Startseite Medizin Tumor-associated exosomal miRNA biomarkers to differentiate metastatic vs. nonmetastatic non-small cell lung cancer
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Tumor-associated exosomal miRNA biomarkers to differentiate metastatic vs. nonmetastatic non-small cell lung cancer

  • Ning Wang , Wei Guo , Xingguo Song , Lisheng Liu , Limin Niu , Xianrang Song und Li Xie EMAIL logo
Veröffentlicht/Copyright: 8. April 2020
Clinical Chemistry and Laboratory Medicine (CCLM)
Aus der Zeitschrift Clinical Chemistry and Laboratory Medicine (CCLM) Band 58 Heft 9

Abstract

Background

Exosomal microRNAs (miRNAs) are proposed to be excellent candidate biomarkers for clinical applications. However, little is known about their potential value as diagnostic biomarkers for metastatic non-small cell lung cancer (NSCLC).

Methods

In this study, microarrays were used to determine distinct miRNA profiles of plasma exosomes in a discovery cohort of healthy donors, metastatic NSCLC and nonmetastatic NSCLC patients. Three potential candidate miRNAs were selected based on the differential expression profiles. The discovery set data were validated by quantitative real-time polymerase chain reaction using a validation cohort.

Results

NSCLC patients (n = 80) and healthy controls (n = 30) had different exosome-related miRNA profiles in plasma. Results demonstrated that the level of let-7f-5p was decreased in plasma exosomes of NSCLC patients (p < 0.0001). Further analysis of three differentially expressed miRNAs revealed that miR-320a, miR-622 and let-7f-5p levels could significantly segregate patients with metastatic NSCLC from patients with nonmetastatic NSCLC (p < 0.0001, p < 0.0001 and p = 0.023, respectively). In addition, the combination of let-7f-5p, CEA and Cyfra21-1 generated an area under the curve (AUC) of 0.981 for the diagnosis of NSCLC patients, and the combination of miR-320a, miR-622, CEA and Cyfra21-1 had an AUC of 0.900 for the diagnosis of patients with metastatic NSCLC.

Conclusions

This novel study demonstrated that plasma exosomal miRNAs are promising noninvasive diagnostic biomarkers for metastatic NSCLC.

Keywords: exosomes; let-7f-5p; metastatic biomarkers; miR-320a; miR-622; non-small cell lung cancer (NSCLC)
Corresponding author: Dr. Li Xie, Department of Clinical Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Ji-Yan Road, Jinan, 250117 Shandong Province, P.R. China; and Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, Shandong Province, P.R. China, Phone: +86 + 15563360367

Acknowledgments

We thank all authors for contributing to the intellectual content of this paper and meeting the following requirements that significant contributions to the conception and design, acquisition of data or analysis and interpretation of data and drafting or revising the article for intellectual content.

  1. Author contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following requirements that significant contributions to the conception and design, acquisition of data or analysis and interpretation of data and drafting or revising the article for intellectual content. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This work was supported by the National Natural Science Foundation of P.R. China (funder id: http://dx.doi.org/10.13039/501100001809, 81773237 and 81672104), the Shandong Provincial Key Research and Development Program (2017GSF18183, 2017CXGC1207 and 2016GSF201151) and the Medicine and Health Science Technology development program of Shandong province (2017WS001).

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Taverna S, Giallombardo M, Gil-Bazo I, Carreca AP, Castiglia M, Chacartegui J, et al. Exosomes isolation and characterization in serum is feasible in non-small cell lung cancer patients: critical analysis of evidence and potential role in clinical practice. Oncotarget 2016;7:28748–60.10.18632/oncotarget.7638Suche in Google Scholar PubMed PubMed Central

2. Liu Q, Yu Z, Yuan S, Xie W, Li C, Hu Z, et al. Circulating exosomal microRNAs as prognostic biomarkers for non-small-cell lung cancer. Oncotarget 2017;8:13048–58.10.18632/oncotarget.14369Suche in Google Scholar PubMed PubMed Central

3. Gray RT, Coleman HG, Hughes C, Murray LJ, Cardwell CR. Statin use and survival in colorectal cancer: results from a population-based cohort study and an updated systematic review and meta-analysis. Cancer Epidemiol 2016;45:71–81.10.1016/j.canep.2016.10.004Suche in Google Scholar PubMed

4. Sikdar KC, Dickinson J, Winget M. Factors associated with mode of colorectal cancer detection and time to diagnosis: a population level study. BMC Health Serv Res 2017;17:7.10.1186/s12913-016-1944-ySuche in Google Scholar PubMed PubMed Central

5. Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem 2010;285:17442–52.10.1074/jbc.M110.107821Suche in Google Scholar PubMed PubMed Central

6. Rana S, Malinowska K, Zoller M. Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia 2013;15:281–95.10.1593/neo.122010Suche in Google Scholar PubMed PubMed Central

7. Khalyfa A, Almendros I, Gileles-Hillel A, Akbarpour M, Trzepizur W, Mokhlesi B, et al. Circulating exosomes potentiate tumor malignant properties in a mouse model of chronic sleep fragmentation. Oncotarget 2016;7:54676–90.10.18632/oncotarget.10578Suche in Google Scholar PubMed PubMed Central

8. Tkach M, Thery C. Communication by extracellular vesicles: where we are and where we need to go. Cell 2016;164:1226–32.10.1016/j.cell.2016.01.043Suche in Google Scholar PubMed

9. Selmaj I, Cichalewska M, Namiecinska M, Galazka G, Horzelski W, Selmaj KW, et al. Global exosome transcriptome profiling reveals biomarkers for multiple sclerosis. Ann Neurol 2017;81:703–17.10.1002/ana.24931Suche in Google Scholar PubMed

10. Sun Y, Liu S, Qiao Z, Shang Z, Xia Z, Niu X, et al. Systematic comparison of exosomal proteomes from human saliva and serum for the detection of lung cancer. Anal Chim Acta 2017;982:84–95.10.1016/j.aca.2017.06.005Suche in Google Scholar PubMed

11. Vickers KC, Remaley AT. Lipid-based carriers of microRNAs and intercellular communication. Curr Opin Lipidol 2012;23:91–7.10.1097/MOL.0b013e328350a425Suche in Google Scholar PubMed PubMed Central

12. Yang R, Fu Y, Zeng Y, Xiang M, Yin Y, Li L, et al. Serum miR-20a is a promising biomarker for gastric cancer. Biomed Rep 2017;6:429–34.10.3892/br.2017.862Suche in Google Scholar PubMed PubMed Central

13. Cho WC. OncomiRs: the discovery and progress of microRNAs in cancers. Mol Cancer 2007;6:60.10.1186/1476-4598-6-60Suche in Google Scholar PubMed PubMed Central

14. Bartels CL, Tsongalis GJ. MicroRNAs: novel biomarkers for human cancer. Clin Chem 2009;55:623–31.10.1373/clinchem.2008.112805Suche in Google Scholar PubMed

15. Silva J, Garcia V, Zaballos A, Provencio M, Lombardia L, Almonacid L, et al. Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival. Eur Respir J 2011;37:617–23.10.1183/09031936.00029610Suche in Google Scholar PubMed

16. Jansson MD, Lund AH. MicroRNA and cancer. Mol Oncol 2012;6:590–610.10.1016/j.molonc.2012.09.006Suche in Google Scholar PubMed PubMed Central

17. Greither T, Grochola LF, Udelnow A, Lautenschlager C, Wurl P, Taubert H. Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival. Int J Cancer 2010;126:73–80.10.1002/ijc.24687Suche in Google Scholar PubMed

18. Lee KH, Lotterman C, Karikari C, Omura N, Feldmann G, Habbe N, et al. Epigenetic silencing of MicroRNA miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer. Pancreatology 2009;9:293–301.10.1159/000186051Suche in Google Scholar PubMed PubMed Central

19. Gailhouste L, Gomez-Santos L, Hagiwara K, Hatada I, Kitagawa N, Kawaharada K, et al. miR-148a plays a pivotal role in the liver by promoting the hepatospecific phenotype and suppressing the invasiveness of transformed cells. Hepatology 2013;58:1153–65.10.1002/hep.26422Suche in Google Scholar PubMed

20. Wang N, Zhu M, Tsao SW, Man K, Zhang Z, Feng Y. MiR-23a-mediated inhibition of topoisomerase 1 expression potentiates cell response to etoposide in human hepatocellular carcinoma. Mol Cancer 2013;12:119.10.1186/1476-4598-12-119Suche in Google Scholar PubMed PubMed Central

21. Duan FT, Qian F, Fang K, Lin KY, Wang WT, Chen YQ. miR-133b, a muscle-specific microRNA, is a novel prognostic marker that participates in the progression of human colorectal cancer via regulation of CXCR4 expression. Mol Cancer 2013;12:164.10.1186/1476-4598-12-164Suche in Google Scholar PubMed PubMed Central

22. Li J, Tan Q, Yan M, Liu L, Lin H, Zhao F, et al. miRNA-200c inhibits invasion and metastasis of human non-small cell lung cancer by directly targeting ubiquitin specific peptidase 25. Mol Cancer 2014;13:166.10.1186/1476-4598-13-166Suche in Google Scholar PubMed PubMed Central

23. Vlassov AV, Magdaleno S, Setterquist R, Conrad R. Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta 2012;1820:940–8.10.1016/j.bbagen.2012.03.017Suche in Google Scholar PubMed

24. Jin X, Chen Y, Chen H, Fei S, Chen D, Cai X, et al. Evaluation of tumor-derived exosomal miRNA as potential diagnostic biomarkers for early-stage non-small cell lung cancer using next-generation sequencing. Clin Cancer Res 2017;23:5311–9.10.1158/1078-0432.CCR-17-0577Suche in Google Scholar PubMed

25. Hsieh IS, Chang KC, Tsai YT, Ke JY, Lu PJ, Lee KH, et al. MicroRNA-320 suppresses the stem cell-like characteristics of prostate cancer cells by downregulating the Wnt/beta-catenin signaling pathway. Carcinogenesis 2013;34:530–8.10.1093/carcin/bgs371Suche in Google Scholar PubMed

26. Zhang T, Zou P, Wang T, Xiang J, Cheng J, Chen D, et al. Down-regulation of miR-320 associated with cancer progression and cell apoptosis via targeting Mcl-1 in cervical cancer. Tumour Biol 2016;37:8931–40.10.1007/s13277-015-4771-6Suche in Google Scholar PubMed

27. Zhang Z, Li X, Sun W, Yue S, Yang J, Li J, et al. Loss of exosomal miR-320a from cancer-associated fibroblasts contributes to HCC proliferation and metastasis. Cancer Lett 2017;397:33–42.10.1016/j.canlet.2017.03.004Suche in Google Scholar PubMed

28. Tadano T, Kakuta Y, Hamada S, Shimodaira Y, Kuroha M, Kawakami Y, et al. MicroRNA-320 family is downregulated in colorectal adenoma and affects tumor proliferation by targeting CDK6. World J Gastrointest Oncol 2016;8:532–42.10.4251/wjgo.v8.i7.532Suche in Google Scholar PubMed PubMed Central

29. Roush S, Slack FJ. The let-7 family of microRNAs. Trends Cell Biol 2008;18:505–16.10.1016/j.tcb.2008.07.007Suche in Google Scholar PubMed

30. Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 2004;64:3753–6.10.1158/0008-5472.CAN-04-0637Suche in Google Scholar PubMed

31. Wang Y, Sun J, Wei X, Luan L, Zeng X, Wang C, et al. Decrease of miR-622 expression suppresses migration and invasion by targeting regulation of DYRK2 in colorectal cancer cells. Onco Targets Ther 2017;10:1091–100.10.2147/OTT.S125724Suche in Google Scholar PubMed PubMed Central

32. Guo XB, Jing CQ, Li LP, Zhang L, Shi YL, Wang JS, et al. Down-regulation of miR-622 in gastric cancer promotes cellular invasion and tumor metastasis by targeting ING1 gene. World J Gastroenterol 2011;17:1895–902.10.3748/wjg.v17.i14.1895Suche in Google Scholar PubMed PubMed Central

Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2019-1329).

Received: 2019-12-29
Accepted: 2020-02-24
Published Online: 2020-04-08
Published in Print: 2020-08-27

©2020 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/cclm-2019-1329
Schlagwörter für diesen Artikel
exosomes; let-7f-5p; metastatic biomarkers; miR-320a; miR-622; non-small cell lung cancer (NSCLC)

Artikel in diesem Heft

  1. Frontmatter
  2. Editorial
  3. Measurement uncertainty: light in the shadows
  4. Review
  5. Childhood obesity: an overview of laboratory medicine, exercise and microbiome
  6. Mini review
  7. The utility of measurement uncertainty in medical laboratories
  8. Opinion Paper
  9. Do genetic polymorphisms in angiotensin converting enzyme 2 (ACE2) gene play a role in coronavirus disease 2019 (COVID-19)?
  10. Opinion Papers
  11. The current status and future prospects of precision medicine
  12. Precision medicine in medical oncology: hope, disappointment and reality
  13. IFCC Papers
  14. Laboratory practices to mitigate biohazard risks during the COVID-19 outbreak: an IFCC global survey
  15. Operational considerations and challenges of biochemistry laboratories during the COVID-19 outbreak: an IFCC global survey
  16. Genetics and Molecular Diagnostics
  17. Diverse fragment lengths dismiss size selection for serum cell-free DNA: a comparative study of serum and plasma samples
  18. General Clinical Chemistry and Laboratory Medicine
  19. Quantification of plasma remdesivir and its metabolite GS-441524 using liquid chromatography coupled to tandem mass spectrometry. Application to a Covid-19 treated patient
  20. Isotope dilution-LC-MS/MS method for quantification of the urinary cotinine-to-creatinine ratio
  21. A liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based assay to profile 20 plasma steroids in endocrine disorders
  22. Assessment of antinuclear antibodies by indirect immunofluorescence assay: report from a survey by the American Association of Medical Laboratory Immunologists
  23. Evaluation of a novel extended automated particle-based multi-analyte assay for the detection of autoantibodies in the diagnosis of primary biliary cholangitis
  24. Reference Values and Biological Variations
  25. Continuous, complete and comparable NT-proBNP reference ranges in healthy children
  26. Reference-mean-centered statistical quality control
  27. Hematology and Coagulation
  28. Top-down and bottom-up approaches for the estimation of measurement uncertainty in coagulation assays
  29. Cancer Diagnostics
  30. Tumor-associated exosomal miRNA biomarkers to differentiate metastatic vs. nonmetastatic non-small cell lung cancer
  31. Analysis of EGFR mutation status in malignant pleural effusion and plasma from patients with advanced lung adenocarcinoma
  32. Cardiovascular Diseases
  33. Establishing the 99th percentile of a novel assay for high-sensitivity troponin I in a healthy blood donor population
  34. The clinically effective use of cardiac markers by restructuring laboratory profiles at Cardiology wards
  35. Infectious Diseases
  36. Lower nasopharyngeal viral load during the latest phase of COVID-19 pandemic in a Northern Italy University Hospital
  37. SARS-CoV-2 RNA identification in nasopharyngeal swabs: issues in pre-analytics
  38. Rapid identification of SARS-CoV-2-infected patients at the emergency department using routine testing
  39. Evaluation of eleven rapid tests for detection of antibodies against SARS-CoV-2
  40. Development and multicenter performance evaluation of fully automated SARS-CoV-2 IgM and IgG immunoassays
  41. Letters to the Editor
  42. Evaluation of seven commercial SARS-CoV-2 RNA detection kits based on real-time polymerase chain reaction (PCR) in China
  43. Blood sampling after COVID-19 − How to organize large scale phlebotomy services in the post SARS CoV-2 era
  44. Diagnostic performance of a SARS-CoV-2 IgG/IgM lateral flow immunochromatography assay in symptomatic patients presenting to the emergency department
  45. Urinalysis parameters for predicting severity in coronavirus disease 2019 (COVID-19)
  46. Neutrophil-to-lymphocyte ratio predicts the clearance of SARS-CoV-2 RNA in mild COVID-19 patients – a retrospective analysis from Dongxihu Fangcang Hospital in Wuhan, China
  47. Low levels of total and ionized calcium in blood of COVID-19 patients
  48. Is “light cannabis” really light? Determination of cannabinoids content in commercial products
  49. Amino-terminal proB-type natriuretic peptide reference values in umbilical cord blood
  50. The new era of LED microscopes in immunofluorescence anti-nuclear antibody (ANA) testing
  51. The centrifuge brake impacts neither routine coagulation assays nor platelet count in platelet-poor plasma
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