Abstract
Long noncoding RNAs (lncRNAs) play diverse roles in biological processes, but their expression profiles and functions in cervical carcinogenesis remain unknown. By RNA-sequencing (RNA-seq) analyses of 18 clinical specimens and selective validation by RT-qPCR analyses of 72 clinical samples, we provide evidence that, relative to normal cervical tissues, 194 lncRNAs are differentially regulated in high-risk (HR)-HPV infection along with cervical lesion progression. One such lncRNA, lnc-FANCI-2, is extensively characterized because it is expressed from a genomic locus adjacent to the FANCI gene encoding an important DNA repair factor. Both genes are up-regulated in HPV lesions and in in vitro model systems of HR-HPV18 infection. We observe a moderate reciprocal regulation of lnc-FANCI-2 and FANCI in cervical cancer CaSki cells. In these cells, lnc-FANCI-2 is transcribed from two alternative promoters, alternatively spliced, and polyadenylated at one of two alternative poly(A) sites. About 10 copies of lnc-FANCI-2 per cell are detected preferentially in the cytoplasm. Mechanistically, HR-HPVs, but not low-risk (LR)-HPV oncogenes induce lnc-FANCI-2 in primary and immortalized human keratinocytes. The induction is mediated primarily by E7, and to a lesser extent by E6, mostly independent of p53/E6AP and pRb/E2F. We show that YY1 interacts with an E7 CR3 core motif and transactivates the promoter of lnc-FANCI-2 by binding to two critical YY1-binding motifs. Moreover, HPV18 increases YY1 expression by reducing miR-29a, which targets the 3' untranslated region of YY1 mRNA. These data have provided insights into the mechanisms of how HR-HPV infections contribute to cervical carcinogenesis.
Keywords:
YY1; human papillomavirus; lncRNA; oncoproteins; transcription.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing
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Base Sequence
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Carcinogenesis / genetics
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Carcinogenesis / metabolism
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Carcinogenesis / pathology
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Cell Line, Tumor
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Cervix Uteri / metabolism
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Cervix Uteri / pathology
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Cervix Uteri / virology
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E2F Transcription Factors / genetics
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E2F Transcription Factors / metabolism
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Fanconi Anemia Complementation Group Proteins / genetics*
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Fanconi Anemia Complementation Group Proteins / metabolism
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Female
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Gene Expression Regulation
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Host-Pathogen Interactions / genetics
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Human papillomavirus 16 / genetics*
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Human papillomavirus 16 / metabolism
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Human papillomavirus 16 / pathogenicity
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Human papillomavirus 18 / genetics
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Human papillomavirus 18 / metabolism
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Human papillomavirus 18 / pathogenicity
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Humans
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Keratinocytes / metabolism
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Keratinocytes / pathology
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Keratinocytes / virology
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Papillomavirus E7 Proteins / genetics
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Papillomavirus E7 Proteins / metabolism
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Papillomavirus Infections / genetics*
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Papillomavirus Infections / metabolism
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Papillomavirus Infections / pathology
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Papillomavirus Infections / virology
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Promoter Regions, Genetic
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RNA, Long Noncoding / genetics*
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RNA, Long Noncoding / metabolism
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism
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Signal Transduction
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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Uterine Cervical Neoplasms / genetics*
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Uterine Cervical Neoplasms / metabolism
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Uterine Cervical Neoplasms / pathology
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Uterine Cervical Neoplasms / virology
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YY1 Transcription Factor / genetics*
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YY1 Transcription Factor / metabolism
Substances
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E2F Transcription Factors
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FANCI protein, human
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Fanconi Anemia Complementation Group Proteins
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MIRN29a microRNA, human
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MicroRNAs
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Papillomavirus E7 Proteins
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RNA, Long Noncoding
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Retinoblastoma Protein
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Tumor Suppressor Protein p53
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YY1 Transcription Factor
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YY1 protein, human
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oncogene protein E7, Human papillomavirus type 16
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UBE3A protein, human
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Ubiquitin-Protein Ligases