Abstract
Background:
miRNAs act in diverse biological processes including development, cell growth, apoptosis, and hematopoiesis, suggesting their role in cancer.
Methods:
We examined the miRNAs perturbed in CD138+ primary multiple myeloma (MM) cells, using microarray analysis and real-time quantitative PCR (RT-qPCR). Serum miR-4449 expression levels were detected from 71 primary MM patients and 46 healthy controls by RT-qPCR.
Results:
Our analysis revealed up-regulation of 54 and down-regulation of 28 miRNAs in MM subjects compared to healthy controls. miR-4449 has not been reported in MM. It was found that the relative expression of bone marrow miR-4449 in MM patients (2.14±1.42) was higher than that in healthy controls (0.815±0.165) (U=8, p=0.0093). The relative expression of serum miR-4449 in MM patients (2.11±2.10) was significantly higher than that in healthy controls (0.357±0.235) (U=374, p<0.0001) and was significantly correlated with β2M, λ light and κ light chain concentration (r=0.480, p=0.0003; r=0.560, p<0.0001; r=0.560, p<0.0001), but not correlated with the lactate dehydrogenase (LDH) concentration (r=0.247, p=0.0611). The area under the curve (AUC) of the receiver-operating characteristics (ROC) curve of serum miR-4449 was 0.885 (95% CI, 0.826–0.945), which is higher than for other markers. Combining miR-4449, λ light chain, and β2M together, the sensitivity was highest compared with λ light chain or β2M alone, or combined.
Conclusions:
The expression levels of serum miR-4449 in MM patients were significantly higher than in healthy controls, suggesting that it may prove to be useful in the auxiliary diagnosis of MM.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: Grand support: the National Nature Science Foundation of China (81301498; 81271920; 81201351); Jiangsu Provincial Medical Innovation Team and Leading Talents (LJ201133); the Scientific Research Subject of Jiangsu Provincial Health Department (H201422; H201526); and translational medicine project of Affiliated Hospital of Nantong University (TDF-zh201407, TDF-zh201406).
Employment or leadership: None declared.
Honorarium: None declared.
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. Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 2007;7:585–98.10.1038/nrc2189Search in Google Scholar PubMed
2. Unno K, Zhou Y, Zimmerman T, Platanias LC, Wickrema A. Identification of a novel microRNA cluster miR-193b-365 in multiple myeloma. Leuk Lymphoma 2009;50:1865–71.10.1080/10428190903221010Search in Google Scholar
3. Dalmay T. MicroRNAs and cancer. J Intern Med 2008;263:366–75.10.1111/j.1365-2796.2008.01926.xSearch in Google Scholar PubMed
4. Lee YS, Dutta A. MicroRNAs in Cancer. Annu Rev Pathol 2009;4:199–227.10.1146/annurev.pathol.4.110807.092222Search in Google Scholar PubMed PubMed Central
5. Bi C, Chng WJ. MicroRNA: important player in the pathobiology of multiple myeloma. Biomed Res Int 2014;2014:521586.10.1155/2014/521586Search in Google Scholar PubMed PubMed Central
6. He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, et al. A microRNA polycistron as a potential human oncogene. Nature 2005;435:828–33.10.1038/nature03552Search in Google Scholar PubMed PubMed Central
7. Löffler D, Brocke-Heidrich K, Pfeifer G, Stocsits C, Hackermüller J, Kretzschmar AK, et al. Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. Blood 2007;110:1330–3.10.1182/blood-2007-03-081133Search in Google Scholar PubMed
8. Peng J, Thakur A, Zhang S, Dong Y, Wang X, Yuan R, et al. Expressions of miR-181a and miR-20a in RPMI8226 cell line and their potential as biomarkers for multiple myeloma. Tumour Biol 2015;36: 8545–52.10.1007/s13277-015-3600-2Search in Google Scholar PubMed
9. Chen L, Li C, Zhang R, Gao X, Qu X, Zhao M, et al. miR-17-92 cluster microRNAs confers tumorigenicity in multiple myeloma. Cancer Lett 2011;309:62–70.10.1016/j.canlet.2011.05.017Search in Google Scholar PubMed
10. Rio-Machin A, Ferreira BI, Henry T, Gómez-López G, Agirre X, Alvarez S, et al. Downregulation of specific miRNAs in hyperdiploid multiple myeloma mimics the oncogenic effect of IgH translocations occurring in the non-hyperdiploid subtype leukemia 2013;27:925–31.10.1038/leu.2012.302Search in Google Scholar PubMed
11. Wu P, Agnelli L, Walker BA, Todoerti K, Lionetti M, Johnson DC, et al. Improved risk stratification in myeloma using a microRNA-based classifier. Br J Haematol 2013;162:348–59.10.1111/bjh.12394Search in Google Scholar PubMed
12. Seckinger A, Meißner T, Moreaux J, Benes V, Hillengass J, Castoldi M, et al. miRNAs in multiple myeloma – a survival relevant complex regulator of gene expression. Oncotarget 2015;6:39165–83.10.18632/oncotarget.5381Search in Google Scholar PubMed PubMed Central
13. Chi J, Ballabio E, Chen XH, Kušec R, Taylor S, Hay D, et al. MicroRNA expression in multiple myeloma is associated with genetic subtype, isotype and survival. Biol Direct 2011;6:23.10.1186/1745-6150-6-23Search in Google Scholar PubMed PubMed Central
14. Huang JJ, Yu J, Li JY, Liu YT, Zhong RQ. Circulating microRNA expression is associated with genetic subtype and survival of multiple myeloma. Med Oncol 2012;29:2402–8.10.1007/s12032-012-0210-3Search in Google Scholar PubMed
15. Rajkumar SV. Multiple myeloma: 2012 update on diagnosis, risk-stratification, and management. Am J Hematol 2012;87:78–88.10.1002/ajh.22237Search in Google Scholar PubMed PubMed Central
16. Agnelli L, Fabris S, Bicciato S, Basso D, Baldini L, Morabito F, et al. Upregulation of translational machinery and distinct genetic subgroups characterise hyperdiploidy in multiple myeloma. Br J Haematol 2007;136:565–73.10.1111/j.1365-2141.2006.06467.xSearch in Google Scholar PubMed
17. Fonseca R, Monge J, Dimopoulos MA. Staging and prognostication of multiple myeloma. Expert Rev Hematol 2014;7:21–31.10.1586/17474086.2014.882224Search in Google Scholar PubMed PubMed Central
18. Di Martino MT, Leone E, Amodio N, Foresta U, Lionetti M, Pitari MR, et al. Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: in vitro and in vivo evidence. Clin Cancer Res 2012;18:6260–70.10.1158/1078-0432.CCR-12-1708Search in Google Scholar PubMed PubMed Central
19. Pichiorri F, Suh SS, Ladetto M, Kuehl M, Palumbo T, Drandi D, et al. MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proc Natl Acad Sci USA 2008;105:12885–90.10.1073/pnas.0806202105Search in Google Scholar PubMed PubMed Central
20. Roccaro AM, Sacco A, Thompson B, Leleu X, Azab AK, Azab F, et al. M icroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma. Blood 2009;113:6669–80.10.1182/blood-2009-01-198408Search in Google Scholar PubMed PubMed Central
21. Zhou Y, Chen L, Barlogie B, Stephens O, Wu X, Williams DR, et al. High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2. Proc Natl Acad Sci USA 2010;107:7904–9.10.1073/pnas.0908441107Search in Google Scholar PubMed PubMed Central
22. Tagliaferri P, Rossi M, Di Martino MT, Amodio N, Leone E, Gulla A, et al. Promises and challenges of MicroRNA-based treatment of multiple myeloma. Curr Cancer Drug Targets 2012;12:838–46.10.2174/156800912802429355Search in Google Scholar PubMed PubMed Central
23. Sevcikova S, Kubiczkova L, Sedlarikova L, Slaby O, Hajek R. Serum miR-29a as a marker of multiple myeloma. Leuk Lymphoma 2013;54:189–91.10.3109/10428194.2012.704030Search in Google Scholar PubMed
24. Kubiczkova L, Kryukov F, Slaby O, Dementyeva E, Jarkovsky J, Nekvindova J, et al. Circulating serum microRNAs as novel diagnostic and prognostic biomarkers for multiple myeloma and monoclonal gammopathy of undetermined significance. Haematologica 2014;99:511–8.10.3324/haematol.2013.093500Search in Google Scholar PubMed PubMed Central
25. Duttagupta R, Jiang R, Gollub J, Getts RC, Jones KW. Impact of cellular miRNAs on circulating miRNA biomarker signatures. PLoS One 2011;6:e20769.10.1371/journal.pone.0020769Search in Google Scholar PubMed PubMed Central
26. Schrauder MG, Strick R, Schulz-Wendtland R, Strissel PL, Kahmann L, Loehberg CR, et al. Circulating micro-RNAs as potential blood-based markers for early stage breast cancer detection. PLoS One 2012;7:e29770.10.1371/journal.pone.0029770Search in Google Scholar PubMed PubMed Central
27. Yu J, Qiu X, Shen X, Shi W, Wu X, Gu G, et al. miR-202 expression concentration and its clinical significance in the serum of multiple myeloma patients. Ann Clin Biochem 2014;51(Pt 5):543–9.10.1177/0004563213501155Search in Google Scholar PubMed
©2017 Walter de Gruyter GmbH, Berlin/Boston
