Abstract
The human insulin-like growth factor-II (IGF-II) gene transcribes four mRNAs (P1 mRNA-P4 mRNA), and P3 mRNA overexpression contributes to hepatocarcinogenesis. IGF-II-derived miR-483-5p is implicated in the development of cancers. Here, we investigated the involvement of miR-483-5p in P3 mRNA overexpression regulation and its role in hepatocellular carcinoma. Our results showed that miR-483-5p up-regulated P3 mRNA transcription by targeting the 5′-untranslated region (5′UTR) of P3 mRNA in hepatocellular carcinoma. The mechanism was involved in recruiting of an argonaute 1(Ago1)-argonaute 2 (Ago2) complex to the P3 mRNA 5′UTR and the P3 promoter of IGF-II gene by miR-483-5p, accompanied by increased enrichment of RNA polymerase II and activating histone marks histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 27 acetylation (H3K27ac), and histone 4 lysine 5/8/12/16 acetylation (H4Kac) at the P3 promoter. High miR-483-5p expression was an independent predictor for shorter survival of HCC patients. The findings suggest that miR-483-5p promotes P3 mRNA transcription by recruiting the Ago1-Ago2 complex to the P3 mRNA 5′UTR and is associated with poor prognosis of HCC. Our results display a potential new model for miRNAs to up-regulate gene expression.
Highlights
The human insulin-like growth factor-RNA polymerase II (II) (IGF-II) is a fetal growth factor that is involved in fetal growth and development [1]
To investigate that if miRNAs are involved in increased P3 messenger RNA (mRNA) expression in hepatocellular carcinoma (HCC), we predicted candidate miRNAs targeting the P3 mRNA 5′-untranslated region (5′UTR) (NM_000612) only, that is to say, they do not bind to the 3′UTR and 5′UTR of the other three transcrips, P1-P4 promoters, and insulin-like growth factor-II (IGF-II) protein coding region of IGFII gene using RegRNA
We identified 70 miRNA candidates (Supplementary Table 1) and the top five miRNAs with a remarkable minimal free energy value were selected for further validation. Quantitative RT-PCR (qRT-PCR) analysis showed that only miR-483-5p expression was up-regulated in human HCC cell lines (Huh7, Hep3B, Bel-7402, HepG2, SMMC-7721) compared with the normal human liver cell line (HL-7702), and the expression level of P3 mRNA and miR-483-5p was positively correlated in the above HCC cell lines (r = 0.960, P = 0.01) (Figure 1A)
Summary
The human insulin-like growth factor-II (IGF-II) is a fetal growth factor that is involved in fetal growth and development [1]. The gene encoding IGF-II contains nine exons and four promoters (P1–P4), and each of these promoters initiates distinct transcription, yielding a promoter-specific transcript (P1 mRNA-P4 mRNA) that has a unique 5′-untranslated region (5′UTR) and an identical 3′UTR [2]. IGF-II is expressed predominantly in fetal liver under physiological conditions through the activation of P2-P4 promoters; its expression is significantly down-regulated shortly after birth because of remarkable decrease or loss of the activity of P2–P4 promoters [3]. Increased level of IGF-II in HCC results mainly from the transcriptional up-regulation of P3 www.impactjournals.com/oncotarget mRNA and P4 mRNA [9, 10]. The reasons and mechanisms responsible for the reactivation of the two fetal transcripts are not well clarified
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