MiR-483-5p promotes IGF-II transcription and is associated with poor prognosis of hepatocellular carcinoma

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.

MiR-129-5p inhibits liver cancer growth by targeting calcium calmodulin-dependent protein kinase IV (CAMK4)

“…A study showed that ~30% of genes received miRNA regulation, and that miRNAs contributed to the occurrence, development, and metastasis of liver cancer 7 . Tang 8 suggested that miR-483–5p was associated with poor prognosis in HCC patients, and that overexpression of miR-483–5p was an independent predictor of short survival in HCC patients. A latest finding also demonstrated that miR-1247–3p participated in lung metastasis of liver cancer by regulating associated fibroblasts (CAFs) 9 .…”

Potential targets and molecular mechanism of miR-331-3p in hepatocellular carcinoma identified by weighted gene coexpression network analysis

“…Differentially expressed microRNAs (DEMs) were screened (P<0.05, |log FC|>1) individually obtained from these datasets were overlapped to get three DEMs (miR-199a-5p, miR-483-5p, miR-331-3p) ( Figure 1). The role of miR-199a-5p [30][31][32][33][34] and miR-483-5p [35][36][37][38][39] in HCC has been extensively studied. However, the molecular mechanism of miR-331-3p in HCC is not clear and remains to be explored.…”

miR-193b-3p Promotes Proliferation of Goat Myoblast Through Directly Targeting IGF2BP1 and Activating Its Transcription

“…Several models elaborating functions of nuclear miRNAs at both transcriptional (transcriptional gene silencing, TGS; transcriptional gene activation, TGA) have been constructed, in which miRNA targets and binds nascent RNA transcripts, gene promoter, or enhancer regions by a sequence complementary and exert further effects via recruiting additional epigenetic and(or) transcriptional factors or altering epigenetic modi cations [45]. For example, miR-483-5p promotes the IGF2 transcription by targeting the P3 5 UTR and promoter, accompanied by enrichment of activating-enhancer marks, including H3K4me3 and H3K27ac [32]. Similarly, the transcription activation of miR-373 on both E-cadherin [53], as well as miR-589 on COX-2 (Cyclooxygenase 2) [46], are via miRNA-promoter-related manner.…”

“…Nevertheless, recently accumulating evidence support that cytoplasmic miRNAs can also activate gene expression unconventionally through enhancing the translation by seed-matching binding on 5 [28] or 3 untranslated region (UTR) [29], or even non-seed-matching sites in the 5 UTR of mRNAs [30]. Meanwhile, nucleus-located miRNAs mediates gene activation epigenetically via targeting enhancers [31] or targeting the 5 -end of gene [32]. Undoubtedly, the functional signi cance of the activating miRNAs in animal normal development remains largely undetermined.…”