Yasemin ÖZTEMUR ISLAKOĞLU, Senem NOYAN, Bala GÜR DEDEOĞLU

hsa-miR-301a- and SOX10-dependent miRNA-TF-mRNA regulatory circuits in breast cancer

Breast cancer is the most common cancer among women and the molecular pathways that play main roles in breast cancerregulation are still not completely understood. MicroRNAs (miRNAs) and transcription factors (TFs) are important regulators of geneexpression. It is important to unravel the relation of TFs, miRNAs, and their targets within regulatory networks to clarify the processesthat cause breast cancer and the progression of it. In this study, mRNA and miRNA expression studies including breast tumors andnormal samples were extracted from the GEO microarray database. Two independent mRNA studies and a miRNA study were selectedand reanalyzed. Differentially expressed (DE) mRNAs and miRNAs between breast tumor and normal samples were listed by using BRBArray Tools. CircuitsDB2 analysis conducted with DE miRNAs and mRNAs resulted in 3 significant circuits that are SOX10- and hsamiR-301a-dependent. The following significant circuits were characterized and validated bioinformatically by using web-based tools:SOX10→hsa-miR-301a→HOXA3, SOX10→hsa-miR-301a→KIT, and SOX10→hsa-miR-301a→NFIB. It can be concluded that regulatorymotifs involving miRNAs and TFs may be useful for understanding breast cancer regulation and for predicting new biomarkers.

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Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K et al (2002). Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. P Natl Acad Sci USA 99: 15524-15529.
Edgar R, Domrachev M, Lash AE (2002). Gene Expression Omnibus : NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30: 207-210.
Enerly E, Steinfeld I, Kleivi K, Leivonen SK, Aure MR, Russnes HG, Ronneberg JA, Johnsen H, Navon R, Rodland E et al (2011). miRNA-mRNA integrated analysis reveals roles for miRNAs in primary breast tumors. PLoS One 6: e16915.
Friard O, Re A, Taverna D, De Bortoli M, Cora D (2010a). CircuitsDB: a database of mixed microRNA/transcription factor feed-forward regulatory circuits in human and mouse. BMC Bioinformatics 11: 435.
Friard O, Re A, Taverna D, De Bortoli M, Corá D (2010b). CircuitsDB: a database of mixed microRNA/transcription factor feed-forward regulatory circuits in human and mouse. BMC Bioinformatics 11: 435.
Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M et al (2005). MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65: 7065-7070.
Jachetti E, Rigoni A, Bongiovanni L, Arioli I, Botti L, Parenza M, Cancila V, Chiodoni C, Festinese F, Bellone M et al (2017). Imatinib spares cKit-expressing prostate neuroendocrine tumors, whereas kills seminal vesicle epithelial–stromal tumors by targeting PDGFR-β. Mol Cancer Ther 16: 365-375.
Joung JG, Fei Z (2009). Identification of microRNA regulatory modules in Arabidopsis via a probabilistic graphical model. Bioinformatics 25: 387-393.
Joung JG, Hwang KB, Nam JW, Kim SJ, Zhang BT (2007). Discovery of microRNA-mRNA modules via population-based probabilistic learning. Bioinformatics 23: 1141-1147.
Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T (2001). Identification of novel genes coding for small expressed RNAs. Science 294: 853-858.
Latchman S (1997). Transcription factors: an overview. Int J Biochem Cell Biol 2725: 1305-1312.
Lee CH, Kuo WH, Lin CC, Oyang YJ, Huang HC, Juan HF (2013). MicroRNA-regulated protein-protein interaction networks and their functions in breast cancer. Int J Mol Sci 14: 11560-11606.
Lee RC, Ambros V (2001). An extensive class of small RNAs in Caenorhabditis elegans. Science 294: 862-864.
Lowery AJ, Miller N, Devaney A, McNeill RE, Davoren PA, Lemetre C, Benes V, Schmidt S, Blake J, Ball G et al (2009). MicroRNA signatures predict oestrogen receptor, progesterone receptor and HER2/neu receptor status in breast cancer. Breast Cancer Res 11: R27.
Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, SweetCordero A, Ebert BL, Mak RH, Ferrando AA et al (2005). MicroRNA expression profiles classify human cancers. Nature 435: 834-838.
Ma F, Zhang J, Zhong L, Wang L, Liu Y, Wang Y, Peng L, Guo B (2014). Upregulated microRNA-301a in breast cancer promotes tumor metastasis by targeting PTEN and activating Wnt / β -catenin signaling. Gene 535: 191-197.
Maragkakis M, Reczko M, Simossis VA, Alexiou P, Papadopoulos GL, Dalamagas T, Giannopoulos G, Goumas G, Koukis E, Kourtis K et al (2009). DIANA-microT web server: elucidating microRNA functions through target prediction. Nucleic Acids Res 37: W273-W276.
McDermott AM, Miller N, Wall D, Martyn LM, Ball G, Sweeney KJ, Kerin MJ (2014). Identification and validation of oncologic miRNA biomarkers for luminal A-like breast cancer. PLoS One 9: e87032.
Moon HG, Hwang KT, Kim JA, Kim HS, Lee MJ, Jung EM, Ko E, Han W, Noh DY (2011). NFIB is a potential target for estrogen receptor-negative breast cancers. Mol Oncol 5: 538-544.
Naeem H, Kuffner R Zimmer R (2011). MIRTFnet : Analysis of miRNA regulated transcription factors. PLoS One 6: e22519.
Nam S, Li M, Choi K, Balch C, Kim S, Nephew KP (2009). MicroRNA and mRNA integrated analysis (MMIA): a web tool for examining biological functions of microRNA expression. Nucleic Acids Res 37: W356-W362.
Richardson AL, Wang ZC, De Nicolo A, Lu X, Brown M, Miron A, Liao X, Iglehart JD, Livingston DM, Ganesan S (2006). X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 9: 121-132.
Romero-Cordoba S, Rodriguez-Cuevas S, Rebollar-Vega R, Quintanar-Jurado V, Maffuz-Aziz A, Jimenez-Sanchez G, Bautista-Piña V, Arellano-Llamas R, Hidalgo-Miranda A (2012). Identification and pathway analysis of microRNAs with no previous involvement in breast cancer. PLoS One 7: e31904.
Ruepp A, Kowarsch A, Schmidl D, Buggenthin F, Brauner B, Dunger I, Fobo G, Frishman G, Montrone C, Theis FJ (2010). PhenomiR: a knowledgebase for microRNA expression in diseases and biological processes. Genome Biol 11: R6.
Shi W, Gerster K, Alajez NM, Tsang J, Waldron L, Pintilie M, Hui AB, Sykes J, P’ng C, Miller N et al (2011). MicroRNA-301 mediates proliferation and invasion in human breast cancer. Cancer Res 71: 2926-2937.
Simon R, Lam A, Li M, Ngan M, Menenzes S, Zhao Y (2007). Analysis of gene expression data using BRB-ArrayTools. Cancer Inform 3: 11-17.
Tran DH, Satou K, Ho TB (2008). Finding microRNA regulatory modules in human genome using rule induction. BMC Bioinformatics 9 (Suppl. 12): S5.
Turashvili G, Bouchal J, Baumforth K, Wei W, Dziechciarkova M, Ehrmann J, Klein J, Fridman E, Skarda J, Srovnal J et al (2007). Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. BMC Cancer 7: 55.
Tusher VG, Tibshirani R, Chu G (2001). Significance analysis of microarrays applied to the ionizing radiation response. P Natl Acad Sci USA 98: 5116-5121.
Vlachos IS, Vergoulis T, Paraskevopoulou MD, Lykokanellos F, Georgakilas G, Georgiou P, Chatzopoulos S, Karagkouni D, Christodoulou F, Dalamagas T et al (2016). DIANA-mirExTra v2.0: Uncovering microRNAs and transcription factors with crucial roles in NGS expression data. Nucleic Acids Res 44: W128-134.
Vlachos IS, Zagganas K, Paraskevopoulou MD, Georgakilas G, Karagkouni D, Vergoulis T, Dalamagas T, Hatzigeorgiou AG (2015). DIANA-miRPath v3.0: Deciphering microRNA function with experimental support. Nucleic Acids Res 43: W460-W466.
Wang J, Duncan D, Shi Z, Zhang B (2013). WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Res 41: W77-W83.
Yoon S, De Micheli G (2005). Prediction of regulatory modules comprising microRNAs and target genes. Bioinformatics 21 (Suppl. 2): ii93-100.
Yu H, Li H, Qian H, Jiao X, Zhu X, Jiang X, Dai G, Huang J (2014). Upregulation of miR-301a correlates with poor prognosis in triple-negative breast cancer. Med Oncol 31: 283.
Zang H, Li N, Pan Y, Hao J (2016). Identification of upstream transcription factors (TFs) for expression signature genes in breast cancer. Gynecol Endocrinol 2017; 33: 193-198.
Zhang HM, Liu T, Liu CJ, Song S, Zhang X, Liu W, Jia H, Xue Y, Guo AY (2015). AnimalTFDB 2.0: a resource for expression, prediction and functional study of animal transcription factors. Nucleic Acids Res 43: D76-D81.
Zhang X, Liu G, Ding L, Jiang T, Shao S, Gao Y, Lu Y (2017). HOXA3 promotes tumor growth of human colon cancer through activating EGFR/Ras/Raf/MEK/ERK signaling pathway. J Cell Biochem (in press).