges and the future promises these approaches hold.
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Affiliation(s)
- Rahul R Singh
- Department of Biological Sciences, North Dakota State University, Fargo, ND 58102, USA; (R.R.S.); (K.M.R.)
| | - Katie M Reindl
- Department of Biological Sciences, North Dakota State University, Fargo, ND 58102, USA; (R.R.S.); (K.M.R.)
| | - Rick J Jansen
- Department of Public Health, North Dakota State University, Fargo, ND 58102, USA
- Biostatistics Core Facility, North Dakota State University, Fargo, ND 58102, USA
- Center for Immunization Research and Education, North Dakota State University, Fargo, ND 58102, USA
- Genomics and Bioinformatics Program, North Dakota State University, Fargo, ND 58102, USA
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27
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Wang J, Wang B, Ren H, Chen W. miR-9-5p inhibits pancreatic cancer cell proliferation, invasion and glutamine metabolism by targeting GOT1. Biochem Biophys Res Commun 2018; 509:241-248. [PMID: 30591220 DOI: 10.1016/j.bbrc.2018.12.114] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 12/15/2018] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) play crucial roles in the pancreatic carcinogenesis and progression. In the present study, we found that miR-9-5p was significantly downregulated in pancreatic cancer tissues and cell lines. The expression levels of miR-9-5p were negatively correlated with tumor stage and vessel invasion. Log-rank tests demonstrated that low expression of miR-9-5p was strongly correlated with poor overall survival in pancreatic cancer patients. Moreover, overexpression of miR-9-5p remarkably inhibited pancreatic cancer cell proliferation by enhancing cell apoptosis and significantly suppressed the invasion of pancreatic cancer cells, whereas low expression of miR-9-5p exhibited the opposite effect. Bioinformatics analysis revealed that GOT1 was a potential target of miR-9-5p, and miR-9-5p inhibited the expression level of GOT1 mRNA by direct binding to its 3'-untranslated region (3'UTR). Expression of miR-9-5p was negatively correlated with GOT1 in pancreatic cancer tissues. Moreover, modulation of miR-9-5p expression could affect the glutamine metabolism and redox homeostasis in pancreatic cancer cells. Furthermore, downregulation of GOT1 counteracted the effects of miR-9-5p repression, whereas its overexpression reversed tumor inhibitory effects of miR-9-5p. Collectively, this study suggested that miR-9-5p regulates GOT1 expression in pancreatic cancer, thereby stunting proliferation, invasion, glutamine metabolism and redox homeostasis, and that miR-9-5p may serve as a prognostic or therapeutic target for pancreatic cancer.
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Affiliation(s)
- Juan Wang
- Department of Endocrinology, The Sixth Hospital of Wuhan, Affiliated Hospital to JiangHan University, Wuhan, Hubei, 430072, PR China
| | - Bo Wang
- Department of Pancreatic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, PR China
| | - HanQiang Ren
- Department of Endocrinology, The Sixth Hospital of Wuhan, Affiliated Hospital to JiangHan University, Wuhan, Hubei, 430072, PR China.
| | - Wei Chen
- Department of Endocrinology, The Sixth Hospital of Wuhan, Affiliated Hospital to JiangHan University, Wuhan, Hubei, 430072, PR China.
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28
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Hopiavuori BR, Anderson RE, Agbaga MP. ELOVL4: Very long-chain fatty acids serve an eclectic role in mammalian health and function. Prog Retin Eye Res 2018; 69:137-158. [PMID: 30982505 PMCID: PMC6688602 DOI: 10.1016/j.preteyeres.2018.10.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 10/17/2018] [Accepted: 10/22/2018] [Indexed: 11/30/2022]
Abstract
ELOngation of Very Long chain fatty acids-4 (ELOVL4) is an elongase responsible for the biosynthesis of very long chain (VLC, ≥C28) saturated (VLC-SFA) and polyunsaturated (VLC-PUFA) fatty acids in brain, retina, skin, Meibomian glands, and testes. Fascinatingly, different mutations in this gene have been reported to cause vastly different phenotypes in humans. Heterozygous inheritance of seven different mutations in the coding sequence and 5' untranslated region of ELOVL4 causes autosomal dominant Stargardt-like macular dystrophy (STGD3), while homozygous inheritance of three more mutant variants causes severe seizures with ichthyosis, hypertonia, and even death. Some recent studies have described heterozygous inheritance in yet another three mutant ELOVL4 variants, two that cause spinocerebellar ataxia-34 (SCA34) with erythrokeratodermia (EKV) and one that causes SCA34 without EKV. We identified the specific enzymatic reactions catalyzed by ELOVL4 and, using a variety of genetically engineered mouse models, have actively searched for the mechanisms by which ELOVL4 impacts neural function and health. In this review, we critically compare and contrast the various animal model and case studies involving ELOVL4 deficiency via either mutation or deletion, and the resulting consequences on neuronal health and function in both the retina and central nervous system.
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Affiliation(s)
- Blake R Hopiavuori
- Oklahoma Center for Neurosciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Robert E Anderson
- Oklahoma Center for Neurosciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Martin-Paul Agbaga
- Oklahoma Center for Neurosciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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29
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Hypermethylation of MDFI promoter with NSCLC is specific for females, non-smokers and people younger than 65. Oncol Lett 2018; 15:9017-9024. [PMID: 29805634 PMCID: PMC5958687 DOI: 10.3892/ol.2018.8535] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Accepted: 01/25/2018] [Indexed: 01/03/2023] Open
Abstract
Non-small cell lung carcinoma (NSCLC) is a major subtype of lung cancer. Aberrant DNA methylation has been frequently observed in NSCLC. The aim of the present study was to investigate the role of MyoD family inhibitor (MDFI) methylation in NSCLC. Formalin-fixed paraffin-embedded tumor tissues and adjacent non-cancerous tissues were collected from a total of 111 patients with NSCLC. A methylation assay was performed using the quantitative methylation-specific polymerase chain reaction method. The percentage of methylated reference was used to represent the methylation level of the MDFI promoter. Data mining of a dataset from The Cancer Genome Atlas (TCGA) demonstrated that MDFI promoter methylation levels were significantly increased in 830 tumor tissues compared with 75 non-tumor tissues (P=0.012). However, the results on tissues obtained in the present study indicated that the MDFI promoter methylation levels in tumor tissues were not significantly different compared with those in the adjacent non-tumor tissues (P=0.159). Subsequent breakdown analysis identified that higher MDFI promoter methylation levels were significantly associated with NSCLC in females (P=0.031), but not in males (P=0.832). Age-based subgroup analysis demonstrated that higher MDFI promoter methylation levels were significantly associated with NSCLC in younger patients (≤65 years; P=0.003), but not in older patients (P=0.327). In addition, the association of MDFI methylation with NSCLC was significant in non-smokers (P=0.014), but not in smokers (P=0.832). Similar results also have been determined from subgroup analysis of the TCGA datasets. The Gene Expression Omnibus database indicated MDFI expression restoration in partial lung cancer cell lines (H1299 and Hotz) following demethylation treatment. However, it was identified that MDFI promoter hypermethylation was not significantly associated with prognosis of NSCLC (P>0.05). In conclusion, the present study indicated that the association of higher methylation of the MDFI promoter with NSCLC may be specific to females, non-smokers and people aged ≤65.
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30
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Abstract
OBJECTIVES Reprimo gene is a cytoplasmic protein belonging to a family of molecules controlled by p53 that inhibits cell cycle progression. Ectopic expression of Reprimo results in cell cycle arrest at the G2 phase. The aim of this study was to investigate the impact of Reprimo expression on tumorigenesis of intraductal papillary mucinous neoplasm (IPMN). METHODS Thirty-seven surgical cases of IPMN were collected retrospectively. Twenty-eight patients had benign IPMNs (low-grade dysplasia, n = 18; intermediate-grade dysplasia, n = 10), and the remaining 9 had malignant IPMNs (high-grade dysplasia, n = 4; invasive carcinoma, n = 5). DNA from tumor samples was extracted. DNA methylation patterns of Reprimo were determined by the methods of methylation-specific polymerase chain reaction and immunohistochemistry. The methylation status of Reprimo was compared between benign IPMNs and malignant IPMNs. RESULTS The incidence of aberrant DNA methylation of Reprimo was significantly higher in malignant IPMNs than in benign IPMNs (78% vs 32%, P = 0.016). Furthermore, the incidence of immunohistochemical Reprimo expression was significantly lower in malignant IPMNs than in benign IPMNs (22% vs 82%, P = 0.002). CONCLUSIONS Reprimo methylation was found more frequently in malignant IPMNs. Reprimo methylation is involved in malignant transformation of IPMNs.
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31
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Epigenetics and MicroRNAs in Cancer. Int J Mol Sci 2018; 19:ijms19020459. [PMID: 29401683 PMCID: PMC5855681 DOI: 10.3390/ijms19020459] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 01/29/2018] [Accepted: 01/30/2018] [Indexed: 02/08/2023] Open
Abstract
The ability to reprogram the transcriptional circuitry by remodeling the three-dimensional structure of the genome is exploited by cancer cells to promote tumorigenesis. This reprogramming occurs because of hereditable chromatin chemical modifications and the consequent formation of RNA-protein-DNA complexes that represent the principal actors of the epigenetic phenomena. In this regard, the deregulation of a transcribed non-coding RNA may be both cause and consequence of a cancer-related epigenetic alteration. This review summarizes recent findings that implicate microRNAs in the aberrant epigenetic regulation of cancer cells.
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Overexpression of ankyrin1 promotes pancreatic cancer cell growth. Oncotarget 2018; 7:34977-87. [PMID: 27144336 PMCID: PMC5085203 DOI: 10.18632/oncotarget.9009] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Accepted: 04/10/2016] [Indexed: 12/30/2022] Open
Abstract
The methylation status of a promoter influences gene expression and aberrant methylation during tumor development has important functional consequences for pancreatic and other cancers. Using methylated CpG island amplification and promoter microarrays, we identified ANK1 as hypomethylated in pancreatic cancers. Expression analysis determined ANK1 as commonly overexpressed in pancreatic cancers relative to normal pancreas. ANK1 was co-expressed with miR-486 in pancreatic cancer cells. Stable knockdown of ANK1 in the pancreatic cancer cell line AsPC1 led to changes in cell morphology, and decreases in colony formation. Stable knockdown of ANK1 also marked reduced the growth of tumors in athymic nude mice. Among patients undergoing pancreaticoduodenectomy, those with pancreatic cancers expressing ANK1 had a poorer prognosis than those without ANK1 expression. These findings indicate a role for ANK1 overexpression in mediating pancreatic cancer tumorigenicity.
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Shang A, Lu WY, Yang M, Zhou C, Zhang H, Cai ZX, Wang WW, Wang WX, Wu GQ. miR-9 induces cell arrest and apoptosis of oral squamous cell carcinoma via CDK 4/6 pathway. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2017; 46:1754-1762. [PMID: 29073835 DOI: 10.1080/21691401.2017.1391825] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Oral cancer remains a major public concern with considerable socioeconomic impact in the world, especially in southeast Asia. Despite substantial advancements have been made in treating oral cancer, the five-year survival rate for OSCC remained undesirable, and 35-55% patients developed recurrence within two years even with multimodality therapeutic strategies. Hence, identification of novel biomarkers for diagnosis and evaluating clinical outcome is of vital importance. MicroRNAs are 22-24 nt non-coding RNAs that could bind to 3' UTR of target mRNAs, thereby inducing degradation of mRNA or inhibiting translation. Due to its implication in regulation of post-transcriptional processes, the role of miRNAs in malignancies has been extensively studied, among which the discovery of functional miR-9 in oral squamous cell carcinoma (OSCC) remained to be elucidated. We first demonstrated that miR-9 was down-regulated in 21 OSCC patients, and we further found that forced expression of miR-9 could result in deterred cell proliferation and decreased ability to migrate and form colonies. Flow cytometry displayed cell-cycle arrested at G0/G1 phase. We next used Targetscan to predict target genes of miR-9. CDK6, a protein highly implicated in cell cycle control, was chosen for verification. Down-regulation of CDK6 and Cyclin D1 in Tca8113 transfected with miR-9 mimics indicate that the complex formed by both proteins may be the effector of the antiproliferative function of miR-9 in OSCCs. Considering small molecules are developed to target CDK4/6, our finding may provide valuable scientific evidence for research and development of therapies and diagnostic methodology in OSCCs.
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Affiliation(s)
- Anquan Shang
- a Department of Laboratory Medicine, , Tongji Hospital of Tongji University , Shanghai , China.,b Department of Laboratory Medicine , The Sixth People's Hospital of Yancheng City , Yancheng , Jiangsu , China
| | - Wen-Ying Lu
- b Department of Laboratory Medicine , The Sixth People's Hospital of Yancheng City , Yancheng , Jiangsu , China
| | - Man Yang
- c Department of Laboratory Medicine , Yancheng TCM Hospital Affiliated to Nanjing University of Chinese Medicine , Yancheng , Jiangsu , China.,d School of Biology & Basic Medical Sciences , Medical College of Soochow University , Suzhou , Jiangsu , China
| | - Cheng Zhou
- b Department of Laboratory Medicine , The Sixth People's Hospital of Yancheng City , Yancheng , Jiangsu , China
| | - Hong Zhang
- b Department of Laboratory Medicine , The Sixth People's Hospital of Yancheng City , Yancheng , Jiangsu , China
| | - Zheng-Xin Cai
- b Department of Laboratory Medicine , The Sixth People's Hospital of Yancheng City , Yancheng , Jiangsu , China
| | - Wei-Wei Wang
- e Department of Pathology , The First People's Hospital of Yancheng City , Yancheng , Jiangsu , China.,f Department of Pathology , The Sixth People's Hospital of Yancheng City , Yancheng , Jiangsu , China
| | - Wan-Xiang Wang
- g Department of Laboratory Medicine , The First People's Hospital of Yancheng City , Yancheng , Jiangsu , China
| | - Gui-Qi Wu
- h Department of General Surgery , The Sixth People's Hospital of Yancheng City , Yancheng , Jiangsu , China
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Syren P, Andersson R, Bauden M, Ansari D. Epigenetic alterations as biomarkers in pancreatic ductal adenocarcinoma. Scand J Gastroenterol 2017; 52:668-673. [PMID: 28301276 DOI: 10.1080/00365521.2017.1301989] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) prognosis remains very poor and has only marginally improved during the last decades. Epigenetic alterations have been the focus of many recent studies and offer valuable options for PDAC detection, prognosis and treatment. DNA methylation, histone modifications and microRNA (miR) level changes can be used as biomarkers. These alterations occur early in carcinogenesis and may be specific for PDAC. Additionally, epigenetic alterations can be analyzed from cell-free DNA, free-circulating nucleosomes or shed tumor cells in blood. High-throughput methods are available for miR and DNA methylation level detection. In particular, multiple promising miR level changes have been discovered. No single epigenetic biomarker that offers a sufficient specificity has been discovered yet, but patterns containing multiple independent biomarkers exist.
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Affiliation(s)
- Pascal Syren
- a Department of Surgery , Clinical Sciences Lund, Lund University and Skåne University Hospital , Lund , Sweden
| | - Roland Andersson
- a Department of Surgery , Clinical Sciences Lund, Lund University and Skåne University Hospital , Lund , Sweden
| | - Monika Bauden
- a Department of Surgery , Clinical Sciences Lund, Lund University and Skåne University Hospital , Lund , Sweden
| | - Daniel Ansari
- a Department of Surgery , Clinical Sciences Lund, Lund University and Skåne University Hospital , Lund , Sweden
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Soozangar N, Sadeghi MR, Jeddi F, Somi MH, Shirmohamadi M, Samadi N. Comparison of genome‐wide analysis techniques to DNA methylation analysis in human cancer. J Cell Physiol 2017; 233:3968-3981. [DOI: 10.1002/jcp.26176] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 08/24/2017] [Indexed: 12/11/2022]
Affiliation(s)
- Narges Soozangar
- Liver and Gastrointestinal Diseases Research CenterTabriz University of Medical SciencesTabrizIran
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences,Tabriz University of Medical SciencesTabrizIran
- Molecular Medicine Research CenterTabriz University of Medical SciencesTabrizIran
| | - Mohammad R. Sadeghi
- Liver and Gastrointestinal Diseases Research CenterTabriz University of Medical SciencesTabrizIran
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences,Tabriz University of Medical SciencesTabrizIran
| | - Farhad Jeddi
- Liver and Gastrointestinal Diseases Research CenterTabriz University of Medical SciencesTabrizIran
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences,Tabriz University of Medical SciencesTabrizIran
| | - Mohammad H. Somi
- Liver and Gastrointestinal Diseases Research CenterTabriz University of Medical SciencesTabrizIran
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences,Tabriz University of Medical SciencesTabrizIran
| | - Masoud Shirmohamadi
- Liver and Gastrointestinal Diseases Research CenterTabriz University of Medical SciencesTabrizIran
| | - Nasser Samadi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences,Tabriz University of Medical SciencesTabrizIran
- Department of Biochemistry, Faculty of MedicineTabriz University of Medical SciencesTabrizIran
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Overexpressed miR-9 promotes tumor metastasis via targeting E-cadherin in serous ovarian cancer. Front Med 2017; 11:214-222. [DOI: 10.1007/s11684-017-0518-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 01/23/2017] [Indexed: 01/15/2023]
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Du Y, Zhao B, Liu Z, Ren X, Zhao W, Li Z, You L, Zhao Y. Molecular Subtyping of Pancreatic Cancer: Translating Genomics and Transcriptomics into the Clinic. J Cancer 2017; 8:513-522. [PMID: 28367231 PMCID: PMC5370495 DOI: 10.7150/jca.17622] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Accepted: 12/23/2016] [Indexed: 12/19/2022] Open
Abstract
Pancreatic cancer remains one of the most lethal malignancies, and insights into both personalized diagnosis and intervention of this disease are urgently needed. The rapid development of sequencing technologies has enabled the successive completion of a series of genetic and epigenetic sequencing studies of pancreatic cancer. The mutational landscape of pancreatic cancer is generally portrayed in terms of somatic mutations, structural variations, epigenetic alterations and the core signaling pathways. In recent years, four significant molecular subtype classifications of pancreatic cancer have been proposed based on the expression of transcription factors and downstream targets or the distribution of structural rearrangements. Increasing researches focus on the identification of somatic mutations and other genetic aberrations that drive pancreatic cancer has led to a new era of precision medicine based on molecular subtyping. However, few known molecular classifications are used to guide clinical strategies. Specific scientific, regulatory and ethical challenges must be overcome before genomic and transcriptomic discoveries can be translated into the clinic.
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Affiliation(s)
- Yongxing Du
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
| | - Bangbo Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
| | - Ziwen Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
| | - Xiaoxia Ren
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
| | - Wenjing Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
| | - Zongze Li
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China
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Hata T, Dal Molin M, Hong SM, Tamura K, Suenaga M, Yu J, Sedogawa H, Weiss MJ, Wolfgang CL, Lennon AM, Hruban RH, Goggins MG. Predicting the Grade of Dysplasia of Pancreatic Cystic Neoplasms Using Cyst Fluid DNA Methylation Markers. Clin Cancer Res 2017; 23:3935-3944. [PMID: 28148542 DOI: 10.1158/1078-0432.ccr-16-2244] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 12/22/2016] [Accepted: 01/17/2017] [Indexed: 02/07/2023]
Abstract
Purpose: Pancreatic cysts are common and pose diagnostic and management challenges. Pancreatic cyst fluid markers have the potential to aid in the management of cysts with concerning imaging findings. Our aim was to evaluate cyst fluid methylated DNA markers for their accuracy for predicting the histologic grade of neoplastic pancreatic cysts.Experimental Design: Pancreatic cyst fluid samples from 183 patients (29 discovery and 154 validation) aspirated after surgical resection were analyzed for methylated DNA at selected genes (SOX17, BNIP3, FOXE1, PTCHD2, SLIT2, EYA4, and SFRP1) using methylation-specific droplet-digital PCR (dd-QMSP). Methylated DNA levels were evaluated for their accuracy at predicting the grade of dysplasia of the pancreatic cyst.Results: All six markers evaluated in the validation set could accurately distinguish high-risk cystic neoplasms (with high-grade dysplasia and/or associated invasive cancer) from low-risk cysts (lower grades of dysplasia) with accuracies from 79.8% to 83.6%. Methylated SOX17 had the highest overall accuracy as a single marker (sensitivity, 78.4%; specificity, 85.6%; accuracy 83.6%, cutoff; 25 methylated DNA molecules/μL cyst fluid). The best four-gene combination had 84.3% sensitivity, 89.4% specificity, and 88.0% accuracy at distinguishing cysts with high-grade dysplasia and/or invasive cancer from those without. All six markers were independent predictors of having invasive cancer/high-grade dysplasia after adjusting for clinical/imaging factors known to be associated with grade of dysplasia. The combination of methylated SOX17 with cytology better predicted neoplastic grade than cytology alone.Conclusions: A panel of methylated gene markers quantified by dd-QMSP can be used to predict the grade of dysplasia of pancreatic cysts. Clin Cancer Res; 23(14); 3935-44. ©2017 AACR.
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Affiliation(s)
- Tatsuo Hata
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Marco Dal Molin
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Koji Tamura
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Masaya Suenaga
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jun Yu
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hiraku Sedogawa
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Matthew J Weiss
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Christopher L Wolfgang
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Anne Marie Lennon
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ralph H Hruban
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Michael G Goggins
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. .,Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression mainly at the posttranscriptional level. Similar to protein-coding genes, their expression is also controlled by genetic and epigenetic mechanisms. Disruption of these control processes leads to abnormal expression of miRNAs in cancer. In this chapter, we discuss the supportive links between miRNAs and epigenetics in the context of carcinogenesis. miRNAs can be epigenetically regulated by DNA methylation and/or specific histone modifications. However, they can themselves (epi-miRNAs) repress key enzymes that drive epigenetic remodeling and also bind to complementary sequences in gene promoters, recruiting specific protein complexes that modulate chromatin structure and gene expression. All these issues affect the transcriptional landscape of cells. Most important, in the cancer clinical scenario, knowledge about miRNAs epigenetic dysregulation can not only be beneficial as a prognostic biomarker, but can also help in the design of new therapeutic approaches.
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Affiliation(s)
- Catia Moutinho
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain
| | - Manel Esteller
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain; School of Medicine and Health Sciences, University of Barcelona (UB), Catalonia, Spain.
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Hackeng WM, Hruban RH, Offerhaus GJA, Brosens LAA. Surgical and molecular pathology of pancreatic neoplasms. Diagn Pathol 2016; 11:47. [PMID: 27267993 PMCID: PMC4897815 DOI: 10.1186/s13000-016-0497-z] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 05/28/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Histologic characteristics have proven to be very useful for classifying different types of tumors of the pancreas. As a result, the major tumor types in the pancreas have long been classified based on their microscopic appearance. MAIN BODY Recent advances in whole exome sequencing, gene expression profiling, and knowledge of tumorigenic pathways have deepened our understanding of the underlying biology of pancreatic neoplasia. These advances have not only confirmed the traditional histologic classification system, but also opened new doors to early diagnosis and targeted treatment. CONCLUSION This review discusses the histopathology, genetic and epigenetic alterations and potential treatment targets of the five major malignant pancreatic tumors - pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumor, solid-pseudopapillary neoplasm, acinar cell carcinoma and pancreatoblastoma.
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MESH Headings
- Biomarkers, Tumor/genetics
- Carcinoma, Acinar Cell/diagnosis
- Carcinoma, Acinar Cell/genetics
- Carcinoma, Acinar Cell/surgery
- Carcinoma, Pancreatic Ductal/diagnosis
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/surgery
- Eye Diseases, Hereditary/diagnosis
- Eye Diseases, Hereditary/genetics
- Eye Diseases, Hereditary/surgery
- Humans
- Neuroendocrine Tumors/diagnosis
- Neuroendocrine Tumors/genetics
- Neuroendocrine Tumors/surgery
- Optic Nerve Diseases/diagnosis
- Optic Nerve Diseases/genetics
- Optic Nerve Diseases/surgery
- Pancreas/pathology
- Pancreatic Neoplasms/diagnosis
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/surgery
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Affiliation(s)
- Wenzel M Hackeng
- Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Ralph H Hruban
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - G Johan A Offerhaus
- Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Lodewijk A A Brosens
- Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
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H4K12 and H3K18 Acetylation Associates With Poor Prognosis in Pancreatic Cancer. Appl Immunohistochem Mol Morphol 2016; 24:337-44. [DOI: 10.1097/pai.0000000000000194] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Zheng L, Leung ET, Wong H, Lui G, Lee N, To KF, Choy K, Chan RC, Ip M. Unraveling methylation changes of host macrophages in Mycobacterium tuberculosis infection. Tuberculosis (Edinb) 2016; 98:139-48. [DOI: 10.1016/j.tube.2016.03.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Revised: 03/07/2016] [Accepted: 03/15/2016] [Indexed: 02/07/2023]
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Amacher DE. A 2015 survey of established or potential epigenetic biomarkers for the accurate detection of human cancers. Biomarkers 2016; 21:387-403. [PMID: 26983778 DOI: 10.3109/1354750x.2016.1153724] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Context The silencing or activation of cancer-associated genes by epigenetic mechanisms can ultimately lead to the clonal expansion of cancer cells. Objective The aim of this review is to summarize all relevant epigenetic biomarkers that have been proposed to date for the diagnosis of some prevalent human cancers. Methods A Medline search for the terms epigenetic biomarkers, human cancers, DNA methylation, histone modifications and microRNAs was performed. Results One hundred fifty-seven relevant publications were found and reviewed. Conclusion To date, a significant number of potential epigenetic cancer biomarkers of human cancer have been investigated, and some have advanced to clinical implementation.
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Marien E, Meister M, Muley T, del Pulgar TG, Derua R, Spraggins JM, Van de Plas R, Vanderhoydonc F, Machiels J, Binda MM, Dehairs J, Willette-Brown J, Hu Y, Dienemann H, Thomas M, Schnabel PA, Caprioli RM, Lacal JC, Waelkens E, Swinnen JV. Phospholipid profiling identifies acyl chain elongation as a ubiquitous trait and potential target for the treatment of lung squamous cell carcinoma. Oncotarget 2016; 7:12582-97. [PMID: 26862848 PMCID: PMC4914306 DOI: 10.18632/oncotarget.7179] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 01/04/2016] [Indexed: 01/19/2023] Open
Abstract
Lung cancer is the leading cause of cancer death. Beyond first line treatment, few therapeutic options are available, particularly for squamous cell carcinoma (SCC). Here, we have explored the phospholipidomes of 30 human SCCs and found that they almost invariably (in 96.7% of cases) contain phospholipids with longer acyl chains compared to matched normal tissues. This trait was confirmed using in situ 2D-imaging MS on tissue sections and by phospholipidomics of tumor and normal lung tissue of the L-IkkαKA/KA mouse model of lung SCC. In both human and mouse, the increase in acyl chain length in cancer tissue was accompanied by significant changes in the expression of acyl chain elongases (ELOVLs). Functional screening of differentially expressed ELOVLs by selective gene knockdown in SCC cell lines followed by phospholipidomics revealed ELOVL6 as the main elongation enzyme responsible for acyl chain elongation in cancer cells. Interestingly, inhibition of ELOVL6 drastically reduced colony formation of multiple SCC cell lines in vitro and significantly attenuated their growth as xenografts in vivo in mouse models. These findings identify acyl chain elongation as one of the most common traits of lung SCC discovered so far and pinpoint ELOVL6 as a novel potential target for cancer intervention.
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Affiliation(s)
- Eyra Marien
- KU Leuven – University of Leuven, LKI - Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium
| | - Michael Meister
- Thoraxklinik at University Hospital Heidelberg, Translational Research Unit, Heidelberg, Germany
- TLRC-H – Translational Lung Research Center Heidelberg, Member of The German Center for Lung Research, Heidelberg, Germany
| | - Thomas Muley
- Thoraxklinik at University Hospital Heidelberg, Translational Research Unit, Heidelberg, Germany
- TLRC-H – Translational Lung Research Center Heidelberg, Member of The German Center for Lung Research, Heidelberg, Germany
| | | | - Rita Derua
- KU Leuven – University of Leuven, Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, Leuven, Belgium
| | - Jeffrey M. Spraggins
- Vanderbilt University Medical Center, Department of Biochemistry and Mass Spectrometry Research Center, Nashville, TN, USA
| | - Raf Van de Plas
- Vanderbilt University Medical Center, Department of Biochemistry and Mass Spectrometry Research Center, Nashville, TN, USA
- Delft University of Technology, Delft Center for Systems and Control, Delft, The Netherlands
| | - Frank Vanderhoydonc
- KU Leuven – University of Leuven, LKI - Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium
| | - Jelle Machiels
- KU Leuven – University of Leuven, LKI - Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium
| | - Maria Mercedes Binda
- KU Leuven – University of Leuven, LKI - Leuven Cancer Institute, Department of Oncology, Abdominal Surgical Oncology, Leuven, Belgium
| | - Jonas Dehairs
- KU Leuven – University of Leuven, LKI - Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium
| | - Jami Willette-Brown
- National Cancer Institute, Centre for Cancer Research, Cancer and Inflammation Program, Frederick, MD, USA
| | - Yinling Hu
- National Cancer Institute, Centre for Cancer Research, Cancer and Inflammation Program, Frederick, MD, USA
| | - Hendrik Dienemann
- TLRC-H – Translational Lung Research Center Heidelberg, Member of The German Center for Lung Research, Heidelberg, Germany
- Thoraxklinik at University Hospital Heidelberg, Department of Surgery, Heidelberg, Germany
| | - Michael Thomas
- TLRC-H – Translational Lung Research Center Heidelberg, Member of The German Center for Lung Research, Heidelberg, Germany
- Thoraxklinik at University Hospital Heidelberg, Department of Thoracic Oncology, Heidelberg, Germany
| | - Philipp A. Schnabel
- TLRC-H – Translational Lung Research Center Heidelberg, Member of The German Center for Lung Research, Heidelberg, Germany
- University of The Saarland, Institut für Allgemeine und Spezielle Pathologie, Homburg/Saar, Germany
| | - Richard M. Caprioli
- Vanderbilt University Medical Center, Department of Biochemistry and Mass Spectrometry Research Center, Nashville, TN, USA
| | - Juan Carlos Lacal
- Fundación Jiménez Díaz, Division of Translational Oncology, Madrid, Spain
| | - Etienne Waelkens
- KU Leuven – University of Leuven, Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, Leuven, Belgium
| | - Johannes V. Swinnen
- KU Leuven – University of Leuven, LKI - Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium
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Singh R, Lillard JW, Singh S. Epigenetic Changes and Potential Targets in Pancreatic Cancer. EPIGENETIC ADVANCEMENTS IN CANCER 2016:27-63. [DOI: 10.1007/978-3-319-24951-3_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Abstract
Epigenetic alterations such as DNA methylation, histone modifications and non-coding RNA (including microRNA) associated gene silencing have been identified as a major characteristic in human cancers. These alterations may occur more frequently than genetic mutations and play a key role in silencing tumor suppressor genes or activating oncogenes, thereby affecting multiple cellular processes. In recent years, studies have shown that microRNAs, that act as posttranscriptional regulators of gene expression are frequently deregulated in colorectal cancer (CRC), via aberrant DNA methylation. Over the past decade, technological advances have revolutionized the field of epigenetics and have led to the identification of numerous epigenetically dysregulated miRNAs in CRC, which are regulated by CpG island hypermethylation and DNA hypomethylation. In addition, aberrant DNA methylation of miRNA genes holds a great promise in several clinical applications such as biomarkers for early screening, prognosis, and therapeutic applications in CRC.
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Suzuki H, Maruyama R, Yamamoto E, Niinuma T, Kai M. Relationship Between Noncoding RNA Dysregulation and Epigenetic Mechanisms in Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 927:109-35. [DOI: 10.1007/978-981-10-1498-7_4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Tuna M, Machado AS, Calin GA. Genetic and epigenetic alterations of microRNAs and implications for human cancers and other diseases. Genes Chromosomes Cancer 2015; 55:193-214. [PMID: 26651018 DOI: 10.1002/gcc.22332] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2015] [Revised: 10/27/2015] [Accepted: 10/28/2015] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) are a well-studied group of noncoding RNAs that control gene expression by interacting mainly with messenger RNA. It is known that miRNAs and their biogenesis regulatory machineries have crucial roles in multiple cell processes; thus, alterations in these genes often lead to disease, such as cancer. Disruption of these genes can occur through epigenetic and genetic alterations, resulting in aberrant expression of miRNAs and subsequently of their target genes. This review focuses on the disruption of miRNAs and their key regulatory machineries by genetic alterations, with emphasis on mutations and epigenetic changes in cancer and other diseases.
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Affiliation(s)
- Musaffe Tuna
- Department of Epidemiology, The University of Texas, MD Anderson Cancer Center, Houston, TX
| | - Andreia S Machado
- Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX
| | - George A Calin
- Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX
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Kusano S, Yoshimitsu M, Hachiman M, Ikeda M. I-mfa domain proteins specifically interact with HTLV-1 Tax and repress its transactivating functions. Virology 2015; 486:219-27. [PMID: 26469549 DOI: 10.1016/j.virol.2015.09.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 05/31/2015] [Accepted: 09/25/2015] [Indexed: 12/21/2022]
Abstract
The I-mfa domain proteins HIC (also known as MDFIC) and I-mfa (also known as MDFI) are candidate tumor suppressor genes that are involved in cellular and viral transcriptional regulation. Here, we show that HIC and I-mfa directly interact with human T-cell leukemia virus type-1 (HTLV-1) Tax protein in vitro. In addition, HIC and I-mfa repress Tax-dependent transactivation of an HTLV-1 long terminal repeat (LTR) reporter construct in COS-1, Jurkat and high-Tax-producing HTLV-1-infected T cells. HIC also interacts with Tax through its I-mfa domain in vivo and represses Tax-dependent transactivation of HTLV-1 LTR and NF-κB reporter constructs in an interaction-dependent manner. Furthermore, we show that HIC decreases the nuclear distribution and stimulates the proteasomal degradation of Tax. These data reveal that HIC specifically interacts with HTLV-1 Tax and negatively regulates Tax transactivational activity by altering its subcellular distribution and stability.
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Affiliation(s)
- Shuichi Kusano
- Division of Persistent and Oncogenic Viruses, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
| | - Makoto Yoshimitsu
- Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Miho Hachiman
- Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Masanori Ikeda
- Division of Persistent and Oncogenic Viruses, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
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Kisiel JB, Raimondo M, Taylor WR, Yab TC, Mahoney DW, Sun Z, Middha S, Baheti S, Zou H, Smyrk TC, Boardman LA, Petersen GM, Ahlquist DA. New DNA Methylation Markers for Pancreatic Cancer: Discovery, Tissue Validation, and Pilot Testing in Pancreatic Juice. Clin Cancer Res 2015; 21:4473-81. [PMID: 26023084 PMCID: PMC4592385 DOI: 10.1158/1078-0432.ccr-14-2469] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 05/12/2015] [Indexed: 12/18/2022]
Abstract
PURPOSE Discriminant markers for pancreatic cancer detection are needed. We sought to identify and validate methylated DNA markers for pancreatic cancer using next-generation sequencing unbiased by known targets. EXPERIMENTAL DESIGN At a referral center, we conducted four sequential case-control studies: discovery, technical validation, biologic validation, and clinical piloting. Candidate markers were identified using variance-inflated logistic regression on reduced-representation bisulfite DNA sequencing results from matched pancreatic cancers, benign pancreas, and normal colon tissues. Markers were validated technically on replicate discovery study DNA and biologically on independent, matched, blinded tissues by methylation-specific PCR. Clinical testing of six methylation candidates and mutant KRAS was performed on secretin-stimulated pancreatic juice samples from 61 patients with pancreatic cancer, 22 with chronic pancreatitis, and 19 with normal pancreas on endoscopic ultrasound. Areas under receiver-operating characteristics curves (AUC) for markers were calculated. RESULTS Sequencing identified >500 differentially hyper-methylated regions. On independent tissues, AUC on 19 selected markers ranged between 0.73 and 0.97. Pancreatic juice AUC values for CD1D, KCNK12, CLEC11A, NDRG4, IKZF1, PKRCB, and KRAS were 0.92*, 0.88, 0.85, 0.85, 0.84, 0.83, and 0.75, respectively, for pancreatic cancer compared with normal pancreas and 0.92*, 0.73, 0.76, 0.85*, 0.73, 0.77, and 0.62 for pancreatic cancer compared with chronic pancreatitis (*, P = 0.001 vs. KRAS). CONCLUSIONS We identified and validated novel DNA methylation markers strongly associated with pancreatic cancer. On pilot testing in pancreatic juice, best markers (especially CD1D) highly discriminated pancreatic cases from controls.
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Affiliation(s)
- John B Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - Massimo Raimondo
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
| | - William R Taylor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Tracy C Yab
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Douglas W Mahoney
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Zhifu Sun
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Sumit Middha
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Saurabh Baheti
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Hongzhi Zou
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
| | | | - Lisa A Boardman
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | - David A Ahlquist
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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