title: Functional analysis of microRNA and transcription factor synergistic regulatory network based on identifying regulatory motifs in non-small cell lung cancer.
abstract: BACKGROUND
  Lung cancer, especially non-small cell lung cancer, is a leading cause of malignant tumor death worldwide. Understanding the mechanisms employed by the main regulators, such as microRNAs (miRNAs) and transcription factors (TFs), still remains elusive. The patterns of their cooperation and biological functions in the synergistic regulatory network have rarely been studied.
  
  
  RESULTS
  Here, we describe the first miRNA-TF synergistic regulation network in human lung cancer. We identified important regulators (MYC, NFKB1, miR-590, and miR-570) and significant miRNA-TF synergistic regulatory motifs by random simulations. The two most significant motifs were the co-regulation of miRNAs and TFs, and TF-mediated cascade regulation. We also developed an algorithm to uncover the biological functions of the human lung cancer miRNA-TF synergistic regulatory network (regulation of apoptosis, cellular protein metabolic process, and cell cycle), and the specific functions of each miRNA-TF synergistic subnetwork. We found that the miR-17 family exerted important effects in the regulation of non-small cell lung cancer, such as in proliferation and cell cycle regulation by targeting the retinoblastoma protein (RB1) and forming a feed forward loop with the E2F1 TF. We proposed a model for the miR-17 family, E2F1, and RB1 to demonstrate their potential roles in the occurrence and development of non-small cell lung cancer.
  
  
  CONCLUSIONS
  This work will provide a framework for constructing miRNA-TF synergistic regulatory networks, function analysis in diseases, and identification of the main regulators and regulatory motifs, which will be useful for understanding the putative regulatory motifs involving miRNAs and TFs, and for predicting new targets for cancer studies.
authors.forename: Kening
authors.initials: K
authors.lastname: Li
authors.forename: Zihui
authors.initials: Z
authors.lastname: Li
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.forename: Yaoqun
authors.initials: Y
authors.lastname: Xu
authors.forename: Yongjing
authors.initials: Y
authors.lastname: Liu
authors.forename: Yuanshuai
authors.initials: Y
authors.lastname: Zhou
authors.forename: Desi
authors.initials: D
authors.lastname: Shang
authors.forename: Fujun
authors.initials: F
authors.lastname: Qiu
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Chang
authors.affiliation: College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. xuyan@ems.hrbmu.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D019295:Computational Biology; D053263:Gene Regulatory Networks; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D059372:Nucleotide Motifs; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D014157:Transcription Factors