title: microRNAs' differential regulations mediate the progress of Human Papillomavirus (HPV)-induced Cervical Intraepithelial Neoplasia (CIN).
abstract: BACKGROUND
  microRNA (miRNA)'s direct regulation on target mRNA is affected by complex factors beyond miRNA. Therefore, at different stages during the course of carcinogenesis, miRNA may regulate different targets, which we termed 'miRNA's differential regulation'. HPV-induced cervical intraepithelial neoplasia (CIN) is an important pre-cancerous course ahead of cervical cancer formation. Currently, the molecular mechanisms of CIN progress remain poorly understood, and it is interesting to unravel this from the perspective of miRNA differential regulation.
  
  
  RESULTS
  In this study, we performed transcriptome analysis of miRNAs and mRNAs for the totally 24 cervical samples in three stages (normal, CIN I, and CIN III) along CIN progress, and proposed the SIG++ algorithm to detect the miRNA - mRNA pairs with significant regulation change, and further proposed the definitions of Efficient Pair, Efficient Target, and Related Effector Biological Process, as the elemental steps to construct miRNA differential regulatory network. Finally, for the course of disease progressing from normal stage to CIN I stage, and for the course of disease progressing from CIN I stage to CIN III stage, miRNA differential regulatory networks were constructed, respectively, based on two distinct strategies: one is founded on the knowledge of human GO biological processes to detect Efficient Targets and Related Effector Biological Processes, the other is solely founded on literature review to detect the targets closely related to cervical carcinogenesis and instructive in revealing mechanisms that promote CIN development.
  
  
  CONCLUSIONS
  This study provided the conception of miRNA's differential regulation, the algorithm for how to identify them during disease development, and the strategy for how to construct miRNA differential regulatory network with instructive biological meanings. The finally constructed networks provide clues for understanding CIN progress.
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Science, and Institute of Biomedical Sciences, Fudan University, 200433, Shanghai, China. wenjuanmo@fudan.edu.cn.|Shanghai Engineering Research Center of Industrial Microorganisms, 200433, Shanghai, China. wenjuanmo@fudan.edu.cn.|Collaborative Innovation Center of Cancer Medicine, 200433, Shanghai, China. wenjuanmo@fudan.edu.cn.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Mo
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Science, and Institute of Biomedical Sciences, Fudan University, 200433, Shanghai, China. chaotong@fudan.edu.cn.|Shanghai Engineering Research Center of Industrial Microorganisms, 200433, Shanghai, China. chaotong@fudan.edu.cn.|Collaborative Innovation Center of Cancer Medicine, 200433, Shanghai, China. chaotong@fudan.edu.cn.
authors.forename: Chao
authors.initials: C
authors.lastname: Tong
authors.affiliation: Department of Gynaecology and Obstetrics in Changhai Hospital, 200433, Shanghai, China. zhangyan186168@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Science, and Institute of Biomedical Sciences, Fudan University, 200433, Shanghai, China. honglu0211@yahoo.com.|Shanghai Engineering Research Center of Industrial Microorganisms, 200433, Shanghai, China. honglu0211@yahoo.com.|Collaborative Innovation Center of Cancer Medicine, 200433, Shanghai, China. honglu0211@yahoo.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
mesh_terms: D000465:Algorithms; D063646:Carcinogenesis / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D027383:Papillomaviridae / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000473:pathology / Q000821:virology
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger