Oncogenic MicroRNAs: miR-155, miR-19a, miR-181b, and miR-24 enable monitoring of early breast cancer in serum

BMC Cancer

Marek Sochor¹  Petra Basova²  Michal Pesta³  Nina Dusilkova²  Jiri Bartos¹  Pavel Burda²  Vit Pospisil²  Tomas Stopka² 

[1] Comprehensive Cancer Centre, Regional Hospital Liberec, Liberec, Czech Republic

[2] 1st Faculty of Medicine, Institute of Pathological Physiology, Charles University in Prague, Prague, Czech Republic

[3] Faculty of Mathematics and Physics, Charles University in Prague, Prague, Czech Republic

关键词: Let-7a;    miR-24;    miR-181b;    miR-19a;    miR-155;    microRNA;    Breast cancer;   

Others  :  855681
DOI  :  10.1186/1471-2407-14-448

 received in 2013-10-24, accepted in 2014-06-10,  发布年份 2014

【 摘 要 】

Background

MicroRNAs (miRs) represent a distinct class of posttranscriptional modulators of gene expression with remarkable stability in sera. Several miRs are oncogenic (oncomiRs) and are deregulated in the pathogenesis of breast cancer and function to inhibit tumor suppressors. Routine blood monitoring of these circulating tumor-derived products could be of significant benefit to the diagnosis and relapse detection of early-stage breast cancer (EBC) patients.

Methods

Aim of this project was to determine expression of miR-155, miR-19a, miR-181b, miR-24, relative to let-7a in sera of 63 patients with EBC and 21 healthy controls. Longitudinal multivariate data analysis was performed to stochastically model the serum levels of each of the oncomiRs during disease phases: from diagnosis, after surgery, and following chemo/radiotherapy. Moreover, this analysis was utilized to evaluate oncomiR levels in EBC patients subgrouped using current clinical prognostic factors including HER2, Ki-67, and grade III.

Results

EBC patients significantly over-express the oncomiRs at the time of diagnosis. Following surgical resection the serum levels of miR-155, miR-181b, and miR-24 significantly decreased (p = 1.89e-05, 5.41e-06, and 0.00638, respectively) whereas the miR-19a decreased significantly after the therapy (p = 0.00869). Furthermore, in case of high-risk patients serum levels of miR-155, miR-19a, miR-181b, and miR-24 are significantly more abundant in comparison to low-risk group (p = 0.026, 0.02567, 0.0250, and 0.00990) and show a decreasing trend upon therapy.

Conclusions

OncomiRs are significantly more abundant in the sera of EBC patients compared to controls at diagnosis. Differences in oncomiR levels reflecting EBC risk were also observed. Testing the oncomiRs may be useful for diagnostic purpose and possibly also for relapse detection in follow-up studies of EBC.

【 授权许可】

   
2014 Sochor et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Schwarzenbach H: Circulating nucleic acids as biomarkers in breast cancer. Breast Cancer Res 2013, 15(5):211.
• [2]Calin GA, Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer 2006, 6(11):857-866.
• [3]Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Ménard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM: MicroRNA gene expression deregulation in human breast cancer. Cancer Res 2005, 65(16):7065-7070.
• [4]Kim K, Chadalapaka G, Lee SO, Yamada D, Sastre-Garau X, Defossez PA, Park YY, Lee JS, Safe S: Identification of oncogenic microRNA-17-92/ZBTB4/specificity protein axis in breast cancer. Oncogene 2012, 31(8):1034-1044.
• [5]Ouchida M, Kanzaki H, Ito S, Hanafusa H, Jitsumori Y, Tamaru S, Shimizu K: Novel direct targets of miR-19a identified in breast cancer cells by a quantitative proteomic approach. PLoS One 2012, 7(8):e44095.
• [6]Li S, Yang C, Zhai L, Zhang W, Yu J, Gu F, Lang R, Fan Y, Gong M, Zhang X, Fu L: Deep sequencing reveals small RNA characterization of invasive micropapillary carcinomas of the breast. Breast Cancer Res Treat 2012, 136(1):77-87.
• [7]Wu Q, Wang C, Lu Z, Guo L, Ge Q: Analysis of serum genome-wide microRNAs for breast cancer detection. Clini Chim Acta 2012, 413(13–14):1058-1065.
• [8]Song J, Bai Z, Han W, Zhang J, Meng H, Bi J, Ma X, Han S, Zhang Z: Identification of suitable reference genes for qPCR analysis of serum microRNA in gastric cancer patients. Dig Dis Sci 2012, 57(4):897-904.
• [9]Zhao H, Shen J, Medico L, Wang D, Ambrosone CB, Liu S: A pilot study of circulating miRNAs as potential biomarkers of early stage breast cancer. PLoS One 2010, 5(10):e13735.
• [10]Newman MA, Thomson JM, Hammond SM: Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. RNA 2008, 14(8):1539-1549.
• [11]Kim SJ, Shin JY, Lee KD, Bae YK, Sung KW, Nam SJ, Chun KH: MicroRNA let-7a suppresses breast cancer cell migration and invasion through downregulation of C-C chemokine receptor type 7. Breast Cancer Res 2012, 14(1):R14.
• [12]Liu Y, Li H, Feng J, Cui X, Huang W, Li Y, Su F, Liu Q, Zhu J, Lv X, Chen J, Huang D, Yu F: Lin28 induces epithelial-to-mesenchymal transition and stemness via downregulation of Let-7a in breast cancer cells. PLoS One 2013, 8(12):e83083.
• [13]Cai WY, Wei TZ, Luo QC, Wu QW, Liu QF, Yang M, Ye GD, Wu JF, Chen YY, Sun GB, Liu YJ, Zhao WX, Zhang ZM, Li BA: The Wnt-beta-catenin pathway represses let-7 microRNA expression through transactivation of Lin28 to augment breast cancer stem cell expansion. J Cell Sci 2013, 126(Pt 13):2877-2889.
• [14]Jiang S, Zhang HW, Lu MH, He XH, Li Y, Gu H, Liu MF, Wang ED: MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res 2010, 70(8):3119-3127.
• [15]Sun Y, Wang M, Lin G, Sun S, Li X, Qi J, Li J: Serum microRNA-155 as a potential biomarker to track disease in breast cancer. PLoS One 2012, 7(10):e47003.
• [16]Farazi TA, Horlings HM, Ten Hoeve JJ, Mihailovic A, Halfwerk H, Morozov P, Brown M, Hafner M, Reyal F, van Kouwenhove M, Kreike B, Sie D, Hovestadt V, Wessels LF, van de Vijver MJ, Tuschl T: MicroRNA sequence and expression analysis in breast tumors by deep sequencing. Cancer Res 2011, 71(13):4443-4453.
• [17]Bisso A, Faleschini M, Zampa F, Capaci V, De Santa J, Santarpia L, Piazza S, Cappelletti V, Daidone M, Agami R, Del Sal G: Oncogenic miR-181a/b affect the DNA damage response in aggressive breast cancer. Cell Cycle 2013, 12(11):1679-1687.
• [18]Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K: STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell 2010, 39(4):493-506.
• [19]Papadimitriou E, Vasilaki E, Vorvis C, Iliopoulos D, Moustakas A, Kardassis D, Stournaras C: Differential regulation of the two RhoA-specific GEF isoforms Net1/Net1A by TGF-beta and miR-24: role in epithelial-to-mesenchymal transition. Oncogene 2012, 31(23):2862-2875.
• [20]Eichelser C, Flesch-Janys D, Chang-Claude J, Pantel K, Schwarzenbach H: Deregulated serum concentrations of circulating cell-free microRNAs miR-17, miR-34a, miR-155, and miR-373 in human breast cancer development and progression. Clin Chem 2013, 59(10):1489-1496.