MiRNAs in Alcohol-Related Liver Diseases and Hepatocellular Carcinoma: A Step toward New Therapeutic Approaches?

Abstract

Alcohol-related Liver Disease (ALD) is the primary cause of chronic liver disorders and hepatocellular carcinoma (HCC) development in developed countries and thus represents a major public health concern. Unfortunately, few therapeutic options are available for ALD and HCC, except liver transplantation or tumor resection for HCC. Deciphering the molecular mechanisms underlying the development of these diseases is therefore of major importance to identify early biomarkers and to design efficient therapeutic options. Increasing evidence indicate that epigenetic alterations play a central role in the development of ALD and HCC. Among them, microRNA importantly contribute to the development of this disease by controlling the expression of several genes involved in hepatic metabolism, inflammation, fibrosis, and carcinogenesis at the post-transcriptional level. In this review, we discuss the current knowledge about miRNAs' functions in the different stages of ALD and their role in the progression toward carcinogenesis. We highlight that each stage of ALD is associated with deregulated miRNAs involved in hepatic carcinogenesis, and thus represent HCC-priming miRNAs. By using in silico approaches, we have uncovered new miRNAs potentially involved in HCC. Finally, we discuss the therapeutic potential of targeting miRNAs for the treatment of these diseases.

Keywords: alcohol-related liver disease; hepatocellular carcinoma; miRNAs-based therapeutics; microRNAs.

Figure 1

Spectrum of Alcohol-related Liver Disease with deregulated microRNAs at each stage and cited in this review and detailed in Table 1. Percentages represent the rate of patients moving from one stage to another [36]. MicroRNAs in red have increased expression and microRNAs in blue have decreased expression. Created by Biorender.com.

Figure 2

Impact of different microRNAs on ethanol metabolism inducing fat accumulation and steatosis within the liver. Black arrows: activation of the pathways. Blue arrows: pathway inhibition. FGF21: fibroblast growth factor 21; CAMKK2: Ca²⁺/calmodulin-dependent protein kinase kinase 2; AMPK: AMP-activated protein kinase; SREBP-1: sterol regulatory element binding protein 1; HNF1β: hepatocyte nuclear factor 1 homeobox β; PPARα: peroxisome proliferator-activated receptor α; ACC: acetyl-coA carboxylase; VLDL: very-low-density lipoprotein.

Figure 3

Effect of alcohol consumption on steatohepatitis. Ethanol acts on different cell types (i.e., hepatocytes, Kupffer cells, neutrophils, hepatic stellate cells) in the liver, on intestinal permeability, and on different microRNAs. Black arrows: activation of the pathways. Blue arrows: pathway inhibition. NFκB: nuclear factor kappa B; iNOS: nitric oxidative synthase; ZO-1: Zonula occludens 1; LPS: lipopolysaccharide; CYP2E1: cytochrome P450 2E1; GRHL2: granyhead-like transcription factor 2; Hif1α: hypoxia-inductible factor 1-alpha; SREBP-1: sterol regulatory element binding protein 1; AMPK: AMP-activated protein kinase; PPARα: peroxisome proliferator-activated receptor α; ALR: Augmenter of Liver Regeneration; ROS: reactive oxygen species; MDA: malondialehyde; HNE: 4-hydroxy-2-nonenal; MAA: malondialdehyde-acetaldehyde; TLR4: Toll-like receptor 4; MCP1: monocyte chemotactic protein 1; IL-1: Interleukin-1; IL-6: Interleukin-6; TGFβ: transforming factor β; TNFR: tumor necrosis factor receptor; MyD88: myeloid differentiation response gene 88; MAPK: mitogen-activated protein kinase; PPARγ: peroxisome proliferator-activated receptor γ; NFATc4: nuclear factor of activated T-cells c4; TNFα: tumor necrosis factor α. Created with Biorender.com.

Figure 4

Expression and effects of different deregulated microRNAs inducing hepatic fibrosis in alcoholic cirrhosis. Black and red arrows: activation of the pathways. Blue arrows: pathway inhibition. LPS: lipopolysaccharide; TGFR: transforming factor receptor; TNFR: tumor necrosis factor receptor; ILR: Interleukin receptor; TLR4: Toll-like receptor 4; ERBB3: receptor tyrosine-protein kinase; MyD88: myeloid differentiation response gene 88; NFκB: nuclear factor kappa B; ROS: reactive oxygen species; Col1A1: Collagen 1a1; αSMA: α-Smooth muscle actin; TNFα: tumor necrosis factor α; IL-1: Interleukin-1; TGFβ: transforming factor β; NOX1: NADPH oxidase 1; HSCs: Hepatic stellate cells. Created with Biorender.com.

Figure 5

(A) A transcriptomic dataset (GSE59492 from Gene Expression Omnibus Database) was used to analyze deregulated miRNAs between control and alcohol-related cirrhotic livers (B) A literature-based screening was used to classify them in oncomiRs or tumor suppressor miRNAs (miRsupressors). (C) Among deregulated miRNAs, some have unknown functions in HCC. (D) Overexpression of some of these microRNAs, such as miR-3622a, can be observed in HCC tumors (data retrieved from miRTV database in July 2023). (E) The same transcriptomic dataset (GSE59492) was used to compare deregulated miRNAs in alcohol-related cirrhosis with NASH related cirrhosis. Only two miRNAs (miR-4725 and miR-150) are commonly upregulated in both conditions, and one miRNA is commonly downregulated (miR-3162).

Figure 6

(A) A transcriptomic dataset (GSE10694) was used to identify new miRNAs deregulated in hepatocellular carcinoma with alcohol abuse. The data are represented in a heatmap showing the log2 fold change of deregulated miRNAs. (B) Significantly deregulated microRNAs were subjected to literature-based screening to classify them in the most common HCC-related pathways. The data were retrieved in July 2023. miRNAs in red bubbles: upregulated; miRNA in blue bubbles: downregulated. Black arrows: activation of the pathway; Blue inhibitory arrows: pathway inhibition. Created with Biorender.com.

Figure 7

Graphical representation of the miRNA suppression and replacement strategies and list of specific receptors of hepatic cell type used for associating targeting moiety to delivery systems. AMO: anti-miRNA oligonucleotide; SMIR: small molecule inhibitor of miRNA; SR-B1: scavenger receptor class B type 1; LDL-R: low-density lipoprotein receptor; CXCR4: C-X-C chemokine receptor type 4, SR-A: scavenger receptor type A; PDGFβ: platelet-derived growth factor beta; Fc: fragment crystallizable; HSC: hepatic stellate cell; KC: Kupffer cell.