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1
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Qi Z, Pan N, Han D, He J, Li JA, Yang L, Wang X, Huang F. Enzymatic response of heparin-protamine complex: Spectroscopic investigation and application for lung adenocarcinoma cells detection. Int J Biol Macromol 2024; 277:134307. [PMID: 39084435 DOI: 10.1016/j.ijbiomac.2024.134307] [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: 04/02/2024] [Revised: 07/25/2024] [Accepted: 07/28/2024] [Indexed: 08/02/2024]
Abstract
Though the heparin-protamine complex (HP complex) is a crucial system utilized in clinical settings, the metabolic pathways of this complex remain inadequately understood. Herein, the enzymatic degradation of the heparin-protamine complex by trypsin and its broader implications were investigated. By utilizing fluorescent gold nanoclusters liganded with the HP complex (AuNCs-HP complex), we observed significant morphological and spectral changes during enzymatic degradation. Experiments showed that AuNCs-HP complex could be degraded and cleaved into small fragments by trypsin. Moreover, the AuNCs-HP complex demonstrated its potential as a highly sensitive spectral sensing platform, enabling precise measurement of trypsin activity with an outstanding detection limit (0.34 ng mL-1). Additionally, we explored its utility for specific tumor cell detection, focusing on lung adenocarcinoma cells, and successfully identified their presence through distinctive fluorescence changes. These remarkable findings not only contribute valuable insights into targeted degradation systems but also offer promising opportunities for cancer biomarker detection. The AuNCs-HP complex serves as an innovative tool for real-time trypsin activity monitoring, paving the way for advanced biomedical applications.
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Affiliation(s)
- Zichun Qi
- State Key Laboratory of Heavy Oil Processing, College of Chemical Engineering, China University of Petroleum (East China), Qingdao 266580, China
| | - Nana Pan
- Department of Cardiology, the Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Dongxue Han
- State Key Laboratory of Heavy Oil Processing, College of Chemical Engineering, China University of Petroleum (East China), Qingdao 266580, China
| | - Jiahua He
- State Key Laboratory of Heavy Oil Processing, College of Chemical Engineering, China University of Petroleum (East China), Qingdao 266580, China
| | - Jin-Ao Li
- State Key Laboratory of Heavy Oil Processing, College of Chemical Engineering, China University of Petroleum (East China), Qingdao 266580, China
| | - Luqi Yang
- State Key Laboratory of Heavy Oil Processing, College of Chemical Engineering, China University of Petroleum (East China), Qingdao 266580, China
| | - Xiaojuan Wang
- State Key Laboratory of Heavy Oil Processing, College of Chemical Engineering, China University of Petroleum (East China), Qingdao 266580, China.
| | - Fang Huang
- State Key Laboratory of Heavy Oil Processing, College of Chemical Engineering, China University of Petroleum (East China), Qingdao 266580, China.
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2
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Wang L, Maolan A, Luo Y, Li Y, Liu R. Knowledge mapping analysis of ground glass nodules: a bibliometric analysis from 2013 to 2023. Front Oncol 2024; 14:1469354. [PMID: 39381043 PMCID: PMC11458373 DOI: 10.3389/fonc.2024.1469354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 09/03/2024] [Indexed: 10/10/2024] Open
Abstract
Background In recent years, the widespread use of computed tomography (CT) in early lung cancer screening has led to an increase in the detection rate of lung ground glass nodules (GGNs). The persistence of GGNs, which may indicate early lung adenocarcinoma, has been a focus of attention for scholars in the field of lung cancer prevention and treatment in recent years. Despite the rapid development of research into GGNs, there is a lack of intuitive content and trend analyses in this field, as well as a lack of detailed elaboration on possible research hotspots. The objective of this study was to conduct a comprehensive analysis of the knowledge structure and research hotspots of lung ground glass nodules over the past decade, employing bibliometric methods. Method The Web of Science Core Collection (WoSCC) database was searched for relevant ground-glass lung nodule literature published from 2013-2023. Bibliometric analyses were performed using VOSviewer, CiteSpace, and the R package "bibliometrix". Results A total of 2,218 articles from 75 countries and 2,274 institutions were included in this study. The number of publications related to GGNs has been high in recent years. The United States has led in GGNs-related research. Radiology has one of the highest visibilities as a selected journal and co-cited journal. Jin Mo Goo has published the most articles. Travis WD has been cited the most frequently. The main topics of research in this field are Lung Cancer, CT, and Deep Learning, which have been identified as long-term research hotspots. The GGNs-related marker is a major research trend in this field. Conclusion This study represents the inaugural bibliometric analysis of applied research on ground-glass lung nodules utilizing three established bibliometric software. The bibliometric analysis of this study elucidates the prevailing research themes and trends in the field of GGNs over the past decade. It also furnishes pertinent recommendations for researchers to provide objective descriptions and comprehensive guidance for future related research.
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Affiliation(s)
| | | | | | | | - Rui Liu
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical
Sciences, Beijing, China
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3
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Ling Z, Yang L. Diagnostic value of miR-200 family in non-small cell lung cancer: a meta-analysis. Biomark Med 2024; 18:419-431. [PMID: 39041844 DOI: 10.2217/bmm-2024-0087] [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: 02/02/2024] [Accepted: 03/19/2024] [Indexed: 07/24/2024] Open
Abstract
Aim: To investigate the diagnostic potential of the miR-200 family for early detection in non-small cell lung cancer (NSCLC). Materials & methods: A systematic search was conducted of PubMed, Embase and Web of Science databases to identify studies of the miR-200 family in NSCLC. Sixteen studies meeting the inclusion criteria were included in the analysis with a total of 20 cohorts. Results: The combined sensitivity and specificity reached 73% and 85%, with an area under the curve of 0.83. Notably, miR-200b introduced heterogeneity. Subgroup analysis highlighted miR-200a and miR-141 as more sensitive, while blood-derived miRNAs showed slightly lower accuracy. Conclusion: The miR-200 family, predominantly assessed in blood, exhibits significant diagnostic potential for NSCLC, especially in distinguishing it from benign diseases.
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Affiliation(s)
- Zhen Ling
- Graduate School, Anhui University of Chinese Medicine, Hefei, 230012, Anhui, China
| | - Lichang Yang
- Graduate School, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
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4
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Fu H, Zhang M, Liu X, Yang Y, Xing Y. Abnormal methylation mediated upregulation of LINC00857 boosts malignant progression of lung adenocarcinoma by modulating the miR-486-5p/NEK2 axis. THE CLINICAL RESPIRATORY JOURNAL 2024; 18:e13765. [PMID: 38721812 PMCID: PMC11079885 DOI: 10.1111/crj.13765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 11/29/2023] [Accepted: 03/12/2024] [Indexed: 05/12/2024]
Abstract
LINC00857 is frequently dysregulated in varying cancers, which in turn exerts carcinogenic effects; however, its DNA methylation status in promoter region and molecular mechanisms underlying the progression of lung adenocarcinoma (LUAD) remain rarely understood. Through bioinformatics analysis, we examined the expression state and methylation site of LINC00857 in LUAD and further investigated the properties of LINC00857 as a competitive endogenous RNA in the cancer progression. The current study revealed that the overexpression of LINC00857 in LUAD tissue and cells was mainly caused by the hypomethylation of the promoter region. LINC00857 knockdown prominently reduced cell proliferation, impeded cell migration and invasion, and restrained lymph node metastasis, with enhancing radiosensitivity. The effects of LINC00857 on tumor growth were also investigated in nude mice models. Subsequently, the downstream factors, miR-486-5p and NEK2, were screened, and the putative regulatory axis was examined. Overall, the regulatory effect of methylation-mediated LINC00857 overexpression on miR-486-5p/NEK2 axis may be a new mechanism for LUAD progression.
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Affiliation(s)
- Haoyu Fu
- Department of Radiation OncologyTangshan People's HospitalTangshanChina
| | - Mingming Zhang
- Department of Thoracic SurgeryTangshan People's HospitalTangshanChina
| | - Xiaohui Liu
- Department of Thoracic SurgeryTangshan People's HospitalTangshanChina
| | - Yiming Yang
- Department of Breast SurgeryTangshan People's HospitalTangshanChina
| | - Ying Xing
- Department of Radiation OncologyTangshan People's HospitalTangshanChina
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5
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Boutabba A, Missaoui F, Dlala A, Kamoun H, Ben Salem K, Gabsi A, Rejeb H, Letessier A, Miotto B, Marrakchi R. Circulating miR-16-5p, miR-92a-3p and miR-451a are biomarkers of lung cancer in Tunisian patients. BMC Cancer 2024; 24:417. [PMID: 38575987 PMCID: PMC10996140 DOI: 10.1186/s12885-024-12181-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 03/26/2024] [Indexed: 04/06/2024] Open
Abstract
Lung cancer is one of the most common type of cancer and, despite significant advances in screening and diagnosis approaches, a large proportion of patients at diagnosis still present advanced stages of the disease with distant metastasis and bad prognosis. Finding and validating biomarkers of lung cancer is therefore essential. Such studies are often conducted on European, American and Asian populations and the relevance of these biomarkers in other populations remains less clear. In that prospect, we investigated the expression level of seven microRNAs, chosen from the medical literature (miR-16-5p, miR-92a-3p, miR-103a-3p, miR-375-3p, miR-451a, miR-520-3p and miR-let-7e-5p), in the blood of Tunisian lung cancer patients, treated or not by chemotherapy, and healthy control individuals. We found that high expression levels of circulating miR-16-5p, miR-92a-3p and miR-451a in the plasma of untreated patients discriminate them from healthy control individuals. In addition, miR-16-5p and miR-451a expression levels are significantly reduced in the plasma of chemotherapy-treated patients compared to untreated patients. Our results confirmed previous work in other populations worldwide and provide further evidence that circulating miR-16-5p, miR-92a-3p and miR-451a potentially regulate key pathways involved in the initiation and progression of cancer.
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Affiliation(s)
- Alya Boutabba
- Laboratory of genetics, immunology, and human pathologies, LR05ES05, Faculty of sciences, University of Tunis El-Manar - Campus Universitaire El-Manar, El-Manar Tunis, 2092, Tunisia
| | - Fadoua Missaoui
- Laboratory of genetics, immunology, and human pathologies, LR05ES05, Faculty of sciences, University of Tunis El-Manar - Campus Universitaire El-Manar, El-Manar Tunis, 2092, Tunisia
| | - Akram Dlala
- Laboratory of genetics, immunology, and human pathologies, LR05ES05, Faculty of sciences, University of Tunis El-Manar - Campus Universitaire El-Manar, El-Manar Tunis, 2092, Tunisia
| | - Hela Kamoun
- Ibn Nafiss Pneumology Department, Abderrahmen Mami Hospital, Ariana, Tunisia
- Faculty of medicine, University Tunis El-Manar, Tunis, Tunisia
| | - Khalil Ben Salem
- Laboratory of genetics, immunology, and human pathologies, LR05ES05, Faculty of sciences, University of Tunis El-Manar - Campus Universitaire El-Manar, El-Manar Tunis, 2092, Tunisia
| | - Amira Gabsi
- Laboratory of genetics, immunology, and human pathologies, LR05ES05, Faculty of sciences, University of Tunis El-Manar - Campus Universitaire El-Manar, El-Manar Tunis, 2092, Tunisia
| | - Hadhemi Rejeb
- Ibn Nafiss Pneumology Department, Abderrahmen Mami Hospital, Ariana, Tunisia
- Faculty of medicine, University Tunis El-Manar, Tunis, Tunisia
| | - Anne Letessier
- Université Paris Cité, INSERM, U1016, CNRS, UMR8104, Institut Cochin, Paris, F-75014, France
- Team "Epigenetics, DNA replication and Cancer", Institut Cochin, Paris, France
| | - Benoit Miotto
- Université Paris Cité, INSERM, U1016, CNRS, UMR8104, Institut Cochin, Paris, F-75014, France.
- Team "Epigenetics, DNA replication and Cancer", Institut Cochin, Paris, France.
| | - Raja Marrakchi
- Laboratory of genetics, immunology, and human pathologies, LR05ES05, Faculty of sciences, University of Tunis El-Manar - Campus Universitaire El-Manar, El-Manar Tunis, 2092, Tunisia
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6
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Gao L, Dhilipkannah P, Holden VK, Deepak J, Sachdeva A, Todd NW, Stass SA, Jiang F. Differential Non-Coding RNA Profiles for Lung Cancer Early Detection in African and White Americans. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.03.27.24304977. [PMID: 38585975 PMCID: PMC10996737 DOI: 10.1101/2024.03.27.24304977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Introduction Lung cancer leads in cancer-related deaths. Disparities are observed in lung cancer rates, with African Americans (AAs) experiencing disproportionately higher incidence and mortality compared to other ethnic groups. Non-coding RNAs (ncRNAs) play crucial roles in lung tumorigenesis. Our objective was to identify ncRNA biomarkers associated with the racial disparity in lung cancer. Methods Using droplet digital PCR, we examined 93 lung-cancer-associated ncRNAs in the plasma and sputum samples from AA and White American (WA) participants, which included 118 patients and 92 cancer-free smokers. Subsequently, we validated our results with a separate cohort comprising 56 cases and 72 controls. Results In the AA population, plasma showed differential expression of ten ncRNAs, while sputum revealed four ncRNAs when comparing lung cancer patients to the control group. In the WA population, the plasma displayed eleven ncRNAs, and the sputum had five ncRNAs showing differential expression between the lung cancer patients and the control group. For AAs, we identified a three-ncRNA panel (plasma miRs-147b, 324-3p, 422a) diagnosing lung cancer in AAs with 86% sensitivity and 89% specificity. For WAs, a four-ncRNA panel was developed, comprising sputum miR-34a-5p and plasma miRs-103-3p, 126-3p, 205-5p, achieving 88% sensitivity and 87% specificity. These panels remained effective across different stages and histological types of lung tumors and were validated in the independent cohort. Conclusions The ethnicity-related ncRNA signatures have promise as biomarkers to address the racial disparity in lung cancer.
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Mohamed E, García Martínez DJ, Hosseini MS, Yoong SQ, Fletcher D, Hart S, Guinn BA. Identification of biomarkers for the early detection of non-small cell lung cancer: a systematic review and meta-analysis. Carcinogenesis 2024; 45:1-22. [PMID: 38066655 DOI: 10.1093/carcin/bgad091] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 11/27/2023] [Accepted: 12/05/2023] [Indexed: 02/13/2024] Open
Abstract
Lung cancer (LC) causes few symptoms in the earliest stages, leading to one of the highest mortality rates among cancers. Low-dose computerised tomography (LDCT) is used to screen high-risk individuals, reducing the mortality rate by 20%. However, LDCT results in a high number of false positives and is associated with unnecessary follow-up and cost. Biomarkers with high sensitivities and specificities could assist in the early detection of LC, especially in patients with high-risk features. Carcinoembryonic antigen (CEA), cytokeratin 19 fragments and cancer antigen 125 have been found to be highly expressed during the later stages of LC but have low sensitivity in the earliest stages. We determined the best biomarkers for the early diagnosis of LC, using a systematic review of eight databases. We identified 98 articles that focussed on the identification and assessment of diagnostic biomarkers and achieved a pooled area under curve of 0.85 (95% CI 0.82-0.088), indicating that the diagnostic performance of these biomarkers when combined was excellent. Of the studies, 30 focussed on single/antigen panels, 22 on autoantibodies, 31 on miRNA and RNA panels, and 15 suggested the use of circulating DNA combined with CEA or neuron-specific enolase (NSE) for early LC detection. Verification of blood biomarkers with high sensitivities (Ciz1, exoGCC2, ITGA2B), high specificities (CYFR21-1, antiHE4, OPNV) or both (HSP90α, CEA) along with miR-15b and miR-27b/miR-21 from sputum may improve early LC detection. Further assessment is needed using appropriate sample sizes, control groups that include patients with non-malignant conditions, and standardised cut-off levels for each biomarker.
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Affiliation(s)
- Eithar Mohamed
- Centre for Biomedicine, Hull York Medical School, University of Hull, Kingston-upon-Hull, HU6 7RX, UK
| | - Daniel J García Martínez
- Department of Biotechnology, Pozuelo de Alarcón, University Francisco De Vitoria, Madrid, 28223, Spain
| | - Mohammad-Salar Hosseini
- Research Centre for Evidence-Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Si Qi Yoong
- Alice Lee Centre for Nursing Studies, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Daniel Fletcher
- Centre for Biomedicine, Hull York Medical School, University of Hull, Kingston-upon-Hull, HU6 7RX, UK
| | - Simon Hart
- Respiratory Medicine, Hull York Medical School, University of Hull, Kingston-upon-Hull, HU6 7RX, UK
| | - Barbara-Ann Guinn
- Centre for Biomedicine, Hull York Medical School, University of Hull, Kingston-upon-Hull, HU6 7RX, UK
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8
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Lobera ES, Varela MA, Jimenez RL, Moreno RB. miRNA as biomarker in lung cancer. Mol Biol Rep 2023; 50:9521-9527. [PMID: 37741809 PMCID: PMC10635960 DOI: 10.1007/s11033-023-08695-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 07/18/2023] [Indexed: 09/25/2023]
Abstract
Lung cancer has a high prevalence and mortality due to its late diagnosis and limited treatment, so it is essential to find biomarkers that allow a faster diagnosis and improve the survival of these patients. In this sense, biomarkers based on miRNAs have supposed a considerable advance. miRNAs, which are small RNA sequences, can regulate gene expression, so they play an essential role not only as a diagnostic biomarker but also as a therapeutic and prognostic one. Also, miRNA biomarkers can be obtained from liquid biopsies, which are less intrusive than lung biopsies, and have better accessibility, safety and repeatability, which allows using those biomarkers both for diagnosis and monitoring of patients. In this review, we highlight the importance of miRNAs and collect the existing evidence of their relationship with lung cancer.
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Affiliation(s)
- Esperanza Salcedo Lobera
- U.G.C. Medico-Quirurgica de Enfermedades Respiratorias, Hospital Regional Universitario de Malaga, Malaga, Spain
| | - Macarena Arroyo Varela
- U.G.C. Medico-Quirurgica de Enfermedades Respiratorias, Hospital Regional Universitario de Malaga, Malaga, Spain.
| | - Rafael Larrosa Jimenez
- Department of Computer Architecture, University of Malaga, Malaga, Spain
- Andalusian Platform for Bioinformatics at SCBI, University of Malaga, Malaga, Spain
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9
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Song Y, Kelava L, Kiss I. MiRNAs in Lung Adenocarcinoma: Role, Diagnosis, Prognosis, and Therapy. Int J Mol Sci 2023; 24:13302. [PMID: 37686110 PMCID: PMC10487838 DOI: 10.3390/ijms241713302] [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: 07/31/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Lung cancer has emerged as a significant public health challenge and remains the leading cause of cancer-related mortality worldwide. Among various types of lung malignancies, lung adenocarcinoma (LUAD) stands as the most prevalent form. MicroRNAs (miRNAs) play a crucial role in gene regulation, and their involvement in cancer has been extensively explored. While several reviews have been published on miRNAs and lung cancer, there remains a gap in the review regarding miRNAs specifically in LUAD. In this review, we not only highlight the potential diagnostic, prognostic, and therapeutic implications of miRNAs in LUAD, but also present an inclusive overview of the extensive research conducted on miRNAs in this particular context.
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Affiliation(s)
- Yongan Song
- Department of Public Health Medicine, University of Pécs Medical School, Szigeti Str. 12, 7624 Pécs, Hungary
| | - Leonardo Kelava
- Department of Thermophysiology, Institute for Translational Medicine, Medical School, University of Pécs, Szigeti Str. 12, 7624 Pécs, Hungary
| | - István Kiss
- Department of Public Health Medicine, University of Pécs Medical School, Szigeti Str. 12, 7624 Pécs, Hungary
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10
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Ye Q, Raese R, Luo D, Cao S, Wan YW, Qian Y, Guo NL. MicroRNA, mRNA, and Proteomics Biomarkers and Therapeutic Targets for Improving Lung Cancer Treatment Outcomes. Cancers (Basel) 2023; 15:cancers15082294. [PMID: 37190222 DOI: 10.3390/cancers15082294] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 03/31/2023] [Accepted: 04/04/2023] [Indexed: 05/17/2023] Open
Abstract
The majority of lung cancer patients are diagnosed with metastatic disease. This study identified a set of 73 microRNAs (miRNAs) that classified lung cancer tumors from normal lung tissues with an overall accuracy of 96.3% in the training patient cohort (n = 109) and 91.7% in unsupervised classification and 92.3% in supervised classification in the validation set (n = 375). Based on association with patient survival (n = 1016), 10 miRNAs were identified as potential tumor suppressors (hsa-miR-144, hsa-miR-195, hsa-miR-223, hsa-miR-30a, hsa-miR-30b, hsa-miR-30d, hsa-miR-335, hsa-miR-363, hsa-miR-451, and hsa-miR-99a), and 4 were identified as potential oncogenes (hsa-miR-21, hsa-miR-31, hsa-miR-411, and hsa-miR-494) in lung cancer. Experimentally confirmed target genes were identified for the 73 diagnostic miRNAs, from which proliferation genes were selected from CRISPR-Cas9/RNA interference (RNAi) screening assays. Pansensitive and panresistant genes to 21 NCCN-recommended drugs with concordant mRNA and protein expression were identified. DGKE and WDR47 were found with significant associations with responses to both systemic therapies and radiotherapy in lung cancer. Based on our identified miRNA-regulated molecular machinery, an inhibitor of PDK1/Akt BX-912, an anthracycline antibiotic daunorubicin, and a multi-targeted protein kinase inhibitor midostaurin were discovered as potential repositioning drugs for treating lung cancer. These findings have implications for improving lung cancer diagnosis, optimizing treatment selection, and discovering new drug options for better patient outcomes.
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Affiliation(s)
- Qing Ye
- West Virginia University Cancer Institute, West Virginia University, Morgantown, WV 26506, USA
| | - Rebecca Raese
- West Virginia University Cancer Institute, West Virginia University, Morgantown, WV 26506, USA
| | - Dajie Luo
- West Virginia University Cancer Institute, West Virginia University, Morgantown, WV 26506, USA
| | - Shu Cao
- West Virginia University Cancer Institute, West Virginia University, Morgantown, WV 26506, USA
| | - Ying-Wooi Wan
- West Virginia University Cancer Institute, West Virginia University, Morgantown, WV 26506, USA
| | - Yong Qian
- Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA
| | - Nancy Lan Guo
- West Virginia University Cancer Institute, West Virginia University, Morgantown, WV 26506, USA
- Department of Occupational and Environmental Health Sciences, School of Public Health, West Virginia University, Morgantown, WV 26506, USA
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11
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Kemper M, Krekeler C, Menck K, Lenz G, Evers G, Schulze AB, Bleckmann A. Liquid Biopsies in Lung Cancer. Cancers (Basel) 2023; 15:1430. [PMID: 36900221 PMCID: PMC10000706 DOI: 10.3390/cancers15051430] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/20/2023] [Accepted: 02/20/2023] [Indexed: 02/27/2023] Open
Abstract
As lung cancer has the highest cancer-specific mortality rates worldwide, there is an urgent need for new therapeutic and diagnostic approaches to detect early-stage tumors and to monitor their response to the therapy. In addition to the well-established tissue biopsy analysis, liquid-biopsy-based assays may evolve as an important diagnostic tool. The analysis of circulating tumor DNA (ctDNA) is the most established method, followed by other methods such as the analysis of circulating tumor cells (CTCs), microRNAs (miRNAs), and extracellular vesicles (EVs). Both PCR- and NGS-based assays are used for the mutational assessment of lung cancer, including the most frequent driver mutations. However, ctDNA analysis might also play a role in monitoring the efficacy of immunotherapy and its recent accomplishments in the landscape of state-of-the-art lung cancer therapy. Despite the promising aspects of liquid-biopsy-based assays, there are some limitations regarding their sensitivity (risk of false-negative results) and specificity (interpretation of false-positive results). Hence, further studies are needed to evaluate the usefulness of liquid biopsies for lung cancer. Liquid-biopsy-based assays might be integrated into the diagnostic guidelines for lung cancer as a tool to complement conventional tissue sampling.
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Affiliation(s)
- Marcel Kemper
- Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Muenster, 48149 Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149 Muenster, Germany
| | - Carolin Krekeler
- Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Muenster, 48149 Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149 Muenster, Germany
| | - Kerstin Menck
- Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Muenster, 48149 Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149 Muenster, Germany
| | - Georg Lenz
- Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Muenster, 48149 Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149 Muenster, Germany
| | - Georg Evers
- Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Muenster, 48149 Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149 Muenster, Germany
| | - Arik Bernard Schulze
- Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Muenster, 48149 Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149 Muenster, Germany
| | - Annalen Bleckmann
- Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Muenster, 48149 Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149 Muenster, Germany
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12
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Non-Invasive Biomarkers for Early Lung Cancer Detection. Cancers (Basel) 2022; 14:cancers14235782. [PMID: 36497263 PMCID: PMC9739091 DOI: 10.3390/cancers14235782] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/18/2022] [Accepted: 07/20/2022] [Indexed: 11/27/2022] Open
Abstract
Worldwide, lung cancer (LC) is the most common cause of cancer death, and any delay in the detection of new and relapsed disease serves as a major factor for a significant proportion of LC morbidity and mortality. Though invasive methods such as tissue biopsy are considered the gold standard for diagnosis and disease monitoring, they have several limitations. Therefore, there is an urgent need to identify and validate non-invasive biomarkers for the early diagnosis, prognosis, and treatment of lung cancer for improved patient management. Despite recent progress in the identification of non-invasive biomarkers, currently, there is a shortage of reliable and accessible biomarkers demonstrating high sensitivity and specificity for LC detection. In this review, we aim to cover the latest developments in the field, including the utility of biomarkers that are currently used in LC screening and diagnosis. We comment on their limitations and summarise the findings and developmental stages of potential molecular contenders such as microRNAs, circulating tumour DNA, and methylation markers. Furthermore, we summarise research challenges in the development of biomarkers used for screening purposes and the potential clinical applications of newly discovered biomarkers.
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Ren Y, Cao L, You M, Ji J, Gong Y, Ren H, Xu F, Guo H, Hu J, Li Z. “SMART” digital nucleic acid amplification technologies for lung cancer monitoring from early to advanced stages. Trends Analyt Chem 2022. [DOI: 10.1016/j.trac.2022.116774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Vykoukal J, Fahrmann JF, Patel N, Shimizu M, Ostrin EJ, Dennison JB, Ivan C, Goodman GE, Thornquist MD, Barnett MJ, Feng Z, Calin GA, Hanash SM. Contributions of Circulating microRNAs for Early Detection of Lung Cancer. Cancers (Basel) 2022; 14:4221. [PMID: 36077759 PMCID: PMC9454665 DOI: 10.3390/cancers14174221] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 05/10/2022] [Accepted: 08/08/2022] [Indexed: 02/04/2023] Open
Abstract
There is unmet need to develop circulating biomarkers that would enable earlier interception of lung cancer when more effective treatment options are available. Here, a set of 30 miRNAs, selected from a review of the published literature were assessed for their predictive performance in identifying lung cancer cases in the pre-diagnostic setting. The 30 miRNAs were assayed using sera collected from 102 individuals diagnosed with lung cancer within one year following blood draw and 212 controls matched for age, sex, and smoking status. The additive performance of top-performing miRNA candidates in combination with a previously validated four-protein marker panel (4MP) consisting of the precursor form of surfactant protein B (Pro-SFTPB), cancer antigen 125 (CA125), carcinoembryonic antigen (CEA) and cytokeratin-19 fragment (CYFRA21-1) was additionally assessed. Of the 30 miRNAs evaluated, five (miR-320a-3p, miR-210-3p, miR-92a-3p, miR-21-5p, and miR-140-3p) were statistically significantly (Wilcoxon rank sum test p < 0.05) elevated in case sera compared to controls, with individual AUCs ranging from 0.57−0.62. Compared to the 4MP alone, the combination of 3-miRNAs + 4MP improved sensitivity at 95% specificity by 19.1% ((95% CI of difference 0.0−28.6); two-sided p: 0.006). Our findings demonstrate utility for miRNAs for early detection of lung cancer in combination with a four-protein marker panel.
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Affiliation(s)
- Jody Vykoukal
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
- McCombs Institute for the Early Detection and Treatment of Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Johannes F. Fahrmann
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Nikul Patel
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Masayoshi Shimizu
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Edwin J. Ostrin
- Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jennifer B. Dennison
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Cristina Ivan
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Gary E. Goodman
- Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | | | - Matt J. Barnett
- Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Ziding Feng
- Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - George A. Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Samir M. Hanash
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
- McCombs Institute for the Early Detection and Treatment of Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Shen X, Li L, Zhang L, Liu W, Wu Y, Ma R. Diagnostic and prognostic value of microRNA-486 in patients with lung cancer: A systematic review and meta-analysis. Int J Biol Markers 2022; 37:377-385. [PMID: 35902998 DOI: 10.1177/03936155221115750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE There are conflicting opinions on whether miR-486 could be used for cancer diagnosis and prognosis. Therefore, this present study investigated the potential effect of miR-486 on lung cancer diagnosis and prognosis. METHODS We researched PubMed, Embase, Wanfang and Chinese National Knowledge Infrastructure databases to select relevant publications. Specificity and sensitivity were obtained for the pooled and subgroup diagnostic meta-analysis while the hazard ratio was for prognostic meta-analysis. Publication analyses and sensitivity analyses were conducted to investigate possible sources of heterogeneity. RESULTS The overall sensitivity and specificity with 95% confidence intervals were 0.8 (0.8-0.9) and 0.9 (0.9-0.9). Results of subgroup analysis showed that high diagnostic efficacy might be obtained by miR-486 combined with other microRNAs (area under the curve (AUC): 0.9 (0.9-1.0)) to distinguish lung cancer patients from healthy controls (AUC: 1.0 (0.9-1.0)), especially for lung adenocarcinoma (AUC: 1.0 (1.0-1.0)) in the Asian population (AUC: 0.9 (0.9-1.0)). For prognosis prediction of miR-486 in overall non-small cell lung cancer, the overall hazard ratio with 95% confidence interval was 1.15 (0.85-1.54) for high versus low expression of miR-486, which indicated that a high miR-486 level was not related to the high risk of poor outcome. However, for the subgroup of progression-free survival and patients with chemotherapy, the hazard ratio was 0.41 (0.21-0.77), indicating that the higher miR-486 level would decrease the risk of poor progression-free survival for lung cancer patients with chemotherapy. CONCLUSION This study suggested circulating miR-486 combined with other microRNAs could be used as ideal biomarkers in early diagnosis and prognosis prediction for lung cancer, especially for lung adenocarcinoma in the Asian population.
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Affiliation(s)
- Xiaoyu Shen
- Medical Oncology Department of Thoracic Cancer (2), 74665Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, People's Republic of China
| | - Linlin Li
- Medical Oncology Department of Thoracic Cancer (2), 74665Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, People's Republic of China
| | - Linlin Zhang
- Medical Oncology Department of Thoracic Cancer (2), 74665Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, People's Republic of China
| | - Wenjing Liu
- Medical Oncology Department of Thoracic Cancer (2), 74665Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, People's Republic of China
| | - Yang Wu
- Medical Oncology Department of Thoracic Cancer (2), 74665Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, People's Republic of China
| | - Rui Ma
- Medical Oncology Department of Thoracic Cancer (2), 74665Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, People's Republic of China
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Identification of the Key miRNAs and Genes Associated with the Regulation of Non-Small Cell Lung Cancer: A Network-Based Approach. Genes (Basel) 2022; 13:genes13071174. [PMID: 35885958 PMCID: PMC9317345 DOI: 10.3390/genes13071174] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/18/2022] [Accepted: 06/20/2022] [Indexed: 11/26/2022] Open
Abstract
Lung cancer is the major cause of cancer-associated deaths across the world in both men and women. Lung cancer consists of two major clinicopathological categories, i.e., small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Lack of diagnosis of NSCLC at an early stage in addition to poor prognosis results in ineffective treatment, thus, biomarkers for appropriate diagnosis and exact prognosis of NSCLC need urgent attention. The proposed study aimed to reveal essential microRNAs (miRNAs) involved in the carcinogenesis of NSCLC that probably could act as potential biomarkers. The NSCLC-associated expression datasets revealed 12 differentially expressed miRNAs (DEMs). MiRNA-mRNA network identified key miRNAs and their associated genes, for which functional enrichment analysis was applied. Further, survival and validation analysis for key genes was performed and consequently transcription factors (TFs) were predicted. We obtained twelve miRNAs as common DEMs after assessment of all datasets. Further, four key miRNAs and nine key genes were extracted from significant modules based on the centrality approach. The key genes and miRNAs reported in our study might provide some information for potential biomarkers profitable to increased prognosis and diagnosis of lung cancer.
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Han B, Molins L, He Y, Viñolas N, Sánchez-Lorente D, Boada M, Guirao A, Díaz T, Martinez D, Ramirez J, Moisés J, Acosta-Plasencia M, Monzo M, Marrades RM, Navarro A. Characterization of the MicroRNA Cargo of Extracellular Vesicles Isolated from a Pulmonary Tumor-Draining Vein Identifies miR-203a-3p as a Relapse Biomarker for Resected Non-Small Cell Lung Cancer. Int J Mol Sci 2022; 23:ijms23137138. [PMID: 35806142 PMCID: PMC9266391 DOI: 10.3390/ijms23137138] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/21/2022] [Accepted: 06/23/2022] [Indexed: 02/05/2023] Open
Abstract
In resected non-small cell lung cancer (NSCLC), post-surgical recurrence occurs in around 40% of patients, highlighting the necessity to identify relapse biomarkers. An analysis of the extracellular vesicle (EV) cargo from a pulmonary tumor-draining vein (TDV) can grant biomarker identification. We studied the pulmonary TDV EV-miRNAome to identify relapse biomarkers in a two-phase study (screening and validation). In the screening phase, a 17-miRNA relapse signature was identified in 18 selected patients by small RNAseq. The most expressed miRNA from the signature (EV-miR-203a-3p) was chosen for further validation. Pulmonary TDV EV-miR-203a-3p was studied by qRT-PCR in a validation cohort of 70 patients, where it was found to be upregulated in relapsed patients (p = 0.0194) and in patients with cancer spread to nearby lymph nodes (N+ patients) (p = 0.0396). The ROC curve analysis showed that TDV EV-miR-203a-3p was able to predict relapses with a sensitivity of 88% (AUC: 0.67; p = 0.022). Moreover, patients with high TDV EV-miR-203a-3p had a shorter time to relapse than patients with low levels (43.6 vs. 97.6 months; p = 0.00703). The multivariate analysis showed that EV-miR-203a-3p was an independent, predictive and prognostic post-surgical relapse biomarker. In conclusion, pulmonary TDV EV-miR-203a-3p is a promising new relapse biomarker for resected NSCLC patients.
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Affiliation(s)
- Bing Han
- Molecular Oncology and Embryology Laboratory, Department of Surgery and Medical Specializations, Human Anatomy Unit, Faculty of Medicine and Health Sciences, Universitat de Barcelona (UB), c. Casanova 143, 08036 Barcelona, Spain; (B.H.); (Y.H.); (T.D.); (M.A.-P.); (M.M.)
| | - Laureano Molins
- Department of Thoracic Surgery, Hospital Clínic de Barcelona, University of Barcelona, 08036 Barcelona, Spain; (L.M.); (D.S.-L.); (M.B.); (A.G.)
- Thoracic Oncology Unit, Hospital Clinic, 08036 Barcelona, Spain; (N.V.); (D.M.); (J.R.); (R.M.M.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain;
| | - Yangyi He
- Molecular Oncology and Embryology Laboratory, Department of Surgery and Medical Specializations, Human Anatomy Unit, Faculty of Medicine and Health Sciences, Universitat de Barcelona (UB), c. Casanova 143, 08036 Barcelona, Spain; (B.H.); (Y.H.); (T.D.); (M.A.-P.); (M.M.)
- School of Basic Medical Sciences, Chengdu University, Chengdu 610106, China
| | - Nuria Viñolas
- Thoracic Oncology Unit, Hospital Clinic, 08036 Barcelona, Spain; (N.V.); (D.M.); (J.R.); (R.M.M.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain;
- Department of Medical Oncology, Institut Clínic de Malalties Hemato-Oncològiques (ICMHO), Hospital Clínic de Barcelona, University of Barcelona, 08036 Barcelona, Spain
| | - David Sánchez-Lorente
- Department of Thoracic Surgery, Hospital Clínic de Barcelona, University of Barcelona, 08036 Barcelona, Spain; (L.M.); (D.S.-L.); (M.B.); (A.G.)
- Thoracic Oncology Unit, Hospital Clinic, 08036 Barcelona, Spain; (N.V.); (D.M.); (J.R.); (R.M.M.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain;
| | - Marc Boada
- Department of Thoracic Surgery, Hospital Clínic de Barcelona, University of Barcelona, 08036 Barcelona, Spain; (L.M.); (D.S.-L.); (M.B.); (A.G.)
- Thoracic Oncology Unit, Hospital Clinic, 08036 Barcelona, Spain; (N.V.); (D.M.); (J.R.); (R.M.M.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain;
| | - Angela Guirao
- Department of Thoracic Surgery, Hospital Clínic de Barcelona, University of Barcelona, 08036 Barcelona, Spain; (L.M.); (D.S.-L.); (M.B.); (A.G.)
- Thoracic Oncology Unit, Hospital Clinic, 08036 Barcelona, Spain; (N.V.); (D.M.); (J.R.); (R.M.M.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain;
| | - Tania Díaz
- Molecular Oncology and Embryology Laboratory, Department of Surgery and Medical Specializations, Human Anatomy Unit, Faculty of Medicine and Health Sciences, Universitat de Barcelona (UB), c. Casanova 143, 08036 Barcelona, Spain; (B.H.); (Y.H.); (T.D.); (M.A.-P.); (M.M.)
| | - Daniel Martinez
- Thoracic Oncology Unit, Hospital Clinic, 08036 Barcelona, Spain; (N.V.); (D.M.); (J.R.); (R.M.M.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain;
- Department of Pathology, Hospital Clínic de Barcelona, University of Barcelona, 08036 Barcelona, Spain
| | - Jose Ramirez
- Thoracic Oncology Unit, Hospital Clinic, 08036 Barcelona, Spain; (N.V.); (D.M.); (J.R.); (R.M.M.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain;
- Department of Pathology, Hospital Clínic de Barcelona, University of Barcelona, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Jorge Moisés
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain;
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Melissa Acosta-Plasencia
- Molecular Oncology and Embryology Laboratory, Department of Surgery and Medical Specializations, Human Anatomy Unit, Faculty of Medicine and Health Sciences, Universitat de Barcelona (UB), c. Casanova 143, 08036 Barcelona, Spain; (B.H.); (Y.H.); (T.D.); (M.A.-P.); (M.M.)
| | - Mariano Monzo
- Molecular Oncology and Embryology Laboratory, Department of Surgery and Medical Specializations, Human Anatomy Unit, Faculty of Medicine and Health Sciences, Universitat de Barcelona (UB), c. Casanova 143, 08036 Barcelona, Spain; (B.H.); (Y.H.); (T.D.); (M.A.-P.); (M.M.)
- Thoracic Oncology Unit, Hospital Clinic, 08036 Barcelona, Spain; (N.V.); (D.M.); (J.R.); (R.M.M.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain;
| | - Ramón M. Marrades
- Thoracic Oncology Unit, Hospital Clinic, 08036 Barcelona, Spain; (N.V.); (D.M.); (J.R.); (R.M.M.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain;
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Pneumology, Institut Clínic Respiratori (ICR), Hospital Clínic de Barcelona, University of Barcelona, 08036 Barcelona, Spain
| | - Alfons Navarro
- Molecular Oncology and Embryology Laboratory, Department of Surgery and Medical Specializations, Human Anatomy Unit, Faculty of Medicine and Health Sciences, Universitat de Barcelona (UB), c. Casanova 143, 08036 Barcelona, Spain; (B.H.); (Y.H.); (T.D.); (M.A.-P.); (M.M.)
- Thoracic Oncology Unit, Hospital Clinic, 08036 Barcelona, Spain; (N.V.); (D.M.); (J.R.); (R.M.M.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain;
- Correspondence: ; Tel.: +34-93-4021903
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Geng W, Qiu M, Zhang D, Li P, Sun G, Zhou X. LncRNA PCAT7 promotes non-small cell lung cancer progression by activating miR-486-5p/CDK4 axis-mediated cell cycle. Am J Transl Res 2022; 14:3003-3016. [PMID: 35702078 PMCID: PMC9185083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 03/05/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVE Lung cancer remains one of the common cancers worldwide. Both LncRNA PCAT7 and miR-486-5p are tightly correlated with NSCLC. However, the relationship between PCAT7 and miR-486-5p and the detailed mechanisms underlying the effect of PCAT7 on NSCLC are not discovered yet. METHODS GEPIA and ENCORI databases were used to determine the expression of PCAT7 in different cancers. CCK8, colony formation and Transwell assay were used to confirm the ability of cells. Luciferase reporter gene assay was employed to estimate the luciferase activity of the gene. Flow cytometry was used to compare cell cycle of NSCLC cells after indicated treatment. RESULTS GEPIA combined ENCORI database illustrated that LncRNA PCAT7 was upregulated dramatically in NSCLC. The mRNA level of PCAT7 cells was higher than that in normal cells. Silencing PCAT7 inhibited the progression of NSCLC cells significantly. Data from ENCORI website showed that miR-486-5p was the target of PCAT7 and was negatively controlled by it. The data also showed that CDK4 could be bound and negatively regulated by miR-486-5p. MiR-486-5p inhibitor or CDK4 could partly restore the inhibitory effect of PCAT7 in NSCLC cells. In addition, silencing PCAT7 could arrest cell cycle to S in addition to G2 stage while transfecting miR-486-5p inhibitor or CDK4 could partially eliminate the retarding effects. CONCLUSION In our study, we elaborated that LncRNA PCAT7 could promote the development of NSCLC cells by accelerating cell cycle via miR-486-5p/CDK4 axis.
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Affiliation(s)
- Wenting Geng
- The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong First Medical University & Shandong Academy of Medical SciencesJinan 250102, Shandong, China
| | - Mengru Qiu
- Occupational Diseases Hospital of Shandong First Medical University & Shandong Province Hospital of Occupational DiseasesJinan 250002, Shandong, China
| | - Dongbin Zhang
- Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinan 250011, Shandong, China
| | - Peng Li
- Occupational Diseases Hospital of Shandong First Medical University & Shandong Province Hospital of Occupational DiseasesJinan 250002, Shandong, China
| | - Gangyi Sun
- Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinan 250011, Shandong, China
| | - Xi Zhou
- Occupational Diseases Hospital of Shandong First Medical University & Shandong Province Hospital of Occupational DiseasesJinan 250002, Shandong, China
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Jin Y, Chen Z, Chen Q, Sha L, Shen C. [Role and Significance of Bioactive Substances in Sputum
in the Diagnosis of Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2021; 24:867-873. [PMID: 34923805 PMCID: PMC8695240 DOI: 10.3779/j.issn.1009-3419.2021.102.46] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
肺癌是我国目前发病率最高的恶性肿瘤之一，其诊断的金标准需要进行组织活检的病理学检查或脱落细胞学检查，二者的有创性和敏感性限制了他们的使用。痰液中含有大量核酸、蛋白质，是肺功能的良好反映物，肺癌组织也会影响痰液中的生物成分，检测其中的生物活性物质可有助于肺癌的诊断。本文综合目前国内外的研究结果，对痰液中可用于肺癌诊断的生物活性物质做一综述。
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Affiliation(s)
- Yuming Jin
- West China School of Medicine, Sichuan University, Chengdu 610041, China
| | - Zixuan Chen
- West China School of Medicine, Sichuan University, Chengdu 610041, China
| | - Quan Chen
- West China School of Medicine, Sichuan University, Chengdu 610041, China
| | - Leihao Sha
- West China School of Medicine, Sichuan University, Chengdu 610041, China
| | - Cheng Shen
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
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Yi M, Liao Z, Deng L, Xu L, Tan Y, Liu K, Chen Z, Zhang Y. High diagnostic value of miRNAs for NSCLC: quantitative analysis for both single and combined miRNAs in lung cancer. Ann Med 2021; 53:2178-2193. [PMID: 34913774 PMCID: PMC8740622 DOI: 10.1080/07853890.2021.2000634] [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: 07/15/2021] [Accepted: 10/26/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) are good candidates as biomarkers for Lung cancer (LC). The aim of this article is to figure out the diagnostic value of both single and combined miRNAs in LC. METHODS Normative meta-analysis was conducted based on PRISMA. We assessed the diagnostic value by calculating the combined sensitivity (Sen), specificity (Spe), positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) and the area under the curve (AUC) of single and combined miRNAs for LC and specific subgroups. RESULTS A total of 80 qualified studies with a total of 8971 patients and 10758 controls were included. In non-small cell lung carcinoma (NSCLC), we involved 20 single-miRNAs and found their Sen, Spe and AUC ranged from 0.52-0.81, 0.66-0.88, and 0.68-0.90, respectively, specially, miR-19 with the maximum Sen, miR-20 and miR-10 with the highest Spe as well as miR-17 with the maximum AUC. Additionally, we detected miR-21 with the maximum Sen of 0.74 [95%CI: 0.62-0.83], miR-146 with the maximum Spe and AUC of 0.93 [95%CI: 0.79-0.98] and 0.89 [95%CI: 0.86-0.92] for early-stage NSCLC. We also identified the diagnostic power of available panel (miR-210, miR-31 and miR-21) for NSCLC with satisfying Sen, Spe and AUC of 0.82 [95%CI: 0.78-0.84], 0.87 [95%CI: 0.84-0.89] and 0.91 [95%CI: 0.88-0.93], and furtherly constructed 2 models for better diagnosis. CONCLUSIONS We identified several single miRNAs and combined groups with high diagnostic power for NSCLC through pooled quantitative analysis, which shows that specific miRNAs are good biomarker candidates for NSCLC and further researches needed.
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Affiliation(s)
- Minhan Yi
- Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
- School of Life Sciences, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zexi Liao
- Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Xiangya Medical School, Central South University, Changsha, Hunan, China
| | - Langmei Deng
- Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Emergency, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Li Xu
- Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
- School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Yun Tan
- School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Kun Liu
- School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Ziliang Chen
- School of Computer Science and Engineering, Central South University, Changsha, Hunan, China
| | - Yuan Zhang
- Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
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Wang H, Xu J, Ding L. MicroRNA-21 was a promising biomarker for lung carcinoma diagnosis: An update meta-analysis. Thorac Cancer 2021; 13:316-321. [PMID: 34837469 PMCID: PMC8807252 DOI: 10.1111/1759-7714.14242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 11/03/2021] [Accepted: 11/05/2021] [Indexed: 11/29/2022] Open
Abstract
Objective To investigate the diagnostic performance of microRNA‐21 detected in serum or sputum as a biomarker for lung carcinoma identification through pooling the open published data. Methods Clinical diagnostic studies related to microRNA‐21 as a biomarker for lung carcinoma identification were electronically searched in the databases of Pubmed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, and Google Scholar. The data of the included studies was extracted and made pooling of diagnostic sensitivity, specificity, diagnostic odds ratio (DOR), area under the summary receiver operating characteristic curve (ROC) (AUC) for microRNA‐21 expression in serum or sputum as a biomarker for lung carcinoma identification. The publication bias was evaluated by Deek's funnel plot. Results Seventeen diagnostic studies were finally included and made data pooling. For the included 17 studies, 4 investigated the microRNA‐21 expression in sputum and 13 studies in serum. The pooled diagnostic sensitivity and specificity were 0.73 (95% CI, 0.67–0.78) and 0.81 (95% CI, 0.75–0.85), respectively, under random effect model. The combined DOR was 9.65 (95% CI, 6.64–14.03) with the AUC of 0.84 (95% CI, 0.80–0.87). Given a pre‐test probability of 50%, the post‐test positive probability and post‐test negative probability were 79% and 25%, respectively, by using microRNA‐21 as a biomarker for lung carcinoma diagnosis. Deek's funnel was obviously asymmetry and indicated significant publication bias (p < 0.05). Conclusion MicroRNA‐21 in serum or sputum was a promising biomarker for lung cancer identification with relative high diagnostic sensitivity and specificity.
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Affiliation(s)
- Haiyan Wang
- Department of Respiratory, Hangzhou Third People's Hospital, Hangzhou, China
| | - Jia Xu
- Department of Respiratory, Hangzhou Third People's Hospital, Hangzhou, China
| | - Ling Ding
- Department of Respiratory, Hangzhou Third People's Hospital, Hangzhou, China
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22
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Cavallari I, Ciccarese F, Sharova E, Urso L, Raimondi V, Silic-Benussi M, D’Agostino DM, Ciminale V. The miR-200 Family of microRNAs: Fine Tuners of Epithelial-Mesenchymal Transition and Circulating Cancer Biomarkers. Cancers (Basel) 2021; 13:5874. [PMID: 34884985 PMCID: PMC8656820 DOI: 10.3390/cancers13235874] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 12/13/2022] Open
Abstract
The miR-200 family of microRNAs (miRNAs) includes miR-200a, miR-200b, miR-200c, miR-141 and miR-429, five evolutionarily conserved miRNAs that are encoded in two clusters of hairpin precursors located on human chromosome 1 (miR-200b, miR-200a and miR-429) and chromosome 12 (miR-200c and miR-141). The mature -3p products of the precursors are abundantly expressed in epithelial cells, where they contribute to maintaining the epithelial phenotype by repressing expression of factors that favor the process of epithelial-to-mesenchymal transition (EMT), a key hallmark of oncogenic transformation. Extensive studies of the expression and interactions of these miRNAs with cell signaling pathways indicate that they can exert both tumor suppressor- and pro-metastatic functions, and may serve as biomarkers of epithelial cancers. This review provides a summary of the role of miR-200 family members in EMT, factors that regulate their expression, and important targets for miR-200-mediated repression that are involved in EMT. The second part of the review discusses the potential utility of circulating miR-200 family members as diagnostic/prognostic biomarkers for breast, colorectal, lung, ovarian, prostate and bladder cancers.
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Affiliation(s)
- Ilaria Cavallari
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Francesco Ciccarese
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Evgeniya Sharova
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Loredana Urso
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padova, Italy
| | - Vittoria Raimondi
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Micol Silic-Benussi
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Donna M. D’Agostino
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Biomedical Sciences, University of Padua, 35131 Padova, Italy
| | - Vincenzo Ciminale
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padova, Italy
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Saviana M, Romano G, Le P, Acunzo M, Nana-Sinkam P. Extracellular Vesicles in Lung Cancer Metastasis and Their Clinical Applications. Cancers (Basel) 2021; 13:5633. [PMID: 34830787 PMCID: PMC8616161 DOI: 10.3390/cancers13225633] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/04/2021] [Accepted: 11/09/2021] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles (EVs) are heterogenous membrane-encapsulated vesicles secreted by every cell into the extracellular environment. EVs carry bioactive molecules, including proteins, lipids, DNA, and different RNA forms, which can be internalized by recipient cells, thus altering their biological characteristics. Given that EVs are commonly found in most body fluids, they have been widely described as mediators of communication in several physiological and pathological processes, including cancer. Moreover, their easy detection in biofluids makes them potentially useful candidates as tumor biomarkers. In this manuscript, we review the current knowledge regarding EVs and non-coding RNAs and their role as drivers of the metastatic process in lung cancer. Furthermore, we present the most recent applications for EVs and non-coding RNAs as cancer therapeutics and their relevance as clinical biomarkers.
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Affiliation(s)
- Michela Saviana
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (M.S.); (G.R.); (P.L.); (M.A.)
- Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy
| | - Giulia Romano
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (M.S.); (G.R.); (P.L.); (M.A.)
| | - Patricia Le
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (M.S.); (G.R.); (P.L.); (M.A.)
| | - Mario Acunzo
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (M.S.); (G.R.); (P.L.); (M.A.)
| | - Patrick Nana-Sinkam
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (M.S.); (G.R.); (P.L.); (M.A.)
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24
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Pehlevan Özel H, Dinç T, Tiryaki RS, Keşküş AG, Konu Ö, Kayilioğlu SI, Coşkun F. Targeted MicroRNA Profiling in Gastric Cancer with Clinical Assessement. Balkan J Med Genet 2021; 24:55-64. [PMID: 36249523 PMCID: PMC9524170 DOI: 10.2478/bjmg-2021-0022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Although several microRNAs (miRNAs) have been associated with gastric cancer there is still the need for identification of stable and validated biomarkers. The purpose of this study was to determine the alterations of a specific set of miRNA levels in gastric adenocarcinoma tissues to identify and validate gastric cancer-specific miRNAs using paired normal and tumor samples in an independent patient cohort. Gastric adenocarcinoma and normal stomach tissue samples of 20 patients who underwent surgery for gastric cancer were studied. The miRNA expression profiling was performed for eight miRNAs in a total of 40 tissue samples using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Six out of these eight miRNAs, namely, miR-375-3p, hsamiR-129-5p, miR-196a-5p, miR-376c-3p, miR-34c-5p and miR-767-5p, were significantly underexpressed in malignant tissues of our cohort. Furthermore, the expression of miR-662 although not significantly different between normal and tumor tissues, was inversely associated with age (r = -0.440, p = 0.049). The levels of miR-129-3p and miR34c-5p were correlated with an increase in the number of metastatic lymph nodes (r = 0.470, p = 0.036; r = 0.510, p = 0.020), while and miR-376c-3p levels were negatively associated with smoking (p = 0.043). In addition, we found that the variability of miRNA expression in cancerous tissues was lower than that in normal tissues. Alterations in miRNA expression in gastric adenocarcinoma tissues in comparison to healthy tissues of each individual serves for identification of consistent biomarkers that can be used for development of diagnostic tools for gastric cancer.
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Affiliation(s)
- H Pehlevan Özel
- Department of General Surgery, Health Sciences University, Ankara City Hospital, Ankara, Turkey
| | - T Dinç
- Department of General Surgery, Health Sciences University, Ankara City Hospital, Ankara, Turkey
| | - RS Tiryaki
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - AG Keşküş
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Ö Konu
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - SI Kayilioğlu
- Department of General Surgery, Sıtkı Koçman University, Muğla, Turkey
| | - F Coşkun
- Department of General Surgery, Health Sciences University, Ankara City Hospital, Ankara, Turkey
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25
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Hsieh FM, Lai ST, Wu MF, Lin CC. Identification and Elucidation of the Protective isomiRs in Lung Cancer Patient Prognosis. Front Genet 2021; 12:702695. [PMID: 34589114 PMCID: PMC8474875 DOI: 10.3389/fgene.2021.702695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 08/16/2021] [Indexed: 11/24/2022] Open
Abstract
MicroRNAs (miRNAs) are approximately 20–22 nucleotides in length, which are well known to participate in the post-transcriptional modification. The mature miRNAs were observed to be varied on 5′ or 3′ that raise another term—the isoforms of mature miRNAs (isomiRs), which have been proven not the artifacts and discussed widely recently. In our research, we focused on studying the 5′ isomiRs in lung adenocarcinoma (LUAD) in The Cancer Genome Atlas (TCGA). We characterized 75 isomiRs significantly associated with better prognosis and 43 isomiRs with poor prognosis. The 75 protective isomiRs can successfully distinguish tumors from normal samples and are expressed differently between patients of early and late stages. We also found that most of the protective isomiRs tend to be with downstream shift and upregulated compared with those with upstream shift, implying that a possible selection occurs during cancer development. Among these protective isomiRs, we observed a highly positive and significant correlation, as well as in harmful isomiRs, suggesting cooperation within the group. However, between protective and harmful, there is no such a concordance but conversely more negative correlation, suggesting the possible antagonistic effect between protective and harmful isomiRs. We also identified that two isomiRs miR-181a-3p|-3 and miR-181a-3p|2, respectively, belong to the harmful and protective groups, suggesting a bidirectional regulation of their originated archetype—miR-181a-3p. Additionally, we found that the protective isomiRs of miR-21-5p, which is an oncomiR, may be evolved as the tumor suppressors through producing isomiRs to hinder metastasis. In summary, these results displayed the characteristics of the protective isomiRs and their potential for developing the treatment of lung cancer.
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Affiliation(s)
- Fu-Mei Hsieh
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Su-Ting Lai
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ming-Fong Wu
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chen-Ching Lin
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan
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26
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Shen HY, Shi LX, Wang L, Fang LP, Xu W, Xu JQ, Fan BQ, Fan WF. Hsa_circ_0001361 facilitates the progress of lung adenocarcinoma cells via targeting miR-525-5p/VMA21 axis. J Transl Med 2021; 19:389. [PMID: 34507559 PMCID: PMC8434718 DOI: 10.1186/s12967-021-03045-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 08/17/2021] [Indexed: 12/13/2022] Open
Abstract
Background Lung adenocarcinoma (LUAD) is a common subtype of lung cancer with high recurrence rate and fatality. Circ_0001361 has been recognized as key regulators in various malignancies, but its roles in LUAD remain ambiguous. Methods Circ_0001361, miR-525-5p, and VMA21 levels were assessed by RT-qPCR. The growth and metastasis of LUAD cells were detected by MTT, colony formation, wound scratch, and transwell assays, respectively. The interaction between circ_0001361/VMA21 and miR-525-5p was detected by dual luciferase, RNA immunoprecipitation, and RNA pull-down assays. VMA21 protein level was detected by Western blotting. Nude mouse xenograft model was established to determine the role of circ_0001361 in tumor growth in vivo. Results Circ_0001361 was up-regulated, while miR-525-5p was down-regulated in LUAD tissues and cells. Functional experiments demonstrated that circ_0001361 drove LUAD cell growth and metastasis. Mechanistically, circ_0001361 functioned as a sponge of miR-525-5p to up-regulate downstream target VMA21 level. MiR-525-5p/VMA21 axis was involved in circ_0001361-mediated malignant phenotypes of LUAD cells. Finally, inhibition of circ_0001361 restrained in vivo xenograft tumor growth via regulating miR-525-5p/VMA21 axis. Conclusion Our findings elucidate that circ_0001361 facilitates the tumorigenesis and development of LUAD through miR-525-5p/VMA21 axis, providing evidence for circ_0001361 as a potential prognosis biomarker and therapeutic target for clinical treatment of LUAD. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-03045-4.
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Affiliation(s)
- Hong-Yu Shen
- Department of Hematology and Oncology, Department of Geriatric Lung Cancer Laboratory, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, No.65 Jiangsu Road, Gulou District, Nanjing, 210000, Jiangsu Province, People's Republic of China
| | - Liu-Xi Shi
- GCP office, The Second Affiliated Hospital of Soochow University, Suzhou, 215000, Jiangsu Province, People's Republic of China
| | - Lin Wang
- Department of Hematology and Oncology, Department of Geriatric Lung Cancer Laboratory, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, No.65 Jiangsu Road, Gulou District, Nanjing, 210000, Jiangsu Province, People's Republic of China
| | - Le-Ping Fang
- Department of Hematology and Oncology, Department of Geriatric Lung Cancer Laboratory, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, No.65 Jiangsu Road, Gulou District, Nanjing, 210000, Jiangsu Province, People's Republic of China
| | - Wei Xu
- Department of Hematology and Oncology, Department of Geriatric Lung Cancer Laboratory, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, No.65 Jiangsu Road, Gulou District, Nanjing, 210000, Jiangsu Province, People's Republic of China
| | - Ju-Qing Xu
- Department of Hematology and Oncology, Department of Geriatric Lung Cancer Laboratory, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, No.65 Jiangsu Road, Gulou District, Nanjing, 210000, Jiangsu Province, People's Republic of China
| | - Bo-Qiang Fan
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, Jiangsu Province, People's Republic of China.
| | - Wei-Fei Fan
- Department of Hematology and Oncology, Department of Geriatric Lung Cancer Laboratory, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, No.65 Jiangsu Road, Gulou District, Nanjing, 210000, Jiangsu Province, People's Republic of China.
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27
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Zakharova N, Kozyr A, Ryabokon AM, Indeykina M, Strelnikova P, Bugrova A, Nikolaev EN, Kononikhin AS. Mass spectrometry based proteome profiling of the exhaled breath condensate for lung cancer biomarkers search. Expert Rev Proteomics 2021; 18:637-642. [PMID: 34477466 DOI: 10.1080/14789450.2021.1976150] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Lung cancer remains the most prevalent cause of cancer mortality worldwide mainly due to insufficient availability of early screening methods for wide-scale application. Exhaled breath condensate (EBC) is currently considered as one of the promising targets for early screening and is particularly attractive due to its absolutely noninvasive collection and possibility for long-term frozen storage. EBC proteome analysis can provide valuable information about the (patho)physiological changes in the respiratory system and may help to identify in time a high risk of lung cancer. Mass spectrometry (MS) profiling of EBC proteome seems to have no alternative in obtaining the most extensive data and characteristic marker panels for screening. AREAS COVERED This special report summarizes the data of several proteomic studies of EBC in normal and lung cancer (from 2012 to 2021, PubMed), focuses on the possible reasons for the significant discrepancy in the results, and discusses some aspects for special attention in further studies. EXPERT OPINION The significant discrepancy in the results of various studies primarily highlights the need to create standardized protocols for the collection and preparation of EBC for proteomic analysis. The application of quantitative and targeted LC-MS/MS based approaches seems to be the most promising in further EBC proteomic studies.
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Affiliation(s)
- Natalia Zakharova
- Laboratory of mass spectrometry of biomacromolecules Emanuel Institute for Biochemical Physics, Russian Academy of Science Moscow
| | - Anna Kozyr
- Laboratory of mass spectrometry of biomacromolecules Emanuel Institute for Biochemical Physics, Russian Academy of Science Moscow
| | - Anna M Ryabokon
- Laboratory of mass spectrometry of biomacromolecules Emanuel Institute for Biochemical Physics, Russian Academy of Science Moscow.,Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
| | - Maria Indeykina
- Laboratory of mass spectrometry of biomacromolecules Emanuel Institute for Biochemical Physics, Russian Academy of Science Moscow.,Laboratory of ion and molecular physics, V.l. Talrose Institute for Energy Problems of Chemical Physics, N.n. Semenov Federal Research Center of Chemical Physics, Russian Academy of Sciences, Moscow, Russia
| | - Polina Strelnikova
- Laboratory of mass spectrometry of biomacromolecules Emanuel Institute for Biochemical Physics, Russian Academy of Science Moscow
| | - Anna Bugrova
- Laboratory of mass spectrometry of biomacromolecules Emanuel Institute for Biochemical Physics, Russian Academy of Science Moscow
| | - Eugene N Nikolaev
- Center for Computational and Data-Intensive Science and Engineering, Skolkovo Institute of Science and Technology, Skolkovo, Russia
| | - Alexey S Kononikhin
- Laboratory of mass spectrometry of biomacromolecules Emanuel Institute for Biochemical Physics, Russian Academy of Science Moscow.,Center for Computational and Data-Intensive Science and Engineering, Skolkovo Institute of Science and Technology, Skolkovo, Russia
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28
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Sui Y, Liu J, Zhang J, Zheng Z, Wang Z, Jia Z, Meng Z. Expression and Gene Regulation Network of Adenosine Receptor A2B in Lung Adenocarcinoma: A Potential Diagnostic and Prognostic Biomarker. Front Mol Biosci 2021; 8:663011. [PMID: 34350210 PMCID: PMC8326519 DOI: 10.3389/fmolb.2021.663011] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 06/17/2021] [Indexed: 12/25/2022] Open
Abstract
Adenosinereceptor A2B (ADORA2B) encodes a protein belonging to the G protein–coupled receptor superfamily. Abnormal expression of ADORA2B may play a pathophysiological role in some human cancers. We investigated whether ADORA2B is a potential diagnostic and prognostic biomarker for lung adenocarcinoma (LUAD). The expression, various mutations, copy number variations, mRNA expression levels, and related network signaling pathways of ADORA2B were analyzed using bioinformatics-related websites, including Oncomine, UALCAN, cBioPortal, GeneMANIA, LinkedOmics, KM Plotter, and TIMER. We found that ADORA2B was overexpressed and amplified in LUAD, and a high ADORA2B expression predicted a poor prognosis for LUAD patients. Pathway analyses of ADORA2B in LUAD revealed ADORA2B-correlated signaling pathways, and the expression level of ADORA2B was associated with immune cell infiltration. Furthermore, ADORA2B mRNA and protein levels were significantly higher in human LUAD cell lines (A549 cells and NCl-H1299 cells) than in normal human bronchial epithelial (HBE) cells, and the transcript levels of genes positively or negatively correlated with ADORA2B were consistent and statistically significant. siRNA transfection experiments and functional experiments further confirmed these results. In vitro results were also consistent with those of bioinformatics analysis. Our findings provide a foundation for studying the role of ADORA2B in tumorigenesis and support the development of new drug targets for LUAD.
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Affiliation(s)
- Yutong Sui
- Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Jiayin Liu
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jing Zhang
- Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Zena Zheng
- Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Ziwei Wang
- Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Zhenghu Jia
- The First Affiliated Hospital, Biomedical Translational Research Institute and Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, China
| | - Ziyu Meng
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
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29
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Naeli P, Yousefi F, Ghasemi Y, Savardashtaki A, Mirzaei H. The Role of MicroRNAs in Lung Cancer: Implications for Diagnosis and Therapy. Curr Mol Med 2021; 20:90-101. [PMID: 31573883 DOI: 10.2174/1566524019666191001113511] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 09/17/2019] [Accepted: 09/19/2019] [Indexed: 12/15/2022]
Abstract
Lung cancer is the first cause of cancer death in the world due to its high prevalence, aggressiveness, late diagnosis, lack of effective treatment and poor prognosis. It also shows high rate of recurrence, metastasis and drug resistance. All these problems highlight the urgent needs for developing new strategies using noninvasive biomarkers for early detection, metastasis and recurrence of disease. MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression post-transcriptionally. These molecules found to be abnormally expressed in increasing number of human disease conditions including cancer. miRNAs could be detected in body fluids such as blood, serum, urine and sputum, which leads us towards the idea of using them as non-invasive biomarker for cancer detection and monitoring cancer treatment and recurrence. miRNAs are found to be deregulated in lung cancer initiation and progression and could regulate lung cancer cell proliferation and invasion. In this review, we summarized recent progress and discoveries in microRNAs regulatory role in lung cancer initiation and progression. In addition, the role of microRNAs in EGFR signaling pathway regulation is discussed briefly.
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Affiliation(s)
- Parisa Naeli
- Department of Biological Sciences, Faculty of Genetics, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Yousefi
- Department of Biological Sciences, Faculty of Genetics, Tarbiat Modares University, Tehran, Iran
| | - Younes Ghasemi
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences Shiraz, Iran.,Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences Shiraz, Iran.,Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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30
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Karimi F, Mollaei H. Potential of miRNAs in cervical cancer chemoresistance. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Li N, Dhilipkannah P, Jiang F. High-Throughput Detection of Multiple miRNAs and Methylated DNA by Droplet Digital PCR. J Pers Med 2021; 11:jpm11050359. [PMID: 33946992 PMCID: PMC8146424 DOI: 10.3390/jpm11050359] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/14/2021] [Accepted: 04/22/2021] [Indexed: 01/04/2023] Open
Abstract
Altered miRNA expression and DNA methylation have highly active and diverse roles in carcinogenesis. Simultaneous detection of the molecular aberrations may have a synergistic effect on the diagnosis of malignancies. Herein, we develop a high-throughput assay for detecting multiple miRNAs and DNA methylation using droplet digital PCR (ddPCR) coupled with a 96-microwell plate. The microplate-based ddPCR could absolutely and reproducibly quantify 15 miRNAs and 14 DNA methylation sites with a high sensitivity (one copy/µL and 0.1%, respectively). Analyzing sputum and plasma of 40 lung cancer patients and 36 cancer-free smokers by this approach identified an integrated biomarker panel consisting of two sputum miRNAs (miRs-31-5p and 210-3p), one sputum DNA methylation (RASSF1A), and two plasma miRNAs (miR-21-5p and 126) for the diagnosis of lung cancer with higher sensitivity and specificity compared with a single type of biomarker. The diagnostic value of the integrated biomarker panel for the early detection of lung cancer was confirmed in a different cohort of 36 lung cancer patients and 39 cancer-free smokers. The high-throughput assay for quantification of multiple molecular aberrations across sputum and plasma could improve the early detection of lung cancer.
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32
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Tu Z, He X, Zeng L, Meng D, Zhuang R, Zhao J, Dai W. Exploration of Prognostic Biomarkers for Lung Adenocarcinoma Through Bioinformatics Analysis. Front Genet 2021; 12:647521. [PMID: 33968130 PMCID: PMC8100590 DOI: 10.3389/fgene.2021.647521] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 03/30/2021] [Indexed: 12/30/2022] Open
Abstract
With the development of computer technology, screening cancer biomarkers based on public databases has become a common research method. Here, an eight-gene prognostic model, which could be used to judge the prognosis of patients with lung adenocarcinoma (LUAD), was developed through bioinformatics methods. This study firstly used several gene datasets from GEO database to mine differentially expressed genes (DEGs) in LUAD tissue and healthy tissue via joint analysis. Later, enrichment analysis for the DEGs was performed, and it was found that the DEGs were mainly activated in pathways involved in extracellular matrix, cell adhesion, and leukocyte migration. Afterward, a TCGA cohort was used to perform univariate Cox, least absolute shrinkage and selection operator method, and multivariate Cox regression analyses for the DEGs, and a prognostic model consisting of eight genes (GPX3, TCN1, ASPM, PCP4, CAV2, S100P, COL1A1, and SPOK2) was established. Receiver operation characteristic (ROC) curve was then used to substantiate the diagnostic efficacy of the prognostic model. The survival significance of signature genes was verified through the GEPIA database, and the results exhibited that the risk coefficients of the eight genes were basically congruous with the effects of these genes on the prognosis in the GEPIA database, which suggested that the results were accurate. Finally, combined with clinical characteristics of patients, the diagnostic independence of the prognostic model was further validated through univariate and multivariate regression, and the results indicated that the model had independent prognostic value. The overall finding of the study manifested that the eight-gene prognostic model is closely related to the prognosis of LUAD patients, and can be used as an independent prognostic indicator. Additionally, the prognostic model in this study can help doctors make a better diagnosis in treatment and ultimately benefit LUAD patients.
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Affiliation(s)
- Zhengliang Tu
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiangfeng He
- Department of Thoracic Surgery, Zhuji People's Hospital, Zhuji, China
| | - Liping Zeng
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Di Meng
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Runzhou Zhuang
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiangang Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wanrong Dai
- Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Hangzhou, China
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Freitas C, Sousa C, Machado F, Serino M, Santos V, Cruz-Martins N, Teixeira A, Cunha A, Pereira T, Oliveira HP, Costa JL, Hespanhol V. The Role of Liquid Biopsy in Early Diagnosis of Lung Cancer. Front Oncol 2021; 11:634316. [PMID: 33937034 PMCID: PMC8085425 DOI: 10.3389/fonc.2021.634316] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 03/19/2021] [Indexed: 12/12/2022] Open
Abstract
Liquid biopsy is an emerging technology with a potential role in the screening and early detection of lung cancer. Several liquid biopsy-derived biomarkers have been identified and are currently under ongoing investigation. In this article, we review the available data on the use of circulating biomarkers for the early detection of lung cancer, focusing on the circulating tumor cells, circulating cell-free DNA, circulating micro-RNAs, tumor-derived exosomes, and tumor-educated platelets, providing an overview of future potential applicability in the clinical practice. While several biomarkers have shown exciting results, diagnostic performance and clinical applicability is still limited. The combination of different biomarkers, as well as their combination with other diagnostic tools show great promise, although further research is still required to define and validate the role of liquid biopsies in clinical practice.
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Affiliation(s)
- Cláudia Freitas
- Department of Pulmonology, Centro Hospitalar e Universitário São João, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
| | - Catarina Sousa
- Department of Pulmonology, Centro Hospitalar e Universitário São João, Porto, Portugal
| | - Francisco Machado
- Department of Pulmonology, Centro Hospitalar e Universitário São João, Porto, Portugal
| | - Mariana Serino
- Department of Pulmonology, Centro Hospitalar e Universitário São João, Porto, Portugal
| | - Vanessa Santos
- Department of Pulmonology, Centro Hospitalar e Universitário São João, Porto, Portugal
| | - Natália Cruz-Martins
- Faculty of Medicine, University of Porto, Porto, Portugal
- Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
| | - Armando Teixeira
- Institute for Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
- Faculty of Engineering, University of Porto, Porto, Portugal
| | - António Cunha
- Institute for Systems and Computer Engineering, Technology and Science (INESC TEC), Porto, Portugal
- Department of Engineering, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
| | - Tania Pereira
- Institute for Systems and Computer Engineering, Technology and Science (INESC TEC), Porto, Portugal
| | - Hélder P. Oliveira
- Institute for Systems and Computer Engineering, Technology and Science (INESC TEC), Porto, Portugal
- Faculty of Sciences, University of Porto, Porto, Portugal
| | - José Luís Costa
- Faculty of Medicine, University of Porto, Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Venceslau Hespanhol
- Department of Pulmonology, Centro Hospitalar e Universitário São João, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
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34
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MacDonagh L, Gallagher MF, Ffrench B, Gasch C, Gray SG, Reidy M, Nicholson S, Leonard N, Ryan R, Young V, O'Leary JJ, Cuffe S, Finn SP, O'Byrne KJ, Barr MP. MicroRNA expression profiling and biomarker validation in treatment-naïve and drug resistant non-small cell lung cancer. Transl Lung Cancer Res 2021; 10:1773-1791. [PMID: 34012792 PMCID: PMC8107736 DOI: 10.21037/tlcr-20-959] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Background In the absence of targetable mutations or immune checkpoints, cisplatin-doublet chemotherapy remains the standard of care in non-small cell lung cancer (NSCLC). Drug resistance has however become a significant clinical challenge. Exploring a role for small non-coding microRNAs (miRNA) as biomarker candidates in cisplatin resistant (CisR) lung cancer is lacking and warrants further investigation. Methods miRNA expression profiling was assessed in a panel of cisplatin sensitive and resistant NSCLC cell lines and validated by qPCR. Modulation of altered miRNAs was studied using antagomiRs and pre-miRs while functional assays were used to assess cisplatin response. The translational relevance of these miRNAs as potential biomarkers was assessed in serum and matched normal and tumour lung tissues from chemo-naïve NSCLC patients, in addition to xenograft formalin-fixed paraffin-embedded (FFPE) tumours derived from cisplatin sensitive and resistant cell lines. Results Differential expression of a 5-miR signature (miR-30a-3p, miR-30b-5p, miR-30c-5p, miR-34a-5p, miR-4286) demonstrated their ability to distinguish between normal and tumour lung tissue and between NSCLC histologies. In squamous cell carcinoma (SqCC), tissue miRNA expression was associated with poor survival. miR-4286 showed promise as a blood-based diagnostic biomarker that could distinguish between adenocarcinoma and SqCC histologies. In a xenograft model of cisplatin resistance, using 7-9 week old female NOD/SCID mice (NOD.CB17-Prkdcscid/NCrCrl), a 5-miRNA panel showed altered expression between sensitive and resistant tumours. Conclusions This study identified a panel of miRNAs which may have diagnostic and prognostic potential as novel biomarkers in lung cancer and furthermore, may have a predictive role in monitoring the emergence of resistance to cisplatin.
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Affiliation(s)
- Lauren MacDonagh
- Thoracic Oncology Research Group, School of Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin, Dublin, Ireland
| | - Michael F Gallagher
- Histopathology Department, Sir Patrick Dun Laboratories, Central Pathology Laboratory, St. James's Hospital & Pathology Research Laboratory, Coombe Women and Infant's University Hospital, Dublin, Ireland
| | - Brendan Ffrench
- Histopathology Department, Sir Patrick Dun Laboratories, Central Pathology Laboratory, St. James's Hospital & Pathology Research Laboratory, Coombe Women and Infant's University Hospital, Dublin, Ireland
| | - Claudia Gasch
- Histopathology Department, Sir Patrick Dun Laboratories, Central Pathology Laboratory, St. James's Hospital & Pathology Research Laboratory, Coombe Women and Infant's University Hospital, Dublin, Ireland
| | - Steven G Gray
- Thoracic Oncology Research Group, School of Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin, Dublin, Ireland
| | - Marie Reidy
- Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | | | - Niamh Leonard
- Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | - Ronan Ryan
- Department of Cardiothoracic Surgery, St. James's Hospital, Dublin, Ireland
| | - Vincent Young
- Department of Cardiothoracic Surgery, St. James's Hospital, Dublin, Ireland
| | - John J O'Leary
- Histopathology Department, Sir Patrick Dun Laboratories, Central Pathology Laboratory, St. James's Hospital & Pathology Research Laboratory, Coombe Women and Infant's University Hospital, Dublin, Ireland
| | - Sinead Cuffe
- Thoracic Oncology Research Group, School of Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin, Dublin, Ireland.,Department of Medical Oncology, St James's Hospital, Dublin, Ireland
| | - Stephen P Finn
- Thoracic Oncology Research Group, School of Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin, Dublin, Ireland.,Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | - Kenneth J O'Byrne
- Cancer & Ageing Research Program, Queensland University of Technology, Brisbane, Australia
| | - Martin P Barr
- Thoracic Oncology Research Group, School of Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin, Dublin, Ireland
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Zhong S, Golpon H, Zardo P, Borlak J. miRNAs in lung cancer. A systematic review identifies predictive and prognostic miRNA candidates for precision medicine in lung cancer. Transl Res 2021; 230:164-196. [PMID: 33253979 DOI: 10.1016/j.trsl.2020.11.012] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 11/05/2020] [Accepted: 11/24/2020] [Indexed: 02/08/2023]
Abstract
Lung cancer (LC) is the leading cause of cancer-related death worldwide and miRNAs play a key role in LC development. To better diagnose LC and to predict drug treatment responses we evaluated 228 articles encompassing 16,697 patients and 12,582 healthy controls. Based on the criteria of ≥3 independent studies and a sensitivity and specificity of >0.8 we found blood-borne miR-20a, miR-10b, miR-150, and miR-223 to be excellent diagnostic biomarkers for non-small cell LC whereas miR-205 is specific for squamous cell carcinoma. The systematic review also revealed 38 commonly regulated miRNAs in tumor tissue and the circulation, thus enabling the prediction of histological subtypes of LC. Moreover, theranostic biomarker candidates with proven responsiveness to checkpoint inhibitor treatments were identified, notably miR-34a, miR-93, miR-106b, miR-181a, miR-193a-3p, and miR-375. Conversely, miR-103a-3p, miR-152, miR-152-3p, miR-15b, miR-16, miR-194, miR-34b, and miR-506 influence programmed cell death-ligand 1 and programmed cell death-1 receptor expression, therefore providing a rationale for the development of molecularly targeted therapies. Furthermore, miR-21, miR-25, miR-27b, miR-19b, miR-125b, miR-146a, and miR-210 predicted response to platinum-based treatments. We also highlight controversial reports on specific miRNAs. In conclusion, we report diagnostic miRNA biomarkers for in-depth clinical evaluation. Furthermore, in an effort to avoid unnecessary toxicity we propose predictive biomarkers. The biomarker candidates support personalized treatment decisions of LC patients and await their confirmation in randomized clinical trials.
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Affiliation(s)
- Shen Zhong
- Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
| | - Heiko Golpon
- Department of Pneumology, Hannover Medical School, Hannover, Germany
| | - Patrick Zardo
- Clinic for Cardiothoracic and Transplantation Surgery, Hannover Medical School, Hannover, Germany
| | - Jürgen Borlak
- Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany.
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Microbiota Biomarkers for Lung Cancer. Diagnostics (Basel) 2021; 11:diagnostics11030407. [PMID: 33673596 PMCID: PMC7997424 DOI: 10.3390/diagnostics11030407] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/20/2021] [Accepted: 02/23/2021] [Indexed: 02/07/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is the number one cancer killer and its early detection can reduce mortality. Accumulating evidences suggest an etiopathogenic role of microorganisms in lung tumorigenesis. Certain bacteria are found to be associated with NSCLC. Herein we evaluated the potential use of microbiome as biomarkers for the early detection of NSCLC. We used droplet digital PCR to analyze 25 NSCLC-associated bacterial genera in 31 lung tumor and the paired noncancerous lung tissues and sputum of 17 NSCLC patients and ten cancer-free smokers. Of the bacterial genera, four had altered abundances in lung tumor tissues, while five were aberrantly abundant in sputum of NSCLC patients compared with their normal counterparts (all p < 0.05). Acidovorax and Veillonella were further developed as a panel of sputum biomarkers that could diagnose lung squamous cell carcinoma (SCC) with 80% sensitivity and 89% specificity. The use of Capnocytophaga as a sputum biomarker identified lung adenocarcinoma (AC) with 72% sensitivity and 85% specificity. The use of Acidovorax as a sputum biomarker had 63% sensitivity and 96% specificity for distinguishing between SCC and AC, the two major types of NSCLC. The sputum biomarkers were further validated for the diagnostic values in a different cohort of 69 NSCLC cases and 79 cancer-free controls. Sputum microbiome might provide noninvasive biomarkers for the early detection and classification of NSCLC.
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Supplitt S, Karpinski P, Sasiadek M, Laczmanska I. Current Achievements and Applications of Transcriptomics in Personalized Cancer Medicine. Int J Mol Sci 2021; 22:1422. [PMID: 33572595 PMCID: PMC7866970 DOI: 10.3390/ijms22031422] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/12/2022] Open
Abstract
Over the last decades, transcriptome profiling emerged as one of the most powerful approaches in oncology, providing prognostic and predictive utility for cancer management. The development of novel technologies, such as revolutionary next-generation sequencing, enables the identification of cancer biomarkers, gene signatures, and their aberrant expression affecting oncogenesis, as well as the discovery of molecular targets for anticancer therapies. Transcriptomics contribute to a change in the holistic understanding of cancer, from histopathological and organic to molecular classifications, opening a more personalized perspective for tumor diagnostics and therapy. The further advancement on transcriptome profiling may allow standardization and cost reduction of its analysis, which will be the next step for transcriptomics to become a canon of contemporary cancer medicine.
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Affiliation(s)
- Stanislaw Supplitt
- Department of Genetics, Wroclaw Medical University, Marcinkowskiego 1, 50-368 Wroclaw, Poland; (P.K.); (M.S.); (I.L.)
| | - Pawel Karpinski
- Department of Genetics, Wroclaw Medical University, Marcinkowskiego 1, 50-368 Wroclaw, Poland; (P.K.); (M.S.); (I.L.)
- Laboratory of Genomics and Bioinformatics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wroclaw, Poland
| | - Maria Sasiadek
- Department of Genetics, Wroclaw Medical University, Marcinkowskiego 1, 50-368 Wroclaw, Poland; (P.K.); (M.S.); (I.L.)
| | - Izabela Laczmanska
- Department of Genetics, Wroclaw Medical University, Marcinkowskiego 1, 50-368 Wroclaw, Poland; (P.K.); (M.S.); (I.L.)
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MicroRNAs: Emerging oncogenic and tumor-suppressive regulators, biomarkers and therapeutic targets in lung cancer. Cancer Lett 2021; 502:71-83. [PMID: 33453304 DOI: 10.1016/j.canlet.2020.12.040] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 11/24/2020] [Accepted: 12/26/2020] [Indexed: 02/05/2023]
Abstract
Lung cancer is one of the most common solid tumors worldwide and the leading cause of cancer-related deaths, causing a devastating impact on human health. The clinical prognosis of lung cancer is usually restricted by delayed diagnosis and resistance to anticancer therapies. MicroRNAs, a range of small endogenous noncoding RNAs 22 nucleotides in length, have emerged as one of the most important players in cancer initiation and progression in recent decades. Current evidence reveals pivotal roles of microRNAs in regulating cell proliferation, migration, invasion and metastasis in lung cancer. An increasing number of preclinical and clinical studies have also explored the potential of microRNAs as promising biomarkers and new therapeutic targets for lung cancer. The current review summarizes the most recent progress on the functional mechanisms of microRNAs involved in lung cancer development and progression and further discusses the clinical application of miRNAs as putative therapeutic targets for molecular diagnosis and prognostic prediction in lung cancer.
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39
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Autoantibodies against tumor-associated antigens in sputum as biomarkers for lung cancer. Transl Oncol 2020; 14:100991. [PMID: 33333369 PMCID: PMC7736713 DOI: 10.1016/j.tranon.2020.100991] [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: 09/25/2020] [Revised: 11/30/2020] [Accepted: 12/07/2020] [Indexed: 12/28/2022] Open
Abstract
Tumor antigens (TAs) can initiate host immune responses and produce TA-associated autoantibody (TAAbs), potential cancer biomarkers. Sputum is directly generated from the upper and lower airways, and thus can be used as a surrogate sample for the diagnosis of lung cancer based on molecular analysis. To develop sputum TAAb biomarkers for the early detection of lung cancer, the leading cause of cancer death, we probed a protein microarray containing more than 9,000 antigens with sputum supernatants of a discovery set of 30 lung cancer patients and 30 cancer-free smokers. Twenty-eight TAs with higher reactivity in sputum of lung cancer cases vs. controls were identified. The diagnostic significance of TAAbs against the TAs was determined by enzyme-linked immunosorbent assays (ELISAs) in sputum of the discovery set and additional 166 lung cancer patients and 213 cancer-free smokers (validation set). Three sputum TAAbs against DDX6, ENO1, and 14-3-3ζ were developed as a biomarker panel with 81% sensitivity and 83% specificity for diagnosis of lung cancer, regardless of stages, locations, and histological types of lung tumors. This study provides the first evidence that sputum TAAbs could be used as biomarkers for the early detection of lung cancer.
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40
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Ying H, FengYing S, YanHong W, YouMing H, FaYou Z, HongXiang Z, XiaoLei T. MicroRNA-155 from sputum as noninvasive biomarker for diagnosis of active pulmonary tuberculosis. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2020; 23:1419-1425. [PMID: 33235699 PMCID: PMC7671418 DOI: 10.22038/ijbms.2020.44029.10324] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Objectives Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a widespread infectious disease around the world. Early diagnosis is always important in order to avoid spreading. At present, many studies have confirmed that microRNA (miRNA) could be a useful tool for diagnosis. This study aimed to evaluate whether miRNAs could be regarded as a noninvasive diagnosis biomarker from sputum for pulmonary tuberculosis (PTB). Materials and Methods The M. tuberculosis strain H37Rv was incubated and cultured with human macrophage line THP-1. The total RNA was extracted from the THP-1 cells for detection. Six increased expressions of miRNAs were selected by miRNA microarray chips and the miRNAs were confirmed by qRT-PCR in the M. tuberculosis infection cell model. At last, the efficiency of other methods was compared with using miRNA. Results Only miR-155 showed a better diagnostic value for PTB than the other five miRNAs to distinguish PTB from non-PTB, including pneumonia, lung cancer, and unexplained pulmonary nodules. Next, we detected and analyzed the results of 68 PTB patients and 122 non-PTB, the sensitivity and specificity of miR-155 detection was 94.1% and 87.7%, respectively. It was higher than sputum smear detection and anti-TB antibody detection. But slightly lower than ELISpot (97%, P=0.404). Interestingly, the ranking of sputum smear by Ziehl-Neelsen staining had positive correlation with the expression level of miR-155 in smear-positive sputum (R2=0.8443, P<0.05). Conclusion Our research suggested that miR-155 may be an efficiency biomarker for active PTB diagnosis and bacteria-loads evaluation.
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Affiliation(s)
- Hua Ying
- Vascular Disease Research Center and Basic Medical Laboratory, the Second Affiliated Hospital of Wannan Medical College, Kangfu Road 10#, Wuhu 241000, Anhui Province, PR China.,School of Nursing, Wannan Medical College, Wenchang Xi Road 22#, Wuhu 241000, Anhui Province, PR China
| | - Sun FengYing
- Department of Clinical Laboratory, the Second Peoples' Hospital of Wuhu city, Jiuhua Zhong Road 259#, Wuhu 241000, Anhui Province, PR China
| | - Wu YanHong
- Department of Microbiology, Wannan Medical College, Wenchang Xi Road 22#, Wuhu 241000, Anhui Province, PR China
| | - Huang YouMing
- Vascular Disease Research Center and Basic Medical Laboratory, the Second Affiliated Hospital of Wannan Medical College, Kangfu Road 10#, Wuhu 241000, Anhui Province, PR China
| | - Zhou FaYou
- Vascular Disease Research Center and Basic Medical Laboratory, the Second Affiliated Hospital of Wannan Medical College, Kangfu Road 10#, Wuhu 241000, Anhui Province, PR China
| | - Zhang HongXiang
- Vascular Disease Research Center and Basic Medical Laboratory, the Second Affiliated Hospital of Wannan Medical College, Kangfu Road 10#, Wuhu 241000, Anhui Province, PR China
| | - Tang XiaoLei
- Vascular Disease Research Center and Basic Medical Laboratory, the Second Affiliated Hospital of Wannan Medical College, Kangfu Road 10#, Wuhu 241000, Anhui Province, PR China
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Pozza DH, De Mello RA, Araujo RLC, Velcheti V. MicroRNAs in Lung Cancer Oncogenesis and Tumor Suppression: How it Can Improve the Clinical Practice? Curr Genomics 2020; 21:372-381. [PMID: 33093800 PMCID: PMC7536806 DOI: 10.2174/1389202921999200630144712] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 06/10/2020] [Accepted: 06/10/2020] [Indexed: 12/18/2022] Open
Abstract
Background Lung cancer (LC) development is a process that depends on genetic mutations. The DNA methylation, an important epigenetic modification, is associated with the expression of non-coding RNAs, such as microRNAs. MicroRNAs are particularly essential for cell physiology, since they play a critical role in tumor suppressor gene activity. Furthermore, epigenetic disruptions are the primary event in cell modification, being related to tumorigenesis. In this context, microRNAs can be a useful tool in the LC suppression, consequently improving prognosis and predicting treatment. Conclusion This manuscript reviews the main microRNAs involved in LC and its potential clinical applications to improve outcomes, such as survival and better quality of life.
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Affiliation(s)
- Daniel Humberto Pozza
- 1Departamento de Biomedicina da Faculdade de Medicina, and Faculdade de Ciências da Nutrição e Alimentação, and I3s, Universidade do Porto, Porto, Portugal; 2Algarve Biomedical Centre, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal; 3Department of Clinical & Experimental Oncology, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil; 4Precision Oncology and Health Economic Group, Nine of July University, São Paulo, Brazil; 5Department of Digestive Surgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, Brazil; 6Department of Oncology, Albert Einstein Israelite Hospital, São Paulo, Brazil; 7Thoracic Oncology Program, NYU Langone, Perlmutter Cancer Center, New York, NY, 10016, USA
| | - Ramon Andrade De Mello
- 1Departamento de Biomedicina da Faculdade de Medicina, and Faculdade de Ciências da Nutrição e Alimentação, and I3s, Universidade do Porto, Porto, Portugal; 2Algarve Biomedical Centre, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal; 3Department of Clinical & Experimental Oncology, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil; 4Precision Oncology and Health Economic Group, Nine of July University, São Paulo, Brazil; 5Department of Digestive Surgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, Brazil; 6Department of Oncology, Albert Einstein Israelite Hospital, São Paulo, Brazil; 7Thoracic Oncology Program, NYU Langone, Perlmutter Cancer Center, New York, NY, 10016, USA
| | - Raphael L C Araujo
- 1Departamento de Biomedicina da Faculdade de Medicina, and Faculdade de Ciências da Nutrição e Alimentação, and I3s, Universidade do Porto, Porto, Portugal; 2Algarve Biomedical Centre, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal; 3Department of Clinical & Experimental Oncology, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil; 4Precision Oncology and Health Economic Group, Nine of July University, São Paulo, Brazil; 5Department of Digestive Surgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, Brazil; 6Department of Oncology, Albert Einstein Israelite Hospital, São Paulo, Brazil; 7Thoracic Oncology Program, NYU Langone, Perlmutter Cancer Center, New York, NY, 10016, USA
| | - Vamsidhar Velcheti
- 1Departamento de Biomedicina da Faculdade de Medicina, and Faculdade de Ciências da Nutrição e Alimentação, and I3s, Universidade do Porto, Porto, Portugal; 2Algarve Biomedical Centre, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal; 3Department of Clinical & Experimental Oncology, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil; 4Precision Oncology and Health Economic Group, Nine of July University, São Paulo, Brazil; 5Department of Digestive Surgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, Brazil; 6Department of Oncology, Albert Einstein Israelite Hospital, São Paulo, Brazil; 7Thoracic Oncology Program, NYU Langone, Perlmutter Cancer Center, New York, NY, 10016, USA
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Wadowska K, Bil-Lula I, Trembecki Ł, Śliwińska-Mossoń M. Genetic Markers in Lung Cancer Diagnosis: A Review. Int J Mol Sci 2020; 21:E4569. [PMID: 32604993 PMCID: PMC7369725 DOI: 10.3390/ijms21134569] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/19/2020] [Accepted: 06/25/2020] [Indexed: 12/14/2022] Open
Abstract
Lung cancer is the most often diagnosed cancer in the world and the most frequent cause of cancer death. The prognosis for lung cancer is relatively poor and 75% of patients are diagnosed at its advanced stage. The currently used diagnostic tools are not sensitive enough and do not enable diagnosis at the early stage of the disease. Therefore, searching for new methods of early and accurate diagnosis of lung cancer is crucial for its effective treatment. Lung cancer is the result of multistage carcinogenesis with gradually increasing genetic and epigenetic changes. Screening for the characteristic genetic markers could enable the diagnosis of lung cancer at its early stage. The aim of this review was the summarization of both the preclinical and clinical approaches in the genetic diagnostics of lung cancer. The advancement of molecular strategies and analytic platforms makes it possible to analyze the genome changes leading to cancer development-i.e., the potential biomarkers of lung cancer. In the reviewed studies, the diagnostic values of microsatellite changes, DNA hypermethylation, and p53 and KRAS gene mutations, as well as microRNAs expression, have been analyzed as potential genetic markers. It seems that microRNAs and their expression profiles have the greatest diagnostic potential value in lung cancer diagnosis, but their quantification requires standardization.
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Affiliation(s)
- Katarzyna Wadowska
- Department of Medical Laboratory Diagnostics, Division of Clinical Chemistry and Laboratory Haematology, Wroclaw Medical University, 50-556 Wroclaw, Poland; (K.W.); (I.B.-L.)
| | - Iwona Bil-Lula
- Department of Medical Laboratory Diagnostics, Division of Clinical Chemistry and Laboratory Haematology, Wroclaw Medical University, 50-556 Wroclaw, Poland; (K.W.); (I.B.-L.)
| | - Łukasz Trembecki
- Department of Radiation Oncology, Lower Silesian Oncology Center, 53-413 Wroclaw, Poland;
- Department of Oncology, Faculty of Medicine, Wroclaw Medical University, 53-413 Wroclaw, Poland
| | - Mariola Śliwińska-Mossoń
- Department of Medical Laboratory Diagnostics, Division of Clinical Chemistry and Laboratory Haematology, Wroclaw Medical University, 50-556 Wroclaw, Poland; (K.W.); (I.B.-L.)
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Visani M, Marucci G, de Biase D, Giangaspero F, Buttarelli FR, Brandes AA, Franceschi E, Acquaviva G, Ciarrocchi A, Rhoden KJ, Tallini G, Pession A. miR-196B-5P and miR-200B-3P Are Differentially Expressed in Medulloblastomas of Adults and Children. Diagnostics (Basel) 2020; 10:diagnostics10050265. [PMID: 32365560 PMCID: PMC7277606 DOI: 10.3390/diagnostics10050265] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 04/21/2020] [Accepted: 04/25/2020] [Indexed: 02/05/2023] Open
Abstract
Medulloblastoma is a highly aggressive brain tumor that typically affects children, while in adults it represents ~1% of all brain tumors. Little is known about microRNA expression profile of the rare adult medulloblastoma. The main aim of this study was to identify peculiar differences in microRNA expression between childhood and adult medulloblastoma. Medulloblastomas were profiled for microRNA expression using the Exiqon Human miRNome panel (I + II) analyzing 752 microRNAs in a training set of six adult and six childhood cases. Then, the most differentially expressed microRNAs were validated in a total of 21 adult and 19 childhood cases. Eight microRNAs (miR-196b-5p, miR-183-5p, miR-200b-3p, miR-196a-5p, miR-193a-3p, miR-29c-3p, miR-33b-5p, and miR-200a-3p) were differentially expressed in medulloblastoma of adults and children. Analysis of the validation set confirmed that miR-196b-5p and miR-200b-3p were significantly overexpressed in medulloblastoma of adults as compared with those of children. We followed an in silico approach to investigate direct targets and the pathways involved for the two microRNAs (miR-196b and miR-200b) differently expressed between adult and childhood medulloblastoma. Adult and childhood medulloblastoma have different miRNA expression profiles. In particular, the differential dysregulation of miR-196b-5p and miR-200b-3p characterizes the miRNA profile of adult medulloblastoma and suggests potential targets for novel diagnostic, prognostic, or therapeutic strategies.
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Affiliation(s)
- Michela Visani
- Department of Specialized, Diagnostic and Experimental Medicine, Anatomic Pathology-Molecular Diagnostic Unit AUSL-IRCCS of Bologna, University of Bologna School of Medicine, 40138 Bologna, Italy; (G.A.); (G.T.)
- Correspondence: (M.V.); (D.d.B.); Tel.: +39-051-214-4717 (M.V. & D.d.B.); Fax: +39-051-636-3682 (M.V. & D.d.B.)
| | - Gianluca Marucci
- Anatomic Pathology Unit, Ospedale Bellaria AUSL-IRCCS of Bologna, 40139 Bologna, Italy;
| | - Dario de Biase
- Department of Pharmacy and Biotechnology (FaBiT), Molecular Diagnostic Unit AUSL of Bologna, University of Bologna, 40138 Bologna, Italy;
- Correspondence: (M.V.); (D.d.B.); Tel.: +39-051-214-4717 (M.V. & D.d.B.); Fax: +39-051-636-3682 (M.V. & D.d.B.)
| | - Felice Giangaspero
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University School of Medicine, 00161 Rome, Italy;
- IRCCS Neuromed, 86077 Pozzilli (Isernia), Italy
| | | | - Alba Ariela Brandes
- Department of Medical Oncology, Bellaria–Maggiore Hospitals AUSL-IRCCS of Bologna, 40139 Bologna, Italy; (A.A.B.); (E.F.)
| | - Enrico Franceschi
- Department of Medical Oncology, Bellaria–Maggiore Hospitals AUSL-IRCCS of Bologna, 40139 Bologna, Italy; (A.A.B.); (E.F.)
| | - Giorgia Acquaviva
- Department of Specialized, Diagnostic and Experimental Medicine, Anatomic Pathology-Molecular Diagnostic Unit AUSL-IRCCS of Bologna, University of Bologna School of Medicine, 40138 Bologna, Italy; (G.A.); (G.T.)
| | - Alessia Ciarrocchi
- Laboratory of Translational Research, Arcispedale Santa Maria Nuova AUSL-IRCCS of Reggio Emilia, 42122 Reggio Emilia, Italy;
| | - Kerry Jane Rhoden
- Department of Medical and Surgical Sciences, Medical Genetics Unit, University of Bologna School of Medicine, 40138 Bologna, Italy;
| | - Giovanni Tallini
- Department of Specialized, Diagnostic and Experimental Medicine, Anatomic Pathology-Molecular Diagnostic Unit AUSL-IRCCS of Bologna, University of Bologna School of Medicine, 40138 Bologna, Italy; (G.A.); (G.T.)
| | - Annalisa Pession
- Department of Pharmacy and Biotechnology (FaBiT), Molecular Diagnostic Unit AUSL of Bologna, University of Bologna, 40138 Bologna, Italy;
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Lin Y, Holden V, Dhilipkannah P, Deepak J, Todd NW, Jiang F. A Non-Coding RNA Landscape of Bronchial Epitheliums of Lung Cancer Patients. Biomedicines 2020; 8:E88. [PMID: 32294932 PMCID: PMC7235744 DOI: 10.3390/biomedicines8040088] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/02/2020] [Accepted: 04/09/2020] [Indexed: 12/16/2022] Open
Abstract
We propose to systematically identify a non-coding RNA (ncRNA) profile of exfoliated bronchial epitheliums of sputum from lung cancer patients. Bronchial epithelial cells enriched from sputum of 32 lung cancer patients and 33 cancer-free smokers were analyzed by next-generation sequencing to comprehensively characterize the ncRNA profiles. In addition, 108 miRNAs, 88 small nucleolar RNAs, 13 piwi-interacting RNAs, 6 transfer RNAs, 4 ribosomal RNAs, 19 small nuclear RNAs, and 25 long-noncoding (lnc) RNAs displayed a significantly different level in bronchial epitheliums of sputum of lung cancer patients versus cancer-free smokers (all <0.001). PCR analysis confirmed their different expression levels in the sputum specimens. A high expression of SNHG9, an lncRNA, was validated in 78 lung tumor tissues, and the expression was inversely associated with overall survival of lung cancer patients (p = 0.002). Knockdown of SNHG9 in cancer cells reduced the cell growth, proliferation, and invasion in vitro and tumorigenesis in vivo. The multiple differentially expressed ncRNAs in bronchial epitheliums may contribute to the development and progression of lung cancer and provide potential biomarkers and therapeutic targets for the disease.
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Affiliation(s)
- Yanli Lin
- Departments of Pathology, University of Maryland School of Medicine, 10 S. Pine St. Baltimore, MD 21201, USA; (Y.L.); (P.D.)
| | - Van Holden
- Department of Medicine, University of Maryland School of Medicine, 22 S. Greene St. Baltimore, MD 21201, USA; (V.H.); (J.D.); (N.W.T.)
| | - Pushpawallie Dhilipkannah
- Departments of Pathology, University of Maryland School of Medicine, 10 S. Pine St. Baltimore, MD 21201, USA; (Y.L.); (P.D.)
| | - Janaki Deepak
- Department of Medicine, University of Maryland School of Medicine, 22 S. Greene St. Baltimore, MD 21201, USA; (V.H.); (J.D.); (N.W.T.)
| | - Nevins W. Todd
- Department of Medicine, University of Maryland School of Medicine, 22 S. Greene St. Baltimore, MD 21201, USA; (V.H.); (J.D.); (N.W.T.)
| | - Feng Jiang
- Department of Medicine, University of Maryland School of Medicine, 22 S. Greene St. Baltimore, MD 21201, USA; (V.H.); (J.D.); (N.W.T.)
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Gupta C, Su J, Zhan M, Stass SA, Jiang F. Sputum long non-coding RNA biomarkers for diagnosis of lung cancer. Cancer Biomark 2020; 26:219-227. [PMID: 31450489 DOI: 10.3233/cbm-190161] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Analysis of molecular changes in sputum may help diagnose lung cancer. Long non-coding RNAs (lncRNAs) play vital roles in various biological processes, and their dysregulations contribute to the development and progression of lung tumorigenesis. Herein, we determine whether aberrant lncRNAs could be used as potential sputum biomarkers for lung cancer. METHODS Using reverse transcription PCR, we measure expressions of lung cancer-associated lncRNAs in sputum of a discovery cohort of 67 lung cancer patients and 65 cancer-free smokers with benign diseases and a validation cohort of 59 lung cancer patients and 60 cancer-free smokers with benign diseases. RESULTS In the discovery cohort, four of the lncRNAs displayed a significantly different level in sputum of lung cancer patients vs.cancer-free smokers with benign diseases (all P< 0.001). From the four lncRNAs, three lncRNAs (SNHG1, H19, and HOTAIR) are identified as a biomarker panel, producing 82.09% sensitivity and 89.23% specificity for diagnosis of lung cancer. Furthermore, the biomarker panel has a higher sensitivity (82.09% vs. 52.24%, P= 0.02) and a similar specificity compared with sputum cytology (89.23% vs. 90.77%, P= 0.45). In addition, the lncRNA biomarker panel had a higher sensitivity (87.50% vs. 70.07%, p= 0.03) for diagnosis of squamous cell carcinoma compared with adenocarcinoma of the lung, while maintaining the same specificity (89.23%). The potential of the sputum lncRNA biomarkers for lung cancer detection is confirmed in the validation cohort. CONCLUSION We have for the first time shown that the analysis of lncRNAs in sputum might be a noninvasive approach for diagnosis of lung cancer.
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Affiliation(s)
- Chhavi Gupta
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jian Su
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Min Zhan
- Departments of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Sanford A Stass
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Feng Jiang
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA
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Asakura K, Kadota T, Matsuzaki J, Yoshida Y, Yamamoto Y, Nakagawa K, Takizawa S, Aoki Y, Nakamura E, Miura J, Sakamoto H, Kato K, Watanabe SI, Ochiya T. A miRNA-based diagnostic model predicts resectable lung cancer in humans with high accuracy. Commun Biol 2020; 3:134. [PMID: 32193503 PMCID: PMC7081195 DOI: 10.1038/s42003-020-0863-y] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 02/19/2020] [Indexed: 01/17/2023] Open
Abstract
Lung cancer, the leading cause of cancer death worldwide, is most frequently detected through imaging tests. In this study, we investigated serum microRNAs (miRNAs) as a possible early screening tool for resectable lung cancer. First, we used serum samples from participants with and without lung cancer to comprehensively create 2588 miRNAs profiles; next, we established a diagnostic model based on the combined expression levels of two miRNAs (miR-1268b and miR-6075) in the discovery set (208 lung cancer patients and 208 non-cancer participants). The model displayed a sensitivity of 99% and specificity of 99% in the validation set (1358 patients and 1970 non-cancer participants) and exhibited high sensitivity regardless of histological type and pathological TNM stage of the cancer. Moreover, the diagnostic index markedly decreased after lung cancer resection. Thus, the model we developed has the potential to markedly improve screening for resectable lung cancer. Asakura, Kadota et al. demonstrate the diagnostic potential of serum microRNAs for resectable lung cancer. Their diagnostic model based on the combined expression levels of two miRNAs predicts resectable lung cancer with 99% sensitivity, regardless of histological types and pathological stages of cancer, suggesting its promising, diagnostic utility.
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Affiliation(s)
- Keisuke Asakura
- Department of Thoracic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.,Division of Thoracic Surgery, Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Tsukasa Kadota
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.,Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Juntaro Matsuzaki
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yukihiro Yoshida
- Department of Thoracic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yusuke Yamamoto
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Kazuo Nakagawa
- Department of Thoracic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Satoko Takizawa
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.,Toray Industries, Inc. 6-10-1 Tebiro, Kamakura city, Kanagawa, 248-0036, Japan
| | - Yoshiaki Aoki
- Dynacom Co., Ltd., World Business Garden E25, 2-6-1 Nakase, Mihama-ku, Chiba city, Chiba, 261-7125, Japan
| | - Eiji Nakamura
- Dynacom Co., Ltd., World Business Garden E25, 2-6-1 Nakase, Mihama-ku, Chiba city, Chiba, 261-7125, Japan
| | - Junichiro Miura
- Dynacom Co., Ltd., World Business Garden E25, 2-6-1 Nakase, Mihama-ku, Chiba city, Chiba, 261-7125, Japan
| | - Hiromi Sakamoto
- Department of Biobank and Tissue Resources, National Cancer Center Research Institute, Tokyo, 104-0045, Japan
| | - Ken Kato
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Shun-Ichi Watanabe
- Department of Thoracic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. .,Institute of Medical Science, Tokyo Medical University, Tokyo, 160-0023, Japan.
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Identification of miR-210 and combination biomarkers as useful agents in early screening non-small cell lung cancer. Gene 2020; 729:144225. [DOI: 10.1016/j.gene.2019.144225] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 09/07/2019] [Accepted: 10/23/2019] [Indexed: 12/21/2022]
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He C, Chen S, Zhao J, Tian J, Zhao S. Ultrasensitive detection of microRNA-21 based on electrophoresis assisted cascade chemiluminescence signal amplification for the identification of cancer cells. Talanta 2020; 209:120505. [DOI: 10.1016/j.talanta.2019.120505] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 10/21/2019] [Accepted: 10/24/2019] [Indexed: 02/08/2023]
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Nishikawa T, Fujii T, Tatsumi S, Sugimoto A, Sekita-Hatakeyama Y, Shimada K, Yamazaki M, Hatakeyama K, Ohbayashi C. Molecular Analysis of Liquid-Based Cytological Specimen Using Virtually Positive Sputum with Adenocarcinoma Cells. Diagnostics (Basel) 2020; 10:diagnostics10020084. [PMID: 32033355 PMCID: PMC7168204 DOI: 10.3390/diagnostics10020084] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 01/29/2020] [Accepted: 02/03/2020] [Indexed: 12/12/2022] Open
Abstract
Liquid-based cytology (LBC) analysis of sputum is a useful diagnostic and prognostic tool for detecting lung cancer. DNA and RNA derived from lung cancer cells can be used for this diagnosis. However, the quality of cytological material is not always adequate for molecular analysis due to the effect of formalin in the commercially available fixation kits. In this study, we examined DNA and RNA extraction methods for LBC analysis with formalin fixation, using lung carcinoma cell lines and sputum. The human non-small cell lung cancer cell lines were fixed with LBC fixation reagents, such as CytoRich red preservative. Quantification of thyroid transcription factor-1 (TTF-1) and actin mRNA, epidermal growth factor receptor (EGFR) DNA in HCC827, H1975, and H1299 cells, and mutation analysis of EGFR in HCC827 and H1975 cells were performed by quantitative PCR (qPCR) and fluorescence resonance energy transfer (FRET)-based preferential homoduplex formation assay (F-PHFA) method, respectively. mRNA and DNA extracted from cell lines using RNA and/or DNA extraction kits for formalin-fixed paraffin-embedded (FFPE) fixed with various LBC solutions were efficiently detected by qPCR. The detection limit of EGFR mutations was at a rate of 5% mutated positive cells in LBC. The detection limit of the EGFR exon 19 deletion in HCC827 was detected in more than 1.5% of the positive cells in sputum. In contrast, the detection limit of the T790M/L858R mutation in H1975 was detected in more than 13% of the positive cells. We also detected EGFR mutations using next generation sequencing (NGS). The detection limit of NGS for EGFR mutation was lower than that of the F-PHFA method. Furthermore, more than 0.1% of positive cells could be cytomorphologically detected. Our results demonstrate that LBC systems are powerful tools for cytopathological and genetic analyses. However, careful attention should be paid to the incidence of false negative results in the genetic analysis of EGFR mutations detected by LBC.
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Affiliation(s)
- Takeshi Nishikawa
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan; (T.N.); (S.T.); (A.S.); (Y.S.-H.); (K.H.); (C.O.)
| | - Tomomi Fujii
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan; (T.N.); (S.T.); (A.S.); (Y.S.-H.); (K.H.); (C.O.)
- Correspondence: ; Tel.: +81-744-22-3051 (ext. 4307); Fax: +81-744-23-5687
| | - Shigenobu Tatsumi
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan; (T.N.); (S.T.); (A.S.); (Y.S.-H.); (K.H.); (C.O.)
| | - Aya Sugimoto
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan; (T.N.); (S.T.); (A.S.); (Y.S.-H.); (K.H.); (C.O.)
| | - Yoko Sekita-Hatakeyama
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan; (T.N.); (S.T.); (A.S.); (Y.S.-H.); (K.H.); (C.O.)
| | - Keiji Shimada
- Department of Diagnostic Pathology, Nara City Hospital, Nara 630-8305, Japan;
| | - Masaharu Yamazaki
- Department of Central Clinical Laboratory, Nara Medical University Hospital, Nara 634-8521, Japan;
| | - Kinta Hatakeyama
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan; (T.N.); (S.T.); (A.S.); (Y.S.-H.); (K.H.); (C.O.)
| | - Chiho Ohbayashi
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan; (T.N.); (S.T.); (A.S.); (Y.S.-H.); (K.H.); (C.O.)
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Liao J, Shen J, Leng Q, Qin M, Zhan M, Jiang F. MicroRNA-based biomarkers for diagnosis of non-small cell lung cancer (NSCLC). Thorac Cancer 2020; 11:762-768. [PMID: 31994346 PMCID: PMC7049510 DOI: 10.1111/1759-7714.13337] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/09/2020] [Accepted: 01/12/2020] [Indexed: 11/27/2022] Open
Abstract
Background The development of biomarkers for the early detection of non‐small cell lung cancer (NSCLC) is clinically important. We have developed miRNA biomarkers in sputum and plasma, respectively, for NSCLC. Herein, we evaluate whether integrated analysis of the miRNAs across the different types of specimens could improve the early detection of NSCLC. Methods Using reverse transcription PCR, we determined expressions of two miRNAs (miRs‐31‐5p and 210‐3p) in sputum and three miRNAs (miRs‐21‐5p, 210‐3p, and 486‐5p) in plasma of a training cohort of 76 NSCLC patients and 72 cancer‐free smokers. The results were validated in a testing cohort of 56 NSCLC patients and 55 cancer‐free smokers. Results The panels of two sputum miRNAs and three plasma miRNAs had 65.8–75.0% sensitivities and 83.3–87.5% specificities for diagnosis of NSCLC in the training cohort. The individual sputum or plasma miRNA panel had a higher sensitivity for squamous cell carcinoma or adenocarcinoma of the lung, respectively. From the miRNAs, we optimized an integrated panel of biomarkers consisting of two sputum miRNAs (miRs‐31‐5p and 210‐3p) and one plasma miRNA (miR‐21‐5p) that had higher sensitivity (85.5%) and specificity (91.7%) for diagnosis of NSCLC compared with the individual panels alone. Furthermore, the performance of the integrated panel of biomarkers was independent of histology and stage of NSCLC, and patients' age, sex, and ethnicity. The performance of the integrated panel of biomarkers was confirmed in the testing cohort. Conclusions Integrating biomarkers across different body fluids would synergistically improve the early detection of NSCLC. Key points
Lung cancer is a heterogeneous disease and develops from complex aberrations. Integrating sputum and plasma miRNAs has higher accuracy than when they are used alone
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Affiliation(s)
- Jipei Liao
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Jun Shen
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Qixin Leng
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Meng Qin
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Min Zhan
- Department of Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Feng Jiang
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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