Identification of miRNA-miRNA synergistic relationships in colorectal cancer.

PURPOSE A large list of microRNAs (miRNAs) which may play important roles in the tumorigenesis of colorectal cancer (CRC) were generated recently. The purpose of our study is to analyze the synergistic regulations among miRNAs which were differentially expressed in tumorigenesis of CRC. METHODS In this study, we downloaded the miRNA microarray and gene expression microarray of CRC from Gene Expression Omnibus (GEO), and identified the differentially expressed miRNAs (DE-miRNAs) and genes (DEGs) in cancer tissues compared with normal controls. In addition, we investigated the complex synergistic relationships among DE-miRNAs and constructed a miRNA-miRNA synergistic network by assembling all synergistic pairs. RESULTS A total of 32 DE-miRNAs formed 8 functional modules in the synergistic network. These miRNAs in functional modules could independently implement specific functions as a whole in CRC, such as endocytosis, cell cycle, and p53 signaling pathway. CONCLUSIONS The network allows for an in-depth analysis of individual miRNAs in the context of their synergistic surroundings.

[1]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[2]  R. Aebersold,et al.  A quantitative targeted proteomics approach to validate predicted microRNA targets in C. elegans , 2010, Nature Methods.

[3]  G. Ruvkun,et al.  Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans , 1993, Cell.

[4]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[5]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[6]  J. Mendell.  miRiad Roles for the miR-17-92 Cluster in Development and Disease , 2008, Cell.

[7]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Minoru Kanehisa,et al.  The KEGG database. , 2002, Novartis Foundation symposium.

[9]  George A Calin,et al.  MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. , 2008, JAMA.

[10]  Kenichi Sugihara,et al.  Microarray Analysis of Colorectal Cancer Stromal Tissue Reveals Upregulation of Two Oncogenic miRNA Clusters , 2012, Clinical Cancer Research.

[11]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[12]  W. Cleveland.  Robust Locally Weighted Regression and Smoothing Scatterplots , 1979 .

[13]  Sarka Pospisilova,et al.  MicroRNA biogenesis, functionality and cancer relevance. , 2006, Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia.

[14]  X. Agirre,et al.  Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues , 2006, Molecular Cancer.

[15]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[16]  Brian S. Roberts,et al.  The colorectal microRNAome. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Ann L Oberg,et al.  Human colon cancer profiles show differential microRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states , 2009, BMC Cancer.

[18]  Anton J. Enright,et al.  MicroRNA targets in Drosophila , 2003, Genome Biology.

[19]  A. Watson,et al.  Colon Cancer: A Civilization Disorder , 2011, Digestive Diseases.

[20]  S. Grimmond,et al.  The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition , 2008, Genome Biology.

[21]  Q. Zeng,et al.  Up-regulated miR-17 promotes cell proliferation, tumour growth and cell cycle progression by targeting the RND3 tumour suppressor gene in colorectal carcinoma. , 2012, The Biochemical journal.

[22]  E. Furth,et al.  Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster , 2006, Nature Genetics.

[23]  Russ B. Altman,et al.  Missing value estimation methods for DNA microarrays , 2001, Bioinform..

[24]  T. Kwok,et al.  The miR-18a* microRNA functions as a potential tumor suppressor by targeting on K-Ras. , 2009, Carcinogenesis.

[25]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[26]  E. Kure,et al.  Differential Expression of miRNAs in Colorectal Cancer: Comparison of Paired Tumor Tissue and Adjacent Normal Mucosa Using High-Throughput Sequencing , 2012, PloS one.

[27]  M. Saif,et al.  Colon Cancer Vaccines : An Update , 2010 .

[28]  Peter Wernet,et al.  MicroRNAs MiR-17, MiR-20a, and MiR-106b Act in Concert to Modulate E2F Activity on Cell Cycle Arrest during Neuronal Lineage Differentiation of USSC , 2011, PloS one.

[29]  R. Vyzula,et al.  Altered Expression of miR-21, miR-31, miR-143 and miR-145 Is Related to Clinicopathologic Features of Colorectal Cancer , 2008, Oncology.

[30]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

[31]  Yun Xiao,et al.  MiRNA–miRNA synergistic network: construction via co-regulating functional modules and disease miRNA topological features , 2010, Nucleic acids research.