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Powrózek T, Otieno MO, Maffeo D, Frullanti E, Martinez-Useros J. Blood circulating miRNAs as pancreatic cancer biomarkers: An evidence from pooled analysis and bioinformatics study. Int J Biol Macromol 2025; 308:142469. [PMID: 40180095 DOI: 10.1016/j.ijbiomac.2025.142469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 03/09/2025] [Accepted: 03/22/2025] [Indexed: 04/05/2025]
Abstract
Pancreatic cancer (PC) is one of the deadliest cancers, characterized by a poor prognosis. Currently, there are no screening programs for the early detection of PC, and existing diagnostic methods are primarily limited to high-risk individuals. Biomarkers such as CA19-9 have not significantly improved early diagnosis, making the identification of new potential biomarkers crucial for routine clinical practice. Among the candidate biomarkers, miRNAs have been most extensively studied due to their role in regulating gene expression (either as oncomiRs or tumor suppressor miRNAs) and their potential for minimally invasive analysis through liquid biopsy techniques. This review aims to summarize the current literature on blood-circulating miRNAs and their diagnostic value in PC detection, considering the context of CA19-9 and benign pancreatic diseases. The data from the collected studies were curated through both statistical and bioinformatics analyses to identify the most promising miRNAs with optimal diagnostic accuracy for PC detection and to assess their role in the molecular processes leading to tumor development.
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Affiliation(s)
- Tomasz Powrózek
- Department of Human Physiology, Medical University of Lublin, Lublin, Poland.
| | - Michael Ochieng' Otieno
- Translational Oncology Division, Oncohealth Institute, Fundacion Jiménez Díaz University Hospital, Madrid, Spain
| | - Debora Maffeo
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy; Cancer Genomics and Systems Biology Lab, Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Elisa Frullanti
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy; Cancer Genomics and Systems Biology Lab, Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Javier Martinez-Useros
- Translational Oncology Division, Oncohealth Institute, Fundacion Jiménez Díaz University Hospital, Madrid, Spain; Area of Physiology, Department of Basic Health Sciences, Faculty of Health Sciences, Rey Juan Carlos University, Madrid, Spain
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Yang Y, Razak SRA, Ismail IS, Ma Y, Yunus MA. Molecular mechanisms of miR-192 in cancer: a biomarker and therapeutic target. Cancer Cell Int 2025; 25:94. [PMID: 40087755 PMCID: PMC11908092 DOI: 10.1186/s12935-025-03666-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 01/29/2025] [Indexed: 03/17/2025] Open
Abstract
Cancer remains a major global health challenge due to its rising prevalence and high mortality rates. The field of microRNAs (miRNAs) has made significant progress in the understanding of tumorigenesis and has broadened our knowledge of their targeting, especially in cancer therapy. miRNAs, a class of small non-coding RNAs, participate in post-transcriptional gene regulation by translational inhibition or mRNA degradation. Among these, microRNA-192 (miR-192) is located on human chromosome 11q13.1, and is highly correlated with the occurrence and development of various human cancers. Dysregulation of miR-192 has been extensively studied in various pathological processes, including tumorigenesis, making it a valuable biomarker for cancer diagnosis and prognosis. The functional role of miR-192 varies across cancer types, acting as either a tumor suppressor or as an oncogene through the modulation of multiple gene expressions and downstream signaling pathways. However, the roles of miR-192 in cancer appear inconsistent across types, with current research often focused on specific genes or pathways, limiting insight into its broader impact on cellular signaling networks. Therefore, this review aims to provide a comprehensive overview of miR-192 research. The paper reviews differences in miR-192 expression in cancer and systematically summarizes the role of miR-192 in cancers. The review further explores the complex roles of miR-192 in various pathological processes, emphasizing its regulatory pathways, interaction networks, and association with tumor progression. This review also illustrates the clinical application of miR-192 as a diagnostic and prognostic biomarker for non-invasive cancer detection, as it is consistently present in both serum and exosomes. A comprehensive summary and analysis of the relationship between miR-192 and various cancers may provide valuable insights, potentially guiding novel approaches in clinical diagnosis, therapeutic strategies, and foundational cancer research.
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Affiliation(s)
- Yang Yang
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Kepala Batas, Pulau Pinang, Malaysia
- School of Medical Technology, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Siti Razila Abdul Razak
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Kepala Batas, Pulau Pinang, Malaysia
| | - Ida Shazrina Ismail
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Kepala Batas, Pulau Pinang, Malaysia
| | - Yanxia Ma
- School of Medical Technology, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China.
| | - Muhammad Amir Yunus
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Kepala Batas, Pulau Pinang, Malaysia.
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Przybyszewski O, Mik M, Nowicki M, Kusiński M, Mikołajczyk-Solińska M, Śliwińska A. Using microRNAs Networks to Understand Pancreatic Cancer-A Literature Review. Biomedicines 2024; 12:1713. [PMID: 39200178 PMCID: PMC11351910 DOI: 10.3390/biomedicines12081713] [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: 05/30/2024] [Revised: 07/26/2024] [Accepted: 07/28/2024] [Indexed: 09/02/2024] Open
Abstract
Pancreatic cancer is a severe disease, challenging to diagnose and treat, and thereby characterized by a poor prognosis and a high mortality rate. Pancreatic ductal adenocarcinoma (PDAC) represents approximately 90% of pancreatic cancer cases, while other cases include neuroendocrine carcinoma. Despite the growing knowledge of the pathophysiology of this cancer, the mortality rate caused by it has not been effectively reduced. Recently, microRNAs have aroused great interest among scientists and clinicians, as they are negative regulators of gene expression, which participate in many processes, including those related to the development of pancreatic cancer. The aim of this review is to show how microRNAs (miRNAs) affect key signaling pathways and related cellular processes in pancreatic cancer development, progression, diagnosis and treatment. We included the results of in vitro studies, animal model of pancreatic cancer and those performed on blood, saliva and tumor tissue isolated from patients suffering from PDAC. Our investigation identified numerous dysregulated miRNAs involved in KRAS, JAK/STAT, PI3/AKT, Wnt/β-catenin and TGF-β signaling pathways participating in cell cycle control, proliferation, differentiation, apoptosis and metastasis. Moreover, some miRNAs (miRNA-23a, miRNA-24, miRNA-29c, miRNA-216a) seem to be engaged in a crosstalk between signaling pathways. Evidence concerning the utility of microRNAs in the diagnosis and therapy of this cancer is poor. Therefore, despite growing knowledge of the involvement of miRNAs in several processes associated with pancreatic cancer, we are beginning to recognize and understand their role and usefulness in clinical practice.
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Affiliation(s)
- Oskar Przybyszewski
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland
| | - Michał Mik
- Department of General and Colorectal Surgery, Medical University of Lodz, 113 Stefana Żeromskiego St., 90-549 Lodz, Poland; (M.M.); (M.N.)
| | - Michał Nowicki
- Department of General and Colorectal Surgery, Medical University of Lodz, 113 Stefana Żeromskiego St., 90-549 Lodz, Poland; (M.M.); (M.N.)
| | - Michał Kusiński
- Department of Endocrinological, General and Oncological Surgery, Medical University of Lodz, 62 Pabianicka St., 93-513 Lodz, Poland;
| | - Melania Mikołajczyk-Solińska
- Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland;
| | - Agnieszka Śliwińska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland
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Li Y, Zhu L, Zhu C, Chen Y, Yu H, Zhu H, Yin P, Liu M, Li Y, Li H, Gong Z, Hanzi Xu, Han J. Circulating micrornas as potential diagnostic biomarkers for cervical intraepithelial neoplasia and cervical cancer: a systematic review and meta-analysis. Discov Oncol 2024; 15:189. [PMID: 38801504 PMCID: PMC11130102 DOI: 10.1007/s12672-024-01028-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 05/08/2024] [Indexed: 05/29/2024] Open
Abstract
BACKGROUND Cervical cancer is a prevalent malignancy of the female reproductive system. Cervical intraepithelial neoplasia (CIN) is a precursor lesion for CC. Various studies have examined circulating microRNAs (miRNAs) as potential early diagnostic markers for CC and CIN. However, the findings have been inconclusive. Therefore, it is necessary to evaluate the diagnostic accuracy and identify potential sources of variability among these studies. METHODS The PubMed, Cochrane Library, Embase, and Web of Science databases were searched to identify relevant literature. Then, Stata 14.0 was utilized to calculate summary estimates for diagnostic parameters, including sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic (ROC). To scrutinize the heterogeneity, the Cochran-Q test and I2 statistic were utilized. As significant heterogeneity was observed, the random effects model was chosen. To explore potential sources of the heterogeneity, subgroup and regression analyses were conducted. RESULTS We analysed 12 articles reporting on 24 studies involving 1817 patients and 1731 healthy controls. The pooled sensitivity was 0.77 (95% CI 0.73-0.81), the specificity was 0.81 (95% CI 0.73-0.86), the PLR was 3.99 (95% CI 2.81-5.65), the NLR was 0.28 (95% CI 0.23-0.35), the DOR was 14.18 (95% CI 8.47-23.73), and the area under the curve (AUC) was 0.85 (95% CI 0.81-0.87). Subgroup analysis revealed that multiple miRNAs can improve diagnostic performance; the pooled sensitivity of multiple miRNAs was 0.78 (95% CI 0.68-0.86), the specificity was 0.85 (95% CI 0.78-0.90), and the AUC was 0.89 (95% CI 0.86-0.91). CONCLUSION This study suggested that circulating microRNAs may be biomarkers for early CC diagnosis.
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Affiliation(s)
- Yue Li
- Jiangsu Cancer Centre, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The AffiliatedCancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Longbiao Zhu
- Department of The Sixth Dental Division, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, Jiangsu, China
| | - Chenjing Zhu
- Jiangsu Cancer Centre, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The AffiliatedCancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yan Chen
- Jiangsu Cancer Centre, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The AffiliatedCancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hui Yu
- Jiangsu Cancer Centre, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The AffiliatedCancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hangju Zhu
- Jiangsu Cancer Centre, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The AffiliatedCancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ping Yin
- Jiangsu Cancer Centre, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The AffiliatedCancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Mengyu Liu
- Jiangsu Cancer Centre, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The AffiliatedCancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yang Li
- Jiangsu Cancer Centre, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The AffiliatedCancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Huixin Li
- Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Woman and Children's HealthCare Hospital, Nanjing, Jiangsu, China
| | - Zhen Gong
- Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Woman and Children's HealthCare Hospital, Nanjing, Jiangsu, China.
| | - Hanzi Xu
- Jiangsu Cancer Centre, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The AffiliatedCancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Jing Han
- Jiangsu Cancer Centre, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The AffiliatedCancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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Reyaz I, Khan B, James N, Azhar H, Rehman A, Younas MW, Rashid H, Al-Shaikhly FF, Almomani MM, I Kh Almadhoun MK, Abdullah Yahya N, Bokhari SFH, Shehzad A. Emerging Horizons in the Diagnosis of Pancreatic Cancer: The Role of Circulating microRNAs as Early Detection Biomarkers for Pancreatic Ductal Adenocarcinoma. Cureus 2024; 16:e53023. [PMID: 38410292 PMCID: PMC10895207 DOI: 10.7759/cureus.53023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2024] [Indexed: 02/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor prognosis, primarily due to a late diagnosis. Recent studies have focused on identifying non-invasive biomarkers for early detection, with microRNAs (miRNAs) emerging as promising candidates. This systematic review aims to evaluate the potential of circulating miRNAs as biomarkers for the early detection of PDAC, analyzing their diagnostic accuracy, specificity, and sensitivity. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive search across PubMed, Embase, and the Cochrane Library was conducted. Studies published from January 2013 to October 2023 focusing on miRNA biomarkers for early PDAC detection were included. Data synthesis was performed through a narrative approach due to the heterogeneity of the studies. Nine studies met the inclusion criteria. Key findings include the elevated levels of specific miRNAs, such as miR-18a, miR-106a, and miR-25, in early-stage PDAC patients compared to controls. The integration of miRNA profiles with traditional biomarkers like CA19-9 showed improved diagnostic performance. However, challenges in the standardization of miRNA evaluation methodologies were noted. Circulating miRNAs demonstrate significant potential as non-invasive biomarkers for early PDAC detection. Despite promising results, further research and standardization are necessary for clinical application.
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Affiliation(s)
- Ibrahim Reyaz
- Internal Medicine, Christian Medical College and Hospital Ludhiana, Ludhiana, IND
| | - Bilal Khan
- Internal Medicine, Jinnah Postgraduate Medical Centre, Karachi, PAK
| | - Neha James
- General Medicine, Rehman Medical Institute, Peshawar, PAK
| | - Hammad Azhar
- Accident and Emergency, Sahiwal Teaching Hospital, Sahiwal, PAK
- General Medicine, King Edward Medical University, Lahore, PAK
| | | | - Muhammad Waqas Younas
- Accident and Emergency, Sahiwal Teaching Hospital, Sahiwal, PAK
- General Medicine, Faisalabad Medical University, Faisalabad, PAK
| | - Hamza Rashid
- Medicine, Pak Medical Centre & Hospital, Peshawar, PAK
| | | | | | | | | | | | - Ahsan Shehzad
- Surgery, King Edward Medical University, Lahore, PAK
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Yang C, Wang M, Huang R, Ou L, Li M, Wu W, Lei R. Circ_0108942 Regulates the Progression of Breast Cancer by Regulating the MiR-1178-3p/TMED3 Axis. Clin Breast Cancer 2023; 23:291-301. [PMID: 36764873 DOI: 10.1016/j.clbc.2022.12.014] [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: 04/23/2022] [Revised: 09/21/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Breast cancer (BC) has posed a fatal threat to women's lives and the search for new methods of diagnosis and treatment is an important way to break the bottleneck of high mortality in BC. Circular RNAs (circRNAs) have been confirmed to be aberrantly expressed in several types of cancers, and this study is intended to elucidate the role and mechanism of circ_0108942 in BC. MATERIALS AND METHODS The levels of circ_0108942, microRNA-1178-3p (miR-1178-3p), and transmembrane p24 trafficking protein 3 (TMED3) were measured using real-time quantitative polymerase chain reaction (RT-qPCR) or western blot. Meanwhile, the cell proliferation, migration, invasion, angiopoiesis, and apoptosis were analyzed using 5-ethynyl-2'-deoxyuridine (EdU), transwell, tubule formation, and flow cytometry assays. Protein levels were determined by western blot. In addition, we used dual-luciferase reporter and RNA pull-down assays to identify the interplay between miR-1178-3p and circ_0108942 or TMED3. Lastly, the impact of circ_0108942 on the growth of BC tumors in vivo was analyzed by xenograft models. RESULTS Circ_0108942 and TMED3 were notably upregulated in BC, and the miR-1178-3p was downregulated. Functionally, silencing circ_0108942 suppressed cell proliferation, migration, invasion and promoted apoptosis in BC cells. In mechanism, circ_0108942 regulated TMED3 expression by sponging miR-1178-3p. Meanwhile, circ_0108942 knockdown also greatly constrained tumor growth in vivo. CONCLUSION Circ_0108942 boosted BC progression by regulating miR-1178-3p and thus upregulating TMED3.
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Affiliation(s)
- Chuansheng Yang
- Department of Head-Neck and Breast Surgery, Yuebei People's Hospital of Shantou University, Shaoguan, Guangdong, China
| | - Meijiao Wang
- Operation room, Yuebei People's Hospital of Shantou University, Shaoguan, Guangdong, China
| | - Renfeng Huang
- Department of Head-Neck and Breast Surgery, Yuebei People's Hospital of Shantou University, Shaoguan, Guangdong, China
| | - Linyang Ou
- Department of Head-Neck and Breast Surgery, Yuebei People's Hospital of Shantou University, Shaoguan, Guangdong, China
| | - Min Li
- Department of Head-Neck and Breast Surgery, Yuebei People's Hospital of Shantou University, Shaoguan, Guangdong, China
| | - Wanming Wu
- Department of Head-Neck and Breast Surgery, Yuebei People's Hospital of Shantou University, Shaoguan, Guangdong, China
| | - Ruiwen Lei
- Department of Head-Neck and Breast Surgery, Yuebei People's Hospital of Shantou University, Shaoguan, Guangdong, China.
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Sharma N, Srivastava S. Diagnosis of Pancreatic Cancer Using miRNA30e Biosensor. Interdiscip Sci 2022; 14:804-813. [PMID: 35781212 DOI: 10.1007/s12539-022-00531-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 05/27/2022] [Accepted: 06/01/2022] [Indexed: 06/15/2023]
Abstract
This work describes miRNA-based electrochemical biosensor for detection of miRNA30e, a pancreatic cancer biomarker. The screen-printed gold electrode was functionalized using cysteine hydrochloride followed by immobilization of synthesized colloidal gold nanorods (10-12 nm diameter and 25-65 nm length). The gold nanorods modified electrode surface was amino functionalized for covalent attachment of single-stranded DNA probe against miRNA30e (miR30e). This platform was utilized for electrochemical measurements and response analysis of target miRNA30e. Electrochemical impedance spectroscopic measurements showed very poor sensitivity (13.51 Ω/µg/mL/cm2) using charge transfer resistance calibration plots. Cyclic voltammetry and differential pulse voltammetry-based miR30e quantification showed decreasing current response with increasing concentration of miR30e with detection range of 0.1 fg/mL-0.1 µg/mL (14.9 aM-14.9 nM). The sensitivity of DPV sensing (104.4 µA/µg/mL/cm2) was found to be 1.3 times higher than that of CV-based quantification (79.6 µA/µg/mL/cm2). miRNA-based biosensors have the potential of replacing current invasive, time consuming and technically difficult diagnostic procedures. Furthermore, the lower limit of detection of 14.9 aM miRNA30e makes it a promising tool for detection of cancer at early stages and hence increasing survival rate.
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Affiliation(s)
- Namita Sharma
- Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, Noida, UP, India
| | - Sudha Srivastava
- Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, Noida, UP, India.
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Overexpression of microRNA-345 Affects the Invasive Capacity of Pancreatic Ductal Adenocarcinoma Cell Lines by Suppressing MUC1 and TJP2 Expression. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12115351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
The majority of pancreatic carcinomas are pancreatic ductal adenocarcinomas (PDAC), and the presence of non-invasive pancreatic intraepithelial neoplasia or intraductal papillary mucinous neoplasm, as an associated lesion, is considered important. These microscopic hyperplastic or grossly papillomatous lesions exhibit varying degrees of morphological atypia and may develop into invasive carcinomas. In this study, we investigated whether mucin-1 (MUC1) is involved in the progression of pancreatic carcinoma and examined the mechanisms by which microRNAs regulate MUC1 expression in vitro. In PDAC cell lines, suppression of MUC1 expression reduced cell proliferation and invasion; PDAC cell lines transfected with an miR-345 precursor suppressed the expression of MUC1, and reduced cell proliferation and invasion. Tight junction protein 2 (TJP2), a putative target of miR-345, is regulated by MUC1. The suppression of TJP2 expression reduced cell proliferation by inducing apoptosis. These results suggest that MUC1 and TJP2, the putative target molecules of miR-345, are critical in maintaining the invasive potential of pancreatic carcinoma cells, and regulating their expression may prevent the progression of non-invasive pancreatic intraductal lesions to invasive carcinomas. This study provides new insights for the development of novel molecular targeted therapies for pancreatic carcinomas.
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Li Y, Zu L, Wu H, Zhang F, Fan Y, Pan H, Du X, Guo F, Zhou Q. MiR-192/NKRF axis confers lung cancer cell chemoresistance to cisplatin via the NF-κB pathway. Thorac Cancer 2021; 13:430-441. [PMID: 34953057 PMCID: PMC8807278 DOI: 10.1111/1759-7714.14278] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 11/29/2021] [Accepted: 11/30/2021] [Indexed: 02/05/2023] Open
Abstract
Background Chemoresistance influences the therapeutic effect of cisplatin and remains a major obstacle to its clinical use. MicroRNAs are associated with drug resistance of various tumors. However, the association between microRNAs and cisplatin in lung cancer remains largely unclear. Methods MicroRNA expression profile was identified by microRNA microarray between the lung cancer cisplatin‐sensitive cell line A549 (A549) and cisplatin‐resistant cell line A549/DDP (A549/DDP) and confirmed by quantitative real‐time‐PCR (qRT‐PCR). In vitro loss‐ and gain‐of‐function studies were performed to reveal the biological function of miR‐192 and related mechanism of the microRNA‐192/NKRF axis in lung cancer cell cisplatin resistance. Results Increased miR‐192 expression was detected in A549/DDP cells compared to A549. High miR‐192 expression significantly suppressed apoptosis, enhanced proliferation, and conferred resistance to cisplatin in lung cancer cells. NF‐κB repressing factor (NKRF), which is involved in the regulation of the NF‐κB signaling pathway, was identified as a direct target of miR‐192. Overexpression of miR‐192 significantly increased the nuclear protein amount and transcriptional activation of NF‐κB and expression of cIAP1, cIAP2, Bcl‐xl and XIAP, whereas decreased miR‐192 expression did the opposite. Inhibition of the NF‐κB signal pathway by curcumin reversed the effect of upregulation of miR‐192 on proliferation, apoptosis and cisplatin‐resistance in lung cancer cells. These results indicated that miR‐192/ NKRF axis enhances the cisplatin resistance of lung cancer cells through activating the NF‐κB pathway in vitro. Conclusions MiR‐192 plays a crucial role in cisplatin‐resistance of lung cancer cells. Thus, MiR‐192 may represent a therapeutic target for overcoming resistance to cisplatin‐based chemotherapy in lung cancer.
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Affiliation(s)
- Yang Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Lingling Zu
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Heng Wu
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Fang Zhang
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yaguang Fan
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Hongli Pan
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Xinxin Du
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Fengjie Guo
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Qinghua Zhou
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.,Sichuan Lung Cancer Institute, Sichuan Lung Cancer Center, West China Hospital, Chengdu, Sichuan University, China
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Schlick K, Kiem D, Greil R. Recent Advances in Pancreatic Cancer: Novel Prognostic Biomarkers and Targeted Therapy-A Review of the Literature. Biomolecules 2021; 11:1469. [PMID: 34680101 PMCID: PMC8533343 DOI: 10.3390/biom11101469] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/27/2021] [Accepted: 10/01/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic adenocarcinoma carries a devastating prognosis. For locally advanced and metastatic disease, several chemotherapeutic regimens are currently being used. Over the past years, novel approaches have included targeting EGFR, NTRK, PARP, K-Ras as well as stroma and fibrosis, leading to approval of NTRK and PARP inhibitors. Moreover, immune check point inhibitors and different combinational approaches involving immunotherapeutic agents are being investigated in many clinical trials. MiRNAs represent a novel tool and are thought to greatly improve management by allowing for earlier diagnosis and for more precise guidance of treatment.
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Affiliation(s)
- Konstantin Schlick
- Oncologic Center, Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Paracelsus Medical University, 5020 Salzburg, Austria; (K.S.); (D.K.)
- Cancer Cluster Salzburg, 5020 Salzburg, Austria
| | - Dominik Kiem
- Oncologic Center, Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Paracelsus Medical University, 5020 Salzburg, Austria; (K.S.); (D.K.)
- Cancer Cluster Salzburg, 5020 Salzburg, Austria
| | - Richard Greil
- Oncologic Center, Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Paracelsus Medical University, 5020 Salzburg, Austria; (K.S.); (D.K.)
- Cancer Cluster Salzburg, 5020 Salzburg, Austria
- Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Salzburg Cancer Research Institute, 5020 Salzburg, Austria
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Wulf MG, Maguire S, Dai N, Blondel A, Posfai D, Krishnan K, Sun Z, Guan S, Corrêa IR. Chemical capping improves template switching and enhances sequencing of small RNAs. Nucleic Acids Res 2021; 50:e2. [PMID: 34581823 PMCID: PMC8754658 DOI: 10.1093/nar/gkab861] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 08/26/2021] [Accepted: 09/14/2021] [Indexed: 12/16/2022] Open
Abstract
Template-switching reverse transcription is widely used in RNA sequencing for low-input and low-quality samples, including RNA from single cells or formalin-fixed paraffin-embedded (FFPE) tissues. Previously, we identified the native eukaryotic mRNA 5′ cap as a key structural element for enhancing template switching efficiency. Here, we introduce CapTS-seq, a new strategy for sequencing small RNAs that combines chemical capping and template switching. We probed a variety of non-native synthetic cap structures and found that an unmethylated guanosine triphosphate cap led to the lowest bias and highest efficiency for template switching. Through cross-examination of different nucleotides at the cap position, our data provided unequivocal evidence that the 5′ cap acts as a template for the first nucleotide in reverse transcriptase-mediated post-templated addition to the emerging cDNA—a key feature to propel template switching. We deployed CapTS-seq for sequencing synthetic miRNAs, human total brain and liver FFPE RNA, and demonstrated that it consistently improves library quality for miRNAs in comparison with a gold standard template switching-based small RNA-seq kit.
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Affiliation(s)
- Madalee G Wulf
- New England Biolabs, Inc., 240 County Road, Ipswich, MA 01938, USA
| | - Sean Maguire
- New England Biolabs, Inc., 240 County Road, Ipswich, MA 01938, USA
| | - Nan Dai
- New England Biolabs, Inc., 240 County Road, Ipswich, MA 01938, USA
| | - Alice Blondel
- New England Biolabs, Inc., 240 County Road, Ipswich, MA 01938, USA
| | - Dora Posfai
- New England Biolabs, Inc., 240 County Road, Ipswich, MA 01938, USA
| | | | - Zhiyi Sun
- New England Biolabs, Inc., 240 County Road, Ipswich, MA 01938, USA
| | - Shengxi Guan
- New England Biolabs, Inc., 240 County Road, Ipswich, MA 01938, USA
| | - Ivan R Corrêa
- New England Biolabs, Inc., 240 County Road, Ipswich, MA 01938, USA
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12
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Label-free impedimetric miRNA-192 genosensor platform using graphene oxide decorated peptide nanotubes composite. Microchem J 2021. [DOI: 10.1016/j.microc.2021.106218] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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13
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Uddin MH, Al-Hallak MN, Philip PA, Mohammad RM, Viola N, Wagner KU, Azmi AS. Exosomal microRNA in Pancreatic Cancer Diagnosis, Prognosis, and Treatment: From Bench to Bedside. Cancers (Basel) 2021; 13:2777. [PMID: 34204940 PMCID: PMC8199777 DOI: 10.3390/cancers13112777] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is the fourth leading cause of cancer death among men and women in the United States, and pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of pancreatic cancer cases. PDAC is one of the most lethal gastrointestinal malignancies with an overall five-year survival rate of ~10%. Developing effective therapeutic strategies against pancreatic cancer is a great challenge. Novel diagnostic, prognostic, and therapeutic strategies are an immediate necessity to increase the survival of pancreatic cancer patients. So far, studies have demonstrated microRNAs (miRNAs) as sensitive biomarkers because of their significant correlation with disease development and metastasis. The miRNAs have been shown to be more stable inside membrane-bound vesicles in the extracellular environment called exosomes. Varieties of miRNAs are released into the body fluids via exosomes depending on the normal physiological or pathological conditions of the body. In this review, we discuss the recent findings on the diagnostic, prognostic, and therapeutic roles of exosomal miRNAs in pancreatic cancer.
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Affiliation(s)
| | | | | | | | | | | | - Asfar S. Azmi
- Departments of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (M.H.U.); (M.N.A.-H.); (P.A.P.); (R.M.M.); (N.V.); (K.-U.W.)
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14
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Non-Invasive Biomarkers for Earlier Detection of Pancreatic Cancer-A Comprehensive Review. Cancers (Basel) 2021; 13:cancers13112722. [PMID: 34072842 PMCID: PMC8198035 DOI: 10.3390/cancers13112722] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/20/2021] [Accepted: 05/27/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC), which represents approximately 90% of all pancreatic cancers, is an extremely aggressive and lethal disease. It is considered a silent killer due to a largely asymptomatic course and late clinical presentation. Earlier detection of the disease would likely have a great impact on changing the currently poor survival figures for this malignancy. In this comprehensive review, we assessed over 4000 reports on non-invasive PDAC biomarkers in the last decade. Applying the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool, we selected and reviewed in more detail 49 relevant studies reporting on the most promising candidate biomarkers. In addition, we also highlight the present challenges and complexities of translating novel biomarkers into clinical use. Abstract Pancreatic ductal adenocarcinoma (PDAC) carries a deadly diagnosis, due in large part to delayed presentation when the disease is already at an advanced stage. CA19-9 is currently the most commonly utilized biomarker for PDAC; however, it lacks the necessary accuracy to detect precursor lesions or stage I PDAC. Novel biomarkers that could detect this malignancy with improved sensitivity (SN) and specificity (SP) would likely result in more curative resections and more effective therapeutic interventions, changing thus the present dismal survival figures. The aim of this study was to systematically and comprehensively review the scientific literature on non-invasive biomarkers in biofluids such as blood, urine and saliva that were attempting earlier PDAC detection. The search performed covered a period of 10 years (January 2010—August 2020). Data were extracted using keywords search in the three databases: MEDLINE, Web of Science and Embase. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was applied for study selection based on establishing the risk of bias and applicability concerns in Patient Selection, Index test (biomarker assay) and Reference Standard (standard-of-care diagnostic test). Out of initially over 4000 published reports, 49 relevant studies were selected and reviewed in more detail. In addition, we discuss the present challenges and complexities in the path of translating the discovered biomarkers into the clinical setting. Our systematic review highlighted several promising biomarkers that could, either alone or in combination with CA19-9, potentially improve earlier detection of PDAC. Overall, reviewed biomarker studies should aim to improve methodological and reporting quality, and novel candidate biomarkers should be investigated further in order to demonstrate their clinical usefulness. However, challenges and complexities in the path of translating the discovered biomarkers from the research laboratory to the clinical setting remain and would have to be addressed before a more realistic breakthrough in earlier detection of PDAC is achieved.
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC.
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16
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Turanli B, Yildirim E, Gulfidan G, Arga KY, Sinha R. Current State of "Omics" Biomarkers in Pancreatic Cancer. J Pers Med 2021; 11:127. [PMID: 33672926 PMCID: PMC7918884 DOI: 10.3390/jpm11020127] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/08/2021] [Accepted: 02/11/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most fatal malignancies and the seventh leading cause of cancer-related deaths related to late diagnosis, poor survival rates, and high incidence of metastasis. Unfortunately, pancreatic cancer is predicted to become the third leading cause of cancer deaths in the future. Therefore, diagnosis at the early stages of pancreatic cancer for initial diagnosis or postoperative recurrence is a great challenge, as well as predicting prognosis precisely in the context of biomarker discovery. From the personalized medicine perspective, the lack of molecular biomarkers for patient selection confines tailored therapy options, including selecting drugs and their doses or even diet. Currently, there is no standardized pancreatic cancer screening strategy using molecular biomarkers, but CA19-9 is the most well known marker for the detection of pancreatic cancer. In contrast, recent innovations in high-throughput techniques have enabled the discovery of specific biomarkers of cancers using genomics, transcriptomics, proteomics, metabolomics, glycomics, and metagenomics. Panels combining CA19-9 with other novel biomarkers from different "omics" levels might represent an ideal strategy for the early detection of pancreatic cancer. The systems biology approach may shed a light on biomarker identification of pancreatic cancer by integrating multi-omics approaches. In this review, we provide background information on the current state of pancreatic cancer biomarkers from multi-omics stages. Furthermore, we conclude this review on how multi-omics data may reveal new biomarkers to be used for personalized medicine in the future.
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Affiliation(s)
- Beste Turanli
- Department of Bioengineering, Marmara University, 34722 Istanbul, Turkey; (B.T.); (E.Y.); (G.G.)
| | - Esra Yildirim
- Department of Bioengineering, Marmara University, 34722 Istanbul, Turkey; (B.T.); (E.Y.); (G.G.)
| | - Gizem Gulfidan
- Department of Bioengineering, Marmara University, 34722 Istanbul, Turkey; (B.T.); (E.Y.); (G.G.)
| | - Kazim Yalcin Arga
- Department of Bioengineering, Marmara University, 34722 Istanbul, Turkey; (B.T.); (E.Y.); (G.G.)
- Turkish Institute of Public Health and Chronic Diseases, 34718 Istanbul, Turkey
| | - Raghu Sinha
- Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA 17033, USA
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Diagnostic and Prognostic Role of miR-192 in Different Cancers: A Systematic Review and Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8851035. [PMID: 33614788 PMCID: PMC7878092 DOI: 10.1155/2021/8851035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/17/2020] [Accepted: 01/15/2021] [Indexed: 12/18/2022]
Abstract
Introduction It has been shown that miR-192 is abnormally expressed in a variety of cancer types and participates in different kinds of signaling pathways. The role of miR-192 in the diagnosis and prognosis of cancer has not been verified. This article is aimed at exploring the diagnostic and prognostic value of miR-192 through a systematic review and meta-analysis. Methods A systematic search was performed through PubMed, Embase, Web of Science, and Cochrane Library databases up to June 16, 2020. A total of 16 studies were enrolled in the meta-analyses, of which 11 articles were used for diagnostic meta-analysis and 5 articles were used for prognostic meta-analysis. The values of sensitivity and specificity using miR-192 expression as a diagnostic tool were pooled in the diagnostic meta-analysis. The hazard ratios (HRs) of overall survival (OS) with 95 confidence intervals (CIs) were extracted from the studies, and pooled HRs were evaluated in the prognostic meta-analysis. Eleven studies including 667 cancer patients and 514 controls met the eligibility criteria for the diagnostic meta-analysis. Five studies including 166 patients with high miR-192 expression and 236 patients with low miR-192 expression met the eligibility criteria for the prognostic meta-analysis. Results The overall diagnostic accuracy was as follows: sensitivity 0.79 (95%CI = 0.75-0.82), specificity 0.74 (95%CI = 0.64-0.82), positive likelihood ratio 3.03 (95%CI = 2.11-4.34), negative likelihood ratio 0.29 (95%CI = 0.23-0.37), diagnostic odds ratio 10.50 (95%CI = 5.89-18.73), and area under the curve ratio (AUC) 0.82 (95%CI = 0.78-0.85). The overall prognostic analysis showed that high expression of miR-192 in patients was associated with positive survival (HR = 0.62, 95%CI : 0.41-0.93, p = 0.020). Conclusion Our results revealed that miR-192 was a potential biomarker with good sensitivity and specificity in cancers. Moreover, highly expressed miR-192 predicted a good prognosis for patients.
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18
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Khan IA, Rashid S, Singh N, Rashid S, Singh V, Gunjan D, Das P, Dash NR, Pandey RM, Chauhan SS, Gupta S, Saraya A. Panel of serum miRNAs as potential non-invasive biomarkers for pancreatic ductal adenocarcinoma. Sci Rep 2021; 11:2824. [PMID: 33531550 PMCID: PMC7854650 DOI: 10.1038/s41598-021-82266-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 01/18/2021] [Indexed: 01/30/2023] Open
Abstract
Early-stage diagnosis of pancreatic ductal adenocarcinoma (PDAC) is difficult due to non-specific symptoms. Circulating miRNAs in body fluids have been emerging as potential non-invasive biomarkers for diagnosis of many cancers. Thus, this study aimed to assess a panel of miRNAs for their ability to differentiate PDAC from chronic pancreatitis (CP), a benign inflammatory condition of the pancreas. Next-generation sequencing was performed to identify miRNAs present in 60 FFPE tissue samples (27 PDAC, 23 CP and 10 normal pancreatic tissues). Four up-regulated miRNAs (miR-215-5p, miR-122-5p, miR-192-5p, and miR-181a-2-3p) and four down-regulated miRNAs (miR-30b-5p, miR-216b-5p, miR-320b, and miR-214-5p) in PDAC compared to CP were selected based on next-generation sequencing results. The levels of these 8 differentially expressed miRNAs were measured by qRT-PCR in 125 serum samples (50 PDAC, 50 CP, and 25 healthy controls (HC)). The results showed significant upregulation of miR-215-5p, miR-122-5p, and miR-192-5p in PDAC serum samples. In contrast, levels of miR-30b-5p and miR-320b were significantly lower in PDAC as compared to CP and HC. ROC analysis showed that these 5 miRNAs can distinguish PDAC from both CP and HC. Hence, this panel can serve as a non-invasive biomarker for the early detection of PDAC.
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Affiliation(s)
- Imteyaz Ahmad Khan
- grid.413618.90000 0004 1767 6103Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Safoora Rashid
- grid.413618.90000 0004 1767 6103Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Nidhi Singh
- grid.413618.90000 0004 1767 6103Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Sumaira Rashid
- grid.413618.90000 0004 1767 6103Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Vishwajeet Singh
- grid.413618.90000 0004 1767 6103Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
| | - Deepak Gunjan
- grid.413618.90000 0004 1767 6103Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Prasenjit Das
- grid.413618.90000 0004 1767 6103Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Nihar Ranjan Dash
- grid.413618.90000 0004 1767 6103Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Ravindra Mohan Pandey
- grid.413618.90000 0004 1767 6103Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
| | - Shyam Singh Chauhan
- grid.413618.90000 0004 1767 6103Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Surabhi Gupta
- grid.413618.90000 0004 1767 6103Department of Reproductive Biology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Anoop Saraya
- grid.413618.90000 0004 1767 6103Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
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19
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Deng F, Mu J, Qu C, Yang F, Liu X, Zeng X, Peng X. A Novel Prognostic Model of Endometrial Carcinoma Based on Clinical Variables and Oncogenomic Gene Signature. Front Mol Biosci 2021; 7:587822. [PMID: 33490103 PMCID: PMC7817972 DOI: 10.3389/fmolb.2020.587822] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 11/23/2020] [Indexed: 12/13/2022] Open
Abstract
Due to the difficulty in predicting the prognosis of endometrial carcinoma (EC) patients by clinical variables alone, this study aims to build a new EC prognosis model integrating clinical and molecular information, so as to improve the accuracy of predicting the prognosis of EC. The clinical and gene expression data of 496 EC patients in the TCGA database were used to establish and validate this model. General Cox regression was applied to analyze clinical variables and RNAs. Elastic net-penalized Cox proportional hazard regression was employed to select the best EC prognosis-related RNAs, and ridge regression was used to construct the EC prognostic model. The predictive ability of the prognostic model was evaluated by the Kaplan-Meier curve and the area under the receiver operating characteristic curve (AUC-ROC). A clinical-RNA prognostic model integrating two clinical variables and 28 RNAs was established. The 5-year AUC of the clinical-RNA prognostic model was 0.932, which is higher than that of the clinical-alone (0.897) or RNA-alone prognostic model (0.836). This clinical-RNA prognostic model can better classify the prognosis risk of EC patients. In the training group (396 patients), the overall survival of EC patients was lower in the high-risk group than in the low-risk group [HR = 32.263, (95% CI, 7.707-135.058), P = 8e-14]. The same comparison result was also observed for the validation group. A novel EC prognosis model integrating clinical variables and RNAs was established, which can better predict the prognosis and help to improve the clinical management of EC patients.
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Affiliation(s)
- Fang Deng
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Jing Mu
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Chiwen Qu
- School of Mathematics and Statistics, Hunan Normal University, Changsha, China
| | - Fang Yang
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xing Liu
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xiaomin Zeng
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xiaoning Peng
- School of Mathematics and Statistics, Hunan Normal University, Changsha, China.,Department of Pathology and Pathophysiology, Hunan Normal University School of Medicine, Changsha, China.,Department of Pathophysiology, Jishou University School of Medicine, Jishou, China
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20
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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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21
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Non-coding RNA biomarkers in pancreatic ductal adenocarcinoma. Semin Cancer Biol 2020; 75:153-168. [PMID: 33049362 DOI: 10.1016/j.semcancer.2020.10.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/20/2020] [Accepted: 10/02/2020] [Indexed: 12/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, which is usually diagnosed at an advanced stage. The late disease diagnosis, the limited availability of effective therapeutic interventions and lack of robust diagnostic biomarkers, are some of the primary reasons for the dismal 5-year survival rates (∼8%) in patients with PDAC. The pancreatic cancer develops through accumulation of a series of genomic and epigenomic alterations which lead to the transformation of normal pancreatic epithelium into an invasive carcinoma - a process that can take up to 15-20 years to develop, from the occurrence of first initiating mutational event. These facts highlight a unique window of opportunity for the earlier detection of PDAC, which could allow timely disease interception and improvement in the overall survival outcomes in patients suffering from this fatal malignancy. Non-coding RNAs (ncRNAs) have been recognized to play a central role in PDAC pathogenesis and are emerging as attractive candidates for biomarker development in various cancers, including PDAC. More specifically, the ncRNAs play a pivotal role in PDAC biology as they affect tumor growth, migration, and invasion by regulating cellular processes including cell cycle, apoptosis, and epithelial-mesenchymal transition. In this review, we focus on three types of well-established ncRNAs - microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) - and discuss their potential as diagnostic, prognostic and predictive biomarkers in PDAC.
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22
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Liang J, Cao D, Zhang X, Liu L, Tan Q, Shi S, Chen K, Liang J, Wang Z. miR-192-5p suppresses uterine receptivity formation through impeding epithelial transformation during embryo implantation. Theriogenology 2020; 157:360-371. [PMID: 32861000 DOI: 10.1016/j.theriogenology.2020.08.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 08/04/2020] [Accepted: 08/09/2020] [Indexed: 12/11/2022]
Abstract
The establishment of uterine receptivity is a prerequisite for embryo implantation and begins with the transformation of the luminal epithelium. MicroRNAs (miRNAs) have been widely reported to be involved in the regulation of embryo implantation, but their roles in establishing uterine receptivity remain unclear. In this study, through small RNA sequencing analysis, we showed that a low level of miR-192-5p is essential for initiating implantation in mice, and transient upregulation of miR-192-5p led to implantation failure. In situ hybridization results revealed that miR-192-5p was primarily expressed in the endometrial epithelium, and dysregulation of miR-192-5p interfered with the performance of the luminal epithelium, resulting in inadequate receptivity. By manipulating miR-192-5p expression in mouse uterus and an endometrial epithelial cell line, we showed that miR-192-5p maintains cell polarity through stabilizing adherens junction protein E-cadherin, thereby preventing epithelial-mesenchymal transition. Furthermore, miR-192-5p preserved the pattern of microvilli as well as Muc1 expression on the apical membrane of epithelial cells, thereby avoiding embryo adhesion. Moreover, miR-192-5p was found to be regulated by ovarian steroids. Collectively, this study demonstrated that the physiological role of miR-192-5p in mouse uterus is to maintain the nonreceptive state of epithelial cells and prevent their transformation to the receptive state. Thus, a sustained high level of miR-192-5p is detrimental to embryo implantation. These findings help elucidate the mechanisms involved in miRNA-based regulation of uterine physiology in early pregnancy, and may even contribute to the diagnosis and treatment of infertility.
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Affiliation(s)
- Jingjie Liang
- College of Animal Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, PR China
| | - Dingren Cao
- College of Animal Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, PR China
| | - Xiaowei Zhang
- Zhejiang Animal Husbandry Techniques Extension Station, Hangzhou, 310020, PR China
| | - Lijun Liu
- Zhejiang Animal Husbandry Techniques Extension Station, Hangzhou, 310020, PR China
| | - Qiang Tan
- College of Animal Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, PR China
| | - Shuang Shi
- College of Animal Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, PR China
| | - Kaiyu Chen
- College of Animal Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, PR China
| | - Junyong Liang
- College of Animal Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, PR China
| | - Zhengguang Wang
- College of Animal Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, PR China.
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Mishan MA, Tabari MAK, Parnian J, Fallahi J, Mahrooz A, Bagheri A. Functional mechanisms of miR-192 family in cancer. Genes Chromosomes Cancer 2020; 59:722-735. [PMID: 32706406 DOI: 10.1002/gcc.22889] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 07/14/2020] [Accepted: 07/21/2020] [Indexed: 12/11/2022] Open
Abstract
By growing research on the mechanisms and functions of microRNAs (miRNAs, miRs), the role of these noncoding RNAs gained more attention in healthcare. Due to the remarkable regulatory role of miRNAs, any dysregulation in their expression causes cellular functional impairment. In recent years, it has become increasingly apparent that these small molecules contribute to development, cell differentiation, proliferation, apoptosis, and tumor growth. In many studies, the miR-192 family has been suggested as a potential prognostic and diagnostic biomarker and even as a possible therapeutic target for several cancers. However, the mechanistic effects of the miR-192 family on cancer cells are still controversial. Here, we have reviewed each family member of the miR-192 including miR-192, miR-194, and miR-215, and discussed their mechanistic roles in various cancers.
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Affiliation(s)
- Mohammad Amir Mishan
- Ocular Tissue Engineering Research Center, Research Institute for Ophthalmology and Vision Science, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Amin Khazeei Tabari
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
- USERN Office, Mazandaran University of Medical Sciences, Sari, Iran
| | - Javad Parnian
- Department of Biotechnology, Iranian Research Organization for Science and Technology, Tehran, Iran
| | - Jafar Fallahi
- Molecular Medicine Department, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abdolkarim Mahrooz
- Department of Clinical Biochemistry and Medical Genetics, Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Abouzar Bagheri
- Department of Clinical Biochemistry and Medical Genetics, Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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24
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Flammang I, Reese M, Yang Z, Eble JA, Dhayat SA. Tumor-Suppressive miR-192-5p Has Prognostic Value in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2020; 12:E1693. [PMID: 32630552 PMCID: PMC7352756 DOI: 10.3390/cancers12061693] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 06/20/2020] [Accepted: 06/22/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by fast tumor progression and diagnosis at advanced, inoperable stages. Previous studies could demonstrate an involvement of miR-192-5p in epigenetic regulation of visceral carcinomas. Due to contradictory results, however, the clinical utility of miR-192-5p in PDAC has yet to be determined. MiR-192-5p expression was analyzed by RT-qRT-PCR in human PDAC and benign tissue (n = 78), blood serum (n = 81) and serum exosomes (n = 74), as well as in PDAC cell lines (n = 5), chemoresistant cell clones (n = 2), and pancreatic duct cell line H6c7. Analysis of EMT-associated (epithelial-to-mesenchymal transition) proteins was performed by immunohistochemistry and Western blot. MiR-192-5p was deregulated in PDAC as compared to healthy controls (HCs), with downregulation in macrodissected tissue (p < 0.001) and upregulation in blood serum of PDAC UICC (Union for International Cancer Control) stage IV (p = 0.016) and serum exosomes of PDAC UICC stages II to IV (p < 0.001). MiR-192-5p expression in tumor tissue was significantly lower as compared to corresponding peritumoral tissue (PDAC UICC stage II: p < 0.001; PDAC UICC stage III: p = 0.024), while EMT markers ZEB1 and ZEB2 were more frequently expressed in tumor tissue as compared to peritumoral tissue, HCs, and chronic pancreatitis. Tissue-derived (AUC of 0.86; p < 0.0001) and exosomal (AUC of 0.83; p = 0.0004) miR-192-5p could differentiate between PDAC and HCs with good accuracy. Furthermore, high expression of miR-192-5p in PDAC tissue of curatively resected PDAC patients correlated with prolonged overall and recurrence-free survival in multivariate analysis. In vitro, miR-192-5p was downregulated in gemcitabine-resistant cell clones of AsPC-1 (p = 0.029). Transient transfection of MIA PaCa-2 cells with miR-192-5p mimic resulted in downregulation of ZEB2. MiR-192-5p seems to possess a tumor-suppressive role and high potential as a diagnostic and prognostic marker in PDAC.
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Affiliation(s)
- Isabelle Flammang
- Department of General, Visceral and Transplantation Surgery, University Hospital Muenster, Albert-Schweitzer-Campus 1 (W1), 48149 Muenster, Germany; (I.F.); (M.R.); (Z.Y.)
| | - Moritz Reese
- Department of General, Visceral and Transplantation Surgery, University Hospital Muenster, Albert-Schweitzer-Campus 1 (W1), 48149 Muenster, Germany; (I.F.); (M.R.); (Z.Y.)
| | - Zixuan Yang
- Department of General, Visceral and Transplantation Surgery, University Hospital Muenster, Albert-Schweitzer-Campus 1 (W1), 48149 Muenster, Germany; (I.F.); (M.R.); (Z.Y.)
| | - Johannes A. Eble
- Department of Physiological Chemistry and Pathobiochemistry, University of Muenster, Waldeyerstrasse 15, 48149 Muenster, Germany;
| | - Sameer A. Dhayat
- Department of General, Visceral and Transplantation Surgery, University Hospital Muenster, Albert-Schweitzer-Campus 1 (W1), 48149 Muenster, Germany; (I.F.); (M.R.); (Z.Y.)
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25
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Terrinoni A, Calabrese C, Basso D, Aita A, Caporali S, Plebani M, Bernardini S. The circulating miRNAs as diagnostic and prognostic markers. Clin Chem Lab Med 2020; 57:932-953. [PMID: 30838832 DOI: 10.1515/cclm-2018-0838] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Accepted: 10/23/2018] [Indexed: 02/07/2023]
Abstract
A large portion of the human genome transcribes RNA sequences that do not code for any proteins. The first of these sequences was identified in 1993, and the best known noncoding RNAs are microRNA (miRNAs). It is now fully established that miRNAs regulate approximately 30% of the known genes that codify proteins. miRNAs are involved in several biological processes, like cell proliferation, differentiation, apoptosis and metastatization. These RNA products regulate gene expression at the post-transcriptional level, modulating or inhibiting protein expression by interacting with specific sequences of mRNAs. Mature miRNAs can be detected in blood plasma, serum and also in a wide variety of biological fluids. They can be found associated with proteins, lipids as well as enclosed in exosome vesicles. We know that circulating miRNAs (C-miRNAs) can regulate several key cellular processes in tissues different from the production site. C-miRNAs behave as endogenous mediators of RNA translation, and an extraordinary knowledge on their function has been obtained in the last years. They can be secreted in different tissue cells and associated with specific pathological conditions. Significant evidence indicates that the initiation and progression of several pathologies are "highlighted" by the presence of specific C-miRNAs, underlining their potential diagnostic relevance as clinical biomarkers. Here we review the current literature on the possible use of this new class of molecules as clinical biomarkers of diseases.
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Affiliation(s)
- Alessandro Terrinoni
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy
| | - Cosimo Calabrese
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Daniela Basso
- Department of Medicine - DIMED; Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy
| | - Ada Aita
- Department of Medicine - DIMED; Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy
| | - Sabrina Caporali
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Mario Plebani
- Department of Medicine - DIMED; Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy
| | - Sergio Bernardini
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
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26
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Cohen SJ, Papoulas M, Graubardt N, Ovdat E, Loewenstein S, Kania-Almog J, Pasmanik-Chor M, Brazowski E, Cagnano E, Nachmany I, Lahat G, Klausner JM, Lubezky N. Micro-RNA Expression Patterns Predict Metastatic Spread in Solid Pseudopapillary Neoplasms of the Pancreas. Front Oncol 2020; 10:328. [PMID: 32232006 PMCID: PMC7082878 DOI: 10.3389/fonc.2020.00328] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 02/25/2020] [Indexed: 12/17/2022] Open
Abstract
Solid pseudopapillary neoplasm (SPN) of pancreas is a rare pancreatic neoplasm with a low metastatic potential. Up to 10% of patients with localized disease at presentation will develop systemic metastases, usually in the peritoneum or the liver. Due to the rarity of SPNs and the overall excellent prognosis, reliable prognostic factors to predict malignant biological behavior remain undetermined. Therefore, we aimed to define clinical, histological, and microRNA patterns that are associated with metastatic disease. We conducted a retrospective single center study on all patients operated for SPN of pancreas between 1995 and 2018. Clinical and pathological data were collected, and expression patterns of 2,578 human microRNAs were analyzed using microRNA array (Affimetrix 4.1) in normal pancreases (NPs), localized tumors (LTs), and metastatic tumors (MTs). The diagnosis of SPN was confirmed in 35 patients who included 28 females and 3 males, with a mean age of 33.8 ± 13.9 years. The only clinical factor associated with metastases was tumor size (mean tumor size 5.20 ± 3.78 in LT vs. 8.13± 1.03 in MT, p < 0.012). Microscopic features of malignancy were not associated with metastases, nor were immunohistochemical stains, including the proliferative index KI67. Higher expressions of miR-184, miR-10a, and miR-887, and lower expressions of miR-375, miR-217, and miR-200c were observed in metastatic tissues on microarray, and validated by real-time polymerase chain reaction. Hierarchal clustering demonstrated that the microRNA expression pattern of MTs was significantly different from that of LTs. The only clinical factor associated with metastases of SPN of pancreas was tumor size. Histological features and immunohistological staining were not predictive of metastases. A panel of six microRNAs was differentially expressed in MTs, and these findings could potentially be used to predict tumor behavior. Validation of these results is needed in larger series.
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Affiliation(s)
- Shmuel Jaffe Cohen
- Surgical Division Research Laboratory, Tel-Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Michail Papoulas
- Department of Surgery, Tel-Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Nadine Graubardt
- Surgical Division Research Laboratory, Tel-Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Esther Ovdat
- Department of Surgery, Tel-Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Shelly Loewenstein
- Surgical Division Research Laboratory, Tel-Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Juliane Kania-Almog
- Surgical Division Research Laboratory, Tel-Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | | | - Eli Brazowski
- Tel-Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Institute of Pathology, Tel-Aviv University, Tel-Aviv, Israel
| | - Emanuela Cagnano
- Tel-Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Institute of Pathology, Tel-Aviv University, Tel-Aviv, Israel
| | - Ido Nachmany
- Department of Surgery, Tel-Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Guy Lahat
- Department of Surgery, Tel-Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Joseph M Klausner
- Department of Surgery, Tel-Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Nir Lubezky
- Surgical Division Research Laboratory, Tel-Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,Department of Surgery, Tel-Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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27
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Huang Q, Hou S, Zhu X, Liu S. MicroRNA-192 promotes the development of nasopharyngeal carcinoma through targeting RB1 and activating PI3K/AKT pathway. World J Surg Oncol 2020; 18:29. [PMID: 32013999 PMCID: PMC6998165 DOI: 10.1186/s12957-020-1798-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 01/20/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The dysregulation of microRNAs (miRNAs) has been found in diseases and cancers, including microRNA-192 (miR-192). This study was designed to investigate the role of miR-192 in nasopharyngeal carcinoma (NPC) progression. METHODS The expression levels of miR-192 and some genes were assessed by qRT-PCR and Western blot. The function of miR-192 was investigated through MTT, Transwell, and dual-luciferase reporter assays. RESULTS The expression of miR-192 was increased in NPC tissues, and high miR-192 expression predicted poor prognosis in NPC patients. Functionally, upregulation of miR-192 promoted NPC cell migration, invasion, and growth. Furthermore, miR-192 activated EMT and PI3K/AKT pathway to regulate NPC progression. In addition, miR-192 directly targeted RB1 and suppressed its expression in NPC. Moreover, overexpression of RB1 weakened the promoted effect of miR-192 in NPC. CONCLUSION miR-192 promoted cell viability and metastasis in NPC through suppressing RB1 expression and activating PI3K/AKT pathway.
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Affiliation(s)
- Qingli Huang
- Department of Otorhinolaryngology Head and Neck Surgery, Liaocheng People's Hospital, No.67 Dongchang West Road, Liaocheng, 252000, Shandong Province, People's Republic of China
| | - Sen Hou
- Department of Otolaryngology, Yanggu People's Hospital, Liaocheng, Shandong Province, People's Republic of China
| | - Xiuqing Zhu
- Department of Otolaryngology, Chiping People's Hospital, Liaocheng, Shandong Province, People's Republic of China
| | - Shouzhou Liu
- Department of Otorhinolaryngology Head and Neck Surgery, Liaocheng People's Hospital, No.67 Dongchang West Road, Liaocheng, 252000, Shandong Province, People's Republic of China.
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28
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Tesfaye AA, Azmi AS, Philip PA. miRNA and Gene Expression in Pancreatic Ductal Adenocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:58-70. [PMID: 30558723 DOI: 10.1016/j.ajpath.2018.10.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/20/2018] [Accepted: 10/04/2018] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease that is mostly diagnosed late in the course of the illness. Unlike other cancers in which measurable successes have been achieved with traditional chemotherapy, targeted therapy, and, recently, immunotherapy, PDAC has proved to be poorly responsive to these treatments, with only marginal to modest incremental benefits using conventional cytotoxic therapy. There is, therefore, a great unmet need to develop better therapies based on improved understanding of biology and identification of predictive and prognostic biomarkers that would guide therapy. miRNAs are small noncoding RNAs that regulate the expression of some key genes by targeting their 3'-untranslated mRNA region. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. A series of miRNAs have been identified as potential tools for early diagnosis, prediction of treatment response, and prognosis of patients with PDAC. In this review, we present a summary of the miRNAs that have been studied in PDAC in the context of disease biology.
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Affiliation(s)
- Anteneh A Tesfaye
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
| | - Asfar S Azmi
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Philip A Philip
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan
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29
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Farzanehpour M, Mozhgani SH, Jalilvand S, Faghihloo E, Akhavan S, Salimi V, Azad TM. Serum and tissue miRNAs: potential biomarkers for the diagnosis of cervical cancer. Virol J 2019; 16:116. [PMID: 31590680 PMCID: PMC6781360 DOI: 10.1186/s12985-019-1220-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 09/05/2019] [Indexed: 12/13/2022] Open
Abstract
Background Finding new biomarkers for the early detection of cervical cancer is an essential requirement in this field. In this study, we aimed to evaluate the expression level of potential biomarkers in progression of cervical cancer in patients with cervical cancer compared to normal subjects. Methods The expression levels of tissue and serum miRNAs, including miR-9, miR-192 and miR-205, were investigated in 36 normal, 18 precancer, and 18 cervical cancer samples using real-time polymerase chain reaction. Results The results showed the higher significant expressions of miR-9, miR-192 and miR-205 in the tissue of cancer samples than those in the normal samples. Moreover, the miR-192 and miR-205 expression were significantly increased in the cancer group in comparison with the precancer group. Examination of serum samples revealed the increase in the expression level in the cancer groups than in the normal samples, for miR-9, miR-192 and miR-205 and the expressions of miR-9, miR-192 and miR-205 were significantly up-regulated in the precancer group in comparison with the normal group. Also the expression of miR-205 was remarkably increased in the cancer group in comparison with the precancer group. The receiver operating characteristic (ROC) analyses showed the highest area under the curve value for miR-192. Conclusions Given the increased expression level of miR-192 in cancer and in precancerous tissue and serum compared with the normal tissue and serum validated by analysing the ROC curve, miR-192 can be used as potential biomarker for the early detection of cervical cancer.
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Affiliation(s)
- Mahdieh Farzanehpour
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 1471613151, Iran
| | - Sayed-Hamidreza Mozhgani
- Department of Microbiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.,Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Somayeh Jalilvand
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 1471613151, Iran
| | - Ebrahim Faghihloo
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Setareh Akhavan
- Department of Gynecology Oncology, Imam Khomeini Hospital Complex, Valiasr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Salimi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 1471613151, Iran
| | - Talat Mokhtari Azad
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 1471613151, Iran.
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30
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Rawat M, Kadian K, Gupta Y, Kumar A, Chain PSG, Kovbasnjuk O, Kumar S, Parasher G. MicroRNA in Pancreatic Cancer: From Biology to Therapeutic Potential. Genes (Basel) 2019; 10:752. [PMID: 31557962 PMCID: PMC6827136 DOI: 10.3390/genes10100752] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/19/2019] [Accepted: 09/20/2019] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer is one of the most aggressive malignancies, accounting for more than 45,750 deaths annually in the U.S. alone. The aggressive nature and late diagnosis of pancreatic cancer, coupled with the limitations of existing chemotherapy, present the pressing need for the development of novel therapeutic strategies. Recent reports have demonstrated a critical role of microRNAs (miRNAs) in the initiation, progression, and metastasis of cancer. Furthermore, aberrant expressions of miRNAs have often been associated with the cause and consequence of pancreatic cancer, emphasizing the possible use of miRNAs in the effective management of pancreatic cancer patients. In this review, we provide a brief overview of miRNA biogenesis and its role in fundamental cellular process and miRNA studies in pancreatic cancer patients and animal models. Subsequent sections narrate the role of miRNA in, (i) cell cycle and proliferation; (ii) apoptosis; (iii) invasions and metastasis; and (iv) various cellular signaling pathways. We also describe the role of miRNA's in pancreatic cancer; (i) diagnosis; (ii) prognosis and (iii) therapeutic intervention. Conclusion section describes the gist of review with future directions.
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Affiliation(s)
- Manmeet Rawat
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
| | - Kavita Kadian
- Department of Biotechnology, Kumaun University, Nainital, Uttarakhand 263001, India.
| | - Yash Gupta
- Department of Internal Medicine, Loyola University Medical Center, Chicago, IL 60153, USA.
| | - Anand Kumar
- Biosecurity and Public Health Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
| | - Patrick S G Chain
- Biosecurity and Public Health Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
| | - Olga Kovbasnjuk
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
| | - Suneel Kumar
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
| | - Gulshan Parasher
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
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31
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Gao Z, Jiang W, Zhang S, Li P. The State of the Art on Blood MicroRNAs in Pancreatic Ductal Adenocarcinoma. Anal Cell Pathol (Amst) 2019; 2019:9419072. [PMID: 31583198 PMCID: PMC6754866 DOI: 10.1155/2019/9419072] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 09/03/2019] [Indexed: 02/07/2023] Open
Abstract
Despite enormous advances being made in diagnosis and therapeutic interventions, pancreatic ductal adenocarcinoma (PDAC) is still recognized as one of the most lethal malignancies. Early diagnosis and timely curative surgery can markedly improve the prognosis; hence, there is an unmet necessity to explore efficient biomarkers for patients' benefit. Recently, blood miRNAs (miRNAs) have been reported to be a novel biomarker in human cancers. Part of it is selectively packaged by plasma exosomes released from cells via exocytosis and is highly sensitive to changes in the tumor microenvironment. Furthermore, due to less invasiveness and technical availability, miRNA-based liquid biopsy holds promise for further wide usage. Therefore, this review is aimed at presenting an update on the association between blood miRNAs and the biology of PDAC, then discussing its clinical utilization further.
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Affiliation(s)
- Zhuqing Gao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Wei Jiang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
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32
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Xue J, Jia E, Ren N, Lindsay A, Yu H. Circulating microRNAs as promising diagnostic biomarkers for pancreatic cancer: a systematic review. Onco Targets Ther 2019; 12:6665-6684. [PMID: 31692495 PMCID: PMC6707936 DOI: 10.2147/ott.s207963] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 07/16/2019] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer (PC) is one of the most common forms of malignant tumors and causes of tumor-related death worldwide. The current prognosis of PC still remains poor due to the lack of effective early detection method. Recently, there is strong support that circulating miRNAs can be used as biomarkers for early detection of various cancers, including PC. The purpose of this review is to provide an overview of previous published studies on circulating miRNAs in plasma/serum for early detection of PC and summarize their diagnostic value. PubMed, Embase and Web of Science were systematically searched for eligible studies on circulating miRNAs for PC detection. Overall, 29 studies published between 2009 and 2018 evaluating 51 individual miRNAs (no P-value exceeding 0.05) and 13 miRNAs panels were included. Generally, the diagnostic performance of circulating miRNAs for PC detection was strong, with both the sensitivity and specificity of 36% individual miRNAs and 40% miRNAs panels exceeding 80%. Moreover, two promising miRNA panels were discovered and verified externally with all AUC values exceeding 0.95. Therefore, circulating miRNAs may hold potential to be used as noninvasive diagnostic biomarkers for PC, but large-scale studies are still needed to validate the promising miRNAs and optimize the miRNA panels. Since, the tremendous heterogeneity of studies in this field hampers translating miRNA markers into clinical practice, miRNA analytical procedures are also needed to be standardized in the future.
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Affiliation(s)
- Jinru Xue
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, People's Republic of China
| | - Erna Jia
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, People's Republic of China
| | - Na Ren
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, People's Republic of China
| | - Andrew Lindsay
- Major Cancer Biology, German Cancer Research Center, Heidelberg, Germany.,Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Haixin Yu
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, People's Republic of China.,Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany
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33
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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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A comprehensive analysis of core polyadenylation sequences and regulation by microRNAs in a set of cancer predisposition genes. Gene 2019; 712:143943. [PMID: 31229581 DOI: 10.1016/j.gene.2019.143943] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 06/18/2019] [Accepted: 06/20/2019] [Indexed: 12/27/2022]
Abstract
Two core polyadenylation elements (CPE) located in the 3' untranslated region of eukaryotic pre-mRNAs play an essential role in their processing: the polyadenylation signal (PAS) AAUAAA and the cleavage site (CS), preferentially a CA dinucleotide. Herein, we characterized PAS and CS sequences in a set of cancer predisposition genes (CPGs) and performed an in silico investigation of microRNAs (miRNAs) regulation to identify potential tumor-suppressive and oncogenic miRNAs. NCBI and alternative polyadenylation databases were queried to characterize CPE sequences in 117 CPGs, including 81 and 17 known tumor suppressor genes and oncogenes, respectively. miRNA-mediated regulation analysis was performed using predicted and validated data sources. Based on NCBI analyses, we did not find an established PAS in 21 CPGs, and verified that the majority of PAS already described (74.4%) had the canonical sequence AAUAAA. Interestingly, "AA" dinucleotide was the most common CS (37.5%) associated with this set of genes. Approximately 90% of CPGs exhibited evidence of alternative polyadenylation (more than one functional PAS). Finally, the mir-192 family was significantly overrepresented as regulator of tumor suppressor genes (P < 0.01), which suggests a potential oncogenic function. Overall, this study provides a landscape of CPE in CPGs, which might be useful in development of future molecular analyses covering these frequently neglected regulatory sequences.
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Jiang X, Hou D, Wei Z, Zheng S, Zhang Y, Li J. Extracellular and intracellular microRNAs in pancreatic cancer: from early diagnosis to reducing chemoresistance. ACTA ACUST UNITED AC 2019. [DOI: 10.1186/s41544-019-0014-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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He B, Chang Y, Yang C, Zhang Z, Xu G, Feng X, Zhuang L. Adenylate cyclase 7 regulated by miR-192 promotes ATRA-induced differentiation of acute promyelocytic leukemia cells. Biochem Biophys Res Commun 2018; 506:543-547. [PMID: 30366671 DOI: 10.1016/j.bbrc.2018.10.125] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 10/20/2018] [Indexed: 12/25/2022]
Abstract
Adenylate cyclase 7 (AC7) has been reported to participate in various biological processes during cancer progression. However, the roles of AC7 in all-trans retinoic acid (ATRA)-induced differentiation of acute promyelocytic leukemia (APL) cells are still unknown. In this study, firstly, our results showed that AC7 affected intracellular cAMP level and influenced ATRA-induced differentiation of APL cells. Secondly, we revealed that miR-192 could directly target AC7 expression and knockdown of miR-192 promoted ATRA-induced APL cell differentiation by regulating AC7 expression. Furthermore, we found that AC7 expression was lower in patients with relapsed APL than that in patients with newly diagnosed APL, while miR-192 expression was relatively higher in patients with relapsed APL. Taken together, our results show that miR-192-mediated AC7 could play important roles in differentiation of APL cells, AC7 and miR-192 might be new biomarkers and therapeutic targets for patients with relapsed APL.
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Affiliation(s)
- Bing He
- Department of General Surgery, The First People's Hospital of Tianmen City, Tianmen, 431700, China
| | - Yanyan Chang
- Department of Haematology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Chao Yang
- Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Zhanglin Zhang
- Department of Laboratorial Examination, The First Affiliated Hospital of Nanchang University, 330006, Nanchang, China
| | - Guiping Xu
- Transfusion Department, The Second Affiliated Hospital of Chongqing Medical University, 400010, Chongqing, China
| | - Xianqi Feng
- Department of Haematology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
| | - Likun Zhuang
- Institute of Transplantation Science, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
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Xu XY, Wu D, Xu SY, Che LQ, Fang ZF, Feng B, Li J, Wu CM, Lin Y. Comparison of microRNA transcriptomes reveals differential regulation of microRNAs in different-aged boars. Theriogenology 2018; 119:105-113. [DOI: 10.1016/j.theriogenology.2018.06.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 06/25/2018] [Accepted: 06/27/2018] [Indexed: 12/13/2022]
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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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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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Tian C, Zhang L, Li X, Zhang Y, Li J, Chen L. Low miR-192 expression predicts poor prognosis in pediatric acute myeloid leukemia. Cancer Biomark 2018; 22:209-215. [PMID: 29689705 DOI: 10.3233/cbm-170657] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Chunmei Tian
- Department of Pediatrics, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong, China
| | - Lin Zhang
- Department of Radiology, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong, China
| | - Xiaohua Li
- Department of Pediatrics, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong, China
| | - Yanjun Zhang
- Department of Pediatrics, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong, China
| | - Jianchang Li
- Department of Pediatrics, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong, China
| | - Liang Chen
- Department of Radiology, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong, China
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Systematic Review and Meta-Analysis of Diagnostic Accuracy of miRNAs in Patients with Pancreatic Cancer. DISEASE MARKERS 2018; 2018:6292396. [PMID: 29887920 PMCID: PMC5977035 DOI: 10.1155/2018/6292396] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 04/23/2018] [Indexed: 12/19/2022]
Abstract
Background It is reported that miRNAs are aberrantly expressed in patients with pancreatic cancer. However, the diagnostic value of miRNAs in pancreatic cancer remains controversial. The meta-analysis was to access diagnostic accuracy of miRNAs in pancreatic cancer. Methods PubMed, Scopus, Web of Science, Chinese National Knowledge Infrastructure (CNKI), WANFANG Data, China Biomedical Literature Database (CBM), and VIP databases were retrieved up to June 30, 2016, to collect articles concerning the diagnosis of miRNAs in pancreatic cancer. The methodological quality of each study was assessed by the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). This meta-analysis was conducted using RevMan5.0, MetaDiSc 1.4, and Stata 12.0 software. Results There are 40 articles including 109 studies. The pooled SEN was 0.81 (95% CI, 0.80–0.82), the pooled SPE was 0.78 (95% CI, 0.77–0.79), the pooled +LR was 3.32 (95% CI, 2.92–3.80), the pooled −LR was 0.27 (95% CI, 0.24–0.31), the pooled DOR was 14.56 (95% CI, 11.55–18.34), and pooled AUC was 0.86 (95% CI, 0.84–0.88). Discussion This meta-analysis demonstrated that miRNA makes a significant impact in the pancreatic cancer diagnosis with a high SEN and SPE, particularly using multiple miRNAs.
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Han H, Wang L, Xu J, Wang A. miR-128 induces pancreas cancer cell apoptosis by targeting MDM4. Exp Ther Med 2018; 15:5017-5022. [PMID: 29805525 DOI: 10.3892/etm.2018.6047] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 02/08/2018] [Indexed: 01/17/2023] Open
Abstract
MicroRNAs (miRNA/miRs) are small, non-coding RNA molecules (19-25 nucleotides in length), which function to regulate gene expression. It has been reported that miR-128 serves an important role in regulating cancer cell growth; increasing evidence has indicated that the expression of miR-128 is decreased in pancreatic cancer (PC) cells. However, the specific mechanisms of miR-128 in regulating PC cell growth are unclear. In the present study, it was confirmed that the expression of miR-128 was significantly decreased within PC tissues compared with adjacent normal tissues via reverse transcription-quantitative polymerase chain reaction analysis. In addition, miR-128 mimics inhibited PC MIA-PaCa2 cell growth by enhancing cell apoptosis in a caspase-dependent manner. Furthermore, the results of the present study demonstrated that double minute 4 (MDM4) may be a direct target for miR-128 via a dual luciferase report assay; miR-128 may inhibit MDM4 expression, and increase p53 and cleaved caspase-3 protein expression levels. In summary, the present study indicated that miR-128 is downregulated in PC, and it may be a promising target for future PC diagnosis and treatment.
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Affiliation(s)
- Hongchao Han
- Department of General Surgery, The Third People's Hospital, Yancheng, Jiangsu 224000, P.R. China
| | - Lisheng Wang
- Department of General Surgery, The Third People's Hospital, Yancheng, Jiangsu 224000, P.R. China
| | - Jie Xu
- Department of Gynecology and Obstetrics, The Third People's Hospital, Yancheng, Jiangsu 224000, P.R. China
| | - Aikun Wang
- Department of General Surgery, The Third People's Hospital, Yancheng, Jiangsu 224000, P.R. China
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Shang G, Mi Y, Mei Y, Wang G, Wang Y, Li X, Wang Y, Li Y, Zhao G. MicroRNA-192 inhibits the proliferation, migration and invasion of osteosarcoma cells and promotes apoptosis by targeting matrix metalloproteinase-11. Oncol Lett 2018; 15:7265-7272. [PMID: 29731885 DOI: 10.3892/ol.2018.8239] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 01/29/2018] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression during stem cell growth, proliferation and differentiation. miRNAs are also involved in the development and progression of a number of cancer types, including osteosarcoma (OS). miR-192 is significantly downregulated in various tumors, including lung, bladder and rectal cancer. miR-192 expression is associated with the migration and invasion of OS cells. However, the expression of miR-192 and its effects on the development of OS have not been reported. In the present study, the involvement of miR-192 and its molecular mechanisms in the development of OS was investigated. The results indicate that miR-192 expression was significantly downregulated in OS tissues compared with non-tumor tissues (P<0.05). Next, a miR-192 agomir was transfected into the OS cell line MG-63 to upregulate miR-192. The effects of miR-192 overexpression were then investigated by examining cell proliferation, apoptosis, migration and invasion. Matrix metalloproteinase (MMP)-11 belongs to a family of nine or more highly homologous Zn2+-endopeptidases. It was demonstrated that the mRNA and protein expression of MMP-11 were upregulated in OS tissues compared with non-tumor tissues (P<0.05). MMP-11 was predicted by TargetScan and miRanda as a miR-192 target, which was confirmed by western blotting and dual-luciferase assays. Finally, it was demonstrated that the overexpression of miR-192 was able to downregulate MMP-11 expression and reduce proliferation, migration and invasion, and promote apoptosis in OS cells. Together, these data indicate that miR-192 may be a tumor suppressor that inhibits the progression and invasion of OS by targeting MMP-11. Therefore, miR-192 may be useful for the diagnosis and treatment of OS.
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Affiliation(s)
- Guowei Shang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Yang Mi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Yingwu Mei
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Guanghui Wang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Yadong Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Xinjie Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Yisheng Wang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Yuebai Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Guoqiang Zhao
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
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Zhang D, Wu Y, Sun G. miR-192 suppresses T follicular helper cell differentiation by targeting CXCR5 in childhood asthma. Scandinavian Journal of Clinical and Laboratory Investigation 2018; 78:236-242. [PMID: 29490514 DOI: 10.1080/00365513.2018.1440628] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
The aim of this study was to investigate the role of miR-192 in differentiation of T follicular helper cells in childhood asthma. Blood samples were taken from eighteen children with acute asthma attacks and fifteen healthy children (HC). Quantitative real-time PCR and Western blotting were used to detect the expression levels of miR-192, C-X-C chemokine receptor type 5 (CXCR5), B-cell lymphoma 6 (BCL-6) and inducible T-cell costimulator (ICOS). The flow cytometry was performed to detect the proportion of CD4 + CXCR5+ Tfh cells on CD4 + T lymphocytes. The enzyme-linked immunosorbent assay (ELISA) was carried out to determine the plasma concentrations of total IgE and IL-21. The effect of miR-192 on the T follicular helper cells differentiation by targeting CXCR5 was determined by dual-luciferase reporter assay. Children with asthma had lower levels of miR-192 than HC. The proportion of CD4 + CXCR + Tfh cells was significantly higher in the acute asthma group than HC. Similarly, the plasma concentration of total IgE and IL-21 in the acute group markedly increased compared with the HC, and IgE concentration was positively correlated with the proportion of CD4 + CXCR5 + Tfh cells. Furthermore, the expression levels of CXCR5, Bcl-6 and ICOS were significantly higher in the acute group than in the HC. While the proportion of CD4 + CXCR5 + Tfh cells, IL-21, CXCR5, Bcl-6 and ICOS were obviously lower in the CD4 + T cells transfected with miR-192 plasmid than that in miR-192 + CXCR5 group and control group. In conclusion, miR-192 blocks the activation pathway of Tfh cells by targeting CXCR5, which is a reasonable cellular target for therapeutic intervention.
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Affiliation(s)
- Defeng Zhang
- a Department of Pediatrics , Anhui Provincial Hospital, Anhui Medical University , Hefei , Anhui , China
| | - Yuanbo Wu
- b Department of Neurology , Anhui Provincial Hospital, Anhui Medical University , Hefei , Anhui , China
| | - Gengyun Sun
- c Department of Respiration , First Affiliated Hospital of Anhui Medical University , Hefei , Anhui , China
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Liu YA, Zhang Y, Zheng Z, Li K, Wu XH, Du QG, Ye X, Wang L, Zhu L. MicroRNA-216b reduces growth, migration and invasion of pancreatic ductal adenocarcinoma cells by directly targeting ρ-associated coiled-coil containing protein kinase 1. Oncol Lett 2018; 15:6745-6751. [PMID: 29616134 DOI: 10.3892/ol.2018.8109] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Accepted: 06/16/2017] [Indexed: 12/20/2022] Open
Abstract
Developments in cancer therapy have greatly improved the survival time for patients with pancreatic ductal adenocarcinoma (PDAC); however, the prognosis of patients with PDAC remains poor. Understanding the expression patterns and functions of microRNAs may provide strategies for the diagnosis and treatment of patients with PDAC. The present study aimed to explore the expression and functions of microRNA-216b (miR-216b) in PDAC. The expression of miR-216b in PDAC tissues and cell lines was quantified with reverse transcription-quantitative polymerase chain reaction. An miR-216b mimic was introduced into PDAC cells to induce the effects of miR-21b overexpression. The effects of miR-216b overexpression on growth, migration and invasion of PDAC cells were evaluated by cell proliferation assay, migration and invasion assays, respectively. The molecular mechanism underlying the suppressive effects of miR-216b on PDAC was also examined; a direct target gene of miR-216b, ρ-associated coiled-coil containing protein kinase 1 (ROCK1), was downregulated by ROCK1 short interfering RNA to investigate the effects on growth, migration and invasion of PDAC cells. The present study revealed that miR-216b was significantly downregulated in PDAC tissues and cell lines. Overexpression of miR-216b inhibited growth, migration and invasion of PDAC cells in vitro. ROCK1 was identified as a direct target gene of miR-216b in pancreatic cancer and the downregulation of ROCK1 resembled the effects of miR-216b overexpression in PDAC cells. Taken together, miR-216b acted as a tumor suppressor in PDAC and may represent a novel therapeutic target in PDAC.
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Affiliation(s)
- Yang-An Liu
- Department of Hepatobiliary and Pancreatic Surgery, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China
| | - Yue Zhang
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. China
| | - Zhi Zheng
- Department of Hepatobiliary and Pancreatic Surgery, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China
| | - Kai Li
- Department of Hepatobiliary and Pancreatic Surgery, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China
| | - Xin-Hua Wu
- Department of Hepatobiliary and Pancreatic Surgery, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China
| | - Qiu-Guo Du
- Department of Hepatobiliary and Pancreatic Surgery, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China
| | - Xiao Ye
- Department of Hepatobiliary and Pancreatic Surgery, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China
| | - Lili Wang
- Department of Hepatobiliary and Pancreatic Surgery, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China
| | - Ling Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China
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Ren L, Yu Y. The role of miRNAs in the diagnosis, chemoresistance, and prognosis of pancreatic ductal adenocarcinoma. Ther Clin Risk Manag 2018; 14:179-187. [PMID: 29416345 PMCID: PMC5790163 DOI: 10.2147/tcrm.s154226] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a very challenging malignancy with late presentation, metastatic potential, chemoresistance, and poor prognosis. Therefore, there is an urgent need for novel diagnostic and prognostic biomarkers. miRNAs are small noncoding RNAs that regulate the expression of multitude number of genes. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. A series of miRNAs have been defined as holding promise for early diagnostics, as indicators of therapy resistance, and even as markers for prognosis in PDAC patients. In this review, we summarize the current knowledge on the role of miRNAs in diagnosis, chemoresistance, and prognosis in PDAC patients.
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Affiliation(s)
- Le Ren
- Department of Gastroenterology, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China
| | - Yue Yu
- Department of Gastroenterology, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China
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Kai K, Dittmar RL, Sen S. Secretory microRNAs as biomarkers of cancer. Semin Cell Dev Biol 2017; 78:22-36. [PMID: 29258963 DOI: 10.1016/j.semcdb.2017.12.011] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 12/11/2017] [Accepted: 12/12/2017] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression predominantly by inhibiting transcription and/or promoting degradation of target mRNAs also in addition to being involved in non-canonical mechanisms regulating transcription, translation and cell signaling processes. Extracellular secretory miRNAs, either in complex with specific proteins or encapsulated in microvesicles called exosomes, are transported between cells as means of intercellular communication. Secretory miRNAs in circulation remain functional after delivery to recipient cells, regulating target genes and their corresponding signaling pathways. Cancer cell secreted miRNA-mediated intercellular communication affects physiological processes associated with the disease, such as, angiogenesis, metabolic reprogramming, immune modulation, metastasis, and chemo-resistance. Given the stability of miRNAs in body fluids and their well-documented roles in deregulating cancer-relevant genetic pathways, there is considerable interest in developing secretory miRNAs as liquid biopsy biomarkers for detection, diagnosis and prognostication of cancer. In this review, we discuss salient features of miRNA biogenesis, secretion and function in cancer as well as the current state of secretory miRNA isolation and profiling methods. Furthermore, we discuss the challenges and opportunities of secretory miRNA biomarker assay development, which need to be addressed for clinical applications.
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Affiliation(s)
- Kazuharu Kai
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States
| | - Rachel L Dittmar
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States; Program in Human and Molecular Genetics, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, 77030, United States
| | - Subrata Sen
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States; Program in Human and Molecular Genetics, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, 77030, United States.
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Keane MG, Shah A, Pereira SP, Joshi D. Novel biomarkers and endoscopic techniques for diagnosing pancreaticobiliary malignancy. F1000Res 2017; 6:1643. [PMID: 28944047 PMCID: PMC5585877 DOI: 10.12688/f1000research.11371.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/06/2017] [Indexed: 12/12/2022] Open
Abstract
The UK incidence of pancreatic ductal adenocarcinoma is 9 per 100,000 population, and biliary tract cancer occurs at a rate of 1–2 per 100,000. The incidence of both cancers is increasing annually and these tumours continue to be diagnosed late and at an advanced stage, limiting options for curative treatment. Population-based screening programmes do not exist for these cancers, and diagnosis currently is dependent on symptom recognition, but often symptoms are not present until the disease is advanced. Recently, a number of promising blood and urine biomarkers have been described for pancreaticobiliary malignancy and are summarised in this review. Novel endoscopic techniques such as single-operator cholangioscopy and confocal endomicroscopy have been used in some centres to enhance standard endoscopic diagnostic techniques and are also evaluated in this review.
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Affiliation(s)
| | - Amar Shah
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Stephen P Pereira
- UCL Institute for Liver and Digestive Health, Royal Free Campus, London, UK
| | - Deepak Joshi
- Institute of Liver Studies, King's College Hospital, London, UK
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Xu YF, Hannafon BN, Zhao YD, Postier RG, Ding WQ. Plasma exosome miR-196a and miR-1246 are potential indicators of localized pancreatic cancer. Oncotarget 2017; 8:77028-77040. [PMID: 29100367 PMCID: PMC5652761 DOI: 10.18632/oncotarget.20332] [Citation(s) in RCA: 141] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 07/28/2017] [Indexed: 12/22/2022] Open
Abstract
Patients with localized pancreatic cancer (stage I and stage IIA) have a much higher survival rate than those presenting at later stages, yet early detection remains a challenge to this malignancy. The aim of this study was to evaluate whether exosome miRNA signatures are indicative of localized pancreatic cancer. Exosomes were collected from the conditioned media of pancreatic cancer cell lines and plasma samples of localized pancreatic cancer patients (Stage I-IIA, n=15), and healthy subjects (n=15). Cellular and exosome miRNAs from pancreatic cancer cell lines were profiled by next-generation small RNA sequencing. Plasma exosome miRNA expression was analyzed by qRT-PCR. We found that certain miRNAs, such as miR-196a and miR-1246, are highly enriched in pancreatic cancer exosomes. Consistently, plasma exosome miR-196a and miR-1246 levels were significantly elevated in pancreatic cancer patients as compared to healthy subjects. An analysis of the cancer subtypes indicated that plasma exosome miR-196a is a better indicator of pancreatic ductal adenocarcinoma (PDAC), whereas plasma exosome miR-1246 is significantly elevated in patients with intraductal papillary mucinous neoplasms (IPMN). In contrast, there were no differences in the plasma exosome miR-196a and miR-1246 levels between patients with pancreatic neuroendocrine tumors (NET) and healthy subjects. In conclusion, we demonstrate that certain miRNA species, such as miR-196a and miR-1246, are highly enriched in pancreatic cancer exosomes and elevated in plasma exosomes of patients with localized pancreatic cancer.
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Affiliation(s)
- Yi-Fan Xu
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, OK 73104, USA
| | - Bethany N Hannafon
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, OK 73104, USA
| | - Yan D Zhao
- Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, OK 73104, USA
| | - Russell G Postier
- Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, OK 73104, USA
| | - Wei-Qun Ding
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, OK 73104, USA
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Moutinho-Ribeiro P, Coelho R, Giovannini M, Macedo G. Pancreatic cancer screening: Still a delusion? Pancreatology 2017; 17:754-765. [PMID: 28739291 DOI: 10.1016/j.pan.2017.07.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 06/17/2017] [Accepted: 07/05/2017] [Indexed: 12/11/2022]
Abstract
Pancreatic adenocarcinoma represents the fourth most common cause of cancer mortality and death due to pancreatic cancer (PC) have increased since 2003. Its incidence has also raised about 30% in the past decade and it is expected to become the second cause of cancer mortality by 2020 in the USA. Most PC present with metastatic disease and improvements in treatment outcomes for this group have been disappointing. These observations support the idea that screening to identify patients at an earlier stage might be an important strategy in improving overall PC outcomes. Many protocols have been tested, nevertheless, by now there is no effective screening program. Given the overall low incidence of disease and the current lack of accurate, inexpensive and noninvasive screening tests, the consensus is that widespread population-based screening for PC in the general population or in patients with only one affected first-degree relative is neither practicable nor indicated in most countries. However, a different scenario is screening patients with higher risk for PC, most of them with hereditary conditions predisposing the development of this neoplasia. In fact, some guidelines are now available helping to select these individuals at risk and to screen them, in order to achieve early detection of PC.
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Affiliation(s)
- Pedro Moutinho-Ribeiro
- Department of Gastroenterology, Centro Hospitalar São João, Porto, Portugal; Faculty of Medicine, University of Porto, Portugal.
| | - Rosa Coelho
- Department of Gastroenterology, Centro Hospitalar São João, Porto, Portugal
| | - Marc Giovannini
- Endoscopic Unit, Paoli-Calmettes Institute, Marseilles, France
| | - Guilherme Macedo
- Department of Gastroenterology, Centro Hospitalar São João, Porto, Portugal; Faculty of Medicine, University of Porto, Portugal
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