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Wang Y, Ni Q, Xu S, Cui M, Wang R, Liu R. MiR-486-5p predicts the progression of severe acute pancreatitis by mediating the inflammatory response and ATG7/p38 MAPK pathway. Am J Med Sci 2025:S0002-9629(25)00982-6. [PMID: 40169118 DOI: 10.1016/j.amjms.2025.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 12/30/2024] [Accepted: 01/30/2025] [Indexed: 04/03/2025]
Abstract
BACKGROUND Acute pancreatitis (AP) is a serious disorder, and is frequently accompanied by shock or organ failure. The study aimed to investigate the predictive value of serum miR-486-5p for the prognosis of SAP patients and the underlying mechanism. METHODS The concentration of mRNAs was detected by Real-Time PCR reaction. The correlation between miRNA and each scoring system was analyzed via Pearson's correlation analysis. ROC curve was performed for diagnostic value evaluation. The predictive value of miRNA expression in the severity of AP was estimated by logistic regression analysis. HPDE6-C7 cells were treated with cerulein (Cer) to mimic AP in vitro. The cell apoptosis, viability, and inflammatory response were detected by flow cytometry, CCK-8, and ELISA, respectively. The targeting relationship was verified by DLR assay and RIP assay. RESULTS The expression of miR-486-5p was elevated in the serum of non-SAP and SAP groups (P < 0.001), which was interconnected with APACHE II, SOFA, and Ranson scores. MiR-486-5p can differentiate SAP patients from non-SAP with the AUC of 0.916, and it was an independent risk for the severity of AP patients. The miR-486-5p/ATG7 axis affected the apoptosis, viability, and inflammatory response of HPDE6-C7 cell models by the p38 MAPK pathway, thus involving the progression of AP. CONCLUSION Serum miR-486-5p may have a certain predictive value for the severity of AP and influence AP development through mediating cell inflammatory response via targeting ATG7.
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Affiliation(s)
- Yang Wang
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Qi Ni
- Department of Endocrinology, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Shuying Xu
- Department of Emergency, Binzhou Medical University Hospital, Binzhou, Shandong 256600, China
| | - Mingli Cui
- Department of Cardiovascular Medicine, Binzhou Medical University Hospital, Binzhou, Shandong 256600, China
| | - Ruixia Wang
- Department of Emergency, Binzhou Medical University Hospital, Binzhou, Shandong 256600, China..
| | - Rong Liu
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China..
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Salahi‐Niri A, Zarand P, Mansouri N, Rastgou P, Yazdani O, Esbati R, Shojaeian F, Jahanbin B, Mohsenifar Z, Aghdaei HA, Ardalan FA, Safavi‐Naini SAA. Potential of Proliferative Markers in Pancreatic Cancer Management: A Systematic Review. Health Sci Rep 2025; 8:e70412. [PMID: 40051490 PMCID: PMC11882395 DOI: 10.1002/hsr2.70412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 11/12/2024] [Accepted: 01/13/2025] [Indexed: 03/09/2025] Open
Abstract
Background and Aims Pancreatic cancer is an aggressive malignancy with poor prognosis and limited treatment options. Chemotherapy remains a primary therapeutic approach, but patient responses vary significantly, emphasizing the need for reliable biomarkers. This review explores the potential role of proliferative markers, including Ki-67, PCNA, Cyclin D1, and PHH3, as predictive and prognostic indicators in pancreatic cancer management, aiming to enhance personalized treatment strategies. Methods We conducted a narrative review by searching Scopus, PubMed, and Google Scholar for studies focusing on Ki-67, PCNA, Cyclin D1, and PHH3 in relation to pancreatic cancer and chemotherapy. The literature was reviewed to evaluate the role of these markers in predicting chemotherapy response, tumor progression, and overall patient survival. Results The review highlights the clinical significance of these markers. Ki-67 and PCNA are associated with cell proliferation, while Cyclin D1 regulates cell cycle progression and PHH3 is linked to mitotic activity. High expression levels of these markers often correlate with increased tumor aggressiveness and poorer patient outcomes. Moreover, they show promise in predicting chemotherapy response, which can inform tailored therapeutic strategies. However, challenges remain, including standardization of detection methods and determination of optimal cutoff values. Conclusion Proliferative markers such as Ki-67, PCNA, Cyclin D1, and PHH3 hold potential as predictive and prognostic tools in pancreatic cancer management. Their integration into clinical practice could improve the accuracy of treatment decisions and enhance patient outcomes. Further research and validation are necessary to overcome existing challenges and optimize their application in personalized oncology.
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Affiliation(s)
- Aryan Salahi‐Niri
- Research, Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Paniz Zarand
- Research, Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Negar Mansouri
- Research, Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Parvaneh Rastgou
- School of MedicineTabriz University of Medical SciencesTabrizIran
| | - Omid Yazdani
- Research, Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Romina Esbati
- Research, Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Fatemeh Shojaeian
- Sidney Kimmel Comprehensive Cancer Research CenterJohns Hopkins School of MedicineBaltimoreMarylandUSA
| | - Behnaz Jahanbin
- Cancer Institute, Pathology Department, Imam Khomeini Hospital ComplexTehran University of Medical SciencesTehranIran
| | - Zhaleh Mohsenifar
- Department of Pathology, Ayatollah Taleghani Educational Hospital, Faculty of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Hamid Asadzadeh Aghdaei
- Research, Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Farid Azmoudeh Ardalan
- Pathology and Laboratory Medicine Department, Imam Khomeini Hospital ComplexTehran University of Medical SciencesTehranIran
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Rouzbahani AK, Khalili-Tanha G, Rajabloo Y, Khojasteh-Leylakoohi F, Garjan HS, Nazari E, Avan A. Machine learning algorithms and biomarkers identification for pancreatic cancer diagnosis using multi-omics data integration. Pathol Res Pract 2024; 263:155602. [PMID: 39357184 DOI: 10.1016/j.prp.2024.155602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 09/21/2024] [Accepted: 09/24/2024] [Indexed: 10/04/2024]
Abstract
PURPOSE Pancreatic cancer is a lethal type of cancer with most of the cases being diagnosed in an advanced stage and poor prognosis. Developing new diagnostic and prognostic markers for pancreatic cancer can significantly improve early detection and patient outcomes. These biomarkers can potentially revolutionize medical practice by enabling personalized, more effective, targeted treatments, ultimately improving patient outcomes. METHODS The search strategy was developed following PRISMA guidelines. A comprehensive search was performed across four electronic databases: PubMed, Scopus, EMBASE, and Web of Science, covering all English publications up to September 2022. The Newcastle-Ottawa Scale (NOS) was utilized to assess bias, categorizing studies as "good," "fair," or "poor" quality based on their NOS scores. Descriptive statistics for all included studies were compiled and reviewed, along with the NOS scores for each study to indicate their quality assessment. RESULTS Our results showed that SVM and RF are the most widely used algorithms in machine learning and data analysis, particularly for biomarker identification. SVM, a supervised learning algorithm, is employed for both classification and regression by mapping data points in high-dimensional space to identify the optimal separating hyperplane between classes. CONCLUSIONS The application of machine-learning algorithms in the search for novel biomarkers in pancreatic cancer represents a significant advancement in the field. By harnessing the power of artificial intelligence, researchers are poised to make strides towards earlier detection and more effective treatment, ultimately improving patient outcomes in this challenging disease.
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Affiliation(s)
- Arian Karimi Rouzbahani
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran; USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Ghazaleh Khalili-Tanha
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yasamin Rajabloo
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Hassan Shokri Garjan
- Department of Health Information Technology, School of Management University of Medical Sciences, Tabriz, Iran
| | - Elham Nazari
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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4
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Khan IA, Saraya A. Circulating MicroRNAs as Noninvasive Diagnostic and Prognostic Biomarkers in Pancreatic Cancer: A Review. J Gastrointest Cancer 2023; 54:720-730. [PMID: 36322366 DOI: 10.1007/s12029-022-00877-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2022] [Indexed: 11/05/2022]
Abstract
Pancreatic cancer (PC) is one of the most lethal human cancers. Currently, most PC cases are diagnosed at an already advanced stage. Early detection of PC is critical to improving survival rates. Therefore, there is an urgent need to identify biomarkers for the early detection of PC. Recently, circulating miRNAs in whole blood and other body fluids have been reported as promising biomarkers for the early detection of various cancers, including PC. Furthermore, due to minimal invasiveness and technical availability, circulating miRNAs hold promise for further wide usage. As a potential novel molecular marker, circulating miRNAs not only represent promising noninvasive diagnostic and prognostic tools but could also improve the evaluation of tumor classification, metastasis, and curative effect. The purpose of this review is to outline the available information regarding circulating miRNAs as biomarkers for the early detection of PC.
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Affiliation(s)
- Imteyaz Ahmad Khan
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
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Ramaekers M, Viviers CGA, Janssen BV, Hellström TAE, Ewals L, van der Wulp K, Nederend J, Jacobs I, Pluyter JR, Mavroeidis D, van der Sommen F, Besselink MG, Luyer MDP. Computer-Aided Detection for Pancreatic Cancer Diagnosis: Radiological Challenges and Future Directions. J Clin Med 2023; 12:4209. [PMID: 37445243 DOI: 10.3390/jcm12134209] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 06/08/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
Radiological imaging plays a crucial role in the detection and treatment of pancreatic ductal adenocarcinoma (PDAC). However, there are several challenges associated with the use of these techniques in daily clinical practice. Determination of the presence or absence of cancer using radiological imaging is difficult and requires specific expertise, especially after neoadjuvant therapy. Early detection and characterization of tumors would potentially increase the number of patients who are eligible for curative treatment. Over the last decades, artificial intelligence (AI)-based computer-aided detection (CAD) has rapidly evolved as a means for improving the radiological detection of cancer and the assessment of the extent of disease. Although the results of AI applications seem promising, widespread adoption in clinical practice has not taken place. This narrative review provides an overview of current radiological CAD systems in pancreatic cancer, highlights challenges that are pertinent to clinical practice, and discusses potential solutions for these challenges.
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Affiliation(s)
- Mark Ramaekers
- Department of Surgery, Catharina Cancer Institute, Catharina Hospital Eindhoven, 5623 EJ Eindhoven, The Netherlands
| | - Christiaan G A Viviers
- Department of Electrical Engineering, Eindhoven University of Technology, 5612 AZ Eindhoven, The Netherlands
| | - Boris V Janssen
- Department of Surgery, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Terese A E Hellström
- Department of Electrical Engineering, Eindhoven University of Technology, 5612 AZ Eindhoven, The Netherlands
| | - Lotte Ewals
- Department of Radiology, Catharina Cancer Institute, Catharina Hospital Eindhoven, 5623 EJ Eindhoven, The Netherlands
| | - Kasper van der Wulp
- Department of Radiology, Catharina Cancer Institute, Catharina Hospital Eindhoven, 5623 EJ Eindhoven, The Netherlands
| | - Joost Nederend
- Department of Radiology, Catharina Cancer Institute, Catharina Hospital Eindhoven, 5623 EJ Eindhoven, The Netherlands
| | - Igor Jacobs
- Department of Hospital Services and Informatics, Philips Research, 5656 AE Eindhoven, The Netherlands
| | - Jon R Pluyter
- Department of Experience Design, Philips Design, 5656 AE Eindhoven, The Netherlands
| | - Dimitrios Mavroeidis
- Department of Data Science, Philips Research, 5656 AE Eindhoven, The Netherlands
| | - Fons van der Sommen
- Department of Electrical Engineering, Eindhoven University of Technology, 5612 AZ Eindhoven, The Netherlands
| | - Marc G Besselink
- Department of Surgery, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Misha D P Luyer
- Department of Surgery, Catharina Cancer Institute, Catharina Hospital Eindhoven, 5623 EJ Eindhoven, The Netherlands
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Saghazadeh A, Rezaei N. MicroRNA expression profiles of peripheral blood and mononuclear cells in myasthenia gravis: A systematic review. Int Immunopharmacol 2022; 112:109205. [PMID: 36087508 DOI: 10.1016/j.intimp.2022.109205] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/21/2022] [Accepted: 08/26/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND Studies have described the role of microRNAs (miRNAs) in thymic function, along with directly observing the altered expression of miRNAs in thymuses of myasthenia gravis (MG) patients; so, miRNAs became a core component in the pathophysiology of MG. However, because the miRNA analysis results are contradictory, the identification of MG-related miRNAs is daunting. OBJECTIVE We did a systematic review of studies analyzing the miRNA expression profile of peripheral blood and mononuclear cells for patients with MG. METHODS We ran a database search in PubMed, Scopus, and Web of Science on August 17, 2021. Original articles that analyzed miRNA profiles in peripheral blood (serum, plasma, and whole blood) and peripheral blood mononuclear cells (PBMCs) for patients with MG in comparison with a non-MG or healthy control (HC) group were eligible. The quality of studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). RESULTS 26 studies were included. The quality of studies was fair (median score, 5). Among 226 different miRNAs that were deregulated in at least one study (range, 1-87), ten miRNAs were significantly deregulated in three or more studies. Five miRNAs (50%) showed the same deregulation: miR-106b-3p and miR-21-5p were consistently upregulated, and miR-20b, miR-15b, and miR-16 were consistently downregulated. Also, there were five miRNAs that were mostly upregulated, miR-150-5p, miR-146a, miR-30e-5p, and miR-338-3p, or downregulated, miR-324-3p, across studies. CONCLUSION These miRNAs contribute to different pathways, importantly neural apoptosis and autophagy, inflammation, T regulatory cell development, and T helper cell balance. Prior to being used for diagnostic and therapeutic purposes, it is required to pursue molecular mechanisms these consistently and mostly dysregulated miRNAs specifically use in the context of MG.
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Affiliation(s)
- Amene Saghazadeh
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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Ohtsubo K, Miyake K, Arai S, Fukuda K, Suzuki C, Kotani H, Tanimoto A, Nishiyama A, Nanjo S, Yamashita K, Takeuchi S, Yano S. Methylation of Tumor Suppressive miRNAs in Plasma from Patients With Pancreaticobiliary Diseases. CANCER DIAGNOSIS & PROGNOSIS 2022; 2:378-383. [PMID: 35530650 PMCID: PMC9066530 DOI: 10.21873/cdp.10120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/04/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND/AIM We previously reported the usefulness of aberrant methylation of tumor suppressive miRNAs in bile to discriminate pancreaticobiliary cancers (PBCs) from benign pancreaticobiliary diseases (BD). Here we performed a methylation analysis of plasma miRNAs to identify miRNAs specific for PBCs. PATIENTS AND METHODS Plasma was collected from 80 patients with pancreatic cancer (PC); 18 with biliary tract cancer (BTC) and 28 with BD. Sequences encoding 3 tumor suppressive miRNAs (miR-200a, -200b, and -1247) were PCR amplified and sequenced, and their methylation rates were determined. RESULTS The methylation rate of miR-1247 was significantly higher in patients with BTC than in those with BD, and tended to be higher in patients with PC than in those with BD. Furthermore, it was significantly higher in three patients with stages I/II BTC than in those with BD. CONCLUSION Methylation of miR-1247 in plasma may be useful to distinguish BTC from BD.
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Affiliation(s)
- Koushiro Ohtsubo
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Kunio Miyake
- Department of Health Sciences, School of Medicine, University of Yamanashi, Chuo, Japan
| | - Sachiko Arai
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Koji Fukuda
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Chiaki Suzuki
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Hiroshi Kotani
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Azusa Tanimoto
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Akihiro Nishiyama
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Shigeki Nanjo
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Kaname Yamashita
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Shinji Takeuchi
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Seiji Yano
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
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Lin KW, Ang TL, Li JW. Role of artificial intelligence in early detection and screening for pancreatic adenocarcinoma. Artif Intell Med Imaging 2022; 3:21-32. [DOI: 10.35711/aimi.v3.i2.21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/12/2022] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic adenocarcinoma remains to be one of the deadliest malignancies in the world despite treatment advancement over the past few decades. Its low survival rates and poor prognosis can be attributed to ambiguity in recommendations for screening and late symptom onset, contributing to its late presentation. In the recent years, artificial intelligence (AI) as emerged as a field to aid in the process of clinical decision making. Considerable efforts have been made in the realm of AI to screen for and predict future development of pancreatic ductal adenocarcinoma. This review discusses the use of AI in early detection and screening for pancreatic adenocarcinoma, and factors which may limit its use in a clinical setting.
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Affiliation(s)
- Kenneth Weicong Lin
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
| | - Tiing Leong Ang
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
| | - James Weiquan Li
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
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Elkady G, Chen Y, Hu C, Chen J, Chen X, Guo A. MicroRNA Profile of MA-104 Cell Line Associated With the Pathogenesis of Bovine Rotavirus Strain Circulated in Chinese Calves. Front Microbiol 2022; 13:854348. [PMID: 35516441 PMCID: PMC9062783 DOI: 10.3389/fmicb.2022.854348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/28/2022] [Indexed: 11/13/2022] Open
Abstract
Bovine rotavirus (BRV) causes massive economic losses in the livestock industry worldwide. Elucidating the pathogenesis of BRV would help in the development of more effective measures to control BRV infection. The MA-104 cell line is sensitive to BRV and is thereby a convenient tool for determining BRV–host interactions. Thus far, the role of the microRNAs (miRNAs) of MA-104 cells during BRV infection is still ambiguous. We performed Illumina RNA sequencing analysis of the miRNA libraries of BRV-infected and mock-infected MA-104 cells at different time points: at 0 h post-infection (hpi) (just after 90 min of adsorption) and at 6, 12, 24, 36, and 48 hpi. The total clean reads obtained from BRV-infected and uninfected cells were 74,701,041 and 74,184,124, respectively. Based on these, 579 were categorized as known miRNAs and 144 as novel miRNAs. One hundred and sixty differentially expressed (DE) miRNAs in BRV-infected cells in comparison with uninfected MA-104 cells were successfully investigated, 95 of which were upregulated and 65 were downregulated. The target messenger RNAs (mRNAs) of the DE miRNAs were examined by bioinformatics analysis. Functional annotation of the target genes with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) suggested that these genes mainly contributed to biological pathways, endocytosis, apoptotic process, trans-Golgi membrane, and lysosome. Pathways such as the mammalian target of rapamycin (mTOR) (mml-miR-486-3p and mml-miR-197-3p), nuclear factor kappa B (NF-κB) (mml-miR-204-3p and novel_366), Rap1 (mml-miR-127-3p), cAMP (mml-miR-106b-3p), mitogen-activated protein kinase (MAPK) (mml-miR-342-5p), T-cell receptor signaling (mml-miR-369-5p), RIG-I-like receptor signaling (mml-miR-504-5p), AMP-activated protein kinase (AMPK) (mml-miR-365-1-5p), and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling (mml-miR-299-3p) were enriched. Moreover, real-time quantitative PCR (qPCR) verified the expression profiles of 23 selected DE miRNAs, which were consistent with the results of deep sequencing, and the 28 corresponding target mRNAs were mainly of regulatory pathways of the cellular machinery and immune importance, according to the bioinformatics analysis. Our study is the first to report a novel approach that uncovers the impact of BRV infection on the miRNA expressions of MA-104 cells, and it offers clues for identifying potential candidates for antiviral or vaccine strategies.
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Affiliation(s)
- Gehad Elkady
- The State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Cooperative Innovation Centre of Substantial Pig Production, Huazhong Agricultural University, Wuhan, China
- Benha University, Benha, Egypt
| | - Yingyu Chen
- The State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Cooperative Innovation Centre of Substantial Pig Production, Huazhong Agricultural University, Wuhan, China
- Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, Huazhong Agricultural University, Wuhan, China
| | - Changmin Hu
- The State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Cooperative Innovation Centre of Substantial Pig Production, Huazhong Agricultural University, Wuhan, China
| | - Jianguo Chen
- The State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Cooperative Innovation Centre of Substantial Pig Production, Huazhong Agricultural University, Wuhan, China
| | - Xi Chen
- The State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Cooperative Innovation Centre of Substantial Pig Production, Huazhong Agricultural University, Wuhan, China
| | - Aizhen Guo
- The State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- College of Veterinary Medicine, Cooperative Innovation Centre of Substantial Pig Production, Huazhong Agricultural University, Wuhan, China
- Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, China
- Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, Huazhong Agricultural University, Wuhan, China
- *Correspondence: Aizhen Guo,
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Perales S, Torres C, Jimenez-Luna C, Prados J, Martinez-Galan J, Sanchez-Manas JM, Caba O. Liquid biopsy approach to pancreatic cancer. World J Gastrointest Oncol 2021; 13:1263-1287. [PMID: 34721766 PMCID: PMC8529923 DOI: 10.4251/wjgo.v13.i10.1263] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/18/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) continues to pose a major clinical challenge. There has been little improvement in patient survival over the past few decades, and it is projected to become the second leading cause of cancer mortality by 2030. The dismal 5-year survival rate of less than 10% after the diagnosis is attributable to the lack of early symptoms, the absence of specific biomarkers for an early diagnosis, and the inadequacy of available chemotherapies. Most patients are diagnosed when the disease has already metastasized and cannot be treated. Cancer interception is vital, actively intervening in the malignization process before the development of a full-blown advanced tumor. An early diagnosis of PC has a dramatic impact on the survival of patients, and improved techniques are urgently needed to detect and evaluate this disease at an early stage. It is difficult to obtain tissue biopsies from the pancreas due to its anatomical position; however, liquid biopsies are readily available and can provide useful information for the diagnosis, prognosis, stratification, and follow-up of patients with PC and for the design of individually tailored treatments. The aim of this review was to provide an update of the latest advances in knowledge on the application of carbohydrates, proteins, cell-free nucleic acids, circulating tumor cells, metabolome compounds, exosomes, and platelets in blood as potential biomarkers for PC, focusing on their clinical relevance and potential for improving patient outcomes.
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Affiliation(s)
- Sonia Perales
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Granada 18071, Spain
| | - Carolina Torres
- Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Sciences, University of Granada, Granada 18071, Spain
| | - Cristina Jimenez-Luna
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
| | - Joaquina Martinez-Galan
- Department of Medical Oncology, Hospital Universitario Virgen de las Nieves, Granada 18011, Spain
| | | | - Octavio Caba
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
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A Set of 17 microRNAs Common for Brain and Cerebrospinal Fluid Differentiates Primary Central Nervous System Lymphoma from Non-Malignant Brain Tumors. Biomolecules 2021; 11:biom11091395. [PMID: 34572608 PMCID: PMC8466839 DOI: 10.3390/biom11091395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/07/2021] [Accepted: 09/16/2021] [Indexed: 12/22/2022] Open
Abstract
The diagnosis of primary central nervous system (CNS) lymphoma, which is predominantly of the diffuse large B-cell lymphoma type (CNS DLBCL), is challenging. MicroRNAs (miRs) are gene expression-regulating non-coding RNAs that are potential biomarkers. We aimed to distinguish miR expression patterns differentiating CNS DLBCL and non-malignant CNS diseases with tumor presentation (n-ML). Next generation sequencing-based miR profiling of cerebrospinal fluids (CSFs) and brain tumors was performed. Sample source-specific (CSF vs. brain tumor) miR patterns were revealed. Even so, a set of 17 miRs differentiating CNS DLBCL from n-ML, no matter if assessed in CSF or in a tumor, was identified. Along with the results of pathway analyses, this suggests their pathogenic role in CNS DLBCL. A combination of just four of those miRs (miR-16-5p, miR-21-5p, miR-92a-3p, and miR-423-5p), assessed in CSFs, discriminated CNS DLBCL from n-ML samples with 100% specificity and 67.0% sensitivity. Analyses of paired CSF-tumor samples from patients with CNS DLBCL showed significantly lower CSF levels of miR-26a, and higher CSF levels of miR-15a-5p, miR-15b-5p, miR-19a-3p, miR-106b-3p, miR-221-3p, and miR-423-5p. Noteworthy, the same miRs belonged to the abovementioned set differentiating CNS DLBCL from non-malignant CNS diseases. Our results not only add to the basic knowledge, but also hold significant translational potential.
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12
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Laoveeravat P, Abhyankar PR, Brenner AR, Gabr MM, Habr FG, Atsawarungruangkit A. Artificial intelligence for pancreatic cancer detection: Recent development and future direction. Artif Intell Gastroenterol 2021; 2:56-68. [DOI: 10.35712/aig.v2.i2.56] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/31/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Artificial intelligence (AI) has been increasingly utilized in medical applications, especially in the field of gastroenterology. AI can assist gastroenterologists in imaging-based testing and prediction of clinical diagnosis, for examples, detecting polyps during colonoscopy, identifying small bowel lesions using capsule endoscopy images, and predicting liver diseases based on clinical parameters. With its high mortality rate, pancreatic cancer can highly benefit from AI since the early detection of small lesion is difficult with conventional imaging techniques and current biomarkers. Endoscopic ultrasound (EUS) is a main diagnostic tool with high sensitivity for pancreatic adenocarcinoma and pancreatic cystic lesion. The standard tumor markers have not been effective for diagnosis. There have been recent research studies in AI application in EUS and novel biomarkers to early detect and differentiate malignant pancreatic lesions. The findings are impressive compared to the available traditional methods. Herein, we aim to explore the utility of AI in EUS and novel serum and cyst fluid biomarkers for pancreatic cancer detection.
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Affiliation(s)
- Passisd Laoveeravat
- Division of Digestive Diseases and Nutrition, University of Kentucky College of Medicine, Lexington, KY 40536, United States
| | - Priya R Abhyankar
- Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY 40536, United States
| | - Aaron R Brenner
- Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY 40536, United States
| | - Moamen M Gabr
- Division of Digestive Diseases and Nutrition, University of Kentucky College of Medicine, Lexington, KY 40536, United States
| | - Fadlallah G Habr
- Division of Gastroenterology, Warren Alpert Medical School of Brown University, Providence, RI 02903, United States
| | - Amporn Atsawarungruangkit
- Division of Gastroenterology, Warren Alpert Medical School of Brown University, Providence, RI 02903, United States
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13
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MiR-4269 suppresses the tumorigenesis and development of pancreatic cancer by targeting ZEB1/OTX1 pathway. Biosci Rep 2021; 40:225115. [PMID: 32484209 PMCID: PMC7286876 DOI: 10.1042/bsr20200010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 05/20/2020] [Accepted: 06/01/2020] [Indexed: 11/25/2022] Open
Abstract
As one of the most prevalent malignant tumors, pancreatic cancer (PC) is a leading fatal cancer worldwide. Surging evidence has unraveled that miRNAs are involved in the occurrence and progression of multiple cancers, including PC. The tumor suppressor effects of miR-4269 have been certified in gastric carcinoma. However, the potential function of miR-4269 remains largely unclear, which drives us to identify the role of miR-4269 in PC development. In the present study, we determined the expression pattern of miR-4269 in PC cells and normal cells. Results of RT-qPCR analysis illuminated that miR-4269 expression level in PC cells was lower than that in normal cells. Functional assays demonstrated that up-regulation of miR-4269 obviously inhibited the proliferation, migration and invasion of PC cells. In order to elucidate the mechanism governing miR-4269 in PC, we carried out bioinformatics analysis and further experimental investigations. Our results validated that ZEB1 was a direct target of miR-4269. Additionally, ZEB1 activated the transcription of OXT1. More importantly, miR-4269 attenuated the expression level of OXT1 via targeting ZEB1. Ultimately, our findings confirmed that miR-4269 served as a cancer suppressor in PC through regulation of ZEB1/OTX1 pathway, which suggested that miR-4269 might represent a promising target for the clinical treatment of PC.
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Calanzani N, Druce PE, Snudden C, Milley KM, Boscott R, Behiyat D, Saji S, Martinez-Gutierrez J, Oberoi J, Funston G, Messenger M, Emery J, Walter FM. Identifying Novel Biomarkers Ready for Evaluation in Low-Prevalence Populations for the Early Detection of Upper Gastrointestinal Cancers: A Systematic Review. Adv Ther 2021; 38:793-834. [PMID: 33306189 PMCID: PMC7889689 DOI: 10.1007/s12325-020-01571-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 11/11/2020] [Indexed: 02/07/2023]
Abstract
Introduction Detecting upper gastrointestinal (GI) cancers in primary care is challenging, as cancer symptoms are common, often non-specific, and most patients presenting with these symptoms will not have cancer. Substantial investment has been made to develop biomarkers for cancer detection, but few have reached routine clinical practice. We aimed to identify novel biomarkers for upper GI cancers which have been sufficiently validated to be ready for evaluation in low-prevalence populations. Methods We systematically searched MEDLINE, Embase, Emcare, and Web of Science for studies published in English from January 2000 to October 2019 (PROSPERO registration CRD42020165005). Reference lists of included studies were assessed. Studies had to report on second measures of diagnostic performance (beyond discovery phase) for biomarkers (single or in panels) used to detect pancreatic, oesophageal, gastric, and biliary tract cancers. We included all designs and excluded studies with less than 50 cases/controls. Data were extracted on types of biomarkers, populations and outcomes. Heterogeneity prevented pooling of outcomes. Results We identified 149 eligible studies, involving 22,264 cancer cases and 49,474 controls. A total of 431 biomarkers were identified (183 microRNAs and other RNAs, 79 autoantibodies and other immunological markers, 119 other proteins, 36 metabolic markers, 6 circulating tumour DNA and 8 other). Over half (n = 231) were reported in pancreatic cancer studies. Only 35 biomarkers had been investigated in at least two studies, with reported outcomes for that individual marker for the same tumour type. Apolipoproteins (apoAII-AT and apoAII-ATQ), and pepsinogens (PGI and PGII) were the most promising biomarkers for pancreatic and gastric cancer, respectively. Conclusion Most novel biomarkers for the early detection of upper GI cancers are still at an early stage of matureness. Further evidence is needed on biomarker performance in low-prevalence populations, in addition to implementation and health economic studies, before extensive adoption into clinical practice can be recommended. Electronic Supplementary Material The online version of this article (10.1007/s12325-020-01571-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Natalia Calanzani
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
| | - Paige E Druce
- Centre for Cancer Research and Department of General Practice, University of Melbourne, Victoria, Australia
| | - Claudia Snudden
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Kristi M Milley
- Centre for Cancer Research and Department of General Practice, University of Melbourne, Victoria, Australia
| | - Rachel Boscott
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Dawnya Behiyat
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Smiji Saji
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Javiera Martinez-Gutierrez
- Centre for Cancer Research and Department of General Practice, University of Melbourne, Victoria, Australia
- Department of Family Medicine, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Jasmeen Oberoi
- Centre for Cancer Research and Department of General Practice, University of Melbourne, Victoria, Australia
| | - Garth Funston
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Mike Messenger
- Leeds Centre for Personalised Medicine and Health, University of Leeds, Leeds, UK
| | - Jon Emery
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Centre for Cancer Research and Department of General Practice, University of Melbourne, Victoria, Australia
| | - Fiona M Walter
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Centre for Cancer Research and Department of General Practice, University of Melbourne, Victoria, Australia
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15
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Peng C, Wang J, Gao W, Huang L, Liu Y, Li X, Li Z, Yu X. Meta-analysis of the Diagnostic Performance of Circulating MicroRNAs for Pancreatic Cancer. Int J Med Sci 2021; 18:660-671. [PMID: 33437201 PMCID: PMC7797557 DOI: 10.7150/ijms.52706] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/23/2020] [Indexed: 12/24/2022] Open
Abstract
Background: Numerous studies have suggested that differentially expressed miRNAs may be promising diagnostic markers for pancreatic cancer (PC), but the results are inconsistent. We aimed to summarize the diagnostic accuracy of circulating miRNAs, carbohydrate antigen 19-9 (CA19-9), and the combination of miRNAs and CA19-9. Material and Methods: A literature search of online databases including PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI) and WanFang was conducted. Relative data were extracted from eligible included studies, and a meta-analysis was performed. Results: A total of 46 studies involving 4,326 PC patients and 4,277 non-PC controls were included. The pooled sensitivity (SEN), specificity (SPE) and AUC of the circulating miRNAs for differentiating PC patients from non-PC controls were 0.79 (0.77-0.81), 0.77 (0.75-0.79), and 0.85 (0.81-0.87), respectively. The combination of miRNAs and CA19-9 greatly improved the SEN, SPE and AUC to 0.84 (0.80-0.87), 0.91 (0.89-0.93) and 0.94 (0.92-0.96), respectively. Moreover, circulating miRNAs also yielded an acceptable diagnostic accuracy for early-stage PC with a SEN of 0.79 (0.76-0.82), a SPE of 0.74 (0.68-0.79) and an AUC of 0.81 (0.77-0.84). Conclusion: Circulating miRNAs exhibited satisfactory diagnostic performance for PC and even early-stage PC. The combination of circulating miRNAs and CA19-9 can further improve the diagnostic accuracy, providing a novel strategy for PC diagnosis.
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Affiliation(s)
- Cheng Peng
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Jiale Wang
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Wenzhe Gao
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Lihua Huang
- Center for Medical Experiments, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Yunfei Liu
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Xia Li
- Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Zhiqiang Li
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Xiao Yu
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
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16
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Exosome-Mediated Differentiation of Mouse Embryonic Fibroblasts and Exocrine Cells into β-Like Cells and the Identification of Key miRNAs for Differentiation. Biomedicines 2020; 8:biomedicines8110485. [PMID: 33182285 PMCID: PMC7695333 DOI: 10.3390/biomedicines8110485] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/03/2020] [Accepted: 11/04/2020] [Indexed: 01/08/2023] Open
Abstract
Diabetes is a concerning health malady worldwide. Islet or pancreas transplantation is the only long-term treatment available; however, the scarcity of transplantable tissues hampers this approach. Therefore, new cell sources and differentiation approaches are required. Apart from the genetic- and small molecule-based approaches, exosomes could induce cellular differentiation by means of their cargo, including miRNA. We developed a chemical-based protocol to differentiate mouse embryonic fibroblasts (MEFs) into β-like cells and employed mouse insulinoma (MIN6)-derived exosomes in the presence or absence of specific small molecules to encourage their differentiation into β-like cells. The differentiated β-like cells were functional and expressed pancreatic genes such as Pdx1, Nkx6.1, and insulin 1 and 2. We found that the exosome plus small molecule combination differentiated the MEFs most efficiently. Using miRNA-sequencing, we identified miR-127 and miR-709, and found that individually and in combination, the miRNAs differentiated MEFs into β-like cells similar to the exosome treatment. We also confirmed that exocrine cells can be differentiated into β-like cells by exosomes and the exosome-identified miRNAs. A new differentiation approach based on the use of exosome-identified miRNAs could help people afflicted with diabetes
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17
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Identification and Validation of Circulating Micrornas as Prognostic Biomarkers in Pancreatic Ductal Adenocarcinoma Patients Undergoing Surgical Resection. J Clin Med 2020; 9:jcm9082440. [PMID: 32751582 PMCID: PMC7464450 DOI: 10.3390/jcm9082440] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 07/25/2020] [Accepted: 07/27/2020] [Indexed: 12/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and aggressive cancers with a less than 6% five-year survival rate. Circulating microRNAs (miRNAs) are emerging as a useful tool for non-invasive diagnosis and prognosis estimation in the various cancer types, including PDAC. Our study aimed to evaluate whether miRNAs in the pre-operative blood plasma specimen have the potential to predict the prognosis of PDAC patients. In total, 112 PDAC patients planned for surgical resection were enrolled in our prospective study. To identify prognostic miRNAs, we used small RNA sequencing in 24 plasma samples of PDAC patients with poor prognosis (overall survival (OS) < 16 months) and 24 plasma samples of PDAC patients with a good prognosis (OS > 20 months). qPCR validation of selected miRNA candidates was performed in the independent cohort of PDAC patients (n = 64). In the discovery phase of the study, we identified 44 miRNAs with significantly different levels in the plasma samples of the group of good and poor prognosis patients. Among these miRNAs, 23 showed lower levels, and 21 showed higher levels in plasma specimens from PDAC patients with poor prognosis. Eleven miRNAs were selected for the validation, but only miR-99a-5p and miR-365a-3p were confirmed to have significantly lower levels and miR-200c-3p higher levels in plasma samples of poor prognosis cases. Using the combination of these 3-miRNA levels, we were able to identify the patients with poor prognosis with sensitivity 85% and specificity 80% (Area Under the Curve = 0.890). Overall, 3-miRNA prognostic score associated with OS was identified in the pre-operative blood plasma samples of PDAC patients undergoing surgical resection. Following further independent validations, the detection of these miRNA may enable identification of PDAC patients who have no survival benefit from the surgical treatment, which is associated with the high morbidity rates.
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18
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Colorectal cancer-derived exosomal miR-106b-3p promotes metastasis by down-regulating DLC-1 expression. Clin Sci (Lond) 2020; 134:419-434. [PMID: 32065214 DOI: 10.1042/cs20191087] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 02/04/2020] [Accepted: 02/17/2020] [Indexed: 12/12/2022]
Abstract
Cancer-derived exosomal miRNAs play an important role in the development of metastasis, but the effects and underlying mechanisms remain unclear. In the present study, we investigated the miRNA expression profiles of 5 paired serum exosomal samples from metastatic colorectal cancer (mCRC) and non-mCRC patients via RNA sequencing. After we evaluated the differentially expressed miRNAs in 80 CRC patients, miR-106b-3p was selected as a metastasis-associated miRNA of CRC. We showed that the expression level of serum exosomal miR-106b-3p was significantly higher in CRC patients with metastasis than those without metastasis. Additionally, high serum exosomal miR-106b-3p expression in patients was correlated with a poor prognosis. Coculture of low-metastatic CRC cells with high-metastatic CRC cell-derived exosomes promoted cell migration, invasion, and epithelial-to-mesenchymal transition (EMT), which was caused by the transport and transduction of miR-106b-3p in vitro. Moreover, exosomal miR-106b-3p promoted lung metastasis of CRC cells in vivo. In addition, we demonstrated that miR-106b-3p regulated metastasis by targeting deleted in liver cancer-1 (DLC-1). A negative correlation was also identified between miR-106b-3p and DLC-1 expression in human CRC tumour tissues and in mouse lung metastatic lesions. Collectively, our study indicated that metastasis-associated miR-106b-3p from serum exosomes could be used as a potential prognostic biomarker and therapeutic target for CRC patients.
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19
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Gablo NA, Prochazka V, Kala Z, Slaby O, Kiss I. Cell-free microRNAs as Non-invasive Diagnostic and Prognostic Bio- markers in Pancreatic Cancer. Curr Genomics 2020; 20:569-580. [PMID: 32581645 PMCID: PMC7290054 DOI: 10.2174/1389202921666191217095017] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 12/01/2019] [Accepted: 12/01/2019] [Indexed: 12/22/2022] Open
Abstract
Pancreatic cancer (PaC) is one of the most lethal cancers, with an increasing global incidence rate. Unfavorable prognosis largely results from associated difficulties in early diagnosis and the absence of prognostic and predictive biomarkers that would enable an individualized therapeutic approach. In fact, PaC prognosis has not improved for years, even though much efforts and resources have been devoted to PaC research, and the multimodal management of PaC patients has been used in clinical practice. It is thus imperative to develop optimal biomarkers, which would increase diagnostic precision and improve the post-diagnostic management of PaC patients. Current trends in biomarker research envisage the unique opportunity of cell-free microRNAs (miRNAs) present in circulation to become a convenient, non-invasive tool for accurate diagnosis, prognosis and prediction of response to treatment. This review analyzes studies focused on cell-free miRNAs in PaC. The studies provide solid evidence that miRNAs are detectable in serum, blood plasma, saliva, urine, and stool, and that they present easy-to-acquire biomarkers with strong diagnostic, prognostic and predictive potential.
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Affiliation(s)
- Natalia A Gablo
- 1Central European Institute of Technology, Masaryk University, Brno, Czech Republic; 2Department of Surgery, Institutions shared with the Faculty Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 3Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Vladimir Prochazka
- 1Central European Institute of Technology, Masaryk University, Brno, Czech Republic; 2Department of Surgery, Institutions shared with the Faculty Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 3Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Zdenek Kala
- 1Central European Institute of Technology, Masaryk University, Brno, Czech Republic; 2Department of Surgery, Institutions shared with the Faculty Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 3Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Ondrej Slaby
- 1Central European Institute of Technology, Masaryk University, Brno, Czech Republic; 2Department of Surgery, Institutions shared with the Faculty Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 3Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Igor Kiss
- 1Central European Institute of Technology, Masaryk University, Brno, Czech Republic; 2Department of Surgery, Institutions shared with the Faculty Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 3Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic
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20
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Wong CH, Lou UK, Li Y, Chan SL, Tong JH, To KF, Chen Y. CircFOXK2 Promotes Growth and Metastasis of Pancreatic Ductal Adenocarcinoma by Complexing with RNA-Binding Proteins and Sponging MiR-942. Cancer Res 2020; 80:2138-2149. [PMID: 32217695 DOI: 10.1158/0008-5472.can-19-3268] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 02/04/2020] [Accepted: 03/18/2020] [Indexed: 11/16/2022]
Abstract
The detailed biological functions of circular RNA (circRNA) are largely unexplored. Using circRNA sequencing, we identified 169 differentially expressed circRNA in pancreatic ductal adenocarcinoma (PDAC) cells compared with nontumor human pancreatic ductal epithelial cells. Among them, circFOXK2 was validated with significant upregulation in PDAC cells and 63% of primary tumors (53 of 84). circFOXK2 promoted cell growth, migration, and invasion and was involved in cell-cycle progression and apoptosis. circFOXK2 contained multiple miRNA binding sites, functioning as a sponge for miR-942, which in turn promoted expression of ANK1, GDNF, and PAX6. A novel and highly specific circRNA-pulldown followed by mass spectrometry analysis identified 94 circFOXK2-interacting proteins, which were involved in cell adhesion, mRNA splicing, and structural molecule activity. Of these, circFOKX2 interactions with YBX1 and hnRNPK enhanced expression of oncogenes NUF2 and PDXK. Knockdown of circFOXK2 reduced binding of YBX1 and hnRNPK to NUF2 and PDXK, in turn decreasing their expression. Collectively, our findings demonstrate that circFOXK2 in complex with YBX1 and hnRNPK promotes expression of oncogenic proteins that contribute to PDAC progression. SIGNIFICANCE: This study reveals a prominent role for the circRNA circFOXK2 in PDAC progression, suggesting that circFOXK2 might be a novel diagnostic marker for PDAC.
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Affiliation(s)
- Chi Hin Wong
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong
| | - Ut Kei Lou
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong
| | - Youjia Li
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong
| | - Stephen L Chan
- Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Joanna Hm Tong
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Ka-Fai To
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Yangchao Chen
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
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21
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Xue X, Wang C, Xue Z, Wen J, Han J, Ma X, Zang X, Deng H, Guo R, Asuquo IP, Qin C, Wang H, Gao Q, Liu S, Wang J. Exosomal miRNA profiling before and after surgery revealed potential diagnostic and prognostic markers for lung adenocarcinoma. Acta Biochim Biophys Sin (Shanghai) 2020; 52:281-293. [PMID: 32073597 DOI: 10.1093/abbs/gmz164] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 11/27/2019] [Accepted: 11/28/2019] [Indexed: 12/24/2022] Open
Abstract
Exosome is a crucial manner for cancer cell to cell communication and circulating exosomes sever as promising diagnostic and prognostic markers for various types of diseases. A predominant type of cargo of exosome is small RNAs, especially miRNAs. Here, we profiled plasma exosomal miRNAs of six lung adenocarcinoma patients before and after surgery, as well as six healthy individuals as normal control. Our profiling revealed 38 upregulated and 37 downregulated exosomal miRNAs in the plasma of lung adenocarcinoma patients. Additionally, we found that most upregulated miRNAs were increased in the lung adenocarcinoma samples of TCGA database. We further evaluated the correlation between the upregulated exosomal miRNAs and overall survival with Kaplan-Meier survival analysis using online databases. Our results suggested that exosomal miR-151a-5p, miR-10b-5p, miR-192-5p, miR-106b-3p, and miR-484 are potential prognostic markers for lung adenocarcinoma. Importantly, we validated candidate miRNAs in lung adenocarcinoma patients before and after surgery as well as in healthy controls and found that miR-484 was significantly increased in the plasma of lung adenocarcinoma patients and strikingly decreased post-surgery. Hence, we provided novel information on lung adenocarcinoma-derived exosomal miRNA and potential non-invasive diagnostic and prognostic markers for lung adenocarcinoma.
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Affiliation(s)
- Xinying Xue
- Department of Respiratory and Critical Care, Chinese PLA General Hospital, Beijing 100853, China
- Department of Respiratory and Critical Care, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Chen Wang
- Shanghai Institute of Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
| | - Zhiqiang Xue
- Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Jiaxin Wen
- Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Jun Han
- Department of Radiology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Xidong Ma
- School of Clinical Medicine, Weifang Medical University, Shandong 261042, China
| | - Xuelei Zang
- Microbiology Department, Chinese PLA General Hospital, Beijing 100853, China
| | - Hui Deng
- Department of Respiratory and Critical Care, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Rui Guo
- Department of Respiratory and Critical Care, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | | | - Chong Qin
- Department of Respiratory and Critical Care, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Haijiao Wang
- Department of Respiratory and Critical Care, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Quansheng Gao
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China
| | - Sanhong Liu
- Shanghai Institute of Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
| | - Jianxin Wang
- Department of Respiratory and Critical Care, Chinese PLA General Hospital, Beijing 100853, China
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22
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Vietsch EE, Peran I, Suker M, van den Bosch TPP, van der Sijde F, Kros JM, van Eijck CHJ, Wellstein A. Immune-Related Circulating miR-125b-5p and miR-99a-5p Reveal a High Recurrence Risk Group of Pancreatic Cancer Patients after Tumor Resection. APPLIED SCIENCES (BASEL, SWITZERLAND) 2019; 9:4784. [PMID: 34484811 PMCID: PMC8415800 DOI: 10.3390/app9224784] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Clinical follow-up aided by changes in the expression of circulating microRNAs (miRs) may improve prognostication of pancreatic ductal adenocarcinoma (PDAC) patients. Changes in 179 circulating miRs due to cancer progression in the transgenic Kras G12D/+; Trp53 R172H/+; P48-Cre (KPC) animal model of PDAC were analyzed for serum miRs that are altered in metastatic disease. In addition, expression levels of 250 miRs were profiled before and after pancreaticoduodenectomy in the serum of two patients with resectable PDAC with different progression free survival (PFS) and analyzed for changes indicative of PDAC recurrence after resection. Three miRs that were upregulated ≥3-fold in progressive PDAC in both mice and patients were selected for validation in 26 additional PDAC patients before and after resection. We found that high serum miR-125b-5p and miR-99a-5p levels after resection are significantly associated with shorter PFS (HR 1.34 and HR 1.73 respectively). In situ hybridization for miR detection in the paired resected human PDAC tissues showed that miR-125b-5p and miR-99a-5p are highly expressed in inflammatory cells in the tumor stroma, located in clusters of CD79A expressing cells of the B-lymphocyte lineage. In conclusion, we found that circulating miR-125b-5p and miR-99a-5p are potential immune-cell related prognostic biomarkers in PDAC patients after surgery.
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Affiliation(s)
- Eveline E. Vietsch
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA
- Department of Surgery, Erasmus MC, University Medical Center Rotterdam, 3015GD Rotterdam, The Netherlands
| | - Ivana Peran
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA
| | - Mustafa Suker
- Department of Surgery, Erasmus MC, University Medical Center Rotterdam, 3015GD Rotterdam, The Netherlands
| | | | - Fleur van der Sijde
- Department of Surgery, Erasmus MC, University Medical Center Rotterdam, 3015GD Rotterdam, The Netherlands
| | - Johan M. Kros
- Department of Pathology, Erasmus MC, University Medical Center Rotterdam, 3015GD Rotterdam, The Netherlands
| | - Casper H. J. van Eijck
- Department of Surgery, Erasmus MC, University Medical Center Rotterdam, 3015GD Rotterdam, The Netherlands
| | - Anton Wellstein
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA
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Chen HL, Li JJ, Jiang F, Shi WJ, Chang GY. MicroRNA-4461 derived from bone marrow mesenchymal stem cell exosomes inhibits tumorigenesis by downregulating COPB2 expression in colorectal cancer. Biosci Biotechnol Biochem 2019; 84:338-346. [PMID: 31631786 DOI: 10.1080/09168451.2019.1677452] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Colorectal cancer (CRC) is one of the main cause of cancer-related deaths. It's reported that bone marrow mesenchymal stem cells (BMSCs) affects tumor development through secreting exosomes. This study aims to investigate the function of BMSCs-derived exosome miR-4461 in CRC. The results of qRT-PCR showed that miR-4461 expression in DLD1, HCT116 and SW480 CRC cells and CRC tissues was lower than that in FHC cells and normal tissues, respectively. And COPB2 mRNA expression was negatively correlated with miR-4461. Western blot was used to detect COPB2 protein expression. Dual-luciferase reporter assay results revealed that miR-4461 targeted COPB2. Transwell assay and CCK-8 assay demonstrated that COPB2 knockdown inhibited HCT116 and SW480 cells proliferation, migration and invasion abilities. Furthermore, BMSCs-derived exosome miR-4461 downregulated COPB2 expression and inhibited HCT116 and SW480 cells migration and invasion. The findings demonstrated that miR-4461 could be a potential target for the diagnosis and treatment of colorectal cancer.
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Affiliation(s)
- Hui-Li Chen
- Department of Oncology and Hematology, Aviation General Hospital of China Medical University, Beijing, P.R. China
| | - Jiu-Jiang Li
- Department of general surgery, Aviation General Hospital of China Medical University, Beijing, P.R. China
| | - Fei Jiang
- Department of Oncology and Hematology, Aviation General Hospital of China Medical University, Beijing, P.R. China
| | - Wen-Jing Shi
- Department of Oncology and Hematology, Aviation General Hospital of China Medical University, Beijing, P.R. China
| | - Ge-Yun Chang
- Department of Oncology and Hematology, Aviation General Hospital of China Medical University, Beijing, P.R. China
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Pardini B, Sabo AA, Birolo G, Calin GA. Noncoding RNAs in Extracellular Fluids as Cancer Biomarkers: The New Frontier of Liquid Biopsies. Cancers (Basel) 2019; 11:E1170. [PMID: 31416190 PMCID: PMC6721601 DOI: 10.3390/cancers11081170] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 08/04/2019] [Accepted: 08/10/2019] [Indexed: 02/06/2023] Open
Abstract
The last two decades of cancer research have been devoted in two directions: (1) understanding the mechanism of carcinogenesis for an effective treatment, and (2) improving cancer prevention and screening for early detection of the disease. This last aspect has been developed, especially for certain types of cancers, thanks also to the introduction of new concepts such as liquid biopsies and precision medicine. In this context, there is a growing interest in the application of alternative and noninvasive methodologies to search for cancer biomarkers. The new frontiers of the research lead to a search for RNA molecules circulating in body fluids. Searching for biomarkers in extracellular body fluids represents a better option for patients because they are easier to access, less painful, and potentially more economical. Moreover, the possibility for these types of samples to be taken repeatedly, allows a better monitoring of the disease progression or treatment efficacy for a better intervention and dynamic treatment of the patient, which is the fundamental basis of personalized medicine. RNA molecules, freely circulating in body fluids or packed in microvesicles, have all the characteristics of the ideal biomarkers owing to their high stability under storage and handling conditions and being able to be sampled several times for monitoring. Moreover, as demonstrated for many cancers, their plasma/serum levels mirror those in the primary tumor. There are a large variety of RNA species noncoding for proteins that could be used as cancer biomarkers in liquid biopsies. Among them, the most studied are microRNAs, but recently the attention of the researcher has been also directed towards Piwi-interacting RNAs, circular RNAs, and other small noncoding RNAs. Another class of RNA species, the long noncoding RNAs, is larger than microRNAs and represents a very versatile and promising group of molecules which, apart from their use as biomarkers, have also a possible therapeutic role. In this review, we will give an overview of the most common noncoding RNA species detectable in extracellular fluids and will provide an update concerning the situation of the research on these molecules as cancer biomarkers.
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Affiliation(s)
- Barbara Pardini
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
- Department of Medical Sciences, University of Turin, 10124 Turin, Italy.
- Unit of Molecular Epidemiology and Exposome, Italian Institute for Genomic Medicine (IIGM), 10126 Turin, Italy.
| | - Alexandru Anton Sabo
- Department of Pediatrics, Marie Curie Emergency Clinical Hospital for Children, 077120 Bucharest, Romania
| | - Giovanni Birolo
- Department of Medical Sciences, University of Turin, 10124 Turin, Italy
- Unit of Molecular Epidemiology and Exposome, Italian Institute for Genomic Medicine (IIGM), 10126 Turin, Italy
| | - George Adrian Calin
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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25
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Fang Y, Zhou W, Rong Y, Kuang T, Xu X, Wu W, Wang D, Lou W. Exosomal miRNA-106b from cancer-associated fibroblast promotes gemcitabine resistance in pancreatic cancer. Exp Cell Res 2019; 383:111543. [PMID: 31374207 DOI: 10.1016/j.yexcr.2019.111543] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 07/22/2019] [Accepted: 07/29/2019] [Indexed: 12/25/2022]
Abstract
Gemcitabine (GEM)-based chemotherapy is commonly used to treat pancreatic cancer. However, acquired resistance to GEM remains a challenge in pancreatic cancer patients. Here we tested whether cancer-associated fibroblasts (CAFs) play vital roles in regulating drug resistance by transferring exosomal miRNA to cancer cells. CAFs were isolated from primary fibroblast of pancreatic cancer patients, and exosomes were collected and identified through transmission electron microscopy and western blotting analysis. The functions of CAFs-derived exosomal miRNA in regulating drug resistance were further investigated. We found that CAFs were innately resistant to GEM. The conditioned medium (CM) and the exosomes derived from CAFs contributed to GEM resistance, and GEM treatment further enhanced the effect of CAFs or CAFs-exosomes on pancreatic cancer cells proliferation. MiR-106b level was upregulated in CAFs and CAFs-exosomes following GEM treatment. MiR-106b was directly transferred from CAFs to pancreatic cancer cells through exosomes. Pretreatment of CAFs with miR-106b inhibitor suppressed miR-106b expression in CAFs-exosomes and resulted in a decreased resistance of cancer cells to GEM. MiR-106b promoted GEM resistance of cancer cells by directly targeting TP53INP1. Summarily, our data demonstrated that CAFs-derived exosomal miR-106b plays a vital role in causing GEM resistance of pancreatic cancer, thus offering a new target for sensitizing pancreatic cancer cells to GEM.
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Affiliation(s)
- Yuan Fang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wentao Zhou
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yefei Rong
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Tiantao Kuang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xuefeng Xu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wenchuan Wu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Dansong Wang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Wenhui Lou
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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26
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Wu DM, Wen X, Han XR, Wang S, Wang YJ, Shen M, Fan SH, Zhang ZF, Shan Q, Li MQ, Hu B, Lu J, Chen GQ, Zheng YL. Bone Marrow Mesenchymal Stem Cell-Derived Exosomal MicroRNA-126-3p Inhibits Pancreatic Cancer Development by Targeting ADAM9. MOLECULAR THERAPY. NUCLEIC ACIDS 2019; 16:229-245. [PMID: 30925451 PMCID: PMC6439275 DOI: 10.1016/j.omtn.2019.02.022] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 01/30/2019] [Accepted: 02/23/2019] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer is a lethal malignancy with relatively few effective therapies. Recent investigations have highlighted the role of microRNAs (miRNAs) as crucial regulators in various tumor processes including tumor progression. Hence the current study aimed to investigate the role of bone marrow mesenchymal stem cell (BMSC)-derived exosomal microRNA-126-3p (miR-126-3p) in pancreatic cancer. Initially, miRNA candidates and related genes associated with pancreatic cancer were screened. PANC-1 cells were transfected with miR-126-3p or silenced a disintegrin and a metalloproteinase-9 (ADAM9) to examine their regulatory roles in pancreatic cancer cells. Additionally, exosomes derived from BMSCs were isolated and co-cultured with pancreatic cancer cells to elucidate the effects of exosomes in pancreatic cancer. Furthermore, the effects of overexpressed miR-126-3p derived from BMSCs exosomes on proliferation, migration, invasion, apoptosis, tumor growth, and metastasis of pancreatic cancer cells were analyzed in connection with lentiviral packaged miR-126-3p in vivo. Restored miR-126-3p was observed to suppress pancreatic cancer through downregulating ADAM9. Notably, overexpressed miR-126-3p derived from BMSCs exosomes inhibited the proliferation, invasion, and metastasis of pancreatic cancer cells, and promoted their apoptosis both in vitro and in vivo. Taken together, the key findings of the study indicated that overexpressed miR-126-3p derived from BMSCs exosomes inhibited the development of pancreatic cancer through the downregulation of ADAM9, highlighting the potential of miR-126-3p as a novel biomarker for pancreatic cancer treatment.
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Affiliation(s)
- Dong-Mei Wu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; College of Health Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China
| | - Xin Wen
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; College of Health Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China
| | - Xin-Rui Han
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; College of Health Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China
| | - Shan Wang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; College of Health Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China
| | - Yong-Jian Wang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; College of Health Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China
| | - Min Shen
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; College of Health Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China
| | - Shao-Hua Fan
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; College of Health Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China
| | - Zi-Feng Zhang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; College of Health Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China
| | - Qun Shan
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; College of Health Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China
| | - Meng-Qiu Li
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; College of Health Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China
| | - Bin Hu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; College of Health Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China
| | - Jun Lu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; College of Health Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China.
| | - Gui-Quan Chen
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, Jiangsu, China.
| | - Yuan-Lin Zheng
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; College of Health Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China.
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27
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Berger AW, Schwerdel D, Reinacher-Schick A, Uhl W, Algül H, Friess H, Janssen KP, König A, Ghadimi M, Gallmeier E, Bartsch DK, Geissler M, Staib L, Tannapfel A, Kleger A, Beutel A, Schulte LA, Kornmann M, Ettrich TJ, Seufferlein T. A Blood-Based Multi Marker Assay Supports the Differential Diagnosis of Early-Stage Pancreatic Cancer. Theranostics 2019; 9:1280-1287. [PMID: 30867830 PMCID: PMC6401492 DOI: 10.7150/thno.29247] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Accepted: 01/10/2019] [Indexed: 12/24/2022] Open
Abstract
The most frequent malignancy of the pancreas is the pancreatic ductal adenocarcinoma (PDAC). Despite many efforts PDAC has still a dismal prognosis. Biomarkers for early disease stage diagnosis as a prerequisite for a potentially curative treatment are still missing. Novel blood-based markers may help to overcome this limitation. Methods: Prior to surgery plasma levels of thrombospondin-2 (THBS2), which was recently published as a novel biomarker, and CA19-9 from 52 patients with histologically proven PDAC were determined, circulating cell-free (cfDNA) was quantified. 15 patients with side-branch IPMNs without worrisome features and 32 patients with chronic pancreatitis served for comparison. Logit (logistic regression) models were used to test the performance of single biomarkers and biomarker combinations. Results: CA19-9 and THBS2 alone showed comparable c-statistics of 0.80 and 0.73, respectively, improving to 0.87 when combining these two markers. The c-statistic was further increased to 0.94 when combining CA19-9 and THBS2 with cfDNA quantification. This marker combination performed best for all PDAC stages but also for PDACs grouped by stage. The greatest improvement over CA19-9 was seen in the group of stage I PDAC, from 0.69 to 0.90 for the three marker combination. Conclusion:These data establish the combination of CA19-9, THBS2 and cfDNA as a composite liquid biomarker for non-invasive diagnosis of early-stage PDAC.
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28
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Satyananda V, Gupta R, Hari DM, Yeh J, Chen KT. Advances in Translational Research and Clinical Care in Pancreatic Cancer: Where Are We Headed? Gastroenterol Res Pract 2019; 2019:7690528. [PMID: 30863442 PMCID: PMC6378762 DOI: 10.1155/2019/7690528] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 01/08/2019] [Indexed: 02/06/2023] Open
Abstract
While significant advances have been made in the treatment of many different solid tumors, pancreatic cancer remains a glaring exception. Overall 5-year survival rates for pancreatic cancer remain in the single digits. While newer chemotherapy regimens such as FOLFIRINOX and nab-paclitaxel/gemcitabine have demonstrated modest improvement in survival benefit for metastatic disease and have improved the resectability rates of previously borderline or locally advanced tumors, clinically significant improvements from immunotherapy and targeted therapy remain to be demonstrated. Regardless, a wealth of basic science research in pancreatic cancer has been directed at understanding its aggressive biology and its resistance to therapy. We present a brief summary of key areas of laboratory research and its translation to clinical care.
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Affiliation(s)
- Vikas Satyananda
- Division of Surgical Oncology, Department of Surgery, Harbor-UCLA Medical Center, USA
| | - Rohan Gupta
- Division of Medical Oncology, Department of Medicine, Harbor-UCLA Medical Center, USA
| | - Danielle M. Hari
- Division of Surgical Oncology, Department of Surgery, Harbor-UCLA Medical Center, USA
| | - James Yeh
- Division of Medical Oncology, Department of Medicine, Harbor-UCLA Medical Center, USA
| | - Kathryn T. Chen
- Division of Surgical Oncology, Department of Surgery, Harbor-UCLA Medical Center, USA
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29
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Karasek P, Gablo N, Hlavsa J, Kiss I, Vychytilova-Faltejskova P, Hermanova M, Kala Z, Slaby O, Prochazka V. Pre-operative Plasma miR-21-5p Is a Sensitive Biomarker and Independent Prognostic Factor in Patients with Pancreatic Ductal Adenocarcinoma Undergoing Surgical Resection. Cancer Genomics Proteomics 2018; 15:321-327. [PMID: 29976637 DOI: 10.21873/cgp.20090] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 04/27/2018] [Accepted: 04/30/2018] [Indexed: 12/21/2022] Open
Abstract
Blood plasma microRNAs (miRNAs) are emerging as a clinically useful tool for non-invasive detection and prognosis estimation in various cancer types including pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to provide an independent validation of circulating miRNAs identified in previous studies as diagnostic and/or prognostic biomarkers in PDAC. Based on the literature search, 6 miRNAs were chosen as candidates for independent validation; miR-21-5p, miR-375, miR-155, miR-17-5p, miR-126-5p and miR-1290. Validation of these miRNAs was performed in a cohort of 25 patients with PDAC undergoing surgical resection and 24 healthy donors. Plasma levels of miRNAs were determined using quantitative real-time PCR. We confirmed significantly higher levels of all tested miRNA in blood plasma of PDAC patients in comparison to healthy controls with miR-21-5p showing the highest analytical performance (p<0.001; AUC>0.99). Increased levels of miR-21-5p (p=0.045) and miR-375 (p=0.013) were significantly associated with overall survival. Multivariate analysis demonstrated that miR-21-5p is a significant unfavorable prognostic factor independent on other clinical variables including adjuvant chemotherapy (hazard ratio 2.95; 95% CI 1.06-8.18; p=0.038). Our preliminary data indicate promising diagnostic and prognostic utility of plasma miR-21-5p in PDAC patients.
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Affiliation(s)
- Petr Karasek
- Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, Brno, Czech Republic
| | - Natalia Gablo
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Jan Hlavsa
- Department of Surgery, Faculty Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Igor Kiss
- Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, Brno, Czech Republic
| | | | - Marketa Hermanova
- Department of Pathological Anatomy, St. Anne's University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Zdenek Kala
- Department of Surgery, Faculty Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Ondrej Slaby
- Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, Brno, Czech Republic.,Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Vladimir Prochazka
- Department of Surgery, Faculty Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
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30
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Samandari M, Julia MG, Rice A, Chronopoulos A, Del Rio Hernandez AE. Liquid biopsies for management of pancreatic cancer. Transl Res 2018; 201:98-127. [PMID: 30118658 DOI: 10.1016/j.trsl.2018.07.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 06/17/2018] [Accepted: 07/17/2018] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is one of the main causes of cancer-related deaths worldwide. It is asymptomatic at an early stage, and most diagnosis occurs when the disease is already at a late stage, by which time the tumor is nonresectable. In order to increase the overall survival of patients with pancreatic cancer, as well as to decrease the cancer burden, it is necessary to perform early diagnosis, prognosis stratifications and cancer monitoring using accurate, minimally invasive, and cost-effective methods. Liquid biopsies seek to detect tumor-associated biomarkers in a variety of extractable body fluids and can help to monitor treatment response and disease progression, and even predict patient outcome. In patients with pancreatic cancer, tumor-derived materials, primarily circulating tumor DNA, circulating tumor cells and exosomes, are being studied for inclusion in the management of the disease. This review focuses on describing the biology of these biomarkers, methods for their enrichment and detection, as well as their potential for clinical application. Moreover, we discuss the future direction of liquid biopsies and introduce how they can be exploited toward point of care personalized medicine for the management of pancreatic cancer.
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Affiliation(s)
- Mohamadmahdi Samandari
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - María Gil Julia
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Alistair Rice
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Antonios Chronopoulos
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Armando E Del Rio Hernandez
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom.
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31
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Wei L, Yao K, Gan S, Suo Z. Clinical utilization of serum- or plasma-based miRNAs as early detection biomarkers for pancreatic cancer: A meta-analysis up to now. Medicine (Baltimore) 2018; 97:e12132. [PMID: 30170450 PMCID: PMC6392607 DOI: 10.1097/md.0000000000012132] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is a lethal disease, however current screening methods unable to achieve early diagnosis. Blood-based microRNAs (miRNAs) are promising molecular biomarkers for detecting PC. This meta-analysis summaries studies identifying serum- or plasma-based miRNAs dysregulated in PC patients compared to non-PC cases to evaluate their diagnostic accuracy for characterizing PC. METHODS A systematically reviews and meta-analysis of published studies was conducted to compare the serum or plasma miRNAs expressions between PC patients and non-PC cases. Summary estimates for sensitivity, specificity, along with other measures of accuracy of miRNAs in the diagnosis of PC were pooled using the random-effects model. I and Q tests were used to assess the heterogeneity of included studies. The Spearman test was used to analyze the threshold effect. RESULTS Twenty-seven eligible studies were identified after electronic search and literature selection. For single miRNA dysregulation, 32 miRNAs were found to be upregulated in PC patients, and 5 miRNAs were downregulated. Four studies identified a 2-miRNA panel, and 10 studies identified a panel consisting of 3 or more miRNAs which were used to detect PC patients. Additionally, 8 studies combined miRNA panels and carbohydrate antigen 19-9 (CA 19-9) to diagnose PC. The pooled sensitivities for these 4 groups were 0.77 to 0.85, and specificities were 0.70 to 0.87. The highest area under the curve (AUC), 0.9308, was identified using 2 miRNA panels with sensitivity and specificity of 0.79 (0.74-0.83) and 0.85 (0.81-0.89), respectively. There was great heterogeneity of these 4 miRNA groups. Results of Spearman test revealed that there existed a threshold effect on single miRNA group (r=-0.437, P=.001), and none of the other groups (P all>.05). CONCLUSIONS Serum- or plasma-based miRNAs are capable of distinguishing PC from non-PC with relatively high sensitivity and specificity. In future, miRNAs may be used as promising diagnostic biomarkers for detection of PC.
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Affiliation(s)
| | - Kunhou Yao
- Department of General Surgery, Huaihe Hospital of Henan University, Henan Province, China
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32
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Wen DY, Pan DH, Lin P, Mo QY, Wei YP, Luo YH, Chen G, He Y, Chen JQ, Yang H. Downregulation of miR‑486‑5p in papillary thyroid carcinoma tissue: A study based on microarray and miRNA sequencing. Mol Med Rep 2018; 18:2631-2642. [PMID: 30015845 PMCID: PMC6102695 DOI: 10.3892/mmr.2018.9247] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 05/17/2018] [Indexed: 12/22/2022] Open
Abstract
Abnormal expression of microRNA (miR) is associated with the occurrence and progression of various types of cancers, including papillary thyroid carcinoma (PTC). In the present study, the aim was to explore miR‑486‑5p expression and its role in PTC, as well as to investigate the biological function of its potential target genes. The expression levels of miR‑486‑5p and its clinicopathological significance were examined in 507 PTC and 59 normal thyroid samples via The Cancer Genome Atlas (TCGA). Subsequently, the results were validated using data from Gene Expression Omnibus (GEO) and ArrayExpress. Receiver operating characteristic and summary receiver operating characteristic curves were used to assess the ability of miR‑486‑5p in distinguishing PTC from normal tissue. Furthermore, potential miR‑486‑5p mRNA targets were identified using 12 prediction tools and enrichment analysis was performed on the encoding genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The expression levels of miR‑486‑5p were consistently downregulated in PTC compared with in normal tissue across datasets from TCGA, GEO (GSE40807, GSE62054 and GSE73182) and ArrayExpress (E‑MTAB‑736). The results also demonstrated that miR‑486‑5p expression was associated with cancer stage (P=0.003), pathologic lymph node (P=0.047), metastasis (P=0.042), neoplasm (P=0.012) and recurrence (P=0.016) in patients with PTC. In addition, low expression of miR‑486‑5p in patients with PTC was associated with a worse overall survival. A total of 80 miR‑486‑5p‑related genes were observed from at least 9 of 12 prediction platforms, and these were involved in 'hsa05200: Pathways in cancer' and 'hsa05206: MicroRNAs in cancer'. Finally, three hub genes, CRK like proto‑oncogene, phosphatase and tensin homolog and tropomyosin 3, were identified as important candidates in tumorigenesis and progression of PTC. In conclusion, it may be hypothesized that miR‑486‑5p contributes towards PTC onset and progression, and may act as a clinical target. However, in vitro and in vivo experiments are required to validate the findings of the present study.
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Affiliation(s)
- Dong-Yue Wen
- Department of Medical Ultrasonics, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Deng-Hua Pan
- Department of Medical Ultrasonics, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Peng Lin
- Department of Medical Ultrasonics, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Qiu-Yan Mo
- Department of Medical Ultrasonics, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yun-Peng Wei
- Department of Medical Ultrasonics, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yi-Huan Luo
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yun He
- Department of Medical Ultrasonics, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jun-Qiang Chen
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Hong Yang
- Department of Medical Ultrasonics, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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Zhou X, Lu Z, Wang T, Huang Z, Zhu W, Miao Y. Plasma miRNAs in diagnosis and prognosis of pancreatic cancer: A miRNA expression analysis. Gene 2018; 673:181-193. [PMID: 29913239 DOI: 10.1016/j.gene.2018.06.037] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 06/12/2018] [Indexed: 02/06/2023]
Abstract
The differential expression of microRNAs (miRNAs) in plasma of pancreatic cancer (PC) patients may act as a diagnostic biomarker. A four-stage study was performed to identify plasma miRNAs with potential in detecting PC. Exiqon panels (20 PC vs. 10 normal controls (NCs)) were applied in the screening phase to obtain miRNA profiling. The identified miRNAs were further assessed in the training (40 PC vs. 40 NCs) and testing stages (112 PC vs. 116 NCs) with qRT-PCR assays. A six-miRNA signature including up-regulated miR-122-5p, miR-125b-5p, miR-192-5p, miR-193b-3p, miR-221-3p and miR-27b-3p was identified. The signature could accurately discriminate PC patients from NCs with areas under the receiver operating characteristic curve of 0.848, 0.833 and 0.937 for the training, testing and the external validation stage (41 PC vs. 50 NCs), respectively. The multivariate Cox regression analyses showed that down-regulated plasma miR-125b-5p could predict worse OS independent from late tumor stage and high CA19-9. All the six miRNAs except miR-122-5p showed high expression levels in PC tissues than those in matched normal tissues. MiR-122-5p and miR-193b-3p were up-regulated, while miR-221-3p was down-regulated in plasma exosomes from PC patients. Bioinformatics analysis demonstrated that the miRNAs might involve in several molecular pathways closely related with PC such as p53 signaling pathway, pancreatic cancer, TGF-beta signaling pathway and so on. In conclusion, we identified a six-miRNA signature in plasma which could act as a non-invasive biomarker in diagnosis and prognosis of PC. Plasma miR-125b-5p might act as an independent biomarker in predicting OS of PC patients.
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Affiliation(s)
- Xin Zhou
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China.
| | - Zipeng Lu
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China; Pancreas Institute, Nanjing Medical University, Nanjing 210029, Jiangsu Province, PR China
| | - Tongshan Wang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China
| | - Zebo Huang
- Department of Oncology, The Affiliated Hospital of Jiangnan University, 200 Huihe Road, Wuxi 214062, Jiangsu Province, PR China
| | - Wei Zhu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China.
| | - Yi Miao
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China; Pancreas Institute, Nanjing Medical University, Nanjing 210029, Jiangsu Province, PR China.
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Zhang X, Shi S, Zhang B, Ni Q, Yu X, Xu J. Circulating biomarkers for early diagnosis of pancreatic cancer: facts and hopes. Am J Cancer Res 2018; 8:332-353. [PMID: 29636993 PMCID: PMC5883088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 02/25/2018] [Indexed: 06/08/2023] Open
Abstract
Pancreatic cancer (PC) is characterized by extremely high mortality and poor prognosis, which are largely ascribed to difficulties in early diagnosis and limited therapeutics. Although there is a sufficient window for intervention before preneoplastic lesions progress to invasive disease, effective early detection of PC remains difficult using current biomarkers and imaging techniques. Biomarkers with satisfactory diagnostic efficacy and convenient analysis methods are urgently required. In this review, we summarized recent advances in the identification of biomarkers in circulation for early detection of PC. A number of novel circulating biomarkers, such as metabolites, cell-free DNA (cfDNA), noncoding RNA, and exosomes, that show promising diagnostic value have been discovered using advances in sequencing techniques and "omics" analyses. Panels comprising several biomarkers may also exhibit better diagnostic performance. In the future, we need more efficient circulating biomarkers for the identification of noninvasive precursor lesions and early disease. Collaborative large-scale studies are also required to show the clinical validity and applicability of potential biomarkers.
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Affiliation(s)
- Xu Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
| | - Quanxing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
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Biswas S, Haleyurgirisetty M, Ragupathy V, Wang X, Lee S, Hewlett I, Devadas K. Differentially expressed host long intergenic noncoding RNA and mRNA in HIV-1 and HIV-2 infection. Sci Rep 2018; 8:2546. [PMID: 29416066 PMCID: PMC5803214 DOI: 10.1038/s41598-018-20791-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 01/23/2018] [Indexed: 12/15/2022] Open
Abstract
Non-coding RNAs and mRNAs have been implicated in replication, pathogenesis and host response in HIV infection. However, the impact of long intergenic non-coding RNAs (lincRNAs) on HIV-1 and HIV-2 infection is not known. In this study, we have analyzed expression profiles of lincRNAs and mRNAs in monocyte derived macrophages (MDMs) infected with HIV-1/HIV-2 using microarrays. Our study identified many differentially expressed lincRNAs and mRNAs in MDMs infected with HIV-1/HIV-2 compared to uninfected MDMs. Genes involved in glutathione metabolism and lysine degradation were differentially regulated only in HIV-1 infected MDMs. In HIV-2 infected MDMs, CUL 2, SFRS9, and RBBP4 genes were differentially expressed. Furthermore, we found that plasma levels of lincRNA: chr2: 165509129-165519404 and lincRNA: chr12: 57761837-57762303 were better indicators of HIV-1 infection while lincRNA: chr10:128586385-128592960, XLOC_001148 and lincRNA: chr5:87580664-87583451, were better indicators of HIV-2 infection. In summary, our study has demonstrated that there is substantial alteration in lincRNA and mRNA expression in response to HIV-1/HIV-2 infection. These differentially expressed lincRNAs and mRNAs could serve as prognostic and diagnostic biomarkers of HIV infection and help in the identification of new targets for therapy.
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Affiliation(s)
- Santanu Biswas
- Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993-0002, USA
| | - Mohan Haleyurgirisetty
- Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993-0002, USA
| | - Viswanath Ragupathy
- Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993-0002, USA
| | - Xue Wang
- Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993-0002, USA
| | - Sherwin Lee
- Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993-0002, USA
| | - Indira Hewlett
- Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993-0002, USA.
| | - Krishnakumar Devadas
- Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993-0002, USA.
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Jiang M, Li X, Quan X, Yang X, Zheng C, Hao X, Qu R, Zhou B. MiR-486 as an effective biomarker in cancer diagnosis and prognosis: a systematic review and meta-analysis. Oncotarget 2018; 9:13948-13958. [PMID: 29568407 PMCID: PMC5862628 DOI: 10.18632/oncotarget.24189] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 12/05/2017] [Indexed: 12/25/2022] Open
Abstract
Purpose MiR-486 was found to be associated with cancer’s diagnosis and prognosis. This meta-analysis aimed to investigate the potential effect of miR-486 on cancer detection and prognosis. Materials and Methods We searched PubMed, Cochrane library, Embase, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases to find all correlated articles. The STATA 11.0 was applied to estimate the pooled effects, heterogeneity and publication bias. Results The pooled sensitivity (SEN), specificity (SPE) and Area under the curve (AUC) were 82% (95% CI: 78–85%), 88% (95% CI: 83–92%) and 0.91 (95% CI: 0.88–0.93). Subgroup analysis indicated miR-486 from circulating samples exhibited higher diagnostic accuracy with the AUC was 0.90 (95% CI: 0.87–0.92) than miR-486 from other specimen with the AUC of 0.78 (95% CI: 0.75–0.82) and miR-486 obtained a better diagnostic value in the Asian population with the AUC of 0.94 (95% CI: 0.91–0.95) than the Caucasian and Caucasian/African population with the AUC of 0.80 (95% CI: 0.76–0.83) and 0.89 (95% CI: 0.86–0.91) respectively. MiR-486 obtained high value for the diagnosis of non-small cell lung cancer with SEN, SPE and AUC were 0.82 (95% CI: 0.0.77–0.87), 0.90 (95% CI: 0.84–0.94) as well as 0.92 (95% CI: 0.89–0.94) respectively. For the 7 prognostic tests, the pooled hazard ratio (HR) was 0.48 (95% CI: –0.13–1.08) for low versus high miR-486 expression. Conclusions This meta-analysis indicated that miR-486 can be used as ideal biomarkers in the cancer’s diagnosis. However, Low miR-486 expression did not increase the risk of poor outcome.
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Affiliation(s)
- Min Jiang
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang, China
| | - Xuelian Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang, China
| | - Xiaowei Quan
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang, China
| | - Xianglin Yang
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang, China
| | - Chang Zheng
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang, China
| | - Xia Hao
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang, China
| | - Ruoyi Qu
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang, China
| | - Baosen Zhou
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang, China.,Department of Clinical Epidemiology, First Affiliated Hospital, China Medical University, Shenyang, China
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37
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Netz U, Carter J, Eichenberger MR, Feagins K, Galbraith NJ, Dryden GW, Pan J, Rai SN, Galandiuk S. Plasma microRNA Profile Differentiates Crohn's Colitis From Ulcerative Colitis. Inflamm Bowel Dis 2018; 24:159-165. [PMID: 29272478 PMCID: PMC5858028 DOI: 10.1093/ibd/izx009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is commonly divided into 2 entities: Crohn's disease (CD) and ulcerative colitis (UC). Differentiating between these entities when dealing with IBD confined to the colon is important, especially when planning surgical treatment. Due to ambiguous histological or endoscopic findings, accurate diagnosis is not possible in up to 15% of cases. The aim of this study was to determine whether plasma microRNAs (miRNAs) can help differentiate Crohn's colitis (CC) from ulcerative colitis. METHODS Patients with isolated CC and with UC were enrolled in our study from January 2010 to May 2016. Peripheral blood was collected, and total RNA was isolated from plasma. Screening was performed for 380 common miRNAs. miRNAs that were differentially expressed between these 2 groups were chosen, and their differential expression was confirmed using single miRNA assays in a larger sample size. A predictive model was generated using these data. Significantly differentially expressed miRNAs were then validated utilizing the predictive model to assess blinded data from the single assays. RESULTS Screening was performed on 8 patients from each group. Seven differentially expressed miRNAs were chosen for single assay confirmation. Two miRNAs (miR-598, miR-642) were consistently different between the patient groups (P = 0.013, P = 0.005). Using blinded data, these 2 miRNAs were validated using the predictive model, achieving an overall accuracy of 75% (95% confidence interval, 40.7-92.9). CONCLUSIONS We identified 2 plasma miRNAs that differentiated CC from UC. Our data indicate the promise and feasibility of a plasma miRNA-based assay to distinguish between these 2 conditions.
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Affiliation(s)
- Uri Netz
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky,Department of Surgery A, Soroka University Medical Center, Beer Sheva,
Israel,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva,
Israel
| | - Jane Carter
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky
| | - M Robert Eichenberger
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky
| | - Kayla Feagins
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky
| | - Norman J Galbraith
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky
| | - Gerald W Dryden
- Department of Medicine, Division of Gastroenterology, Hepatology, and
Nutrition University of Louisville School of Medicine Louisville, Kentucky
| | - Jianmin Pan
- Department of Bioinformatics and Biostatistics, University of Louisville
School of Public Health and Information Sciences, Louisville, Kentucky
| | - Shesh N Rai
- Department of Bioinformatics and Biostatistics, University of Louisville
School of Public Health and Information Sciences, Louisville, Kentucky
| | - Susan Galandiuk
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky,Address correspondence to: Susan Galandiuk, MD, FACG, AGAF, The Hiram C.
Polk Jr, MD Department of Surgery, 550 South Jackson Street, Louisville, KY 40202 (e-mail:
)
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Ke D, Li H, Zhang Y, An Y, Fu H, Fang X, Zheng X. The combination of circulating long noncoding RNAs AK001058, INHBA-AS1, MIR4435-2HG, and CEBPA-AS1 fragments in plasma serve as diagnostic markers for gastric cancer. Oncotarget 2017; 8:21516-21525. [PMID: 28423525 PMCID: PMC5400602 DOI: 10.18632/oncotarget.15628] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 02/14/2017] [Indexed: 12/13/2022] Open
Abstract
Background Suitable diagnostic markers for cancers are urgently required in clinical practice. Long non-coding RNAs, which have been reported in many cancer types, are a potential new class of biomarkers for tumor diagnosis. Results Five lncRNAs, including AK001058, INHBA-AS1, MIR4435-2HG, UCA1 and CEBPA-AS1 were validated to be increased in gastric cancer tissues. Furthermore, we found that plasma level of these five lncRNAs were significantly higher in gastric cancer patients compared with normal controls. By receiver operating characteristic analysis, we found that the combination of plasma lncRNAs with the area under the curve up to 0.921, including AK001058, INHBA-AS1, MIR4435-2HG, and CEBPA-AS1, is a better indicator of gastric cancer than their individual levels or other lncRNA combinations. Simultaneously, we found that the expression levels of a series of MIR4435-2HG fragments are different in gastric cancer plasma samples, but most of them higher than that in healthy control plasma samples. Materials and Methods LncRNA gene expression profiles were analyzed in two pairs of human gastric cancer and adjacent non-tumor tissues by microarray analysis. Nine gastric cancer-associated lncRNAs were selected and assessed by quantitative real-time polymerase chain reaction in gastric tissues, and 5 of them were further analyzed in gastric cancer patients’ plasma. Conclusions Our results demonstrate that certain lncRNAs, such as AK001058, INHBA-AS1, MIR4435-2HG, and CEBPA-AS1, are enriched in human gastric cancer tissues and significantly elevated in the plasma of patients with gastric cancer. These findings indicate that the combination of these four lncRNAs might be used as diagnostic or prognostic markers for gastric cancer patients.
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Affiliation(s)
- Dong Ke
- General Surgery, The Second Hospital of Jilin University, Changchun, 130041, China.,Beijing Key Laboratory for Radiobiology, Beijing institute of Radiation Medicine, Beijing, 100850, China.,Gastrointestinal Colorectal and Anal Surgery, The China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Hanwei Li
- Beijing Key Laboratory for Radiobiology, Beijing institute of Radiation Medicine, Beijing, 100850, China
| | - Yi Zhang
- Beijing Key Laboratory for Radiobiology, Beijing institute of Radiation Medicine, Beijing, 100850, China.,Gastrointestinal Colorectal and Anal Surgery, The China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Yinghong An
- Clinical Laboratory Center, Chinese PLA Air Force General Hospital, Beijing, 100142, China
| | - Hanjiang Fu
- Beijing Key Laboratory for Radiobiology, Beijing institute of Radiation Medicine, Beijing, 100850, China
| | - Xuedong Fang
- General Surgery, The Second Hospital of Jilin University, Changchun, 130041, China.,Gastrointestinal Colorectal and Anal Surgery, The China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Xiaofei Zheng
- Beijing Key Laboratory for Radiobiology, Beijing institute of Radiation Medicine, Beijing, 100850, China
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Chen D, Wu X, Xia M, Wu F, Ding J, Jiao Y, Zhan Q, An F. Upregulated exosomic miR‑23b‑3p plays regulatory roles in the progression of pancreatic cancer. Oncol Rep 2017; 38:2182-2188. [PMID: 28849236 PMCID: PMC5652966 DOI: 10.3892/or.2017.5919] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 08/14/2017] [Indexed: 12/21/2022] Open
Abstract
Pancreatic cancer (PC) is one of the most lethal malignances. Identification of biomarkers for early diagnosis of PC is a key imperative. MicroRNAs (miRNAs) have been shown to be valuable biomarkers in the context of several cancers. Exosomes refer to vesicles released by the tumor cells at the early stage of disease. Thus, detection of miRNA in exosomes can be used as a potential biomarker for PC. In this study, we profiled serum levels of miRNAs in patients with chronic pancreatitis (CP) and PC; the role of miR-23b-3p in PC progression was assessed in vitro. Additionally, we assessed, the expression of miR-23b-3p in exosomes isolated from serum samples and assessed the correlation between the expression of miR-23b-3p and carbohydrate antigen 19-9 (CA19-9). Three serum samples each were randomly selected from healthy controls (n=20), and patients with CP (n=18) and PC (n=16) for miRNA microarray profiling. The dysregulated miRNAs were confirmed using qRT-PCR. Four dysregulated miRNAs common to patients with CP and PC were identified on miRNA microarray analysis and confirmed by qRT-PCR. miR-23b-3p level was consistently higher in serum samples from PC patients as compared to those from healthy controls and CP patients (p<0.05). Overexpression of miR-23b-3p promoted proliferation, migration, and invasion capability of PC cells in vitro (p<0.05). Furthermore, miR-23b-3p was upregulated in exosomes of PC serum samples and the supernatant of pancreatic cancer cells (PANC-1), and the expression levels of miR-23b-3p were associated with those of serum CA19-9 levels. This study provides insights into the potential role of miR-23b-3p as a novel biomarker and target for treatment of PC.
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Affiliation(s)
- Dayang Chen
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
| | - Xiongbo Wu
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
| | - Min Xia
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
| | - Fang Wu
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
| | - Junli Ding
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
| | - Yang Jiao
- School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Medical School of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Qiang Zhan
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
| | - Fangmei An
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
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Li CF, Li YC, Jin JP, Yan ZK, Li DD. miR-938 promotes colorectal cancer cell proliferation via targeting tumor suppressor PHLPP2. Eur J Pharmacol 2017; 807:168-173. [PMID: 28433657 DOI: 10.1016/j.ejphar.2017.04.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 04/13/2017] [Accepted: 04/19/2017] [Indexed: 01/06/2023]
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Although the development of therapy approaches, the outcome of CRC patients still is poor, understanding the biological mechanism of CRC progression is critical to improve the treatment strategies. miRNAs regulate CRC progression, we found miR-938 was upregulated in CRC tissues and cells, MTT assay, colony formation assay and soft agar growth assay suggested miR-938 overexpression promoted CRC cell proliferation, miR-938 knockdown inhibited CRC cell proliferation. Tumor suppressor PH domain Leucine-rich-repeats Protein Phosphatase 2 (PHLPP2) was a target of miR-938, miR-938 inhibited PHLPP2, luciferase activity assay suggested miR-938 directly bound to the 3'UTR of PHLPP2, meanwhile, we found miR-938 promoted c-Myc and Cyclin D1 expression, confirming miR-938 promoted CRC cell proliferation. Double knockdown of miR-938 and PHLPP2 promoted CRC cell proliferation, suggesting miR-938 promoted CRC cell proliferation by inhibiting PHLPP2.
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Affiliation(s)
- Chang-Feng Li
- Department of Endoscopy Center, China-Japan Union Hospital, Jilin University, Changchun 130033, China
| | - Yong-Chao Li
- Department of Gastrointestinal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China.
| | - Jing-Peng Jin
- Department of Endoscopy Center, China-Japan Union Hospital, Jilin University, Changchun 130033, China
| | - Zhen-Kun Yan
- Department of Endoscopy Center, China-Japan Union Hospital, Jilin University, Changchun 130033, China
| | - Dan-Dan Li
- Department of Endoscopy Center, China-Japan Union Hospital, Jilin University, Changchun 130033, China
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Pei Z, Liu SM, Huang JT, Zhang X, Yan D, Xia Q, Ji C, Chen W, Zhang X, Xu J, Wang J. Clinically relevant circulating microRNA profiling studies in pancreatic cancer using meta-analysis. Oncotarget 2017; 8:22616-22624. [PMID: 28186984 PMCID: PMC5410249 DOI: 10.18632/oncotarget.15148] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 01/25/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Pancreatic cancer (PaCa) is the most lethal gastrointestinal (GI) tumor. Although many studies on differentially expressed miRNAs as candidate biomarkers of pancreatic cancer have been published, reliability of these findings generated from investigations performed in single laboratory settings remain unclear. RESULTS There were 29 articles with a total of 2,225 patients and 1,618 controls included in this meta-analysis. The pooled sensitivity was 82% (95% CI, 79-85%); the specificity was 85% (95% CI, 79-89%); and area under the curve (AUC) was 0.89 (95% CI, 0.86-0.92). Subgroup analyses indicated that there were significant divergences between Caucasian and Asian subgroups for circulating miRNA analysis. MATERIALS AND METHODS To comprehensively investigate the potential utility of miRNAs as biomarkers of the disease, we searched publications diagnosing PaCa using miRNAs from PubMed, Medline, Embase, Google Scholar and Chinese National Knowledge Infrastructure (CNKI) databases. The sensitivity (SEN), specificity (SPE), and summary receiver operating characteristic (SROC) curve were used to examine the overall test performance, and heterogeneity was analyzed with the I2 test. CONCLUSIONS Our analysis demonstrated that multiple miRNAs (SEN: 85%; SPE: 89%; AUC: 0.93) were more accurate for diagnosing PaCa than a single miRNA (SEN: 78%; SPE: 79%; AUC: 0.84), and future studies are still needed to confirm the diagnostic value of these pooled miRNAs for PaCa.
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Affiliation(s)
- Zenglin Pei
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai 201508, P.R. China
| | - Song-Mei Liu
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Jing-Tao Huang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Xuan Zhang
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai 201508, P.R. China
| | - Dong Yan
- Department of Medical Oncology, Beijing Chaoyang Hospital affiliated to Capital Medical University, Beijing, China
| | - Qianlin Xia
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai 201508, P.R. China
| | - Chunxia Ji
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai 201508, P.R. China
| | - Weiping Chen
- Genomics Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Xiaoyan Zhang
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai 201508, P.R. China
| | - Jianqing Xu
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai 201508, P.R. China
| | - Jin Wang
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai 201508, P.R. China
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Zhou B, Xu JW, Cheng YG, Gao JY, Hu SY, Wang L, Zhan HX. Early detection of pancreatic cancer: Where are we now and where are we going? Int J Cancer 2017; 141:231-241. [PMID: 28240774 DOI: 10.1002/ijc.30670] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 01/25/2017] [Accepted: 02/20/2017] [Indexed: 12/11/2022]
Abstract
Pancreatic cancer (PC) is one of the most lethal malignancies. Recent studies indicate that patients with incidentally diagnosed PC have better prognosis than those with symptoms and that there is a sufficient window for early detection. However, effective early diagnosis remains difficult and depends mainly on imaging modalities and the development of screening methodologies with highly sensitive and specific biomarkers. This review summarizes recent advances in effective screening for early diagnosis of PC using imaging modalities and novel molecular biomarkers discovered from various "omics" studies including genomics, epigenomics, non-coding RNA, metabonomics, liquid biopsy (CTC, ctDNA and exosomes) and microbiomes, and their use in body fluids (feces, urine and saliva). Although many biomarkers for early detection of PC have been discovered through various methods, larger scale and rigorous validation is required before their application in the clinic. In addition, more effective and specific biomarkers of PC are urgently needed.
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Affiliation(s)
- Bin Zhou
- Department of Hepatopancreatobiliary Surgery, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, 266003, China
| | - Jian-Wei Xu
- Department of General Surgery, Qilu hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Yu-Gang Cheng
- Department of General Surgery, Qilu hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Jing-Yue Gao
- Department of Basic Medicine, Medical College of Shandong University, Jinan, 250012, China
| | - San-Yuan Hu
- Department of General Surgery, Qilu hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Lei Wang
- Department of General Surgery, Qilu hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Han-Xiang Zhan
- Department of General Surgery, Qilu hospital, Shandong University, Jinan, Shandong Province, 250012, China
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A Panel of CA19-9, Ca125, and Ca15-3 as the Enhanced Test for the Differential Diagnosis of the Pancreatic Lesion. DISEASE MARKERS 2017; 2017:8629712. [PMID: 28356610 PMCID: PMC5357521 DOI: 10.1155/2017/8629712] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Revised: 01/29/2017] [Accepted: 02/01/2017] [Indexed: 12/16/2022]
Abstract
Background. Proper diagnosis of pancreatic lesion etiology is a challenging clinical dilemma. Studies suggest that surgery for suspected pancreatic ductal adenocarcinoma (PDAC) reveals a benign lesion in 5% to 13% of cases. The aim of our study was to assess whether routinely used biomarkers such as CA19-9, Ca125, Ca15-3, and CEA, when combined, can potentially yield an accurate test predicting pancreatic lesion etiology. Methods. We retrospectively analyzed data of 326 patients who underwent a diagnostic process due to pancreatic lesions of unknown etiology. Results. We found statistically significant differences in mean levels of all biomarkers. In logistic regression model, we applied levels CA19-9, Ca125, and Ca15-3 as variables. Two validation methods were used, namely, random data split into training and validation groups and bootstrapping. Afterward, we built ROC curve using the model that we had created, reaching AUC = 0,801. With an optimal cut-off point, it achieved specificity of 81,2% and sensitivity of 63,10%. Our proposed model has superior diagnostic accuracy to both CA19-9 (p = 0,0194) and CA125 (p = 0,0026). Conclusion. We propose a test that is superior to CA19-9 in a differential diagnosis of pancreatic lesion etiology. Although our test fails to reach exceptionally high accuracy, its feasibility and cost-effectiveness make it clinically useful.
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Zhang Q, Chen S, Zeng L, Chen Y, Lian G, Qian C, Li J, Xie R, Huang KH. New developments in the early diagnosis of pancreatic cancer. Expert Rev Gastroenterol Hepatol 2017; 11:149-156. [PMID: 27937041 DOI: 10.1080/17474124.2017.1271323] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Pancreatic cancer is an aggressive carcinoma of the digestive system and radical resection, which is available to very few patients, is the only possibility for cure. Since therapeutic choices are limited at the advanced stage, screening and early diagnostic tools are indispensable for a better prognosis. Areas covered: This review illustrates serologic and imaging examinations, and carbohydrate antigens, microRNAs, methylation biomarkers, molecules in exosomes, ultrasound, computed tomography, magnetic resonance imaging, positron emission tomography and endoscopic retrograde cholangiopancreatography, among other topics. No matter which approach is used, the accuracy of early diagnosis is extremely low. Combining different methods greatly improves the accuracy of early diagnosis. This review was conducted utilizing PubMed with key search words pancreatic cancer, early diagnosis, biomarkers and imaging. Expert commentary: Appropriate combination of biomarkers and imaging technologies will become standard practice in the future. Because the incidence of and mortality from pancreatic cancer is rising, further study of new approaches for the early detection of pancreatic tumors is essential.
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Affiliation(s)
- QiuBo Zhang
- a Department of Gastroenterology , Lihuili Hospital of Ningbo Medical Center , Ningbo , China
| | - ShaoJie Chen
- b Department of Oncology , the Fifth Affiliated Hospital of Sun Yat-Sen University , Zhuhai , China
| | - LinJuan Zeng
- b Department of Oncology , the Fifth Affiliated Hospital of Sun Yat-Sen University , Zhuhai , China
| | - YinTing Chen
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - GuoDa Lian
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - ChenChen Qian
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - JiaJia Li
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - RuiJie Xie
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - Kai-Hong Huang
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
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Xu Y, Xu W, Lu T, Dai Y, Liang W. miR-126 affects the invasion and migration of glioma cells through GATA4. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2016; 45:1-7. [PMID: 27598297 DOI: 10.1080/21691401.2016.1226179] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
We aimed to explore the relationship between miR-126 and glioma. miR-126 was highly expressed in low-grade clinical glioma tissue samples but lowly expressed in high-grade ones (P < .01). A human endogenous miR-126 expression vector was constructed. The migration capacity of cells transfected with the vector significantly decreased (P < .05). Up-regulation of miR-126 suppressed GATA4 protein expression. After transfection, they slightly contracted and became ovally or spherically shaped. F-actin significantly reduced, and microfilaments shortened or disappeared. The number of membrane-penetrating cells significantly decreased (P < .01). miR-126 inhibits the migration and invasion of glioma cells, which may be linked to GATA4 as a target gene.
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Affiliation(s)
- Yifan Xu
- a Department of Neurosurgery , Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School , Nanjing , China
| | - Wu Xu
- a Department of Neurosurgery , Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School , Nanjing , China
| | - Tianyu Lu
- a Department of Neurosurgery , Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School , Nanjing , China
| | - Yuxiang Dai
- a Department of Neurosurgery , Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School , Nanjing , China
| | - Weibang Liang
- a Department of Neurosurgery , Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School , Nanjing , China
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Lewis AR, Valle JW, McNamara MG. Pancreatic cancer: Are "liquid biopsies" ready for prime-time? World J Gastroenterol 2016; 22:7175-7185. [PMID: 27621566 PMCID: PMC4997639 DOI: 10.3748/wjg.v22.i32.7175] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 06/10/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a disease that carries a poor prognosis. Accurate tissue diagnosis is required. Tumours contain a high content of stromal tissue and therefore biopsies may be inconclusive. Circulating tumour cells (CTCs) have been investigated as a potential “liquid biopsy” in several malignancies and have proven to be of prognostic value in breast, prostate and colorectal cancers. They have been detected in patients with localised and metastatic pancreatic cancer with sensitivities ranging from 38%-100% using a variety of platforms. Circulating tumour DNA (ctDNA) has also been detected in pancreas cancer with a sensitivity ranging from 26%-100% in studies across different platforms and using different genetic markers. However, there is no clear consensus on which platform is the most effective for detection, nor which genetic markers are the most useful to use. Potential roles of liquid biopsies include diagnosis, screening, guiding therapies and prognosis. The presence of CTCs or ctDNA has been shown to be of prognostic value both at diagnosis and after treatment in patients with pancreatic cancer. However, more prospective studies are required before this promising technology is ready for adoption into routine clinical practice.
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