Skip to main content
Top
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Gastritis | Research article

Identification of non-invasive biomarkers for chronic atrophic gastritis from serum exosomal microRNAs

Authors: Hong Liu, Pei-wu Li, Wei-qin Yang, Hong Mi, Jing-lin Pan, Yuan-cheng Huang, Zheng-kun Hou, Qiu-ke Hou, Qi Luo, Feng-bin Liu

Published in: BMC Cancer | Issue 1/2019

Login to get access

Abstract

Background

Serum exosomal microRNAs (miRNAs) have been suggested as novel biomarkers for various diseases, especially gastric cancer (GC). But circulating biomarkers for Chronic atrophic gastritis (CAG) which is defined as precancrerous lesions of GC remain largely elusive. To investigate serum exosomal miRNAs that are differently expressed in CAG patients and Chronic nonatrophic gastritis (CNAG) may be helpful for its diagnosis and therapy.

Methods

Patients were recruited according to the diagnosis and exclusioncriteria. RNA was extracted from serum exosomes of 30 CAG and 30 CNAG patients. The miRNA expression profiles were analyzed by next generation sequencing and were validated by qRT-PCR. Receiver operating characteristic (ROC) analysis has been used to evaluate the diagnostic value.

Results

30 CAG patients and 30 CNAG patients were recruited in our study. sRNA-seq results showed that hsa-miR-3591-3p, − 122-3p, and − 122-5p of the top 10 miRNAs (hsa-miR-148a-3p, − 122-3p, − 486-3p, −451a, − 122-5p, − 3591-3p, − 486-5p, −151a-3p, −92a-3p, −320a) were significantly upregulated in exosomes from CAG patients versus those from CNAG patients, but hsa-miR-451a, −151a-3p, and -92a-3p were significantly downregulated. Furthermore, qRT-PCR analysis confirmed that hsa-miR-122-5p and hsa-miR-122-3p were significantly upregulated in CAG samples, but hsa-miR-122-3p hadnot a steable expression. ROC curves showed that the AUC for hsa-miR-122-5p was 0.67 (95% CI 0.52–0.82, SE 62%, SP 86%). A sum of the four miRNAs (panel 1, hsa-miR-122-5p, −451a, −151a-3p, and -92a-3p) did not significantly improve the diagnostic potential (AUC 0.63, 95% CI 0.47 to 0.78). Correlation analysis showed that the expression of hsa-miR-122-5p differed significantly between patients based on atrophic (Moderate atrophic vs. Absent, P value was 0.036.) and IM (compare moderate-severe, absent and mild P values were 0.001 and 0.014, respectively). However, there were no differences between groups based on age, gender, dysplasia, or chronic or active inflammation.

Conclusion

These results suggested that hsa-miR-122-5p in serum exosomes might serve as a potential biomarker for CAG diagnosis.

Trial registration

Chinese Clinical Trial Registy (ChiCTR-IOR-16008027, Date of Registration:2016-03-01).
Appendix
Available only for authorised users
Literature
1.
go back to reference Sugano K. Screening of gastric cancer in Asia. Best Pract Res Clin Gastroenterol. 2015;29:895–905.CrossRef Sugano K. Screening of gastric cancer in Asia. Best Pract Res Clin Gastroenterol. 2015;29:895–905.CrossRef
2.
go back to reference Ming SC. Cellular and molecular pathology of gastric carcinoma and precursor lesions: A critical review. Gastric Cancer. 1999;1:31-50. Ming SC. Cellular and molecular pathology of gastric carcinoma and precursor lesions: A critical review. Gastric Cancer. 1999;1:31-50.
3.
go back to reference de Vries AC, van Grieken NCT, Looman CWN, Casparie MK, de Vries E, Meijer GA, et al. Gastric cancer risk in patients with premalignant gastric lesions: a nationwide cohort study in the Netherlands. Gastroenterology. 2008;134:945–52.CrossRef de Vries AC, van Grieken NCT, Looman CWN, Casparie MK, de Vries E, Meijer GA, et al. Gastric cancer risk in patients with premalignant gastric lesions: a nationwide cohort study in the Netherlands. Gastroenterology. 2008;134:945–52.CrossRef
4.
go back to reference The gastroenterology branch of Chinese medical associati. Consensus on chronic gastritis in China. Zhonghua Xiaohua Zazhi. 2007;27:45–9. The gastroenterology branch of Chinese medical associati. Consensus on chronic gastritis in China. Zhonghua Xiaohua Zazhi. 2007;27:45–9.
5.
go back to reference Jayavelu ND. Metabolomic studies of human gastric cancer: review. World J Gastroentero. 2014;20:8092–101.CrossRef Jayavelu ND. Metabolomic studies of human gastric cancer: review. World J Gastroentero. 2014;20:8092–101.CrossRef
6.
go back to reference The gastroenterology branch of Chinese medical associati. Consensus on chronic gastritis in China. Gastroenterology. 2013;18:24–36. The gastroenterology branch of Chinese medical associati. Consensus on chronic gastritis in China. Gastroenterology. 2013;18:24–36.
7.
go back to reference SYRJÄNEN K. A panel of serum biomarkers (GastroPanel®) in non-invasive diagnosis of atrophic gastritis. Systematic review and meta-analysis. Anticancer Res. 2016;36:5133–44.CrossRef SYRJÄNEN K. A panel of serum biomarkers (GastroPanel®) in non-invasive diagnosis of atrophic gastritis. Systematic review and meta-analysis. Anticancer Res. 2016;36:5133–44.CrossRef
8.
go back to reference Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10:472–84.CrossRef Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10:472–84.CrossRef
9.
go back to reference Torrano V, Royo F, Peinado H, Loizaga-Iriarte A, Unda M, Falcón-Perez JM, et al. Vesicle-MaNiA: extracellular vesicles in liquid biopsy and cancer. Curr Opin Pharmacol. 2016;29:47–53.CrossRef Torrano V, Royo F, Peinado H, Loizaga-Iriarte A, Unda M, Falcón-Perez JM, et al. Vesicle-MaNiA: extracellular vesicles in liquid biopsy and cancer. Curr Opin Pharmacol. 2016;29:47–53.CrossRef
10.
go back to reference Fais S, O Driscoll L, Borras FE, Buzas E, Camussi G, Cappello F, et al. Evidence-based clinical use of nanoscale extracellular vesicles in nanomedicine. ACS Nano 2016;10:3886–3899. Fais S, O Driscoll L, Borras FE, Buzas E, Camussi G, Cappello F, et al. Evidence-based clinical use of nanoscale extracellular vesicles in nanomedicine. ACS Nano 2016;10:3886–3899.
11.
go back to reference Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol. 2009;11:1143–9.CrossRef Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol. 2009;11:1143–9.CrossRef
12.
go back to reference Alexander M, Hu R, Runtsch MC, Kagele DA, Mosbruger TL, Tolmachova T, et al. Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat Commun. 2015;6:7321.CrossRef Alexander M, Hu R, Runtsch MC, Kagele DA, Mosbruger TL, Tolmachova T, et al. Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat Commun. 2015;6:7321.CrossRef
13.
go back to reference Wang N, Wang L, Yang Y, Gong L, Xiao B, Liu X. A serum exosomal microRNA panel as a potential biomarker test for gastric cancer. Biochem Bioph Res Co. 2017;493:1322–8.CrossRef Wang N, Wang L, Yang Y, Gong L, Xiao B, Liu X. A serum exosomal microRNA panel as a potential biomarker test for gastric cancer. Biochem Bioph Res Co. 2017;493:1322–8.CrossRef
14.
go back to reference Schlemper RJ. The Vienna classification of gastrointestinal epithelial neoplasia. Gut. 2000;47:251–5.CrossRef Schlemper RJ. The Vienna classification of gastrointestinal epithelial neoplasia. Gut. 2000;47:251–5.CrossRef
15.
go back to reference Pesta M, Klecka J, Kulda V, Topolcan O, Hora M, Eret V, et al. Importance of miR-20a expression in prostate cancer tissue. Anticancer Research. 2010;30:3579–83. Pesta M, Klecka J, Kulda V, Topolcan O, Hora M, Eret V, et al. Importance of miR-20a expression in prostate cancer tissue. Anticancer Research. 2010;30:3579–83.
16.
go back to reference Zhang ZN, Xu JJ, Fu YJ, Liu J, Jiang YJ, Cui HL, et al. Transcriptomic analysis of peripheral blood mononuclear cells in rapid progressors in early HIV infection identifies a signature closely correlated with disease progression. Clin Chem. 2013;59:1175–86.CrossRef Zhang ZN, Xu JJ, Fu YJ, Liu J, Jiang YJ, Cui HL, et al. Transcriptomic analysis of peripheral blood mononuclear cells in rapid progressors in early HIV infection identifies a signature closely correlated with disease progression. Clin Chem. 2013;59:1175–86.CrossRef
17.
go back to reference Caradec J, Kharmate G, Hosseini-Beheshti E, Adomat H, Gleave M, Guns E. Reproducibility and efficiency of serum-derived exosome extraction methods. Clin Biochem. 2014;47:1286–92.CrossRef Caradec J, Kharmate G, Hosseini-Beheshti E, Adomat H, Gleave M, Guns E. Reproducibility and efficiency of serum-derived exosome extraction methods. Clin Biochem. 2014;47:1286–92.CrossRef
18.
go back to reference Li Y, Zhang L, Liu F, Xiang G, Jiang D, Pu X. Identification of endogenous controls for analyzing serum exosomal miRNA in patients with hepatitis b or hepatocellular carcinoma. Dis Markers. 2015;2015:1–12. Li Y, Zhang L, Liu F, Xiang G, Jiang D, Pu X. Identification of endogenous controls for analyzing serum exosomal miRNA in patients with hepatitis b or hepatocellular carcinoma. Dis Markers. 2015;2015:1–12.
19.
go back to reference Huang Y. Circulating microRNAs and long non-coding RNAs in gastric cancer diagnosis: an update and review. World J Gastroentero. 2015;21:9863–86.CrossRef Huang Y. Circulating microRNAs and long non-coding RNAs in gastric cancer diagnosis: an update and review. World J Gastroentero. 2015;21:9863–86.CrossRef
20.
go back to reference Xu Q, Wu Y, Li Y, He C, Sun L, Liu J, et al. SNP-SNP interactions of three new pri-miRNAs with the target gene PGC and multidimensional analysis of H. Pylori in the gastric cancer/atrophic gastritis risk in a Chinese population. Oncotarget. 2016;7:23700–14.PubMedPubMedCentral Xu Q, Wu Y, Li Y, He C, Sun L, Liu J, et al. SNP-SNP interactions of three new pri-miRNAs with the target gene PGC and multidimensional analysis of H. Pylori in the gastric cancer/atrophic gastritis risk in a Chinese population. Oncotarget. 2016;7:23700–14.PubMedPubMedCentral
21.
go back to reference Rodríguez M, Bajo-Santos C, Hessvik NP, Lorenz S, Fromm B, Berge V, et al. Identification of non-invasive miRNAs biomarkers for prostate cancer by deep sequencing analysis of urinary exosomes. Mol Cancer. 2017;16:156.CrossRef Rodríguez M, Bajo-Santos C, Hessvik NP, Lorenz S, Fromm B, Berge V, et al. Identification of non-invasive miRNAs biomarkers for prostate cancer by deep sequencing analysis of urinary exosomes. Mol Cancer. 2017;16:156.CrossRef
22.
go back to reference Wu Q, Yang Z, Wang F, Hu S, Yang L, Shi Y, et al. MiR-19b/20a/92a regulates the self-renewal and proliferation of gastric cancer stem cells. J Cell Sci. 2013;126:4220–9.CrossRef Wu Q, Yang Z, Wang F, Hu S, Yang L, Shi Y, et al. MiR-19b/20a/92a regulates the self-renewal and proliferation of gastric cancer stem cells. J Cell Sci. 2013;126:4220–9.CrossRef
23.
go back to reference Kim CH, Kim HK, Rettig RL, Kim J, Lee ET, Aprelikova O, et al. MiRNA signature associated with outcome of gastric cancer patients following chemotherapy. BMC Med Genet. 2011;4:79. Kim CH, Kim HK, Rettig RL, Kim J, Lee ET, Aprelikova O, et al. MiRNA signature associated with outcome of gastric cancer patients following chemotherapy. BMC Med Genet. 2011;4:79.
24.
go back to reference Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S, et al. Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol. 2010;11:136–46.CrossRef Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S, et al. Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol. 2010;11:136–46.CrossRef
25.
go back to reference Bandres E, Bitarte N, Arias F, Agorreta J, Fortes P, Agirre X, et al. MicroRNA-451 regulates macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells. Clin Cancer Res. 2009;15:2281–90.CrossRef Bandres E, Bitarte N, Arias F, Agorreta J, Fortes P, Agirre X, et al. MicroRNA-451 regulates macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells. Clin Cancer Res. 2009;15:2281–90.CrossRef
26.
go back to reference Hommers L, Raab A, Bohl A, Weber H, Scholz C, Erhardt A, et al. MicroRNA hsa-miR-4717-5p regulates RGS2 and may be a risk factor for anxiety-related traits. Am J Med Genet B Neuropsychiatr Genet. 2015;168:296–306.CrossRef Hommers L, Raab A, Bohl A, Weber H, Scholz C, Erhardt A, et al. MicroRNA hsa-miR-4717-5p regulates RGS2 and may be a risk factor for anxiety-related traits. Am J Med Genet B Neuropsychiatr Genet. 2015;168:296–306.CrossRef
27.
go back to reference Naderi M, Pazouki A, Arefian E, Hashemi SM, Jamshidi-Adegani F, Gholamalamdari O, et al. Two triacylglycerol pathway genes, CTDNEPI and LPIN1 are Down-Regulated by hsa-miR-122-5p in hepatocytes. 2017;20:165–71. Naderi M, Pazouki A, Arefian E, Hashemi SM, Jamshidi-Adegani F, Gholamalamdari O, et al. Two triacylglycerol pathway genes, CTDNEPI and LPIN1 are Down-Regulated by hsa-miR-122-5p in hepatocytes. 2017;20:165–71.
28.
go back to reference Raitoharju E, Seppälä I, Lyytikäinen L, Viikari J, Ala-Korpela M, Soininen P, et al. Blood hsa-miR-122-5p and hsa-miR-885-5p levels associate with fatty liver and related lipoprotein metabolism—the young Finns study. Sci Rep-Uk. 2016;6:38262.CrossRef Raitoharju E, Seppälä I, Lyytikäinen L, Viikari J, Ala-Korpela M, Soininen P, et al. Blood hsa-miR-122-5p and hsa-miR-885-5p levels associate with fatty liver and related lipoprotein metabolism—the young Finns study. Sci Rep-Uk. 2016;6:38262.CrossRef
29.
go back to reference Tan Y, Ge G, Pan T, Wen D, Gan J. Serum MiRNA panel as potential biomarkers for chronic hepatitis B with persistently normal alanine aminotransferase. Clin Chim Acta. 2015;451:232–9.CrossRef Tan Y, Ge G, Pan T, Wen D, Gan J. Serum MiRNA panel as potential biomarkers for chronic hepatitis B with persistently normal alanine aminotransferase. Clin Chim Acta. 2015;451:232–9.CrossRef
30.
go back to reference TAN Y, LIN B, YE Y, WEN D, CHEN LI. ZHOU X. Differential expression of serum microRNAs in cirrhosis that evolve into hepatocellular carcinoma related to hepatitis B virus. Oncol Rep. 2015;33:2863–70.CrossRef TAN Y, LIN B, YE Y, WEN D, CHEN LI. ZHOU X. Differential expression of serum microRNAs in cirrhosis that evolve into hepatocellular carcinoma related to hepatitis B virus. Oncol Rep. 2015;33:2863–70.CrossRef
31.
go back to reference Qin Q, Yin Z, Li Y, Wang B, Zhang M. Long intergenic noncoding RNA 01296 aggravates gastric cancer cells progress through miR-122/MMP-9. Biomed Pharmacother. 2018;97:450–7.CrossRef Qin Q, Yin Z, Li Y, Wang B, Zhang M. Long intergenic noncoding RNA 01296 aggravates gastric cancer cells progress through miR-122/MMP-9. Biomed Pharmacother. 2018;97:450–7.CrossRef
32.
go back to reference Chen Y, Wang C, Liu Y, Tang L, Zheng M, Xu C, et al. MiR-122 targets NOD2 to decrease intestinal epithelial cell injury in Crohn’s disease. Biochem Bioph Res Co. 2013;438:133–9.CrossRef Chen Y, Wang C, Liu Y, Tang L, Zheng M, Xu C, et al. MiR-122 targets NOD2 to decrease intestinal epithelial cell injury in Crohn’s disease. Biochem Bioph Res Co. 2013;438:133–9.CrossRef
33.
go back to reference Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.CrossRef Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.CrossRef
34.
go back to reference Witwer KW. Circulating MicroRNA biomarker studies: pitfalls and potential solutions. Clin Chem. 2014;61:56–63.CrossRef Witwer KW. Circulating MicroRNA biomarker studies: pitfalls and potential solutions. Clin Chem. 2014;61:56–63.CrossRef
35.
go back to reference Stefan CP, Koehler JW, Minogue TD. Targeted next-generation sequencing for the detection of ciprofloxacin resistance markers using molecular inversion probes. Sci Rep. 2016;6:25904.CrossRef Stefan CP, Koehler JW, Minogue TD. Targeted next-generation sequencing for the detection of ciprofloxacin resistance markers using molecular inversion probes. Sci Rep. 2016;6:25904.CrossRef
36.
go back to reference Backes C, et al. Bias in high-throughput analysis of miRNAs and implications for biomarker studies. Anal Chem. 2016;88:2088–95.CrossRef Backes C, et al. Bias in high-throughput analysis of miRNAs and implications for biomarker studies. Anal Chem. 2016;88:2088–95.CrossRef
Metadata
Title
Identification of non-invasive biomarkers for chronic atrophic gastritis from serum exosomal microRNAs
Authors
Hong Liu
Pei-wu Li
Wei-qin Yang
Hong Mi
Jing-lin Pan
Yuan-cheng Huang
Zheng-kun Hou
Qiu-ke Hou
Qi Luo
Feng-bin Liu
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-5328-7

Other articles of this Issue 1/2019

BMC Cancer 1/2019 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine