Dataset Information

MicroRNAs' differential regulations mediate the progress of Human Papillomavirus (HPV)-induced Cervical Intraepithelial Neoplasia (CIN).

ABSTRACT: 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.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.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.

SUBMITTER: Mo W

PROVIDER: S-EPMC4337110 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Mo Wenjuan W Tong Chao C Zhang Yan Y Lu Hong H

BMC systems biology 20150207

<h4>Background</h4>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 t ...[more]

PMID: 25889737

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Project description:In most cases human papillomavirus (HPV) infections are cleared from the cervical cells by the immune system itself, but in a few cases, where there is persistent HPV infection, it can lead to cervical intraepithelial neoplasia (CIN) progression and ultimately invasive cervical carcinoma. The cytopathic effect is in general accompanied by chronic inflammation, which produces inflammation cytokines that contribute to DNA damage, and at the same time, aberrations occurred in the host DNA repair mechanisms, thus lead to HPV genomic integration into the host cells which propels cell immortalization. In this study, we reported the genome-wide expression profiles of both microRNAs (miRNAs) and mRNAs from 24 cervical samples with consecutive stages of normal, CIN I (mild dysplasia) and CIN III (severe dysplasia and carcinoma in situ), and presented the SIG++ algorithm which is founded on the evolution process of intermolecular regulation change during disease progression, to identify the significant change of miRNA-mRNA regulations rather than the expression change, across different disease stages, thereupon elucidating the molecular mechanisms of increasing host genomic instability as disease progresses. As reconstructing miRNA differential networks, we found that at each stage of CIN, there respectively exists specific miRNA regulations mediating chronic inflammation persistence, genome instability and cell survival, which coordinately carrys out the integration of HPV genomes into the host cell genomes, and finally results in cell immortalization. Beyond the specific implications for cervical carcinogenesis, this work establishes a new framework for studying the biology of miRNAs in pathogenesis from the perspective of miRNA differential regulation, and helps ensure the comprehensiveness of miRNA-mediated genetic regulatory pathways. There are totally 24 clinical samples in this study comprises three stages: 7 normal cervix samples (HPV-), 9 CIN I samples (HPV+) and CIN III samples (HPV+), where normal refers to the adjacent tissue of early lesions. For each sample, its total RNA was extracted and purified, then separately hybridized to Illumina HumanHT-12 V4.0 expression beadchip (gene symbol) and Illumina Human v2 MicroRNA Expression BeadChip, for examining the expression profiles of mRNAs and miRNAs, respectively.

Project description:BACKGROUND: The development of cervical cancer and its high-grade precursor lesions (Cervical Intraepithelial Neoplasia grade 2/3 [CIN2/3]) result from a persistent infection with high-risk human papillomavirus (hrHPV) types and the accumulation of (epi)genetic host cell aberrations. Epidemiological studies have demonstrated variable CIN2/3 and cancer risks between different hrHPV types. Recent genomic profiling studies revealed substantial heterogeneity in the chromosomal aberrations detected in morphologically indistinguishable CIN2/3 suggestive of varying cancer risk. The current study aimed to investigate whether CIN2/3 with different hrHPV types vary with respect to their chromosomal profiles, both in terms of the number of aberrations and chromosomal loci affected. METHODS: Chromosomal profiles were determined of 43 p16INK4a-immunopositive CIN2/3 of women with long-term hrHPV infection (? 5 years). Sixteen lesions harboured HPV16, 3 HPV18, 14 HPV31, 1 HPV33, 4 HPV45, 1 HPV51, 2 HPV52 and 2 HPV58. RESULTS: Unsupervised hierarchical clustering analysis of the chromosomal profiles revealed two major clusters, characterised by either few or multiple chromosomal aberrations, respectively. A majority of 87.5% of lesions with HPV16 were in the cluster with relatively few aberrations, whereas no such unbalanced distribution was seen for lesions harbouring other hrHPV types. Analysis of the two most prevalent types (HPV16 and HPV31) in this data set revealed a three-fold increase in the number of losses in lesions with HPV31 compared to HPV16-positive lesions. In particular, losses at chromosomes 2q, 4p, 4q, 6p, 6q, 8q & 17p and gain at 1p & 1q were significantly more frequent in HPV31-positive lesions (FDR < 0.2). CONCLUSIONS: Chromosomal aberrations in CIN2/3 are at least in part related to the hrHPV type present. The relatively low number of chromosomal aberrations observed in HPV16-positive CIN2/3 suggests that the development of these lesions is less dependent on genetic insult than those caused by other types like HPV31.

Dataset Information

MicroRNAs' differential regulations mediate the progress of Human Papillomavirus (HPV)-induced Cervical Intraepithelial Neoplasia (CIN).

Publications

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

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