microRNAs’ differential regulations mediate the progress of Human Papillomavirus (HPV)-induced Cervical Intraepithelial Neoplasia (CIN)

Abstract

BackgroundmicroRNA (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.ResultsIn 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0145-3) contains supplementary material, which is available to authorized users.

MicroRNA-466 with tumor markers for cervical cancer screening

“…Genome sequence analysis and bioinformatics prediction indicate that microRNA-466 is highly homologous with the LCR region prediction miRNA of HPVl6/18, while the LCR region is the regulatory region of carcinogenic key protein expression [ 30 ]. Lots of evidence has shown that high-risk type HPV (HPV16/18) infection is a prominent risk factor for cervical cancer development [ 31 ]. MiRNAs may act as a bio-marker in cervical cancer tissue or cervical lesions which are related to HPV16/18 infection [ 32 , 33 ].…”

A New MicroRNA Expression Signature for Cervical Cancer

“…16 Lots of evidences have shown that high-risk type HPV infection is a high-risk factor for cervical cancer development. 17 MiRNAs may act as biomarkers in cervical cancer tissue or cervical lesions, which is related with HPV16/18 infection. 18,19 However, there is no study concentrating on the expression levels of miR-466 in cervical cancer.…”

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“…CERNIA can be used to study the ceRNA competition among different tissue types, and different classes of genes. The ceRNAs prediction method is based on the DT-Hybrid recommendation algorithm [ 39 , 40 ].…”