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A three-plasma miRNA signature serves as novel biomarkers for osteosarcoma

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Abstract

Osteosarcoma is the most common human primary malignant bone tumor in children and young adults. Sensitive and non-invasive biomarkers that can facilitate disease detection at early stage are highly desirable to improve survival rate and help to determine optimized treatment for osteosarcoma. The small non-coding RNAs, microRNAs (miRNAs), have recently been identified as critical regulators for various diseases including cancer and may represent a novel class of cancer biomarkers. In this study, we aimed to detect the potential of circulating miRNAs as biomarkers for osteosarcoma. Levels of six candidate miRNAs (miR-21, miR-199a-3p, miR-143, miR-34, miR-140, and miR-132) that were previously demonstrated to be regulated in osteosarcoma were examined in plasma of 40 osteosarcoma patients and 40 matched healthy controls by quantitative reverse-transcription polymerase chain reaction assays. The results showed that circulating levels of miR-21 were significantly higher in osteosarcoma patients than controls, while miR-199a-3p and miR-143 were decreased in osteosarcoma patients. We replicated the findings in an independent study of 40 osteosarcoma patients and 40 matched controls and confirmed the results. Receiver operating characteristics curve analysis of the combined populations demonstrated that the three-miRNA signature could discriminate cases from controls with an area under the curve of 0.953 (95 % CI 0.924–0.984). In addition, circulating miR-21 and miR-143 were correlated with both metastasis status and histological subtype of the patients, while miR-199a-3p only correlated with histological subtype. Our data suggest that altered levels of circulating miRNAs might have great potential to serve as novel, non-invasive biomarkers for osteosarcoma.

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References

  1. Ma O, Cai WW, Zender L, Dayaram T, Shen J, Herron AJ, et al. MMP13, Birc2 (cIAP1), and Birc3 (cIAP2), amplified on chromosome 9, collaborate with p53 deficiency in mouse osteosarcoma progression. Cancer Res. 2009;69(6):2559–67.

    Article  PubMed  CAS  Google Scholar 

  2. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002;20(3):776–90.

    Article  PubMed  Google Scholar 

  3. Ambros V. The functions of animal microRNAs. Nature. 2004;431(7006):350–5.

    Article  PubMed  CAS  Google Scholar 

  4. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.

    Article  PubMed  CAS  Google Scholar 

  5. Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. miRBase: tools for microRNA genomics. Nucleic Acids Res. 2008;36(Database issue):D154–8.

    PubMed  CAS  Google Scholar 

  6. Kobayashi E, Hornicek FJ, Duan Z. MicroRNA involvement in osteosarcoma. Sarcoma. 2012;2012:359739.

    Article  PubMed  Google Scholar 

  7. He C, Xiong J, Xu X, Lu W, Liu L, Xiao D, et al. Functional elucidation of MiR-34 in osteosarcoma cells and primary tumor samples. Biochem Biophys Res Commun. 2009;388(1):35–40.

    Article  PubMed  CAS  Google Scholar 

  8. Ziyan W, Shuhua Y, Xiufang W, Xiaoyun L. MicroRNA-21 is involved in osteosarcoma cell invasion and migration. Med Oncol. 2011;28(4):1469–74.

    Article  PubMed  Google Scholar 

  9. Duan Z, Choy E, Harmon D, Liu X, Susa M, Mankin H, et al. MicroRNA-199a-3p is downregulated in human osteosarcoma and regulates cell proliferation and migration. Mol Cancer Ther. 2011;10(8):1337–45.

    Article  PubMed  CAS  Google Scholar 

  10. Osaki M, Takeshita F, Sugimoto Y, Kosaka N, Yamamoto Y, Yoshioka Y, et al. MicroRNA-143 regulates human osteosarcoma metastasis by regulating matrix metalloprotease-13 expression. Mol Ther. 2011;19(6):1123–30.

    Article  PubMed  CAS  Google Scholar 

  11. Song B, Wang Y, Xi Y, Kudo K, Bruheim S, Botchkina GI, et al. Mechanism of chemoresistance mediated by miR-140 in human osteosarcoma and colon cancer cells. Oncogene. 2009;28(46):4065–74.

    Article  PubMed  CAS  Google Scholar 

  12. Gougelet A, Pissaloux D, Besse A, Perez J, Duc A, Dutour A, et al. Micro-RNA profiles in osteosarcoma as a predictive tool for ifosfamide response. Int J Cancer. 2011;129(3):680–90.

    Article  PubMed  CAS  Google Scholar 

  13. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA. 2008;105(30):10513–8.

    Article  PubMed  CAS  Google Scholar 

  14. Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008;18(10):997–1006.

    Article  PubMed  CAS  Google Scholar 

  15. Limmahakhun S, Pothacharoen P, Theera-Umpon N, Arpornchayanon O, Leerapun T, Luevitoonvechkij S, et al. Relationships between serum biomarker levels and clinical presentation of human osteosarcomas. Asian Pac J Cancer Prev. 2011;12(7):1717–22.

    PubMed  Google Scholar 

  16. Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65(14):6029–33.

    Article  PubMed  CAS  Google Scholar 

  17. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133(2):647–58.

    Article  PubMed  CAS  Google Scholar 

  18. Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 2008;27(15):2128–36.

    Article  PubMed  CAS  Google Scholar 

  19. Zhu S, Si ML, Wu H, Mo YY. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem. 2007;282(19):14328–36.

    Article  PubMed  CAS  Google Scholar 

  20. Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo YY. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res. 2008;18(3):350–9.

    Article  PubMed  CAS  Google Scholar 

  21. Fornari F, Milazzo M, Chieco P, Negrini M, Calin GA, Grazi GL, et al. MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res. 2010;70(12):5184–93.

    Article  PubMed  CAS  Google Scholar 

  22. Ichimi T, Enokida H, Okuno Y, Kunimoto R, Chiyomaru T, Kawamoto K, et al. Identification of novel microRNA targets based on microRNA signatures in bladder cancer. Int J Cancer. 2009;125(2):345–52.

    Article  PubMed  CAS  Google Scholar 

  23. Michael MZ, OC SM, van Holst Pellekaan NG, Young GP, James RJ. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res. 2003;1(12):882–91.

    PubMed  CAS  Google Scholar 

  24. Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T. MicroRNA expression profiling in prostate cancer. Cancer Res. 2007;67(13):6130–5.

    Article  PubMed  CAS  Google Scholar 

  25. Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007;67(18):8699–707.

    Article  PubMed  CAS  Google Scholar 

  26. Lui WO, Pourmand N, Patterson BK, Fire A. Patterns of known and novel small RNAs in human cervical cancer. Cancer Res. 2007;67(13):6031–43.

    Article  PubMed  CAS  Google Scholar 

  27. Takagi T, Iio A, Nakagawa Y, Naoe T, Tanigawa N, Akao Y. Decreased expression of microRNA-143 and -145 in human gastric cancers. Oncology. 2009;77(1):12–21.

    Article  PubMed  CAS  Google Scholar 

  28. Chen X, Guo X, Zhang H, Xiang Y, Chen J, Yin Y, et al. Role of miR-143 targeting KRAS in colorectal tumorigenesis. Oncogene. 2009;28(10):1385–92.

    Article  PubMed  CAS  Google Scholar 

  29. Akao Y, Nakagawa Y, Kitade Y, Kinoshita T, Naoe T. Downregulation of microRNAs-143 and -145 in B-cell malignancies. Cancer Sci. 2007;98(12):1914–20.

    Article  PubMed  CAS  Google Scholar 

  30. Bacci G, Longhi A, Versari M, Mercuri M, Briccoli A, Picci P. Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer. 2006;106(5):1154–61.

    Article  PubMed  Google Scholar 

  31. Tang N, Song WX, Luo J, Haydon RC, He TC. Osteosarcoma development and stem cell differentiation. Clin Orthop Relat Res. 2008;466(9):2114–30.

    Article  PubMed  Google Scholar 

  32. Hauben EI, Weeden S, Pringle J, Van Marck EA, Hogendoorn PC. Does the histological subtype of high-grade central osteosarcoma influence the response to treatment with chemotherapy and does it affect overall survival? A study on 570 patients of two consecutive trials of the European Osteosarcoma Intergroup. Eur J Cancer. 2002;38(9):1218–25.

    Article  PubMed  CAS  Google Scholar 

  33. Hu Z, Chen X, Zhao Y, Tian T, Jin G, Shu Y, et al. Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J Clin Oncol. 2010;28(10):1721–6.

    Article  PubMed  Google Scholar 

  34. Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res. 2010;107(6):810–7.

    Article  PubMed  CAS  Google Scholar 

  35. Liu R, Zhang C, Hu Z, Li G, Wang C, Yang C, et al. A five-microRNA signature identified from genome-wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis. Eur J Cancer. 2011;47(5):784–91.

    Article  PubMed  CAS  Google Scholar 

  36. Fichtlscherer S, De Rosa S, Fox H, Schwietz T, Fischer A, Liebetrau C, et al. Circulating microRNAs in patients with coronary artery disease. Circ Res. 2010;107(5):677–84.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are particularly grateful to all the patients with osteosarcoma and volunteers for participating in the present study and to the medical personnel of Union Hospital and Liyuan Hospital, and Dr. Ye’s laboratory in Wuhan city, Hubei Province, China for their kind assistance in collecting the data and samples.

Conflict of interest

All authors declared no conflict of interest.

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Authors and Affiliations

  1. Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, 430030, Hubei, China

    Liu Ouyang, Shuhua Yang, Shunan Ye, Weihua Xu & Xianzhe Liu

  2. Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Ping Liu

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  1. Liu Ouyang
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Correspondence to Shunan Ye.

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Liu Ouyang and Ping Liu contributed equally to this work.

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Ouyang, L., Liu, P., Yang, S. et al. A three-plasma miRNA signature serves as novel biomarkers for osteosarcoma. Med Oncol 30, 340 (2013). https://doi.org/10.1007/s12032-012-0340-7

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