Hepatitis B virus (HBV) genome and cellular microRNA (miRNA) target sites. The partially double-stranded genome is presented with transcription regulatory elements. The viral open reading frames are shown as arrows immediately surrounding the genome. Viral enhancer I and II, promoters, DR1, and DR2 are indicated. The binding positions of transcription factors and nuclear receptors on the HBV genome are shown (C/EBP: CAAT enhancer-binding protein; CREB: C-AMP-response element binding protein; FXRA: farnesoid X receptor alpha; PPARα: peroxisome proliferator-activated receptor alpha; NFIB: nuclear factor I/B). Cellular factors known for regulating hepatitis B virus (HBV) transcription and the positions of the binding sequences in HBV transcripts targeted by miRNAs are shown. Arrows indicate activation, while the bars indicate an inhibitory effect of miRNAs on HBV transcription.

Hepatitis B virus (HBV) infection alters microRNA (miRNA) profiles by acting on multiple steps of miRNA processing. At the transcriptional level, the HBV x protein (HBx) can interact with some transcription factors such as p53, nuclear factor-kappa B (NF-κB), and c-Myc, subsequently regulating miRNA transcription. HBx can also regulate the epigenetic machinery, which can determine whether the miRNA genes are accessible. Moreover, HBx may influence miRNA processing by inhibiting Drosha, which serves as a processor of the miRNA machinery. Finally, when mature miRNAs are released, they may be counteracted by HBV mRNAs, which act as sponges of endogenous miRNAs, forming the miRNA-induced silencing complexes (miRISC). Arrows indicate an activating effect of HBx on other transcriptional factors and proteins, whereas the bars indicate an inhibitory effect. The red crosses indicate an inhibitory effect on gene transcription.

Aberrant microRNAs and their targets involved in HBV-related hepatocarcinogenesis. HMGA2: high mobility group AT-hook 2; E2F3: E2F transcription factor 3; STAT3: signal transducer and activator of transcription 3; PTEN: phosphatase and tensin homolog; HDAC: histone deacetylase; PBF: pituitary tumor-transforming gene 1 binding factor; CDKN2A: cyclin-dependent kinase inhibitor 2A; ERα: estrogen receptor; PDCD4: programmed cell death 4; DNMT: DNA methyltransferase; GSTP1: glutathione S-transferase pi; RASSF1: Ras association (RalGDS/AF-6) domain family member 1; CDH1: E-cadherin 1; TSLC1: tumor suppressor in lung cancer-1 gene; EZH2: enhancer of zeste homolog 2; FUT2: fucosyltransferase 2. Arrows indicate an activating effect of miRNAs on their targets, whereas the bars indicate an inhibitory effect. Green miRNA: upregulated; Red miRNA: downregulated.

Involvement of microRNAs (miRNAs) in epithelial-mesenchymal transition (EMT)-related metastasis. miRNAs can regulate EMT by acting on several EMT-related pathways, including transforming growth factor-β (TGF-β) signaling, receptor tyrosine kinase (RTK)-mediated pathways, and Wnt/β-catenin signaling. miR-140-5p can directly target TGF-β receptor 1, miR-122 can target Ras homolog family member A (RHOA), and miR-192 and miR-200 can negatively regulate zinc finger E-box 1 (ZEB1) and ZEB2, respectively, thus inhibiting TGF-β-mediated metastasis. The RTK-related pathways, including the Ras-Raf-MEK-ERK cascades and phosphatidylinositol 3-kinase (PI3K)-Akt pathway, are also regulated by miRNAs. miR-1, miR-23b, miR-34a, and miR-148a can target c-Met, a RTK for hepatocyte growth factor (HGF). MiR-199a/b-3P can target p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4), subsequently inhibiting Raf-MEK-ERK cascades. On the contrary, phosphatase and tensin homolog (PTEN) can be negatively regulated by miR-21 and miR-29a, and miR-222 and miR-222 simultaneously target PP2A. miR-148a can also negatively regulate pre-B cell leukemia transcription factor-interacting protein (HPIP), an activator of both ERK and AKT. Moreover, miR-148a can target Wnt1 mRNA, thus blocking EMT mediated by Wnt/β-catenin-signaling in hepatocellular carcinoma. EGF: epidermal growth factor; FGF: fibroblast growth factor. Arrows indicate an activating effect of miRNAs on their targets, whereas the bars indicate an inhibitory effect. Green miRNA: upregulated; Red miRNA: downregulated.