MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases

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Abstract

MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression by binding to specific mRNA targets and promoting their degradation and/or translational inhibition. miRNAs regulate both physiological and pathological liver functions. Altered expression of miRNAs is associated with liver metabolism dysregulation, liver injury, liver fibrosis and tumour development, making miRNAs attractive therapeutic strategies for the diagnosis and treatment of liver diseases. Here, we review recent advances regarding the regulation and function of miRNAs in liver diseases with a major focus on miRNAs that are specifically expressed or enriched in hepatocytes (miR-122, miR-194/192), neutrophils (miR-223), hepatic stellate cells (miR-29), immune cells (miR-155) and in circulation (miR-21). The functions and target genes of these miRNAs are emphasised in alcohol-associated liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, viral hepatitis and hepatocellular carcinoma, as well liver fibrosis and liver failure. We touch on the roles of miRNAs in intercellular communication between hepatocytes and other types of cells via extracellular vesicles in the pathogenesis of liver diseases. We provide perspective on the application of miRNAs as biomarkers for early diagnosis, prognosis and assessment of liver diseases and discuss the challenges in miRNA-based therapy for liver diseases. Further investigation of miRNAs in the liver will help us better understand the pathogeneses of liver diseases and may identify biomarkers and therapeutic targets for liver diseases in the future.

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Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours

David S. Hong, Yoon-Koo Kang, Mitesh J. Borad … (2020)

Background In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. Methods Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles. Results Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m2 for hepatocellular carcinoma (HCC) and 93 mg/m2 for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting ≥4 cycles (median, 19 weeks, range, 11–55). Conclusion MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy. Clinical trial registration NCT01829971.

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Endoplasmic Reticulum Stress Causes Liver Cancer Cells to Release Exosomal miR‐23a‐3p and Up‐regulate Programmed Death Ligand 1 Expression in Macrophages

Jiatao Liu, Lulu Fan, Hanqing Yu … (2019)

Endoplasmic reticulum (ER) stress promotes tumor cell escape from immunosurveillance. However, the underlying mechanisms remain unknown. We hypothesized that ER stress induces hepatocellular carcinoma (HCC) cells to release exosomes, which attenuate antitumor immunity by modulating the expression of programmed death ligand 1 (PD-L1) on macrophages. In this study, we demonstrated that expression of several ER stress markers (glucose-regulated protein 78 [GRP78], activating transcription factor 6 [ATF6], PKR-like endoplasmic reticulum kinase [PERK], inositol-requiring enzyme 1α [IRE1α]) was up-regulated in HCC tissues and negatively correlated with the overall survival and clinicopathological scores in HCC patients. Expression of ER stress-related proteins positively correlated with cluster of differentiation 68-positive (CD68 + ) macrophage recruitment and PD-L1 expression in HCC tissues. High-throughput sequencing analysis identified microRNA (miRNA/miR)-23a-3p as one of the most abundant miRNAs in exosomes derived from the ER stress inducer tunicamycin treated HCC cells (Exo-TM). miR-23a-3p levels in HCC tissues negatively correlated with overall survival. Treatment with Exo-TM up-regulated the expression of PD-L1 in macrophages in vitro and in vivo . Bioinformatics analysis suggests that miR-23a-3p regulates PD-L1 expression through the phosphatase and tensin homolog (PTEN)- phosphoinositide-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (AKT) pathway. This notion was confirmed by in vitro transfection and co-culture experiments, which revealed that miR-23a-3p inhibited PTEN expression and subsequently elevated phosphorylated AKT and PD-L1 expression in macrophages. Finally, co-culture of T cells with Exo-TM-stimulated macrophages decreased CD8 + T-cell ratio and interleukin-2 production but increased T-cell apoptosis in vitro . ER-stressed HCC cells release exosomes to up-regulate PD-L1expression in macrophages, which subsequently inhibits T-cell function via an exosome miR-23a-PTEN-AKT pathway. Our findings provide a new insight into the mechanism how tumor cells escape from antitumor immunity.

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Lipotoxic Hepatocyte‐Derived Exosomal MicroRNA 192‐5p Activates Macrophages Through Rictor/Akt/Forkhead Box Transcription Factor O1 Signaling in Nonalcoholic Fatty Liver Disease

Xiao-Lin Liu, Qin Pan, Hai‐Xia Cao … (2020)

Hepatic macrophages can be activated by many factors such as gut-derived bacterial components and factors released from damaged hepatocytes. Macrophage polarization toward a proinflammatory phenotype (M1) represents an important event in the disease progression of nonalcoholic fatty liver disease (NAFLD). However, the underlying molecular mechanisms remain incompletely understood. Exosomes have been identified as important mediators for cell-cell communication by transferring various biological components such as microRNAs (miRs), proteins, and lipids. The role of exosomes in crosstalk between hepatocytes and macrophages in disease progression of NAFLD is yet to be explored.